Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

Authors: JACC State-of-the-Art ReviewAzita H. Talasaz, PharmD,a,bParham Sadeghipour, MD,cHessam Kakavand, PharmD,a,bMaryam Aghakouchakzadeh, PharmD,aElaheh Kordzadeh-Kermani, PharmD,aBenjamin W. Van Tassell, PharmD,d,eAzin Gheymati, PharmD,aHamid Ariannejad, MD,bSeyed Hossein Hosseini, PharmD,aSepehr Jamalkhani,cMichelle Sholzberg, MDCM, MSc,f,gManuel Monreal, MD, PhD,hDavid Jimenez, MD, PhD,iGregory Piazza, MD, MS,jSahil A. Parikh, MD,k,lAjay J. Kirtane, MD, SM,k,lJohn W. Eikelboom, MBBS,mJean M. Connors, MD,nBeverley J. Hunt, MD,oStavros V. Konstantinides, MD, PhD,p,qMary Cushman, MD, MSc,r,sJeffrey I. Weitz, MD,t,uGregg W. Stone, MD,k,vHarlan M. Krumholz, MD, SM,w,x,yGregory Y.H. Lip, MD,z,aaSamuel Z. Goldhaber, MD,j and Behnood Bikdeli, MD, MSj,k,w,∗


Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Thromboembolism in Patients With Coronavirus Disease-2019

Microvascular and macrovascular thrombotic complications, including arterial and especially venous thromboembolism (VTE), seem to be common clinical manifestations of coronavirus disease-2019 (COVID-19), particularly among hospitalized and critically ill patients (1234). Pooled analyses have helped in providing aggregate estimates of thrombotic events (4,5). In a recent systematic review and meta-analysis, the overall incidence of VTE among inpatients with COVID-19 was estimated at 17% (95% confidence interval [CI]: 13.4 to 20.9), with variation based on study design and method of ascertainment; there was a four-fold higher incidence rate in patients in the intensive care units (ICUs) compared with non-ICU settings (28% vs. 7%) (6). In addition, postmortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19 (7,8). The influence of these events on mortality rates remains unknown (9).Go to:

Pathophysiology of Thromboembolism in COVID-19: Virchow’s Triad in Action

COVID-19 can potentiate all 3 components of Virchow’s triad and increases the risk of thrombosis (Figure 1 ). First, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection may trigger endothelial dysfunction. Using the angiotensin-converting enzyme 2, which is expressed on the surface of many cells, SARS-CoV-2 enters endothelial cells and may impair their intrinsic antithrombotic properties. It is proposed that viremia, hypoxia, the inflammatory response, increased expression of tissue factor, and elevated levels of neutrophil extracellular traps (NETs) can together disrupt the hemostasis equilibrium and promote endothelial activation (101112). This induction of a procoagulant state along with the reduction in plasminogen activators further results in increased platelet reactivity (131415). Inflammatory cytokines and endothelial activation can lead to downregulation of antithrombin and protein C expression. They can also lead to an increase in the levels of plasminogen activator inhibitor; fibrinogen; factors V, VII, VIII, and X; and von Willebrand factor (16). Increased platelet reactivity, NETosis, and alterations in the aforementioned hemostatic factors result in a hypercoagulable state (171819202122).

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COVID-19 vaccines and thrombosis with thrombocytopenia syndrome

Authors: Chih-Cheng Lai 1Wen-Chien Ko 2Chih-Jung Chen 3Po-Yen Chen 4Yhu-Chering Huang 3Ping-Ing Lee 5Po-Ren Hsueh 6 7


Introduction: To combat COVID-19, scientists all over the world have expedited the process of vaccine development. Although interim analyses of clinical trials have demonstrated the efficacy and safety of COVID-19 vaccines, a serious but rare adverse event, thrombosis with thrombocytopenia syndrome (TTS), has been reported following COVID-19 vaccination.

Areas covered: This review, using data from both peer-reviewed and non-peer-reviewed studies, aimed to provide updated information about the critical issue of COVID-19 vaccine-related TTS.

Expert opinion: : The exact epidemiological characteristics and possible pathogenesis of this adverse event remain unclear. Most cases of TTS developed in women within 2 weeks of the first dose of vaccine on the receipt of the ChAdOx1 nCoV-19 and Ad26.COV2.S vaccines. In countries with mass vaccination against COVID-19, clinicians should be aware of the relevant clinical features of this rare adverse event and perform related laboratory and imaging studies for early diagnosis. Non-heparin anticoagulants, such as fondaparinux, argatroban, or a direct oral anticoagulant (e.g. apixaban or rivaroxaban) and intravenous immunoglobulins are recommended for the treatment of TTS. However, further studies are required to explore the underlying mechanisms of this rare clinical entity.

Plain language summary: What is the context? Thrombosis with thrombocytopenia syndrome (TTS) usually develops within 2 weeks of the first doses of the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines. TTS mainly occurs in patients aged < 55 years and is associated with high morbidity and mortality. What is new? TTS mimics autoimmune heparin-induced thrombocytopenia and can be mediated by platelet-activating antibodies against platelet factor 4. Non-heparin anticoagulants, such as fondaparinux, argatroban, or a direct oral anticoagulant (e.g. apixaban or rivaroxaban) should be considered as the treatment of choice if the platelet count is > 50 × 109/L and there is no serious bleeding. Intravenous immunoglobulins and glucocorticoids may help increase the platelet count within days and reduce the risk of hemorrhagic transformation when anticoagulation is initiated. What is the impact? TTS should be a serious concern during the implementation of mass COVID-19 vaccination, and patients should be educated about this complication along with its symptoms such as severe headache, blurred vision, seizure, severe and persistent abdominal pain, painful swelling of the lower leg, and chest pain or dyspnea. The incidence of TTS is low; therefore, maintenance of high vaccination coverage against COVID-19 should be continued.

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Anticoagulation in COVID-19: current concepts and controversies

  1. Authors: Chandra16289Uddalak Chakraborty2, Shrestha Ghosh1, Sugata Dasgupta3


Rising incidence of thromboembolism secondary to COVID-19 has become a global concern, with several surveys reporting increased mortality rates. Thrombogenic potential of the SARS-CoV-2 virus has been hypothesised to originate from its ability to produce an exaggerated inflammatory response leading to endothelial dysfunction. Anticoagulants have remained the primary modality of treatment of thromboembolism for decades. However, there is no universal consensus regarding the timing, dosage and duration of anticoagulation in COVID-19 as well as need for postdischarge prophylaxis. This article seeks to review the present guidelines and recommendations as well as the ongoing trials on use of anticoagulants in COVID-19, identify discrepancies between all these, and provide a comprehensive strategy regarding usage of these drugs in the current pandemic.

This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.


The novel beta-coronavirus, appropriately named SARS-CoV-2 by the International Committee of Taxonomy of Viruses, belongs to a family of single-stranded RNA viruses, members of which have been recognised as causative agents of the SARS-CoV and Middle East respiratory syndrome coronavirus outbreak in 2002 and 2012, respectively.1 2 Presently, the novel COVID-19 poses a major global health crisis, having been declared a pandemic on 11 March 2020 by the WHO.

Over the past several months, an overwhelming amount of literature suggests an increased risk of thromboembolic manifestations associated with COVID-19.2 Several hypotheses have been suggested to understand the underlying pathophysiology behind development of a prothrombotic state in COVID-19 such as exaggerated inflammatory response resulting in activation of the coagulation cascade and endothelial injury.3 4 Usage of anticoagulants in COVID-19 remains an area of conjecture with no definite guidelines published to date highlighting the timing, dosage and duration of anticoagulation as well as the drug of choice. Most internationally published guidelines, based on consensus statements and expert opinions, recommend therapeutic doses of heparin only in patients diagnosed with or highly suspected of developing macrothrombi such as pulmonary embolism (PE) or deep vein thrombosis (DVT). However, these guidelines including those by CHEST, rarely address the requirement of post discharge thromboprophylaxis.5

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