Nuts and bolts of COVID-19 associated coagulopathy: the essentials for management and treatment

Authors: Patrick J Lindsay, a Rachel Rosovsky, b Edward A Bittner, c and Marvin G. Chang c

ABSTRACT

Introduction

COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure. Major societal guidelines that have published on the management of CAC are based on consensus of expert opinion, with the current evidence available. As a result of limited studies, there are many clinical scenarios that are yet to be addressed, with expert opinion varying on a number of important clinical issues regarding CAC management.

Methods

In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC. We have also provided three clinical scenarios that implement important principles of anticoagulation in patients with COVID-19.

Conclusion

Overall, decisions should be made on a case by cases basis and based on the providers understanding of each patient’s medical history, clinical course and perceived risk.

Introduction

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 in Wuhan, China. The disease was initially identified as a cluster of pneumonia cases; however, the disease dispersed rapidly and was formally declared a pandemic by the World Health Organization (WHO) in March 2020. As of June 2021, there have been greater than 172 million cases reported worldwide, including more than 3.7 million deaths [1]. The initial manifestations of SARS-CoV-2 vary, and usually occur between one and 14 days from exposure to the virus. Risk factors identified for COVID-19 include male gender, obesity, cardiovascular disease, diabetes mellitus, and older age [2–5]. The most common initial symptoms include fever, cough, fatigue, and loss of smell or taste [6]. During this period, the virus infects the epithelial cells through the angiotensin-converting enzyme 2 receptors and may eventually present as a viral pneumonia.

Although the disease primarily affects the respiratory system, multi-system organ involvement can occur with increasing severity of disease [6–8]. COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure [7,9]. This identification has led to significant clinical questions regarding the optimal prevention and management of CAC, which in turn, has led to many ongoing clinical trials. To help guide the management of these patients in the interim, numerous major societies have put forth recommendations regarding diagnosis, monitoring, and treatment of CAC. In this report, we discuss the pathogenesis, prevalence, diagnosis, and treatment of CAC to help providers understand this complicated condition and to apply best practices to the care of their patients.

From a practical perspective, societal guidelines are based on consensus of expert opinion, with the current evidence available. Major societal guidelines that have published on the management of CAC include but are not limited to Centers for Disease Control and Prevention (CDC), International Society on Thrombosis and Hemostasis interim guidance (ISTH-IG), American Society of Hematology (ASH), American College of Chest Physicians (ACCP), Scientific and Standardization Committee of ISTH (SCC-ISTH), Anticoagulation Forum (ACF), and American College of Cardiology (ACC) [9–13]. As a result of limited studies, there are many clinical scenarios that are yet to be addressed, with expert opinion varying on a number of important clinical issues regarding CAC management. In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC. To supplement the manuscript, we have provided three clinical scenarios (supplemental material) which implement important principles of anticoagulation in patients with COVID-19. Overall, decisions should be made on a case by cases basis and based on the providers understanding of each patient’s medical history, clinical course and perceived risk.

Prevalence

There is an increasing body of evidence suggesting patients with COVID-19 demonstrate a higher incidence of thromboembolic disease compared to historical data [14,15], with patients admitted to the ICU being at highest risk [16,17]. The true incidence of thromboembolism in patients admitted to hospital remains controversial with rates as low as 1% in those admitted to the medical ward and up to 69% of patients in the ICU [5,18]. In one study of 107 ICU patients, 91% of whom received VTE prophylaxis and 9% who received therapeutic anticoagulation, the prevalence of PE was 20.4%. In comparison to patients admitted to ICU for other reasons, patients with COVID-19 were 3–4 fold more likely to develop a pulmonary embolism (PE) [19]. However, there is also data to suggest that the prevalence of VTE is similar to that of patients admitted to hospital with similar non COVID illnesses, of similar severity [20,21]. The reported increase in prevalence of VTE remains despite thromboprophylaxis in some studies and not in others [15,22]. In addition to macro-vascular thrombosis, autopsy studies have demonstrated significant microvascular thrombosis in the lungs of patients who have died from COVID-19’s [7,23]. It is hypothesized that these microvascular thrombi cause end organ dysfunction such as renal failure [7,23,24]. Although the prevalence of microvascular thrombosis is yet to be determined, it may be greater than in patients with non COVID respiratory viral illnesses [24].

The majority of data on the prevalence of thromboembolic disease in patients with COVID-19 have been observational studies of VTE. However, there is emerging evidence suggesting an increase in arterial thromboses in COVID-19 patients as well. One study identified five cases of acute ischemic stroke in a two-week period in COVID-19 patients under the age of 50, in comparison to 0.7 large vessel strokes per two-weeks prior to the pandemic [25]. There are also studies reporting an increase in the prevalence of acute limb ischemia in patients hospitalized with COVID-19 compared to the general population [26,27].

The micro- and macro-thrombosis associated with CAC often leads to multisystem complications resulting in increased morbidity and mortality [8]. Despite many policies aimed at curbing viral spread, many countries/regions still see their weekly ICU admissions related to COVID-19 increasing [1]. With the introduction of vaccinations and targeted novel treatments for COVID-19, the prevalence and incidence of CAC and its related complications will hopefully decrease.

Pathogenesis

Although the pathogenesis of CAC has not been fully elucidated, there are multiple contributing factors that include hypercoagulability, endothelial dysfunction and abnormal blood flow (especially in the pulmonary vasculature) [28]. In severe COVID-19 disease, excess proinflammatory cytokines trigger the coagulation system resulting in a hypercoagulable state [29]. In addition to direct damage by viral invasion, this cytokine storm also results in endothelial injury and dysfunction, leading to endothelial cell activation [30]. The dysfunctional endothelial cells produce excess thrombin as well as shutdown fibrinolysis, leading to a prothrombotic state [31]. Furthermore, infection induced inflammatory changes in endothelial cells have been shown to increase coagulation biomarkers, including factor VIII, von Willebrand Factor (vWF), fibrinogen and P-selectin [24,32]. All of these mechanisms create an imbalance in the normal hemostatic system, with a resulting prothrombotic state, manifesting as both macro and micro-vascular thrombosis [30].

In patients with CAC, biomarkers supporting the hypercoagulability pathogenesis have been demonstrated to be elevated in vivo. Specifically, the procoagulant markers Factor VIII, Von Willebrand antigen and Von Willebrand activity have been found to be markedly elevated in patients with COVID-19 who develop thromboembolism [33]. Biochemically, this hypercoagulable state appears to be most significant in those patients with the most severe form of the disease. One study demonstrated that many prothrombotic markers are increased above their upper limit of normal in patients with COVID-19, with the greatest increase in patients admitted to the intensive care unit (ICU) as compared to non-ICU patients [34]. In support of this recognition, descriptive studies using viscoelastic hemostasis assays including thromboelastography (TEG) and rotational thromboelastometry (ROTEM) in patients with COVID-19 are more consistent with a hypercoagulable state rather than acute disseminated intravascular coagulation (DIC). For example, in a study of 24 ICU patients with COVID-19, TEG parameters demonstrated a hypercoagulable state with decreased K (kinetic) time (increased fibrinogen activity), increased alpha angle (increased fibrinogen activity), increased maximum amplitude (Ma) (increased platelet activity), and decreased LY30 (decreased fibrinolysis) [33]. These findings suggest decreased time to clot accumulation, increased strength and stability of the clot, and decreased breakdown of the clot. This study also found that fibrinogen, D-dimer, C-reactive protein, Factor VIII, vWF and protein C were all increased, while platelet count was normal or increased, prothrombin time (PT) and partial thromboplastin time (PTT) were near normal and antithrombin (AT) was marginally decreased. These discoveries are all consistent with a hypercoagulable state rather than DIC where one would expect decreased platelet count and increased PT and PTT. In another study of 21 ICU patients with COVID-19, the TEG MA was significantly higher in those with high thrombotic events (≥2 thrombotic events, defined as an arterial, central venous, or dialysis catheter or filter thromboses) compared to those with low thrombotic events (0–1 thrombotic events) [35]. Moreover, the mean fibrinogen and D-dimer levels were elevated in those with high thrombotic events although there was no significant differences in PT, international normalized ratio (INR), PTT or platelets between the two groups.

D-dimer elevation has also been associated with severity of COVID-19 and may be useful as a prognostic marker [36]. D-dimers are fibrin degradation product which can be measured in the blood after a clot is broken down through fibrinolysis [37]. As a result, elevated D-dimer levels are suggestive of venous thromboembolism (VTE), pulmonary embolism (PE) or DIC; however, it is also elevated in the context of systemic inflammation, which has been demonstrated in numerous clinical settings [20,38]. With COVID-19 stimulating a systemic inflammatory response, it is likely that D-dimers are elevated whether thromboembolic disease is present or not.

Despite the increased inflammatory response associated with COVID-19, patients are less likely to develop a reactive thrombocytosis and often have a mild thrombocytopenia [39]. Platelets in patients with COVID-19 have been found to have increased activity compared to healthy patients, with increased aggregation, thromboxane generation and platelet activation [40]. It is unclear whether these changes in platelet function are associated with an increased risk of thrombosis [39,41]. One study in hospitalized patients with COVID-19 found that a platelet count >450 × 109/L on admission was associated with an increased risk of VTE (adjusted OR of 3.56 [95% CI, 1.27–9.97]) [20]. However, another study of 1476 patients hospitalized with COVID-19 found that the platelet count was inversely associated with risk of in-hospital mortality, although, it is unclear if this increased risk in mortality was a result of consumption in the context of DIC [42]. The appropriate workup of a decreasing platelet count and thrombocytopenia should be pursued in the COVID-19 patient as it would be for non-COVID patients. Given that the majority of patients with COVID-19 receive some form of heparin, a diagnosis of heparin-induced thrombocytopenia (HIT) may be considered, and the subsequent use of Platelet Factor 4 (PF4) and platelet serotonin release assay (SRA) can be used to diagnose this potentially life-threatening condition.

Upon initial screening, many patients with COVID-19 have an elevated PTT in the context of minimal clinical bleeding. This finding raises the question of whether the thrombotic related biomarker, lupus anticoagulant is affected by COVID-19 disease [43,44]. The lupus anticoagulant is an immunoglobulin which binds to phospholipids and proteins associated with the cell membrane. When evaluated in vitro, these immunoglobulins interfere with the phospholipids which induce coagulation, leading to a prolonged PTT. In vivo, however, these antibodies are often prothrombotic [45]. Two studies of patients with COVID-19 and prolonged PTT on initial presentation have demonstrated high rates of lupus anticoagulant positivity [15,43]. However, it has been noted that upon repeat testing, many patients become negative, suggesting that the lupus anticoagulant positivity may be transient and associated with severe viral illness [46]. Overall, more studies are needed to determine if lupus anticoagulant is truly associated with COVID-19 and related to an increase in VTE, and if so, whether the use of anticoagulation should be changed based on the presence of this abnormality [47].

Antithrombin deficiency, a marker of thrombophilia, can be acquired or inherited and may place patients at increased risk of thrombosis. Antithrombin is a natural anticoagulant that inhibits thrombin and factor Xa, thereby helping to prevent thrombosis. There have been case reports of AT deficiency in COVID-19 patients which may place such patients are at higher risk of thrombosis [48]. However, as with the other biochemical testing, more studies are needed to determine if this knowledge is related to adverse outcomes such as thrombosis and if these results should be used to help guide anticoagulation practices.

Manifestations

Since the emergence of COVID-19, the associated increased risk of thrombotic complications such as deep vein thrombosis (DVT), pulmonary embolism (PE) and microvascular thrombosis have been well described [17]. The spectrum of CAC is broad and may present with either or both arterial and venous thromboembolic disease [22]. In general, the majority of the thrombotic events when present are DVT or PE, however catheter associated thrombosis, other venous thrombosis and arterial events, including stroke, acute limb ischemia, bowel ischemia and myocardial infarction, have been reported [14]. Patients also appear to be at risk for microvascular thrombosis. Multiple autopsy studies have demonstrated microvascular thrombosis in the lungs of patients who have died from COVID-19’s, suggesting the multisystem organ failure often seen in COVID-19 may be a result of microvascular thrombosis [23,49].

Bleeding was initially believed to be much less common than thrombosis in patients with COVID-19, however, further data has emerged suggesting the rates of bleeding may be similar to the rates of thrombosis [20]. One autopsy study involving 82 patients found that, 6% died from hemorrhage and that over 80% of patients had some kind of hemorrhagic complication [50]. Another study of 400 hospitalized COVID-19 patients found a radiographically confirmed VTE rate of 4.8% (95% confidence interval [CI], 2.9–7.3), which was identical to the overall bleeding rate of 4.8% (95% CI, 2.9–7.3) [20].

Although clinically significant DIC is uncommon in COVID-19 patients, and if suspected, it is important to identify and aggressively treat the underlying etiology, including any superimposed bacterial infections in addition to managing the coagulopathy [51].

Diagnosis

Currently, there are no diagnostic criteria for CAC. At present, there is no evidence or guideline to support routine screening for VTE, PE or other thrombotic complications in patients with COVID-19. However, the threshold to investigate for DVT or PE should be low given the frequency with which these complications may occur in patients with COVID-19. If thromboembolic disease is suspected, appropriate investigations should depend on the clinical context, acuity of disease and resources available. A position paper from the National Pulmonary Embolism Response Team (PERT) Consortium provides a step wise approach to a suspected PE, which includes ordering a computed tomography pulmonary angiogram (CTPA) if available [52]. If the computed tomography (CT) is not available or the patient is too unstable, a lower limb ultrasound to assess for a proximal DVT, or an echocardiography to assess right heart strain may be pursued. However, it should be noted that neither of these investigations are sensitive. If none of those modalities are available, nor do they rule in a PE/DVT, and there is a high clinical suspicion for a PE, therapeutic anticoagulation should be considered pending no absolute contraindications [52].

In patients with COVID-19, many routine biomarkers of the coagulation cascade have been found to fall outside the normal range, including PTT/PT, platelet count, and fibrinogen [53]. Derangement of these tests may suggest increased disease severity. A D-dimer elevated by three- to fourfold, a prolonged prothrombin time and a platelet count <100 × 109 are all predictors of a poorer prognosis [13,54]. Despite this evidence, most of the major societal guidelines (ACF, ACCP, SCC-ISTH, CDC) have either not recommended nor commented on the routine monitoring of laboratory values to guide management, risk stratification, or triage of patients with COVID-19. For instance, the SCC-ISTH guidelines state that further study is required before using laboratory testing for risk stratification and triage of CAC. The CDC guidelines state that there is a lack of prospective data demonstrating laboratory testing as a way to risk stratify patients, and that there are insufficient data to recommend for or against using laboratory values to guide management. If a patient is bleeding or has a confirmed, or is highly suspected of having a VTE; then, the patient should be treated based on clinical context. Repeat testing of CBC, coagulation studies, fibrinogen, and d-dimer should also be performed based on the clinical setting.

When considering the use of D-dimer assays, a negative D-dimer can be useful in excluding a VTE in patients with COVID-19. However, a positive D-dimer does not necessarily equate to a diagnosis of VTE as this test is not specific and can be elevated in many other pathological and non-pathological processes [55]. Moreover, studies have demonstrated that D-dimer levels tend to be higher in severe COVID-19 cases and may be used as a potential prognostic marker [56]. Despite this connection, none of the major societal guidelines recommend routine monitoring of D-dimer nor using it to guide anticoagulation practices.

Treatment

At least seven major societal guidelines have been published to address prevention and treatment of CAC in the critical care settings, with all authors of these guidelines having prior expertise in the management of VTE [57]. Some of the societies with published guidelines include Centers for Disease Control and Prevention (CDC), International Society on Thrombosis and Hemostasis interim guidance (ISTH-IG), American Society of Hematology (ASH), American College of Chest Physicians (ACCP), Scientific and Standardization Committee of ISTH (SCC-ISTH), Anticoagulation Forum (ACF), and American College of Cardiology (ACC) [9–13]. Currently, there are no separate recommendations for prevention or management of arterial thrombosis in CAC; therefore, this patient population should follow the recommendations of the clinical syndrome in question (e.g., acute myocardial infarction requires dual antiplatelets).

Here, we review the recommendations for prevention, treatment, and monitoring of anticoagulation for CAC in the critical care setting by reviewing the common questions. A summary of the recommendations can be seen in Table 1Table 2 and Table 3:

  1. How should biomarkers be used to guide management?
  2. What are the preferred prophylactic anticoagulation regimens?
  3. When should the intensity of anticoagulation be increased?
  4. What are the preferred therapeutic anticoagulation regimens?
  5. When are thrombolytics recommended?
  6. When should anticoagulation be held?
  7. What is the utility of mechanical thromboprophylaxis?
  8. What is the appropriate method of monitoring anticoagulation?
  9. What is the recommended approach for correction of active bleeding?
  10. Should patients receive post-discharge prophylactic anticoagulation and if so, what regimens are recommended?

Table 1.

Major societal recommendations regarding using biomarkers to guide anticoagulation, choice of prophylactic anticoagulation and when to consider increasing intensity of anticoagulation

 How should biomarkers be used to guide management?What are the preferred prophylactic anticoagulation regimens?When should the intensity of anticoagulation be increased?
CDCInsufficient data to recommend for or against using hematologic and coagulation parameters to guide management decisions.LMWH or UFH (standard dosing). Insufficient data to recommend for or against the increase of anticoagulation intensity outside of a
clinical trial.
Consider when a clinically suspected thromboembolic event is present or highly suspected despite imaging confirmation. Insufficient data to recommend for or against the increase of anticoagulation intensity outside the context of a clinical trial. Mentions patients who have thrombosis of catheters or extracorporeal filters should be treated accordingly to standard institutional protocols for patients without COVID-19.
ISTH-IGNot mentionedLMWH (standard dosing)No specific recommendations
ACFBiomarker thresholds such as D-dimer for guiding anticoagulation management should not be done outside the setting of a clinical trial.Suggests an increased intensity of venous thromboprophylaxis be considered for critically ill patients# (i.e. LMWH 40 mg SC twice daily, LMWH 0.5 mg/kg subcutaneous twice daily, heparin 7500 SC three times daily, or low-intensity heparin infusion) that they state is based largely on expert opinion.Consider when a clinically suspected thromboembolic event is present or highly suspected despite imaging confirmation.
ASHNo particular change to regimen recommended for patients with lupus like inhibitors. TEG and ROTEM should not be used routinely to guide management.LMWH over UFH (standard dosing) to reduce exposure unless risk of bleeding outweighs risk of thrombosis.Consider increasing the intensity of anticoagulation regimen (i.e. from standard to intermediate intensity, from intermediate to therapeutic intensity) or change anticoagulants in patients who have recurrent thrombosis of catheters and extracorporeal circuits (i.e. ECMO, CRRT) on prophylactic anticoagulation regimens.
ACCPNot mentionedLMWH (standard dosing)Patients with PE or proximal DVT.
SCC-ISTHD-dimer levels should not be used solely to guide anticoagulation regimens.LMWH or UFH. Intermediate intensity LMWH can be considered in high risk critically ill patients (50% of responders) and may be considered in non-critically ill hospitalized patients (30% of respondents). Mentions that there are several advantages of LMWH over UFH including once vs twice or more injections and less heparin-induced thrombocytopenia. Regimens may be modified based on extremes of body weight (50% increase in dose if obese), severe thrombocytopenia*, or worsening renal function.Therapeutic anticoagulation should not be considered for
primary prevention until randomized controlled trials are available. Increased intensity of anticoagulation regimen (i.e. from standard or intermediate intensity to therapeutic intensity) can be considered in patients without confirmed VTE or PE but have deteriorating pulmonary status or ARDS.
ACCFurther investigation is required to determine the role of antiphospholipid antibodies in pathophysiology of COVID-19- associated thrombosis. D-dimer > 2 times the upper limit may suggest that patient is at high risk for VTE and consideration of extended prophylaxis (up to 45 days) in patients at low risk of bleeding. Mentions that therapeutic anticoagulation is the key to VTE treatment. Does not make distinction between confirmed or suspected VTE. Hemodynamically stable patients with submassive PE should receive anticoagulation rather than thrombolytics

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Table 2.

Major societal recommendations regarding therapeutic anticoagulation regimens, when thrombolytics should be used and when anticoagulation should be held

 What are the preferred therapeutic anticoagulation regimens?When should anticoagulation be held?When are thrombolytics recommended?
CDCStandard regimens for non-COVID-19 patients.Active hemorrhage or severe thrombocytopenia (Platelet count not defined)Insufficient data to recommend for or against thrombolytic therapy outside the context of a clinical trial. In pregnant patients, thrombolytic therapy should only be used for acute PE with life-threatening hemodynamic instability due to risk for maternal hemorrhage.
ISTH-IGNot mentionedHold when signs of active bleeding or platelet count < 25 x 109/L. Abnormal PT or PTT is not a contraindication to thromboprophylaxis.Not mentioned
ACFLMWH over UFH whenever possible to avoid additional laboratory monitoring, exposure, and personal protective equipment. In patients with AKI or creatinine clearance < 15–30 mL/min, UFH is recommended over LMWH.Active bleeding or profound thrombocytopenia (Platelet count not defined)Consider if clinical indication such as STEMI, acute ischemic stroke, or high-risk massive PE with hemodynamic instability. Otherwise, it is not recommended outside context of a clinical trial.
ASHLMWH or UFH over direct oral anticoagulants due to reduced drug-drug interactions and shorter half-life.Thromboprophylaxis is recommended even with abnormal coagulation tests in the absence of active bleeding and held only if platelet count < 25 x 109/L or fibrinogen < 0.5 g/L. Abnormal PT or PTT is not a contraindication to thromboprophylaxis. Therapeutic anticoagulation may need to be held if platelet count < 30–50 x 109/L or fibrinogen < 1.0 g/L.Not mentioned
ACCPLMWH or fondaparinux over UFH. UFH preferred in patients at high bleeding risk and in renal failure or needing imminent procedures. Recommend increasing dose of LMWH by 25–30% in patients with recurrent VTE despite therapeutic LMWH anticoagulation.Not mentionedThrombolytics over no such therapy in patients with objectively confirmed PE with hemodynamic instability or signs of obstructive shock who are not at high risk of bleeding. Peripheral thrombolysis recommended over catheter-directed thrombolysis
SCC-ISTHNot mentionedNo specific recommendations. Reports that 50% of respondents report holding if platelet count < 25 x 109/L.Not mentioned
ACCMedication regimen likely to change depending on comorbidities (i.e. renal or hepatic dysfunction, gastrointestinal function, thrombocytopenia). Parenteral anticoagulation (i.e. UFH) may be preferred in many ill patients given it may be withheld temporarily and has no known drug-drug interactions with COVID-19 therapies. LMWH may be preferred in patients who are unlikely to need procedures as there are concerns with UFH regarding the time to achieve therapeutic PTT and increased exposure to healthcare workers. DOACs have advantages including lack of monitoring that is ideal for outpatient management but may have risks in settings of organ dysfunction related to clinical deterioration and lack of timely reversal at some centers.In patients with moderate or severe COVID-19 on chronic therapeutic anticoagulation who develop suspected or confirmed DIC without overt bleeding,
it is reasonable to consider the indication of anticoagulation and risk of bleeding for adjusting dose or discontinuation of anticoagulation. The majority of authors recommended reducing the intensity of anticoagulation unless there was an exceedingly high risk of thrombosis.
A multidisciplinary PERT may be helpful for intermediate and high-risk patient with VTE. For hemodynamically high-risk PE, systemic fibrinolysis is indicated with catheter-based therapies reserved for situations that are not amenable to systemic fibrinolysis. Patients with hemodynamically stable intermediate-low or intermediate-high risk PE should receive anticoagulation and rescue systemic fibrinolysis should be considered in cases of further deterioration with catheter-directed therapies as an alternative. Catheter directed therapies should be limited to most critical situations given minimal data showing mortality benefit. When considering fibrinolysis vs percutaneous coronary intervention for STEMI, clinicians should weigh risks and severity of STEMI presentation, severity of COVID-19 in patient, risk of COVID-19 to individual clinicians and healthcare system.

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Table 3.

Major societal recommendations regarding monitoring of anticoagulation, correction of active bleeding and prophylactic anticoagulation post-discharge

 What is the appropriate method of monitoring anticoagulation?What is the recommended approach for correction of active bleeding?Should patients receive post-discharge prophylactic anticoagulation
CDCPer standard of care for patients without COVID-19Not mentionedRoutine venous thromboprophylaxis post-discharge is not recommended. FDA-approved prophylactic anticoagulation regimen (rivaroxaban and betrixaban) can be considered if high risk for VTE and low risk for bleeding using criteria from clinical trials.
ISTH-IGNot mentionedTransfuse to keep platelet count > 50 x 109/L, fibrinogen > 1.5 g/L, PT ratio < 1.5No specific recommendations
ACFRecommend monitoring anti-Xa levels to monitor UFH due to potential baseline PTT abnormalities. Reasonable to monitor anti-Xa or PTT in patients with normal baseline PTT levels and do not exhibit heparin resistance (> 35,000 u heparin over 24 h).Not mentionedNo evidence for anticoagulation beyond hospitalization, but reasonable to consider if low risk for bleeding and high risk for VTE including intubated, sedated, and paralyzed for multiple days.
ASHMay necessitate anti-Xa monitoring of UFH given artefactual increases in PTT.Transfuse one adult unit of platelets if platelets < 50 x 109/L, give 4 units of plasma if INR > 1.8, and fibrinogen concentrate (4 g) or cryoprecipitate (10 u) if fibrinogen < 1.5 g/L. In patients with severe coagulopathy and bleeding can consider 4 F-PCC (25 u/kg) instead of plasma.Reasonable to consider FDA-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) or aspirin if criteria from trials for post-discharge thromboprophylaxis are met.
ACCPMonitor anti-Xa levels in all patients receiving UFH given potential of heparin resistance.Not mentionedCan be considered in patients who are at low risk of bleeding if emerging data suggests a clinical benefit.
SCC-ISTHNo specific recommendations. Mentions that expert clinical guidance statements and clinical pathways from large academic healthcare systems target an anti-factor Xa level of 0.3–0.7 IU/mL for UFH.Not mentionedEither LMWH or FDA-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) should be considered in patients with high VTE risk criteria. Duration is 14 days at least and up to 30 days. Of note, they report that none of the respondents recommended aspirin for post-discharge thromboprophylaxis.
ACCNot mentionedTransfuse platelets to maintain platelets > 50 x 109/L in DIC and active bleeding or if platelets < 20 x 109/L in patients at high risk of bleeding or requiring invasive procedures. FFP (15 to 25 mL/kg) in patients with active bleeding with either prolonged PT or PTT ratios (> 1.5 times normal) or decreased fibrinogen (< 1.5 g/L). Fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (< 1.5 g/L). Prothrombin complex concentrate if FFP is not possible. Tranexamic acid should not be used routinely in patients with COVID-19-associated DIC given the existing data.Reasonable to consider extended prophylaxis with LMWH or DOACs for up to 45 days in patients at high risk for VTE (i.e. D-dimer > 2 times the upper limit, reduced mobility, active cancer) and low risk of bleeding.

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How should biomarkers be used to guide management?

Despite CAC being associated with biomarker abnormalities, none of the major societies to date recommend the use of biomarkers to help guide inpatient anticoagulation decisions. Most notably, D-dimer elevation has been associated with severity of COVID-19, and may be useful as a prognostic marker [36]. With COVID-19 triggering a systemic inflammatory response, it is likely D-dimers will be elevated whether thromboembolic disease is present or not. Therefore, none of the major societies recommend any role for routine monitoring of D-dimer, with its use limited to risk stratification as per ISTH-IG and ASH. Furthermore, the CDC guidelines specifically state that there is insufficient data to recommend for or against using hematologic and coagulation parameters to guide management decisions in CAC. The ACF guidelines also states that using biomarkers such as D-dimer for guiding anticoagulation management should only be done in the setting of a clinical trial. One society’s guidelines, the ACC, mentions a potential role for the use of biomarkers in decision-making: in patients with a D-dimer >2 times the upper limit may be considered for extended prophylaxis (up to 45 days) if patients are at low risk of bleeding. Currently, a multicenter randomized controlled trial is underway to evaluate the efficacy and safety of antithrombotic strategies in COVID-19 adults not requiring hospitalization at time of diagnosis. The trial is designed to compare aspirin, low dose and regular dose apixaban prophylaxis and placebo, with the results of VTE compared across increasing D-dimer levels [58]. This study will help ascertain the value of baseline D-dimer levels in this population. Another clinical trial, ATTACC, was performed to determine whether therapeutic anticoagulation improved organ support-free days [59]. This study also assessed the efficacy of therapeutic anticoagulation across subgroups based on initial D-dimer level. The D-dimer level did not appear to be useful in risk stratification.

When considering other biomarkers, none of the major societal guidelines recommend a change to the anticoagulation regimen in patients with COVID19 who have positive antiphospholipid antibodies or any other biomarker abnormality. Finally, although viscoelastic hemostasis assays such as TEG and ROTEM may suggest hypercoagulability, the ASH guidelines specifically recommend against the routine use of these tests to guide management.

What are the preferred prophylactic anticoagulation regimens?

VTE prophylaxis should be provided to all hospitalized patients with COVID-19 unless contraindicated. The majority of societal guidelines have recommended once daily administration using low molecular weight heparin (LMWH) to reduce healthcare worker exposure given the lower frequency of administration compared to unfractionated heparin (UFH), to conserve personal protective equipment and because it has a lower risk for heparin-induced thrombocytopenia. LMWH may not be preferred over UFH when the risk of bleeding outweighs the risk of thrombosis and in patients with renal dysfunction (i.e. creatinine clearance <30 mL/min). An additional benefit of heparin is its possible anti-inflammatory effects in both the vasculature and the airway [59]. With COVID-19 stimulating a proinflammatory state in both the airways and vasculature, heparin not only provides value as an anticoagulant but also may exert benefit as an anti-inflammatory agent [60]. The efficacy of heparin as an anti-inflammatory agent in patients with COVID-19 warrants further investigation.

The dosing of prophylactic anticoagulation remains controversial given that some studies have demonstrated that up to one quarter of patients with COVID in the ICU develop VTE despite thromboprophylaxis [17,22,61]. As a result, it has been suggested that intermediate or therapeutic doses of LMWH could be considered [10,12,62,63]. There is emerging evidence that initiation of therapeutically dosed anticoagulation in place of prophylactically dosed anticoagulation may decrease the need for mechanical ventilation and other life supporting interventions in non-critically ill hospitalized population but this has not been published in a peer review journal [59]. With thrombosis being a prominent feature of COVID-19, three clinical trials conducted a multiplatform clinical trial (ATTACC) to determine whether therapeutic anticoagulation improved organ support-free days (ICU level care and receipt of mechanical ventilation, vasopressors, extracorporeal membrane oxygenation (ECMO) or high-flow nasal oxygen). Although full results have not been published, the pre-publication, non-peer-reviewed, interim results show that patients who are moderately ill (hospitalized but not on ICU organ-support) had improved organ support-free days with therapeutically dosed anticoagulation in comparison to standard of care [64]. However, full-dose anticoagulation when started in critically ill patients with COVID19 was not found to be beneficial and may be harmful. Current societal guidelines which do not account for these interim findings do not recommend the use of therapeutically dosed anticoagulation as a replacement for prophylactically dosed anticoagulation. Until the results of these studies are published and validated, following current guidelines seems reasonable. Of note, ASH published new guidelines in March 2021 which continue to recommend prophylactically dosed anticoagulation in the context of hospitalized patients diagnosed with COVID-19 [65].

A retrospective analysis of 4389 COVID-19 patients found that compared with no anticoagulation, therapeutic and prophylactic anticoagulation were associated with a lower in-hospital mortality and intubation. Furthermore, when anticoagulation was initiated ≤48 h from admission, there was no statistically significant difference in outcomes between the patients that received therapeutic vs. prophylactic doses [66].

Finally, aspirin has been a proposed treatment for CAC given its anti-inflammatory and anti-thrombotic effects [67–70]. A recent meta-analysis demonstrated no association between the use of aspirin and mortality in COVID-19 [71]. The RECOVERY trial conducted a multicentre randomized control trial (RCT) testing aspirin against usual care [72]. The results of this trial released in preprint showed that aspirin was not associated with a reduction in 28-day mortality or in risk of progressing to invasive mechanical ventilation or death.

When to increase intensity of anticoagulation

At this stage, there is no consensus as to when to increase the intensity of anticoagulation with the exception of documented thromboembolism. The ACF states that increased intensity of anticoagulation regimen (i.e., from standard or intermediate intensity to therapeutic intensity) can be considered in patients, without confirmed VTE or PE, who have deteriorating pulmonary function or ARDS without clear underlying cause. They also suggest an increased intensity of venous thromboprophylaxis could be considered for critically ill patients (i.e. LMWH 40 mg SC twice daily, LMWH 0.5 mg/kg subcutaneous twice daily, heparin 7500 SC three times daily, or low-intensity heparin infusion). The SCC-ISTH guidelines state that intermediate intensity LMWH may be considered in high risk critically ill patients. They also suggest anticoagulation prophylaxis regimens may be modified based on extremes of body weight. If the patient is obese (BMI >30 kg/m2), an increase of 50% in dose has been deemed reasonable.

ASH guidelines state that in patients who have recurrent thrombosis of catheters and extracorporeal circuits (i.e., ECMO, continuous renal replacement therapy (CRRT)) on prophylactic anticoagulation regimens, may have the intensity of anticoagulation increased (i.e. from standard to intermediate intensity, from intermediate to therapeutic intensity) or change the anticoagulant regimen. The CDC guidelines state that patients who have thrombosis of catheters or extracorporeal filters should be treated according to standard institutional protocols (which may include increasing anticoagulation intensity) for patients without COVID-19. Our institution, the Massachusetts General Hospital found that a low dose heparinized saline protocol is associated with improved duration of arterial line patency in critically ill COVID-19 patients [73]. Additionally, we also found that a protocol where systemic unfractionated heparin is dosed by anti-factor Xa levels lead to lower rates of CRRT filter clotting and loss [74].

What is the preferred therapeutic anticoagulation regimens?

Several of societal guidelines (ACF, ACCP, and ACC) recommend LMWH over UFH to avoid additional laboratory monitoring, minimize healthcare worker exposure, preserve personal protective equipment (PPE) utilization, benefit from the greater anti-inflammatory effects, and decrease time to achieve therapeutic anticoagulation levels. LMWH is preferred over UFH when no imminent procedures are planned, the risk of thrombosis is greater than the risk of bleeding, and patients do not have significant renal failure. In addition to LMWH, the ACCP guidelines also recommend fondaparinux over UFH with a similar rationale, and fondaparinux may be used in patients with suspected or confirmed HIT. UFH may be preferred in patients who need imminent procedures, are at high risk of bleeding or have significant renal failure. In patients with recurrent VTE despite therapeutic LMWH anticoagulation, the ACCP guidelines recommends increasing the dose of LMWH by 25–30%. While direct oral anticoagulants (DOACs) have advantages including no need for monitoring, none of the major societal guidelines recommend their use in this critical care setting given their lack of timely reversal at some hospitals. Parenteral anticoagulants also have no known drug–drug interactions with COVID-19 therapies, and this may not be true with DOACs.

When are thrombolytics recommended?

Given autopsy findings of patients with COVID-19 revealing significant pulmonary micro- and macro-thrombosis, the question has been raised as to whether there is a role for thrombolytic therapy. There are a number of case series that suggest the use of thrombolytics in patients with severe ARDS and COVID-19 may lead clinical improvement [75,76]. Given this potential benefit, there are a number of ongoing clinical trials investigating the use of parenteral and nebulized thrombolytic therapy for patients with severe COVID-19 ARDS. If a PE is suspected, consultation with a pulmonary embolism response team (PERT) is advised if available. These teams can provide expert advice regarding issues related to diagnosis and management of a PE in patients with COVID-19. If PERT consultation is unavailable, the National PERT Consortium paper has provided an algorithm to assist in decision-making for patients with a suspected PE [52]. Our institution, the Massachusetts General Hospital, has a PERT team which is a multidisciplinary team composed of experts from cardiology, cardiac surgery, emergency medicine, hematology, pulmonary and critical care, radiology, and vascular medicine and delivers immediate and evidence-based care to patients with suspected or confirmed high risk PE [77]. When major societal guidelines do recommend thrombolytic therapy, it is in the clinical context where their use would otherwise be clinically indicated such as STEMI, acute ischemic stroke, or high-risk massive PE with hemodynamic instability and when the benefits outweigh the risks of administration. In general, thrombolytic therapy is not recommended in patients who have a PE and are hemodynamically stable [57].

When to hold anticoagulation?

Most major society’s guidelines (CDC, ISTH-IG, ACF, ASH, SCC-ISTH) advise holding therapeutic and prophylactic anticoagulation in patients who have significant active bleeding and/or severe thrombocytopenia. Both the ACF and SCC-ISTH guidelines suggest holding anticoagulation if platelet count <25 x 10^9/L. ASH recommends holding prophylactic anticoagulation if platelet count is <25 x 10^9/L or fibrinogen <0.5 g/L, and holding therapeutic anticoagulation may necessary if platelet count is <30–50 x 10^9/L or fibrinogen <1.0 g/L. Of note, many patients with COVID-19 may have abnormal baseline PT or PTT, which is not a contraindication to thromboprophylaxis according to the ISTH-IG and ASH guidelines. Therefore, PT and PTT should not be used as a guide to hold prophylactic or therapeutic anticoagulation.

What is the utility of mechanical thromboprophylaxis?

Most of the major society’s guidelines (ACF, ASH, ACCP, SCC-ISTCH, and ACC) recommend or suggest mechanical thromboprophylaxis when pharmacological thromboprophylaxis is contraindicated. Intermittent pneumatic compression devices are the preferred type of mechanical thromboprophylaxis. ACCP suggests against the additional use of mechanical thromboprophylaxis in critically ill patients receiving pharmacological prophylaxis but mentions that its addition is unlikely to cause harm.

What is the appropriate method of monitoring anticoagulation?

Monitoring of patients receiving therapeutic anticoagulation with LMWH

Currently, none of the major society guidelines recommend the routine monitoring of anti-Xa levels of patients receiving LMWH. LMWH is generally preferred if there are no contraindications given the added benefit of not needing routine monitoring. However, the ISTH-IG guidelines state that monitoring of LMWH is advised in patients with severe renal impairment, a patient population generally for which LMWH is not routinely recommended. However, the ACCP guidelines state that body weight adjusted doses for LMWH do not require laboratory monitoring in majority of patients, and the ACF guidelines state that anti-Xa level monitoring is not recommended in patients with elevated PTT levels given the lack of evidence on outcomes for thrombosis or bleeding.

Monitoring of patients receiving therapeutic anticoagulation with UFH

The PTT measures the intrinsic coagulation pathway and is the most commonly used test to monitor UFH [78]. It is not uncommon for patients with COVID-19 to have baseline coagulation abnormalities of PT and PTT. Although these abnormalities are not contraindications to anticoagulation, it may lead to difficulties measuring heparin effectiveness. When in doubt, the majority of society guidelines (ACF, ASH, ACF and ACCP) advise that therapeutic anticoagulation should be monitored with an anti-Xa level rather than PTT. The SCC-ISTH guideline does not make any particular recommendations but does mention that expert clinical guidance statements and clinical pathways from large academic healthcare systems target for therapeutic anticoagulation, an anti-factor Xa level of 0.3–0.7 IU/mL for UFH. While the ACF guideline recommends monitoring of anti-Xa levels to monitor UFH due to potential baseline PTT abnormalities and heparin resistance (>35,000 U heparin over 24 hours), they also mention that it is reasonable to monitor anti-Xa or PTT in patients with normal baseline PTT levels and in those unlikely to have heparin resistance. There is evidence in the value of implementing an anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels. At our institution, The Massachusetts General Hospital, we found that patients with COVID-19 infection on CRRT had lower rates of CRRT filter clotting and loss when using this protocol where systemic unfractionated heparin was dosed by anti-factor Xa levels [74]. However, this needs to be studied further in clinical trials.

Heparin resistance

An important consideration when making decisions about DVT prophylaxis and monitoring of anticoagulation in COVID-19 patients is the concern for heparin resistance, which has been well documented [79]. Heparin resistance should be suspected when disproportionately large doses of heparin are required to achieve therapeutic anticoagulation. This problem is usually due to low heparin concentrations, which results from binding of heparin to acute phase proteins in the context of systemic inflammation. There is also some evidence of AT deficiency in COVID-19 patients which may contribute to suspected heparin resistance [48]. Heparin functions as an anticoagulant by binding to AT, activating it, and then inhibiting clotting factors, most notably factor Xa [80]. A way to measure the capacity of the heparin-AT complex is with anti-Xa levels. It has been well documented that patients with COVID-19 may have artefactual increases in PTT, and therefore measuring anti-Xa levels may be a more accurate way to assess the level of anticoagulation in these situations. Additionally, LMWH can’t be measured with PTT, and as a result, anti-Xa levels may be used to ensure appropriate anticoagulation levels have been achieved if necessary. Unfortunately, not all centers have the capacity to monitor anti-Xa levels.

What is the recommended approach to control active bleeding?

When addressing active bleeding, the major society guidelines recommend holding both prophylactic and therapeutic anticoagulation. However, only the ISTH-IG, ASH and ACC guidelines provide specific recommendations for blood product replacement. The ISTH-IG guidelines recommend transfusing to keep platelet count >50 x 10^9/L, fibrinogen concentrate to target fibrinogen >1.5 g/L, and FFP to target PT ratio <1.5. ASH guidelines recommend transfusing one adult unit of platelets if platelet count <50 x 10^9/L, 4 units of plasma if INR > 1.8 and fibrinogen concentrate (4 g) or cryoprecipitate (10 units) if fibrinogen <1.5 g/L. The ACC guidelines recommend transfusing platelets in patients with active bleeding or requiring invasive procedures if platelet count <20 x 10^9/L, and providing FFP (15 to 25 mL/kg) in patients with active bleeding with either prolonged PT or PTT ratios (>1.5 times normal) as well as transfusing fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (<1.5 g/L).

If volume overload is a concern in patients with active bleeding and severe COVID-19, ASH and ACC guidelines recommend the use of 4 F-PCC (25 u/kg) instead of FFP. The ACC guidelines also state that tranexamic acid should not be routinely used in patients with COVID-19 associated DIC given the lack of existing data. None of the major societies mention the use of TEG to monitor coagulopathy in patients who are actively bleeding.

DIC is an uncommon but serious complication in patients with COVID-19 [81]. It’s important to note that DIC is a clinical diagnosis with exclusion of alternate explanations for coagulation dysfunction. In patients with COVID-19, a superimposed bacterial infection is the most likely precipitant, however other causes such as HIT, drug-induced DIC and malignancy may also be contributing. Treating the underlying cause is the most important component of treating DIC, with transfusion targets the same as for active bleeding. If there is no active bleeding, replacement of fibrinogen and coagulation factors remain controversial. However, if platelet count is <10 x 10^9/L, platelets should be transfused.

Should patients receive post-discharge prophylactic anticoagulation and what regimens are available?

There is no evidence to support post-discharge DVT prophylaxis in patients who were hospitalized with COVID-19 infection. A number of studies have identified very low rates of post-discharge VTE; therefore, there is no universal recommendation for VTE prophylaxis for all patients post-discharge [82–84]. However, in high-risk patients and those who are at low risk of bleeding, the majority of major societal guidelines (CDC, ACF, ASH, ACCP, SCC-ISTH and ACC) state that it is reasonable to consider post-discharge prophylactic anticoagulation. Currently, there is an ongoing randomized trial evaluating the effectiveness and safety of low-dose apixaban in reducing thrombosis in patients who have been discharged from the hospital [85].

At the point of discharge, if a patient is deemed high risk (i.e., D-dimer >2 times the upper limit, reduced mobility, active cancer) of thrombosis and low risk of bleeding, it is reasonable to use criteria from clinical trials involving FDA-approved prophylactic anticoagulation regimens such as LMWH, rivaroxaban and betrixaban for thromboprophylaxis [57]. In terms of how long to provide thromboprophylaxis once discharged, the SCC guidelines recommend following post-discharge prophylactic anticoagulation regimen for 14–30 days. The ACC guideline states that it is reasonable to consider extended prophylaxis with LMWH or DOACs for up to 45 days in patients with high risk for VTE. For those diagnosed with COVID-19, and not admitted to hospital, there is no recommendation for DVT prophylaxis as an outpatient. However, a multicenter randomized controlled trial is underway to evaluate the efficacy and safety of antithrombotic strategies (aspirin compared with low dose and regular dose apixaban, and with placebo) in adults with COVID-19 not requiring hospitalization at time of diagnosis [58]. However, this trial is evaluating outpatients, not patients admitted post-discharge.

Conclusion

CAC is associated with macro- and micro-thrombosis, which can lead to a myriad of different presentations, and may result in multiorgan injury and ultimately death. As a result, important clinical questions regarding the optimal prevention and management of thrombosis has led to many ongoing clinical trials. Whilst data continues to be collected, major hematological societies have put forth recommendations regarding diagnosis, monitoring, and treatment of CAC. Overall, decisions should be made based on the providers understanding of a patient’s medical history, clinical course and perceived risk, in conjunction with the major societal guidelines and results from emerging clinical trial results.

Acknowledgments

We thank the educational division of Roche for allowing us to incorporate this manuscript into their CoagYOUlation platform (http://www.coagYOUlation.com). This manuscript incorporates literature and guidelines available at the time of submission. It is anticipated that the guidelines and practice management provided on the platform will be updated as additional literature becomes available.

Declaration of funding

We would also like to thank Roche for providing support for the article processing fees required in publishing this article and for initial compensation related to the creation of educational content provided in this article.Go to:

Declaration of financial/other relationships

No potential conflict of interest was reported by the author.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authors contributions

PJL, RPR, EAB, MGC wrote and reviewed the manuscript.

Take home message

COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure. In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC.

COVID-19: Coronavirus disease 2019

WHO: World Health Organization

CAC: COVID-19 associated coagulopathy

CDC: Centers for Disease Control and Prevention (CDC),

ISTH-IG: International Society on Thrombosis and Hemostasis interim guidance (ISTH-IG)

ASH: American Society of Hematology (ASH)

ACCP: American College of Chest Physicians

SCC-ISTH: Scientific and Standardization Committee of ISTH

ACF: Anticoagulation Forum

ACC: American College of Cardiology

vWF: von Willebrand Factor

ICU: Intensive Care Unit

TEG: Thromboelastography

ROTEM: Rotational thromboelastometry

DIC: Disseminated intravascular coagulation

PT: Prothrombin time

PTT: Partial thromboplastin time

AT: Antithrombin

MA: Maximum amplitude

INR: International normalized ratio

VTE: Venous thromboembolism

HIT: Heparin-induced thrombocytopenia

SRA: Serotonin release assay

PE: Pulmonary embolism

CTPA: Computed tomography pulmonary angiogram (CTPA)

LMWH: Low molecular weight heparin

UFH: Unfractionated heparin

RCT: Randomized control trial

DOAC: Direct oral anticoagulants

PPE: Personal protective equipment

CRRT: Continuous renal replacement therapyGo to:

Declaration of interest

No potential conflict of interest was reported by the author(s).Go to:

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Factor VIII and Functional Protein C Activity in Critically Ill Patients With Coronavirus Disease 2019: A Case Series

Ali Tabatabai 1Joseph Rabin 2Jay Menaker 2Ronson Madathil 3Samuel Galvagno 4Ashley Menne 5Jonathan H Chow 4Alison Grazioli 6Daniel Herr 1Kenichi Tanaka 4Thomas Scalea 2Michael Mazzeffi 4Affiliations expand

PMID: 32539272 PMCID: PMC7242090 DOI: 10.1213/XAA.0000000000001236

Abstract

Critically ill patients with coronavirus disease 2019 (COVID-19) have been observed to be hypercoagulable, but the mechanisms for this remain poorly described. Factor VIII is a procoagulant factor that increases during inflammation and is cleaved by activated protein C. To our knowledge, there is only 1 prior study of factor VIII and functional protein C activity in critically ill patients with COVID-19. Here, we present a case series of 10 critically ill patients with COVID-19 who had severe elevations in factor VIII activity and low normal functional protein C activity, which may have contributed to hypercoagulability.

The novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a global pandemic accounting for over 190,000 deaths as of April 24, 2020. In hospitalized patients, mortality is reported to be approximately 25%, and in critically ill patients, who require mechanical lung ventilation mortality is between 65% and 85%.13 Most patients who die progress to septic shock and half develop coagulopathy with progressively increasing D-dimer.1 Age, coronary artery disease, and elevated D-dimer are independent predictors of mortality.1

Several reports suggest that SARS-CoV-2 infection is associated with coagulation derangements, particularly hypercoagulability, and that anticoagulation with heparin may improve survival.46 In our own experience, we have noted marked hypercoagulability in critically ill patients with coronavirus disease 2019 (COVID-19), including thrombosis of renal replacement therapy filters and extracorporeal membrane oxygenation (ECMO) circuits.

Factor (F) VIII is a procoagulant factor that is stored in endothelial cells and is released during inflammation. It has a critical role in coagulation, because it is a cofactor in the tenase complex, which converts factor X into activated factor X. Protein C is an endogenous anticoagulant protein that, when activated, cleaves FVIII into its inactive form. When FVIII overwhelms activated protein C, prolonged thrombin generation can occur leading to hypercoagulability. To our knowledge, there have been no studies of FVIII activity and functional protein C activity in patients with COVID-19 in the United States. We describe a case series of 10 critically ill patients with COVID-19 who had both FVIII and functional protein C activity measured during their clinical course. The University of Maryland, Baltimore institutional review board approved the case review and exempted the study from written informed consent.

CASE DESCRIPTIONS

Methods

Critically ill adult patients with COVID-19 who were on mechanical lung ventilation in the R Adams Cowley Shock Trauma Center bio-containment unit between April 1, 2020 and April 5, 2020 and had FVIII and functional protein C activity measured were included. FVIII activity and functional protein C activity were measured as part of a comprehensive coagulation evaluation in patients who had clinical evidence of hypercoagulability, including thrombosis in central and peripheral access lines, purpuric skin changes, and elevated D-dimer concentration. All patients had the following coagulation factor and inflammatory markers measured: FVIII activity, functional protein C activity, fibrinogen, antithrombin activity, C-reactive protein, and ferritin. Patients also had standard plasma-based coagulation tests and complete blood counts performed.

Continuous patient variables were summarized as the mean value ± standard deviation, and categorical patient variables were summarized as the number and percentage of patients. Coagulation factor and inflammatory marker concentrations were summarized as the mean value ± standard deviation or median value and interquartile range, depending on whether data were normally distributed or skewed. Normality was checked with the Shapiro-Wilk test. The relationships between age and coagulation factor concentrations were explored using scatterplots with fitted Loess curves. A 95% confidence band was added to Loess curves. Statistical analysis was performed using SAS 9.3 (SAS Corporation, Cary, NC).Go to:

RESULTS

Ten critically ill patients were included in the case series (Table ​(Table1).1). All patients were on mechanical lung ventilation with acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 infection. The mean number of mechanical lung ventilation days was 9 ± 6 at the time of patients’ coagulation evaluation. Diabetes mellitus was the most common comorbidity, occurring in 70% of patients. Eighty percent of patients were men and 70% had type O blood.

Table 1.

Patient Characteristics

VariableMean ± SD, or n (%)
Age (y)53 ± 16
Male sex8 (80)
Body mass index (kg/m2)33 ± 8
Diabetes mellitus7 (70)
Chronic arterial hypertension4 (40)
Chronic kidney disease2 (20)
Peripheral vascular disease1 (10)
Cerebral vascular disease1 (10)
Chronic obstructive pulmonary
disease or asthma
0 (0)
Coronary artery disease1 (10)
Dyslipidemia3 (30)
Blood type
O7 (70)
A2 (20)
B1 (10)
AB0 (0)
Acute respiratory distress syndrome
Severity
Mild4 (40)
Moderate3 (30)
Severe3 (30)
Days on mechanical lung ventilation9 ± 6
Extracorporeal membrane
oxygenation
2 (20)
Acute renal failure requiring renal
replacement
3 (30)

Open in a separate window

n = 10.

Abbreviation: SD, standard deviation.

Table ​Table22 shows coagulation factor and inflammatory marker concentrations. Median prothrombin time and mean activated partial thromboplastin time were normal. Both median fibrinogen concentration and FVIII activity were markedly elevated in patients with COVID-19, while median antithrombin activity and mean functional protein C activity were low normal. Seven of 10 patients had a FVIII activity above the maximum detectable range for the assay, which is 400%. The 3 patients who did not have an FVIII activity above 400% were all less than 50 years old and 2 of them were female. Median D-dimer and ferritin concentration along with mean C-reactive protein concentration were elevated for all patients in the cohort.

Table 2.

Coagulation Factors and Inflammatory Markers

VariableMean ± SD or Median [Q1, Q3]
Prothrombin time (normal = 12–15 s)15 [14, 15]
International normalized ratio1.1 [1.1, 1.2]
Activated partial thromboplastin timea (normal = 25–38 s)30 ± 5
Fibrinogen concentration (mg/dL) (normal = 216–438 mg/dL)763 [478, 1092]
Factor VIII activityb (normal = 50%–200%)400 [369, 400]
Functional protein C activity (normal = 83%–168%)104 ± 40
Antithrombin activity (normal = 75%–135%)84 [70, 90]
D-dimerc (normal < 649 ng/mL FEU)2820 [2410, 20,000]
C-reactive protein (normal < 1 mg/dL)17 ± 14
Ferritin concentration (normal = 18–464 ng/mL)1343 [748, 2116]

Open in a separate window

n = 10.

Abbreviations: FEU, fibrinogen equivalence units; SD, standard deviation.

aExcludes 3 patients who were receiving therapeutic heparin.

bUpper limit of assay is 400% and 7 of 10 patients were at upper limit.

cUpper limit of assay is 20,000 ng/mL FEU and 3 of 10 patients were at upper limit.

Older patients appeared to have higher fibrinogen concentrations and FVIII activity along with lower antithrombin activity and functional protein C activity (Figure). The 1 patient who died in the cohort at the time of our analysis was 82 years old. He had a fibrinogen concentration of 1092 mg/dL, antithrombin activity of 37%, and functional protein C activity of 37%. Among the remaining 9 patients, 7 were extubated, 4 were discharged from the hospital and 2 remained on ECMO at the time of our report. No patient was diagnosed with symptomatic deep venous thrombosis or pulmonary embolism.Figure.

Relationships between age and coagulation factor concentration and activity.Go to:

DISCUSSION

Extensive cross talk occurs between the immune and coagulation systems. Prior studies have shown that interleukin (IL)-6 and other cytokines activate coagulation.7,8 COVID-19 is associated with a profound inflammatory response in many patients that is characterized by high IL-6, fibrinogen, and ferritin concentrations.1 COVID-19 is also associated with high D-dimer, suggesting extensive thrombin generation and fibrinolysis.1 This pattern may reflect hypercoagulability related to severe inflammation.9 Our case series demonstrates that some critically ill patients with COVID-19 in the United States have a coagulation profile characterized by severely elevated fibrinogen concentration and FVIII activity, as well as low normal antithrombin and functional protein C activity. This hypercoagulable pattern appears to be accentuated with age, particularly in men. These findings have similarities with and differences from a recent study by Panigada et al9 where functional protein C activity was normal in most patients and mean FVIII activity was elevated to 297%. Mean fibrinogen concentration in their study was 680 mg/dL compared to 763 mg/dL in our study. The authors did not explore the impact of age on coagulation profile and there were few details provided about the patients’ comorbidities. We postulate that differences between the 2 studies could be related to a higher prevalence of metabolic syndrome and other comorbidities among adults in the United States leading to more severe coagulation abnormalities.

FVIII and fibrinogen are acute phase reactants that increase during infection, pregnancy, and other inflammatory states.10,11 Antithrombin and protein C are endogenous anticoagulant proteins, both of which decrease in men as they age.12 An imbalance in procoagulant and anticoagulant factor concentrations can predispose patients to thrombotic complications and perhaps microthrombosis. Hypercoagulability has been reported in critically ill patients with COVID-19 and there are recent reports of ischemic stroke and limb ischemia.13,14

Some patients with COVID-19 have been found to have antiphospholipid antibodies.13 Our data suggest that an imbalance in the FVIII-protein C system also contributes to hypercoagulability. Given this imbalance, there may be a role for systemic anticoagulation or low-dose thrombolysis in some patients. Although not commercially available in the United States, recombinant thrombomodulin could be a potential treatment for hypercoagulable patients with COVID-19. It has immunomodulatory effects and increases protein C activation in the presence of thrombin.15 There are no high-quality studies to support systemic anticoagulation at this time, but the observational study by Tang et al6 strongly suggests that patients with an elevated D-dimer concentration have better survival when treated with anticoagulation.

The main strength of our case series is that it is the first, to our knowledge, to report FVIII activity and functional protein C activity in critically ill patients with COVID-19 in the United States. An important limitation is that our cohort was comprised overwhelmingly obese men with diabetes mellitus, which may limit generalizability. Also, patients in our study had FVIII and functional protein C activity measured once, not multiple times during their stay.

In summary, in a case series of 10 critically ill patients with COVID-19, who were mostly older men, we found that fibrinogen concentration and FVIII activity were severely elevated, while antithrombin activity and functional protein C activity were low normal. These findings suggest that an imbalance in procoagulant and anticoagulant factor concentrations may contribute to hypercoagulability in some critically ill patients with COVID-19.Go to:

DISCLOSURES

Name: Ali Tabatabai, MD.

Contribution: This author helped conceive the study, review the analysis of the data, write and approve the final manuscript.

Name: Joseph Rabin, MD.

Contribution: This author conceived the study, saw the original data, reviewed the analysis of the data, wrote and approved the final manuscript.

Name: Jay Menaker, MD.

Contribution: This author helped conceive the study, review the analysis of the data, write and approve the final manuscript.

Name: Ronson Madathil, MD.

Contribution: This author helped conceive the study, review the analysis of the data, write and approve the final manuscript.

Name: Samuel Galvagno, DO, PhD.

Contribution: This author helped conceive the study, review the analysis of the data, write and approve the final manuscript.

Name: Ashley Menne, MD.

Contribution: This author helped review the analysis of the data, write and approve the final manuscript.

Name: Jonathan H. Chow.

Contribution: This author helped review the analysis of the data, write and approve the final manuscript.

Name: Alison Grazioli, MD.

Contribution: This author helped review the analysis of the data, write and approve the final manuscript.

Name: Daniel Herr, MD.

Contribution: This author helped review the analysis of the data, write and approve the final manuscript.

Name: Kenichi Tanaka, MD, MSc.

Contribution: This author helped conceive the study, review the analysis of the data, and write and approve the final manuscript.

Name: Thomas Scalea, MD.

Contribution: This author helped review the analysis of the data, write and approve the final manuscript.

Name: Michael Mazzeffi, MD, MPH, MSc.

Contribution: This author conceived the study, saw the original data, reviewed the analysis of the data, wrote and approved the final manuscript.

Whole genome sequencing reveals host factors underlying critical Covid-19

Authors: Athanasios KousathanasErola Pairo-CastineiraJ. Kenneth BaillieArticle

Published:  nature  articles  article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2–4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical Covid-19. We identify 16 new independent associations, including variants within genes involved in interferon signalling (IL10RBPLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELEICAM5CD209) and coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.

Author information

Author notes

  1. These authors contributed equally: Athanasios Kousathanas, Erola Pairo-Castineira
  2. These authors jointly supervised this work: Sara Clohisey Hendry, Loukas Moutsianas, Andy Law, Mark J Caulfield, J. Kenneth Baillie
  3. A list of authors and their affiliations appears in the Supplementary Information

Affiliations

  1. Genomics England, London, UKAthanasios Kousathanas, Alex Stuckey, Christopher A. Odhams, Susan Walker, Daniel Rhodes, Afshan Siddiq, Peter Goddard, Sally Donovan, Tala Zainy, Fiona Maleady-Crowe, Linda Todd, Shahla Salehi, Greg Elgar, Georgia Chan, Prabhu Arumugam, Christine Patch, Augusto Rendon, Tom A. Fowler, Richard H. Scott, Loukas Moutsianas & Mark J. Caulfield
  2. Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, UKErola Pairo-Castineira, Konrad Rawlik, Clark D. Russell, Jonathan Millar, Fiona Griffiths, Wilna Oosthuyzen, Bo Wang, Marie Zechner, Nick Parkinson, Albert Tenesa, Sara Clohisey Hendry, Andy Law & J. Kenneth Baillie
  3. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UKErola Pairo-Castineira, Lucija Klaric, Albert Tenesa, Chris P. Ponting, Veronique Vitart, James F. Wilson, Andrew D. Bretherick & J. Kenneth Baillie
  4. Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UKClark D. Russell & J. Kenneth Baillie
  5. Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UKTomas Malinauskas, Katherine S. Elliott & Julian Knight
  6. Institute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaYang Wu
  7. Biostatistics Group, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, ChinaXia Shen
  8. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Teviot Place, Edinburgh, UKXia Shen, Albert Tenesa & James F. Wilson
  9. Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UKKirstie Morrice, Angie Fawkes & Lee Murphy
  10. Intensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh, UKSean Keating, Timothy Walsh & J. Kenneth Baillie
  11. Department of Critical Care Medicine, Queen’s University and Kingston Health Sciences Centre, Kingston, ON, CanadaDavid Maslove
  12. Clinical Research Centre at St Vincent’s University Hospital, University College Dublin, Dublin, IrelandAlistair Nichol
  13. NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences University of Liverpool, Liverpool, UKMalcolm G. Semple
  14. Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UKMalcolm G. Semple
  15. Illumina Cambridge, 19 Granta Park, Great Abington, Cambridge, UKDavid Bentley & Clare Kingsley
  16. Regeneron Genetics Center, 777 Old Saw Mill River Rd., Tarrytown, USAJack A. Kosmicki, Julie E. Horowitz, Aris Baras, Goncalo R. Abecasis & Manuel A. R. Ferreira
  17. Geisinger, Danville, PA, USAAnne Justice, Tooraj Mirshahi & Matthew Oetjens
  18. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADaniel J. Rader, Marylyn D. Ritchie & Anurag Verma
  19. Test and Trace, the Health Security Agency, Department of Health and Social Care, Victoria St, London, UKTom A. Fowler
  20. Department of Intensive Care Medicine, Guy’s and St. Thomas NHS Foundation Trust, London, UKManu Shankar-Hari
  21. Department of Medicine, University of Cambridge, Cambridge, UKCharlotte Summers
  22. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKCharles Hinds
  23. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UKPeter Horby
  24. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, ChinaLowell Ling
  25. Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UKDanny McAuley
  26. Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, Northern Ireland, UKDanny McAuley
  27. UCL Centre for Human Health and Performance, London, UKHugh Montgomery
  28. National Heart and Lung Institute, Imperial College London, London, UKPeter J. M. Openshaw
  29. Imperial College Healthcare NHS Trust: London, London, UKPeter J. M. Openshaw
  30. Imperial College, London, UKPaul Elliott
  31. Intensive Care National Audit & Research Centre, London, UKKathy Rowan
  32. School of Life Sciences, Westlake University, Hangzhou, Zhejiang, ChinaJian Yang
  33. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, ChinaJian Yang
  34. Great Ormond Street Hospital, London, UKRichard H. Scott
  35. William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UKMark J. Caulfield

Consortia

GenOMICC Investigators

23andMe

Covid-19 Human Genetics Initiative

Corresponding authors

Correspondence to Mark J. Caulfield or J. Kenneth Baillie.

Supplementary information

Supplementary Information

This file contains Supplementary Figures; Supplementary Tables and Supplementary References

Role of von Willebrand Factor in COVID-19 Associated Coagulopathy

Authors: Zhen W MeiXander M R van WijkHuy P PhamMaximo J Marin

The Journal of Applied Laboratory Medicine, Volume 6, Issue 5, September 2021, Pages 1305–1315,  https://doi.org/10.1093/jalm/jfab042Published: 13 June 2021

Abstract

Background

COVID-19, the disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) can present with symptoms ranging from none to severe. Thrombotic events occur in a significant number of patients with COVID-19, especially in critically ill patients. This apparent novel form of coagulopathy is termed COVID-19-associated coagulopathy (CAC), and endothelial derived von Willebrand factor (vWF) may play an important role in its pathogenesis.Content

vWF is a multimeric glycoprotein molecule that is involved in inflammation, primary and secondary hemostasis. Studies have shown that patients with COVID-19 have significantly elevated levels of vWF antigen and activity, likely contributing to an increased risk of thrombosis seen in CAC. The high levels of both vWF antigen and activity have been clinically correlated with worse outcomes. Furthermore, the severity of a COVID-19 infection appears to reduce molecules that regulate vWF level and activity such as ADAMTS-13 and high-density lipoproteins (HDL). Finally, studies have suggested that patients with group O blood (a blood group with lower baseline levels of vWF) have a lower risk of infection and disease severity compared to other ABO blood groups; however, more studies are needed to elucidate the role of vWF.Summary

CAC is a significant contributor to morbidity and mortality. Endothelial dysfunction with the release of prothrombotic factors, such as vWF, needs further examination as a possible important component in the pathogenesis of CAC.von Willebrand FactorCOVID-19coagulopathyendothelial injurythrombosisIssue Section: Mini-review

Introduction and Background

COVID-19 Pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in Wuhan, China in 2019. COVID-19, the disease caused by SARS-CoV-2, quickly evolved into a global pandemic. According to the Johns Hopkins COVID-19 Dashboard, there were more than 20 million confirmed cases and almost 350,000 deaths in the US alone, by the end of 2020. Although COVID-19 may present with a variety of symptoms, a large majority of infected individuals may have none to only mild symptoms (1). However, the mortality rate is dominated by a subset of patients with severe respiratory failure that meet the criteria for acute respiratory distress syndrome (ARDS) and require respiratory support (12). The development of severe disease is related to interstitial viral pneumonia, systemic inflammation, respiratory failure, and multiorgan dysfunction (3).Impact Statement

COVID-19 is a global pandemic with no current effective treatment. COVID-19-associated coagulopathy contributes to patient morbidity and mortality. von Willebrand factor (vWF) may play an important role in the pathogenesis of this coagulopathy. Currently, available studies have demonstrated that patients with COVID-19 have significantly elevated levels of vWF antigen and activity as well as reduced regulatory molecules, which could contribute to an increased risk of thrombosis seen in patients who develop coagulopathy. Elucidation of vWF role in patients with COVID-19 may offer additional insights into developing novel therapies for this disease.

Viral Pathophysiology

SARS-CoV-2 preferentially binds to host cells that express the angiotensin-converting enzyme-2 receptor (ACE2) through the viral spike protein structure. The initiation and progression of the SARS-CoV-2 infection is likely dependent on a combination of factors, including, but not limited to, host cell expression of ACE2, anatomic contiguity with the environment, inoculation dose at the time of exposure, and the host immune response to the infection. In general, the initial infection by the SARS-CoV-2 virus targets the cells of the respiratory system such as nasal or bronchial epithelial cells and pneumocytes. However, if the severity of the infection progresses to a systemic inflammatory phase, the mechanism is likely a complex combination of the virus entering the blood stream, infection of other cells expressing ACE2 receptors, tissue/organ specificity, and the inflammatory milieu. However, the extent to which each factor contributes to the systemic severity remains unclear. Additionally, in severe COVID-19 cases, endothelial cells (ECs), which also express ACE2 receptors, are activated, leading to endothelial dysfunction and possible injury that parallels clinical manifestations, such as coagulopathy and prothrombotic tendency (4).

COVID-19 Associated Coagulopathy

It is clear that a significant component of the observed morbidity and mortality is directly related to lung injury as supported by COVID-19 related autopsies (56). The predominant pattern of injury was found to be diffuse alveolar damage, which includes hyaline membrane formation, capillary congestion, inflammation, and pneumocyte necrosis. In addition, the study also identified platelet-fibrin thrombi in small arterial vessels in 87% of their cases (6). A more recent, albeit small, series showed that all COVID-19 related autopsies demonstrated platelet-fibrin thrombi in multiple organs, including the liver, kidney, heart, and lungs (5). Another autopsy case series compared lung tissue from equally severe, age-matched patients with ARDS with either COVID-19 or influenza A (H1N1) and found that alveolar capillary microthrombi were more prevalent in COVID-19 than influenza (7). This study also observed that COVID-19 lung tissue showed significant EC injury associated with intracellular SARS-CoV-2 infection (7). Furthermore, there is some evidence to suggest that COVID-19 associated coagulopathy (CAC) might be different from other coagulopathic conditions, such as disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA), which are associated with other underlying causes such as infections, malignancy, autoimmune, and hereditary diseases (Table 1) (8). Taken together, the data indicate that a distinct coagulopathy may be occurring in COVID-19 patients, particularly those with severe symptoms.

Table 1

Laboratory data in COVID-19 and other coagulopathies.

Platelet countD-dimerPT/INR; aPTTFibrinogenAntithrombin activityComplement activationInflammatory cytokinesADAMTS-13vWF antigen
Normal within reference range within reference range within reference range within reference range within reference range within reference range within reference range within reference range within reference range 
COVID-19 generally, mildly elevated early and decreases as severity increases elevated no change to mildly elevated elevated no change increased activation, may result in lower antigen levels due to consumption elevated mildly decreased elevated 
DIC/SIC decreased elevated elevated no change to decreased decreased no increase elevated normal decreased 
TTP Severely decreased no change to elevated no change to elevated no change no change normal to mildly increased decreased severely decreased normal to mildly elevated 
HUS decreased no change to elevated no change to elevated no change no change usually mildly increased but may be normal decreased normal normal to mildly elevated 
Atypical HUS decreased no change to elevated no change to elevated no change no change moderate to severely increased decreased normal to moderately decreased normal to mildly elevated 

Normal values will vary among laboratories due to varying methodologies and reagents. Given that there are multiple markers for complement activation, inflammation, and acute phase reactants, reference ranges for these (patho)-physiological events are not provided. Of note, ADAMTS13 measurement is generally the reliable biomarker distinguishing TTP from HUS/atypical HUS. HUS can be distinguished from aHUS if the patient has history of Shiga-toxin or Streptococcus exposure. Other biomarkers may be overlapping in the spectrum from DIC/SIC to TTP/HUS/aHUS. DIC: disseminated intravascular coagulation, SIC: sepsis-induced coagulopathy, TMA: thrombotic microangiopathy, TTP: thrombotic thrombocytopenia purpura, aHUS: atypical hemolytic uremic syndrome, PT: prothrombin time, aPTT: activated partial thromboplastin time, vWF: von Willebrand factor. Adapted from Iba et al. (8).Open in new tab

Incidence of CAC, especially in severe COVID-19 cases, was apparent from early reports in Wuhan (9). A number of studies have shown that the development of CAC is an important prognostic indicator of poor outcomes (10–12). One study evaluated the rate of arterial and venous thrombotic events in COVID-19 pneumonia patients admitted into the intensive care unit (ICU) and found that the incidence of thrombotic events in 184 patients was 49% (after adjustment for competing risk of death) despite receiving routine pharmacologic thromboprophylaxis; not surprisingly, these thrombotic complications led to a higher risk of death (13). Additional studies have shown similar incidence rates of thrombotic events in COVID-19 ICU patients (1415). Collectively, clinical studies suggest that CAC leads to a prothrombotic state even with standard pharmacologic thromboprophylaxis treatment.

Laboratory Patterns

In general, CAC is characterized by mild thrombocytopenia, slight prolongation of the prothrombin time (PT), high levels of D-dimer, and elevated fibrinogen (81216) (Table 1). Recent International Society for Thrombosis and Hemostasis (ISTH) interim guidance recommends monitoring these 4 parameters in the management of patients with CAC. D-dimer was designated the highest level of priority as many studies have shown that elevated levels are associated with increasing severity of disease and mortality risk (3101117–20). These studies reported a range of associations of higher D-dimer levels in COVID patients, including greater risk of mortality (31118), increased disease severity (1011), increased incidence of pulmonary emboli (17), and need for intensive care (20). Based on this data, clinical services can order a baseline D-dimer level to determine the current morbidity and mortality risk that a COVID-19 patient carries and can follow a D-dimer level to predict progression to more severe disease.

D-dimer is a breakdown product of mature clots (cross-linked fibrin mesh) that undergoes fibrinolysis. Though some studies reported data where the association with D-dimer and death may not be as compelling (2122), D-dimer levels do play a role during the follow-up and treatment of patients with CAC. There is, however, another biomarker, von Willebrand factor (vWF), which may also play an important role in the evaluation of CAC patients due to its direct relationship to hemostasis, inflammation, and EC activation/injury, which are all important aspects of COVID-19 pathogenesis. The biological role of vWF and its association with CAC will be the focus of the remainder of this review.

vWF Physiology and Laboratory Testing

vWF Biology

vWF is a multimeric glycoprotein ranging from 2 to >60 prepropolypeptide units that are each 2138 amino acids in length. The vWF propeptide sequence serves to align 2 units together to allow proper cross-linking during the multimerization process. Further post-translational modification leads to removal of the propeptide sequence as well as glycosylation, including the addition of blood group determinants. This addition of an A or B blood group determinant only occurs during EC glycosylation. Following these processes, a heterogenous mix of ultra-large-vWF (UL-vWF) molecules are synthesized and stored in megakaryocytes and ECs, respectively, in alpha granules and Weibel–Palade bodies (WPB). Additionally, other processing components such as vWF propeptides are found in the WPB of ECs. Although platelets do play an important role in both storage and secretion of vWF, this review will focus on ECs.

When ECs are activated, UL-vWF molecules are released and can either remain free-floating in the plasma or localized on endothelial surfaces. UL-vWF have greater prothrombotic activity than smaller vWF multimers. Therefore, as UL-vWF molecules are secreted, ADAMTS-13 (a disintegrase and metalloproteinase with a thrombospondin type 1 motif, member 13), cleaves vWF into smaller multimers to mitigate unwanted thrombus formation and leads to a variation in the sizes of vWF found both in the plasma and on endothelial surfaces. Elevated vWF activity levels depend on the presence of the largest vWF multimers and activation by shear stress in the circulatory system. vWF responds to shear stress by unfolding and exposing sites for activity such as self-association, platelet binding, and ADAMTS-13 cleavage. Accordingly, the imbalance of these components may lead to a prothrombotic state.

Role in Primary Hemostasis

Primary hemostasis is the process of the platelet clot formation at the site of blood vessel injury. For proper primary hemostasis to occur, platelet adhesion and aggregation must occur. During platelet adhesion at the site of blood vessel injury, platelets can bind directly to the exposed subendothelial collagen (via GPIa-IIa or GPVI receptors) or indirectly via vWF. In the latter case, platelets bind to the vWF molecule via the platelet glycoprotein Ib-V-IX receptor (GPIb) while vWF is bound to subendothelial collagen. Additionally, vWF also promotes platelet aggregation (platelet–platelet interaction) by binding to platelet surface receptor GPIIb/IIIa. Although GPIIb/IIIa is better known as a fibrinogen receptor, it can bind to both fibrinogen and vWF. In summary, vWF plays a vital role in platelet adhesion and aggregation in clot formation.

Role in Secondary Hemostasis

vWF also performs an important role in secondary hemostasis. Secondary hemostasis involves coagulation factors and the coagulation cascade to produce a fibrin meshwork at the site of vessel injury. vWF facilitates the secondary hemostasis process in two ways. First, vWF serves as a carrier protein for Factor VIII, extending Factor VIII’s half-life in the plasma. Although this may initially seem trivial, the vWF carrier activity stabilizes Factor VIII and significantly extends its half-life 4 to 6-fold. Second, it releases and concentrates Factor VIII at the site of injury. Factor VIII is a clotting factor that, when activated, complexes with other factors to ultimately produce fibrin. To highlight the significance of vWF in this process, mutations affecting the vWF binding site for Factor VIII leads to decreased levels of Factor VIII, known as Type 2N von Willebrand disease (vWD), resulting in a clinical presentation similar to hemophilia A, which is a bleeding disorder that occurs when an individual lacks the ability to produce adequate amounts of Factor VIII for proper clotting.

vWF, Inflammation, and Endothelial Activation/Injury

During the inflammatory process, various chemical mediators are released. These inflammatory molecules activate ECs to release their WPB contents, including vWF and other molecules such as P-selectin, which has been directly linked to leukocyte recruitment (2324). In addition, UL-vWF molecules that remain bound to EC surface will subsequently bind platelets and may have the ability to act as a molecular surface for leukocyte interaction (25). With increased release of vWF, the inflammatory process is expected to induce a prothrombotic state. Studies show that inflammation enhances vWF self-association, which may lead to increased adhesiveness of platelets while decreasing ADAMTS-13 cleavage (24). Additionally, high-density lipoprotein (HDL) decreases during inflammation in both chronic and acute phases. HDL may play a vital role in preventing shear stress-induced vWF self-association, thus decreasing prothrombotic risk under normal circumstances (24). This concept will become a point of discussion later in the review. In summary, the data indicate that during the inflammatory process there is an increased thrombotic risk due to the imbalance of increased vWF and activity levels via EC activation and reduced ADAMTS-13 activity.

Laboratory Testing of vWF

To understand the studies that will be mentioned in connection with CAC, it is important to briefly discuss basic vWF laboratory testing. There are 3 basic tests performed to assess vWF; the exact methods may vary between manufacturers for those that are highly automated but the fundamental parameters rest on testing vWF quantity, activity, and multimer size.

The quantity of the vWF level in a specimen is commonly referred to as antigenic testing (vWF:Ag). An immunoturbidimetric method is commonly used for vWF:Ag measurement. However, the details of the assays vary by manufacturer. This allows for quantitative determination of the physical presence of the molecule without assessment of function. ABO blood typing and Factor VIII levels are also performed concurrently; it is well documented that individuals of blood group O have physiologically lower levels of vWF, and therefore Factor VIII (since vWF binds and stabilizes it) levels are also slightly lower than individuals of non-O blood groups (see the “vWF Association with Blood Type” section).

The quality of present vWF is known as functional or activity testing; this involves testing the ability of vWF to bind to platelet receptor GPIb, collagen, and Factor VIII (vWF:RCo). There are a number of assays and methods that revolve around testing the ability of vWF to bind its natural physiologic substrates (with or without ristocetin). Depending on the substrate used to assess its binding function, these tests will often carry an acronym such as vWF:Ac, vWF:RCo, vWF:Co, or vWF:VIII. It is important to note that there are important and distinct differences amongst these tests; however, this is beyond the scope of the review.

Additionally, the qualitative variation of vWF multimers is performed to visualize the presence and size distribution of vWF located in the plasma using gel electrophoresis and vWF labeling. This assessment is important since multimer presence and size is directly correlated to the function and activity level of the vWF molecule.

Finally, although not a laboratory test, the results of the activity and antigenic assays may be juxtaposed to obtain the ratio of vWF activity to antigen (RCo:Ag ratio). A ratio that is less than 0.5–0.7 would indicate that a qualitative defect in the vWF molecules is likely and this helps categorize the pattern and subtypes of vWD, if present.

Examination of vWF in COVID-19 Associated Coagulopathy

Endothelial Activation and vWF

As a molecule present in ECs that plays a fundamental role in hemostasis and thrombosis, vWF is a reasonable candidate marker to consider when monitoring clinical issues related to endothelial injury and coagulopathy in COVID-19. Early studies duly noted that D-dimer levels were an important prognostic marker in COVID-19. However, studies also began to recognize and demonstrate that significantly elevated levels of vWF were also present (14161926). Further, studies then recognized that vWF activity is also increased and that ADAMTS-13 activity levels are relatively mild to moderately reduced, leading to an imbalance favoring thrombosis (2728). Similarly, in a well-recognized pathological entity, thrombotic thrombocytopenic purpura (TTP) is associated with reduced activity levels of ADAMTS-13. TTP is generally due to an extremely hindered or absent ADAMTS-13 activity by either an acquired inhibitor or congenital absence. The decreased activity levels of ADAMTS-13 result in an excess of overactive UL-vWF multimers that promote microthrombi formation.

However, in contrast to TTP, the mild to moderately decreased ADAMTS-13 activity levels observed in CAC may not lead to excessive UL-vWF. Thus, it is important to distinguish that activity levels of ADAMTS-13 may not be low enough in CAC cases to detect an excessive increase in UL-vWF as seen in severe deficiency such as in TTP. In line with this, a recent study showed decreased activity levels of ADAMTS-13 in patients with severe COVID-19 but found no evidence of UL-vWF multimers in the plasma (29). Further, the authors of this study emphasized the significance of the elevated vWF:Ag to ADAMTS-13 activity ratio in association with increasing severity of disease. This suggests that an increased risk of thrombosis seen in patients with COVID-19 may, in part, be due to a relative decrease of ADAMTS-13 activity rather than an absolute decrease as seen in TTP.

The high levels of both vWF antigen and activity have been correlated clinically with increased thrombotic events (14), increased likelihood for treatment in ICUs (19), and increased need for oxygen support (26), as well as correlated with other laboratory testing such as decreased clotting times, increased clot formation velocities as demonstrated by whole blood viscoelastic testing (16) and increased levels of other markers of platelet and endothelial activation, such as Factor VIII and thrombomodulin (161926–2830). As new biomarkers to assess CAC severity emerge, reexamining the synthetic pathway of vWF may have some utility. One promising avenue is to examine levels of vWF propeptide; its physiologic role in the multimerization process would suggest that elevated levels of vWF propeptide indicate elevated vWF release. In addition, a greater level of increase in vWF and propeptide in comparison to an increase in Factor VIII suggest that this is due to release of vWF from pulmonary ECs involved in the COVID-19 pathophysiologic process (31). The ratio of propeptide levels to vWF levels can also examined; this ratio seems to decrease with disease progression suggesting that while the propeptide is cleared normally, levels of vWF may stay elevated due to decreased clearance (29). Further examination of propeptide levels in patients with COVID-19 are indicated to elucidate these possible relationships.

High-Density Lipoprotein and vWF

Aside from endothelial activation and injury, a more indirect mechanism may contribute to increased vWF activity levels. In general, infection leads to an inflammatory state and, as mentioned previously, this decreases HDL levels. Although most commonly known for its important role in preventing atherosclerotic disease, additional physiologic functions include activity as an antiinflammatory, antiapoptotic, and antioxidant agent. However, lesser-known roles include preventing thrombosis through binding to ECs to ramp up nitric oxide (a vasodilatory molecule) production and preventing shear stress-induced vWF self-association, thus decreasing prothrombotic risk (2432). Interestingly, a retrospective analysis of total cholesterol, LDL and HDL levels of patients in Changsha, China showed that HDL levels were lower in patients with COVID-19 than normal and patients with severe disease had lower HDL levels than patients with mild disease (33). Beyond the general infectious inflammatory state that may reduce HDL levels, a study showed that patients with COVID-19 had reduced apolipoprotein A1 (ApoA1) levels, which is a major protein component of HDL molecules (34). The study also showed that as patients went from nonsevere to severe disease, apolipoprotein decreased. Indeed, it has been shown, both in vivo and vitro models, that ApoA1 prevents vWF self-association and binding to vessel walls (32). Additional studies in the future could shed light on the role of HDL in CAC patients and possibly lead to novel treatment options.

vWF Association with Blood Type and COVID-19 Susceptibility

If increased levels of vWF can be monitored as a marker of endothelial damage and used to predict prognosis in patients with COVID-19, then decreased levels of vWF may be protective. One naturally existing population of patients who have baseline lower levels of vWF are patients of blood group O. Group O individuals naturally have a baseline level of vWF ∼25% less than the non-group O cohort (blood groups A and B). Although the exact molecular mechanism by which group O individuals have lower vWF levels is not fully elucidated, it has been hypothesized that perhaps theadditional glycosylation status, which occurs within ECs, by non-group O individuals prevents the activity of ADAMTS-13 to cleave vWF. This leads to reduced clearance and an increased half-life that is demonstrated by baseline higher levels of vWF when compared to group O individuals (31).

Initial data from China found a greater than expected proportion of group A and a smaller than expected proportion of group O individuals among patients with COVID-19. However, this involved a small cohort of patients with limited analysis due to lack of available clinical information (35). Following this, a genome-wide association study on patients in Italy and Spain also found group O individuals to have a lower relative risk than non-group O individuals (36). Another study showed a similar pattern of this phenomenon in a cohort of patients treated at the New York Presbyterian Hospital System (37). However, conflicting information is reported among these and other studies with some reporting no significant difference in severity and some reporting contradicting patterns in terms of need for mechanical ventilation. Preliminary data from these studies do potentially suggest that the lower vWF levels may be associated with decreased severity of disease in group O patients but more data is needed to clarify this relationship.

Conclusion

CAC is a significant contributor to patient morbidity and mortality. We highlight the role of vWF in CAC and compare and contrast it to the normal physiological response, mild and severe COVID-19 disease, and TTP (Fig. 1). Direct infection of ECs with SARS-CoV-2 and/or activation of ECs due to high levels of inflammatory mediators results in release of prothrombotic factors such as vWF. vWF, bound to the ECs or in plasma, promotes platelet aggregation and thrombus formation. It is likely that multiple mechanisms contribute to an imbalance of the vWF-ADAMTS-13 axis, pushing patients with CAC toward a more prothrombotic tendency. For example, in this review we discussed HDL and role it plays in reducing vWF activity, in which little discussion has been seen in other review articles of CAC and vWF. Nevertheless, the range of clinical presentation may be a reflection of the severity of this imbalance since reports show that though vWF is elevated in patients who are both critically ill and noncritically ill (19), there is a significant difference in vWF and ADAMTS-13 levels in patients who suffer thrombotic events versus those that do not (38). Multiple biomarkers, including vWF-associated proteins such as vWF propeptide and P-selectin, may help demonstrate the level of imbalance, as well as the mechanisms causing the imbalance. This would clarify the roles of therapies that would counter the actions of these prothrombotic molecules, whether by mitigating their release by reducing inflammation, such as N-acetylcysteine (39), or by inhibiting their activity once released or activated, such as caplacizumab (anti-vWF) or crizanlizumab (anti-P-selectin). Regardless, vWF has clearly demonstrated that it plays a role in the progression of CAC in patients with COVID-19, however, to what extent remains unclear. Further studies are needed to elucidate the many roles of vWF and the mechanism by which it becomes imbalanced.Fig. 1Proposed mechanism and distinguishing characteristics in mild and severe cases of COVID-19 associated coagulopathy and a comparison to a normal physiological response and thrombotic thrombocytopenic purpura. (A), Normal physiological response to stress and or injury. After endothelial activation, vWF multimers are bound to the endothelial surface, ADAMTS-13 actively cleaves large multimers and HDL assists in the regulation of vWF self-association resulting in well-controlled thrombus formation during a physiologic response. (B), COVID-19 associated coagulopathy in mild disease. Localized infection and minimal systemic inflammation lead to a higher level of endothelial cell activation. Regardless, in this scenario, infection and inflammation remains fairly well regulated. Furthermore, the HDL and ADAMTS-13 mechanisms are mostly intact, leading to only a slight increase of pathologic thrombotic events. (C), COVID-19 associated coagulopathy in severe disease. Infection and or inflammation becomes overwhelmingly dysregulated, leading to an extremely elevated level of endothelial activation. Additionally, both HDL and ADAMTS-13 levels are decreased, leading to a much higher increase risk of pathologic thrombotic events. (D), Thrombotic thrombocytopenia purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than observed in COVID-19 coagulopathy. TTP leads to increased levels of ultralarge and large multimers of vWF. Subsequently, there are increased levels of platelet binding, which leads to highly increased thrombotic risk.Open in new tabDownload slide

Proposed mechanism and distinguishing characteristics in mild and severe cases of COVID-19 associated coagulopathy and a comparison to a normal physiological response and thrombotic thrombocytopenic purpura. (A), Normal physiological response to stress and or injury. After endothelial activation, vWF multimers are bound to the endothelial surface, ADAMTS-13 actively cleaves large multimers and HDL assists in the regulation of vWF self-association resulting in well-controlled thrombus formation during a physiologic response. (B), COVID-19 associated coagulopathy in mild disease. Localized infection and minimal systemic inflammation lead to a higher level of endothelial cell activation. Regardless, in this scenario, infection and inflammation remains fairly well regulated. Furthermore, the HDL and ADAMTS-13 mechanisms are mostly intact, leading to only a slight increase of pathologic thrombotic events. (C), COVID-19 associated coagulopathy in severe disease. Infection and or inflammation becomes overwhelmingly dysregulated, leading to an extremely elevated level of endothelial activation. Additionally, both HDL and ADAMTS-13 levels are decreased, leading to a much higher increase risk of pathologic thrombotic events. (D), Thrombotic thrombocytopenia purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than observed in COVID-19 coagulopathy. TTP leads to increased levels of ultralarge and large multimers of vWF. Subsequently, there are increased levels of platelet binding, which leads to highly increased thrombotic risk.

Proposed mechanism and distinguishing characteristics in mild and severe cases of COVID-19 associated coagulopathy and a comparison to a normal physiological response and thrombotic thrombocytopenic purpura. (A), Normal physiological response to stress and or injury. After endothelial activation, vWF multimers are bound to the endothelial surface, ADAMTS-13 actively cleaves large multimers and HDL assists in the regulation of vWF self-association resulting in well-controlled thrombus formation during a physiologic response. (B), COVID-19 associated coagulopathy in mild disease. Localized infection and minimal systemic inflammation lead to a higher level of endothelial cell activation. Regardless, in this scenario, infection and inflammation remains fairly well regulated. Furthermore, the HDL and ADAMTS-13 mechanisms are mostly intact, leading to only a slight increase of pathologic thrombotic events. (C), COVID-19 associated coagulopathy in severe disease. Infection and or inflammation becomes overwhelmingly dysregulated, leading to an extremely elevated level of endothelial activation. Additionally, both HDL and ADAMTS-13 levels are decreased, leading to a much higher increase risk of pathologic thrombotic events. (D), Thrombotic thrombocytopenia purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than observed in COVID-19 coagulopathy. TTP leads to increased levels of ultralarge and large multimers of vWF. Subsequently, there are increased levels of platelet binding, which leads to highly increased thrombotic risk.

Author Contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and(d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors’ Disclosures or Potential Conflicts of Interest:Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:Employment or Leadership: H.P. Pham, University of Southern California. Consultant or Advisory Role: H.P. Pham, Sanofi Genzyme. Stock Ownership: None declared. Honoraria: H.P. Pham, Alexion. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared.

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Post-acute COVID-19 syndrome

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Main

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally1. Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems2. Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life3,4,5. Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae6,7,8. Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19 (refs. 9,10,11,12,13,14,15).

Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19 (refs. 16,17), as replication-competent SARS-CoV-2 has not been isolated after 3 weeks18. For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses17,19. Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensive care of these patients in COVID-19 clinics 

For More Information: https://www.nature.com/articles/s41591-021-01283-z

Better Anticoagulated Than Not! Hypercoagulability in COVID-19

Authors: Dhauna P. Karam, MD1

Incidence of thrombotic complications in patients with COVID-19 who are critically ill is high, with an estimated incidence of 31% for arterial or venous thromboembolism (VTE), acute pulmonary embolism, ischemic stroke, and myocardial infarction. On the basis of the study by Klok et al,1 pulmonary embolism was the most common thrombotic complication in critically ill patients with COVID-19 despite being on standard anticoagulation. Prevention of thromboembolism with anticoagulants is recommended in all critically ill patients with COVID-19.

The American Society of Hematology (ASH) guideline panel (updated April 7, 2021) recommends prophylactic anticoagulation in all critically ill patients with COVID-19 without suspected or confirmed venous thromboembolism (VTE). ASH defines patients with COVID-19 critical illness as someone who is suffering from a life-threatening condition, typically admitted in an intensive care unit. It is recommended that individualized assessment of the patient’s thrombotic and bleeding risk needs to be performed before deciding on anticoagulation.2 What about hospitalized patients with COVID-19 who are not critically ill? What are some clinical parameters that can be used to guide decisions on anticoagulant use in such patients?

The accompanying manuscript by Gaddh et al3 reports guidelines used in a large academic institution, Emory University School of Medicine, Atlanta, Georgia, to determine anticoagulation in hospitalized patients with COVID-19. The guidelines were created by a multidisciplinary panel of experts and were incorporated into frontline care at Emory. The three-tiered algorithm was used to risk stratify patients admitted with a primary diagnosis of COVID-19. It was not recommended for use in patients incidentally found to have COVID-19 during hospitalization for other causes. On the basis of the guidelines, patients with normal D-dimer, no evidence of thromboembolism and not critically ill were given prophylactic anticoagulation (group 1). Patients with elevated D-dimer (> 6 times upper limit normal) with no evidence of thromboembolism and not critically ill were given intermediate-dose anticoagulation. Patients critically ill without any evidence of thromboembolism and without elevation of D-dimer were also given intermediate-dose anticoagulation. Patients with confirmed thromboembolism or those with other markers of possible thromboembolism (worsening hypoxia or pulmonary status without identifiable cause and limb edema) received therapeutic anticoagulation. Anticoagulation was continued for 1 week after discharge in group 1 patients. Group 2 received anticoagulation for 4-6 weeks after discharge. Finally, group 3 received anticoagulation for minimum 3 months postdischarge. Preliminary findings revealed low bleeding complications. Data on type of anticoagulant used, incidence of thromboembolism in the hospitalized group following the above guidelines, and improvement in morbidity and mortality rates were not provided. The algorithm is a simple, practical statement, which can guide frontline caregivers until evidence-based recommendations become available. Group 1 and 3 recommendations are supported by major organizational guidelines such as ASH and International Society on Thrombosis and Haemostasis (ISTH). Preliminary guidelines from these organizations refrain from commenting strongly on intermediate-dose anticoagulation in the absence of supporting data from clinical trials but do support anticoagulant dose escalation on the basis of clinician’s assessment for high-risk patients.2,4

For More Information: https://ascopubs.org/doi/full/10.1200/OP.21.00359

COVID-19 – A vascular disease

Authors: Hasan K. Siddiqi,a,bPeter Libby,a,⁎ and Paul M Ridkera,b

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to multi-system dysfunction with emerging evidence suggesting that SARS-CoV-2-mediated endothelial injury is an important effector of the virus. Potential therapies that address vascular system dysfunction and its sequelae may have an important role in treating SARS-CoV-2 infection and its long-lasting effects.

SARS-CoV-2 infection and vascular dysfunction

In health, the vascular endothelium maintains homeostasis through regulation of immune competence, inflammatory equilibrium, tight junctional barriers, hemodynamic stability as well as optimally balanced thrombotic and fibrinolytic pathways. In the novel coronavirus disease of 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), dysregulation of many of these pathways has emerged as a mediator of severe disease. The constellation of clinical and biomarker derangements seen in COVID-19 can be classified into disruption of the immune, renin-angiotensin-aldosterone (RAA), and thrombotic balance, all of which converge on the vascular endothelium as a common pathway. Accumulating evidence from basic science, imaging and clinical observations, has clarified the picture of COVID-19 as a vascular disease. Understanding the disease in this context may provide novel avenues of understanding COVID-19 and lead to critically needed improvements in therapeutic strategies.

SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) to facilitate entry into target cells and initiate infection. This viral entry into the cell is further mediated by transmembrane serine protease 2 (TMPRSS2) and cathepsin L which cleave the S protein on the viral particle to permit engagement with ACE2 [1]. Endothelial cells (ECs) in general and cardiac pericytes in particular express abundant ACE2, making them a direct target of SARS-CoV-2 infection (Fig. 1 ) [2]. Examination of the pulmonary vascular bed shows severe derangements in COVID-19, compared to control and influenza patients, particularly with widespread thrombosis and microangiopathy, endothelial activation and extensive angiogenesis [3]. These studies and pervasive findings establish the role of viral injury to the vascular system with resulting vascular dysfunction in COVID-19 patients [4].

Fig. 1

Open in a separate windowFig. 1

SARS-CoV-2 Induced Endothelial Injury

Legend: A schematic of SARS-CoV-2 infection and proposed resulting endothelial injury, involving immune activation, pro-thrombotic milieu, and RAAS dysregulation. These insults interact with each other to cause end-organ dysfunction that is manifest in many COVID-19 patients.

TMPRSS2 = Transmembrane protease serine 2; ADAM17 = A disintegrin and metalloproteinase 17; TNF = Tumor necrosis factor; TNFr = Tumor necrosis factor receptor; TLR = toll-like receptor; DAMPs = Damage-associated molecular patterns; PAMPs = Pathogen-associated molecular patterns; PAI-1 = plasminogen activator inhibitor-1; vWF = von Willebrand factor; eNOS = endothelial nitric oxide; tPA = tissue plasminogen activator; AT1R = angiotensin 1 receptor; ARDS = acute respiratory distress syndrome.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556303/

Peer-Reviewed Publications about COVID-19 (Coronavirus) by Yale Authors

Sharing knowledge about COVID-19 (coronavirus) is vital to our efforts as we fight the pandemic. Yale researchers are publishing their discoveries about COVID-19 (coronavirus) in peer-reviewed publications. Check back frequently to access the latest findings.

Peer-Reviewed COVID-19 Publications from Yale

  • A new positive SARS-CoV-2 test months after severe COVID-19 illness: reinfection or intermittent viral shedding?Tuan J, Spichler-Moffarah A, Ogbuagu OA new positive SARS-CoV-2 test months after severe COVID-19 illness: reinfection or intermittent viral shedding? BMJ Case Reports CP 2021;14:e240531.
  • Hydroxychloroquine treatment does not reduce COVID-19 mortality; underdosing to the wrong patients? – Authors’ replyRentsch CT, DeVito NJ, MacKenna B, Morton CE, Bhaskaran K, Brown JP, Schultze A, Hulme WJ, Croker R, Walker AJ, Williamson EJ, Bates C, Bacon S, Mehrkar A, Curtis HJ, Evans D, Wing K, Inglesby P, Mathur R, Drysdale H, Wong AYS, McDonald HI, Cockburn J, Forbes H, Parry J, Hester F, Harper S, Smeeth L, Douglas IJ, Dixon WG, Evans SJW, Tomlinson L, Goldacre B. Hydroxychloroquine treatment does not reduce COVID-19 mortality; underdosing to the wrong patients? – Authors’ reply. Lancet Rheumatology 2021; epub ahead of print. DOI: 10.1016/S2665-9913(21)00030-8
  • Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United StatesRentsch CT, Beckman JA, Tomlinson L, Gellad WF, Alcorn C, Kidwai-Khan F, Skanderson M, Brittain E, King JT, Ho Y-L, Eden S, Kundu S, Lann MF, Greevy RA, Ho PM, Heidenreich PA, Jacobson DA, Douglas IJ, Tate JP, Evans SJ, Atkins D, Justice AC, Freiberg MS. Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States. BMJ 2021; (in press)
  • Factors associated with COVID-19-related death using OpenSAFELY.Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, Curtis HJ, Mehrkar A, Evans D, Inglesby P, Cockburn J, McDonald HI, MacKenna B, Tomlinson L, Douglas IJ, Rentsch CT, Mathur R, Wong AYS, Grieve R, Harrison D, Forbes H, Schultze A, Croker R, Parry J, Hester F, Harper S, Perera R, Evans SJW, Smeeth L, Goldacre B. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020, 584:430-436.
  • Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.Schultze A, Walker AJ, MacKenna B, Morton CE, Bhaskaran K, Brown JP, Rentsch CT, Williamson E, Drysdale H, Croker R, Bacon S, Hulme W, Bates C, Curtis HJ, Mehrkar A, Evans D, Inglesby P, Cockburn J, McDonald HI, Tomlinson L, Mathur R, Wing K, Wong AYS, Forbes H, Parry J, Hester F, Harper S, Evans SJW, Quint J, Smeeth L, Douglas IJ, Goldacre B, OpenSAFELY Collaborative.. Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform. Lancet Respir Med 2020, 8:1106-1120.
  • Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.Rentsch CT, DeVito NJ, MacKenna B, Morton CE, Bhaskaran K, Brown JP, Schultze A, Hulme WJ, Croker R, Walker AJ, Williamson EJ, Bates C, Bacon S, Mehrkar A, Curtis HJ, Evans D, Wing K, Inglesby P, Mathur R, Drysdale H, Wong AYS, McDonald HI, Cockburn J, Forbes H, Parry J, Hester F, Harper S, Smeeth L, Douglas IJ, Dixon WG, Evans SJW, Tomlinson L, Goldacre B. Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the Open SAFELY platform. Lancet Rheumatol 2021, 3:e19-e27.

For More Information: https://covid.yale.edu/research/publications/peer-reviewed/

What Does COVID Do to Your Blood?

Authors: Panagis Galiatsatos, M.D., M.H.S., Robert Brodsky, M.D.

COVID-19 is a very complex illness. The coronavirus that causes COVID-19 attacks the body in many different ways, ranging from mild to life threatening. Different organs and tissues of the body can be affected, including the blood.

Robert Brodsky, a blood specialist who directs the Division of Hematology, and Panagis Galiatsatos, a specialist in lung diseases and critical care medicine, talk about blood problems linked to SARS-CoV-2 — the coronavirus that causes COVID-19 — and what you should know.

Coronavirus Blood Clots

Blood clots can cause problems ranging from mild to life threatening. If a clot blocks blood flow in a vein or artery, the tissue normally nourished by that blood vessel can be deprived of oxygen, and cells in that area can die.

Some people infected with SARS-CoV-2 develop abnormal blood clotting. “In some people with COVID-19, we’re seeing a massive inflammatory response, the cytokine storm that raises clotting factors in the blood,” says Galiatsatos, who treats patients with COVID-19.

“We are seeing more blood clots in the lungs (pulmonary embolism), legs (deep vein thrombosis) and elsewhere,” he says.

Brodsky notes that other serious illnesses, especially ones that cause inflammation, are associated with blood clots. Research is still exploring if the blood clots seen in severe cases of COVID-19 are unique in some way. 

The Impact of Coronavirus Blood Clots Throughout the Body

In addition to the lungs, blood clots, including those associated with COVID-19, can also harm:

The nervous system. Blood clots in the arteries leading to the brain can cause a stroke. Some previously young, healthy people who have developed COVID-19 have suffered strokes, possibly due to abnormal blood clotting.

The kidneys. Clogging of blood vessels in the kidney with blood clots can lead to kidney failure. It can also complicate dialysis if the clots clog the filter of the machine designed to remove impurities in the blood.

Peripheral blood vessels and “COVID toe.” Small blood clots can become lodged in tiny blood vessels. When this happens close to the skin, it can result in a rash. Some people who test positive for COVID-19 develop tiny blood clots that cause reddish or purple areas on the toes, which can itch or be painful. Sometimes called COVID toe, the rash resembles frostbite.

For More Information: https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/what-does-covid-do-to-your-blood

The complement system in COVID-19: friend and foe?

Authors: Anuja Java,1 Anthony J. Apicelli,2 M. Kathryn Liszewski,3 Ariella Coler-Reilly,3 John P. Atkinson,3 Alfred H.J. Kim,3 and Hrishikesh S. Kulkarni4

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19–related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

For More Information: https://insight.jci.org/articles/view/140711