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The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management

  • Author Footnotes
    1 These authors have shared first-authorship.
    Mouhamed Yazan Abou-Ismail
    Footnotes
    1 These authors have shared first-authorship.
    Affiliations
    University Hospitals, Cleveland Medical Center, Cleveland, OH, United States of America

    Case Western Reserve University, Cleveland, OH, United States of America
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  • Author Footnotes
    1 These authors have shared first-authorship.
    Akiva Diamond
    Footnotes
    1 These authors have shared first-authorship.
    Affiliations
    University Hospitals, Cleveland Medical Center, Cleveland, OH, United States of America

    Case Western Reserve University, Cleveland, OH, United States of America
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  • Author Footnotes
    1 These authors have shared first-authorship.
    Sargam Kapoor
    Footnotes
    1 These authors have shared first-authorship.
    Affiliations
    Alaska Native Medical Center, Anchorage, AK, United States of America
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  • Yasmin Arafah
    Affiliations
    University Hospitals, Cleveland Medical Center, Cleveland, OH, United States of America

    Case Western Reserve University, Cleveland, OH, United States of America
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  • Lalitha Nayak
    Correspondence
    Corresponding author at: Department of Medicine, University Hospitals Cleveland Medical Center, Joan and Richard Ainsworth Chair in Hematologic Research Case Western Reserve University, 2103 Cornell Road, WRB2-122, Cleveland, OH 44106-7284, United States of America.
    Affiliations
    University Hospitals, Cleveland Medical Center, Cleveland, OH, United States of America

    Case Western Reserve University, Cleveland, OH, United States of America
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  • Author Footnotes
    1 These authors have shared first-authorship.

      Highlights

      • COVID-19 generates a significantly increased risk for thrombosis
      • Pulmonary inflammation and localized vasculopathy are central to the hypercoagulable state
      • Immune dysregulation is notable in severe illness
      • Rising D-dimer levels correlate with worse outcomes
      • Anticoagulant guidelines are rapidly evolving as we gather further insights

      Abstract

      The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.

      Keywords

      1. Introduction

      The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China at the end of 2019 and is now a pandemic [
      • Zhu H.
      • Wei L.
      • Niu P.
      The novel coronavirus outbreak in Wuhan, China.
      ]. The disease it causes, coronavirus disease 2019 (COVID-19), has affected more than 7 million people worldwide and claimed more than 400,000 lives as of June 2020 [,

      Coronavirus Disease (COVID-2019): Cases in the U.S. 2020 5/14/2020 5/14/2020; Available from: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html.

      ]. The disease ranges from asymptomatic, or mild to severe illness with multi-organ failure and death [
      • Emami A.
      • et al.
      Prevalence of underlying diseases in hospitalized patients with COVID-19: a systematic review and meta-analysis.
      ,
      • Yi Y.
      • et al.
      COVID-19: what has been learned and to be learned about the novel coronavirus disease.
      ,
      • Severe Outcomes Among Patients with Coronavirus Disease 2019
      (COVID-19) - United States, February 12-March 16, 2020.
      ]. Coagulopathy, in the form of venous and arterial thromboembolism, is emerging as one of the most severe sequela of the disease, and has been prognostic of poorer outcomes [
      • Zhou F.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Tang N.
      • et al.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ]. Reports of high incidence of thrombosis despite prophylactic and therapeutic dose anticoagulation raise question about a pathophysiology unique to COVID-19 [

      Klok, F., et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19, (in Thromb Res).

      ,
      • Llitjos J.F.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ]. Proposed hypotheses include a severely heightened inflammatory response that leads to thrombo-inflammation, through mechanisms such as cytokine storm, complement activation, and endotheliitis[
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Campbell C.M.
      • Kahwash R.
      Will Complement Inhibition be the New Target in Treating COVID-19 Related Systemic Thrombosis?.
      ,
      • Varga Z.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ]. It has also been suggested that the virus itself can possibly activate the coagulation cascade [

      Oudkerk, M., et al., Diagnosis, prevention, and treatment of thromboembolic complications in covid-19: report of the National Institute for Public Health of the Netherlands. Radiology. 0(0): p. 201629.

      ]. Although individual institutions have developed guidelines and protocols to institute prophylactic and therapeutic anticoagulation, the optimal management is rapidly evolving as we continue to gather new insights into the pathophysiology of this disease.
      Retrospective studies have identified clinical parameters that predict poor prognosis. In addition to markers of coagulopathy such as D-dimer other hematologic parameters have been studied[
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Tang N.
      • et al.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ,
      • Cui S.
      • et al.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Fogarty H.
      • et al.
      COVID-19 coagulopathy in Caucasian patients.
      ,
      • Zhang L.
      • et al.
      D-dimer levels on admission to predict in-hospital mortality in patients with covid-19.
      ,
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ]. Neutrophil count, lymphocyte count, neutrophil/lymphocyte ratio, and platelet count correlate with disease severity[
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Fan B.E.
      • et al.
      Hematologic parameters in patients with COVID-19 infection.
      ,
      • Lagunas-Rangel F.A.
      Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis.
      ,
      • Yang X.
      • et al.
      Thrombocytopenia and its association with mortality in patients with COVID-19.
      ]. At present, it is clear that patients with COVID-19 infection have a significantly increased risk of thrombosis that prevails despite anticoagulation. A better understanding of the pathophysiology accompanied by identification of biomarkers predictive of disease outcomes are critical to develop appropriate interventional strategies for this devastating disease.
      In this review, we summarize results of key studies, and discuss the current understanding of coagulopathy and hematological parameters in COVID-19 patients, as well as the pathophysiology and management of thrombosis.

      2. The hypercoagulable state with COVID-19

      Previous outbreaks of coronaviruses, including SARS-CoV-1 and Middle-Eastern respiratory syndrome (MERS-CoV) have been associated with increased risk of thrombosis [
      • Giannis D.
      • Ziogas I.A.
      • Gianni P.
      Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past.
      ]. Similarly, the novel SARS-CoV-2 appears to generate a profoundly prothrombotic milieu as evidenced by a surge in global reports of arterial, venous and catheter-related thrombosis [
      • Zhou F.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Klok F.A.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Middeldorp S.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ]. We summarize the current literature on the incidence of venous and arterial thrombosis in Table 1, as well as ongoing observational studies on the incidence of thrombotic outcomes in Table 2.
      Table 1Table summarizing global incidence of venous and arterial thromboembolic disease in COVID-19.
      Location (first author)Type of studySample sizeUse of thromboprophylaxisVenous thromboembolism incidenceArterial thrombosis incidenceKey characteristics of patient population/other salient features of the study
      Wuhan, China (Cui et al)Retrospective; hospitalized patients81NoVTE 25%; all lower extremity thrombiNone41% patients had other comorbidity (HTN, DM, CAD) and 43% were smokers
      Netherlands (Klok et al)Retrospective; multicenter; hospitalized patients184Yes (nadroparin at different doses)VTE (n = 28) 27%; of those PE (n = 25) was most common finding in 81%Ischemic strokes (n = 3) 3.7%76% were male, 2.7% had active cancer and 9.2% were on therapeutic anticoagulation from prior. Mean age was 64 and mean weight was 87 kg
      Netherlands (Middeldorp et al)Retrospective; single center; hospitalized patients198Yes (nadroparin 2850 units daily for <100 kg and 5700 units daily for >100 kg)7-day incidence of VTE (15%) and 14-day incidence of VTE (34%)NoneThe 7-day and 14-day incidence of VTE was higher in the ICU (25% and 48% respectively) than the general wards (6.5% and 10% respectively)
      Italy (Lodigiani et al)Retrospective; single center; hospitalized patients388Yes (LMWH)

      Ward: 75% used (41% prophylactic dose, 21% intermediate dose; 23% therapeutic dose)

      ICU: 100% used
      VTE 21% (cumulative rate)



      ICU 27.6% and general ward 6.6%
      Ischemic stroke 2.5% and ACS/MI 1.1%68% were male, 24.1% had BMI ≥ 30, 47.2% had HTN, 22.7% with DM, 11.6% smokers, 6.4% with active cancer and 3.1% with history of prior VTE.
      France (Llitjos et al)Retrospective study; 2 ICUs26Yes (31% with prophylactic dose and 69% with therapeutic dose)VTE 69%None77% were male, 85% had HTN, 27% consumed tobacco, median BMI 30.2 kg/m2; median D-dimer was 1750 ng/mL.

      56% of patients on therapeutic dose and 100% on prophylactic dose had VTE.
      France (Helms et al)Prospective study; COVID-19 ARDS patients at 4 ICUs in 2 centers150Yes (LMWH)PE 16.7%; DVT 2%Ischemic stroke 1.3%; limb ischemia 0.7%; mesenteric ischemia 0.7%Patients with COVID-19 ARDS had significantly higher thrombotic events, especially PE (11.7% vs. 2.1%, OR 6.2, p = 0.008)
      France (Poissy et al)Retrospective case series; ICU107YesPE (20.6%)None59.1% were male, median age was 57, median BMI was 30.

      Incidence of VTE was 2×- higher than a historical control period
      Netherlands (Beun et al)Retrospective; ICU75UnknownPE (26.6%; 21.3% subsegmental and 5.3% central); DVT 4%Ischemic stroke 2.7%4 patients had heparin resistance apparent by PTT based methods probably due to elevated factor VIII levels
      New York, USA (Oxley et al)Case series5NoNoneIschemic stroke 5 young patients in 2 week periodAll patients were < 50 years of age. Historical incidence was 0.73 patients in a 2 week period
      Beijing, China (Zhang et al)Case series3UnknownNoneIschemic strokes in 3 patientsAge 65-70, 2/3 were male, all with cardiovascular comorbidities including 2/3 with history of ischemic stroke. All with anti-phospholipid antibodies
      Italy (Bellosta et al)Observational cohort study2025% were on anticoagulation at baseline due to atrial fibrillationNoneAcute limb ischemia in 20 patients (16.3%)90% patients were male, mean age was 75 years, 55% had HTN. Incidence increased at 16.3% compared with a baseline rate of 1.8% in this region
      DVT = deep venous thrombosis.
      PE = pulmonary embolism.
      LMWH = low molecular weight heparin.
      Table 2Summary of ongoing observational trials on incidence of coagulopathic changes or thrombosis in patients with COVID-19.
      Clinical trialLocationStatusStudy description
      NCT04335162

      (CovCardiovasc)
      FranceRecruiting

      (100 patients)
      Screening of cardiovascular complications in COVID-19
      NCT04356950FranceNot yet recruiting

      (175 patients)
      Analysis of coagulopathy developed in COVID-19 patients
      NCT04356144

      (TGA-TM)
      AustriaNot yet recruiting

      (60 patients)
      Diagnostic TGA and TGA-thrombomodulin (TGA-TM) in critically ill patients
      NCT04363528FranceNot yet recruiting

      (50 patients)
      Incidence of DVT in COVID patients in the ICU
      NCT04366778FranceNot yet recruiting

      (330 patients)
      Thromboelastography with tPA to detect patients with high risk of thrombosis
      NCT04373486

      (COVID-APE)
      FranceNot yet recruiting

      (160 patients)
      Assessment of acute PE on CT angiography and relationship to D-dimer
      NCT04357847

      (COVID-Thelium)
      FranceNot yet recruiting

      (100 patients)
      Assessment of endothelial and hemostatic changes in Severe SARS-CoV-2 infection
      NCT04366752

      (THROMBOCOVID)
      FranceRecruiting

      (100 patients)
      Thrombembolic events in critical care patients with acute pneumopathy
      NCT04359212

      (VTE-COVID)
      ItalyNot yet recruiting

      (90 patients)
      Thromboprophylaxis with LMWH or fondaparinux in patients recovered in ICU or medical ward
      Observational Clinical Trials presently listed on ClinicalTrials.gov.
      LMWH = low-molecular-weight heparin; TGA = thrombin generation assay.

      2.1 Venous thromboembolism

      Pulmonary embolism is the most common thrombotic manifestation of COVID-19[
      • Han H.
      • et al.
      Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
      ]. One of the first substantial datasets on risk of venous thromboembolism (VTE) in critically ill patients with COVID-19, reported a VTE incidence of 25%[
      • Cui S.
      • et al.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ]. In a larger study in the Netherlands, 184 ICU patients with COVID-19 who were all on at least standard thromboprophylaxis had a 27% cumulative incidence of VTE, with pulmonary embolism (PE) being most frequent (81%) [
      • Klok F.A.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ]. Middeldorp et al. reported a higher incidence of thrombotic complications in their ICU patient population (7-day and 14-day cumulative incidence of 25% and 48% respectively) compared to the patients admitted on the wards. All patients initially received standard of care thromboprophylaxis that was intensified later on[
      • Middeldorp S.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ]. Another data set from France that included 150 patients with COVID-19 associated acute respiratory distress syndrome (ARDS) showed a VTE rate of 18%, with PE being most common. When compared to a historical prospective cohort of non-COVID-19 ARDS after matching, patients with COVID-19 ARDS demonstrated a significantly higher rate of thrombotic events, mainly PEs (11.7% vs 2.1%, OR 6.2, p = 0.008) [
      • Helms J.
      • et al.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      ]. Current data is too scant to determine the demographic characteristics of patients with COVID-19 that are more likely to develop thrombosis. It has however been suggested that this hypercoagulability may be more pronounced in older age, male gender, Caucasian and African-American ethnicities[
      • Cui S.
      • et al.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Fogarty H.
      • et al.
      COVID-19 coagulopathy in Caucasian patients.
      ,
      • Leonard-Lorant I.
      • et al.
      Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels.
      ].

      2.2 Arterial thrombosis

      In comparison to venous thrombosis, the incidence of arterial thrombosis in COVID-19 appears to be minor (Table 1). It is nevertheless of significant concern and merits further study.

      2.2.1 Myocardial infarction

      Myocardial infarction (MI) has not been commonly reported with COVID-19. In the Italian study by Lodigiani et al which included 388 patients with COVID-19, the incidence of MI or acute coronary syndromes was 1.1% [
      • Lodigiani C.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan.
      ]. Troponin levels have been noted to be significantly higher in the non-survivors, and may provide prognostic value [
      • Zhou F.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Guo T.
      • et al.
      Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
      ]. While there are many explanations for elevated troponins (renal injury, myocarditis), ischemic injury as a result of plaque rupture and consequent infarction or secondary to demand ischemia has been reported, and is postulated as another cause of myocardial injury [
      • Varga Z.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ].

      2.2.2 Stroke

      Ischemic strokes were first reported by Dutch investigators[
      • Klok F.A.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ]. Oxley et al have reported an alarming seven-fold increase in large vessel strokes in the <50-year-old age group in New York City, New York (5 patients in a 2-week period during COVID-19 pandemic compared with 0.7 patients pre-COVID) [
      • Oxley T.J.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      ]. Another case series reports three patients with COVID-19 presenting with strokes and limb ischemia[
      • Zhang Y.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      ]. Clinical presentation with ischemic strokes was also noted by Klok et al (3.7%) and Lodigiani et al (2.5%) [
      • Klok F.A.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Lodigiani C.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan.
      ].

      2.2.3 Microvascular thrombosis

      Several clinical reports have demonstrated evidence of thrombotic microangiopathy (TMA) in patients with COVID-19, most notably in lung autopsies [
      • Wichmann D.
      • et al.
      Autopsy findings and venous thromboembolism in patients with COVID-19.
      ,
      • Menter T.
      • et al.
      Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction.
      ,
      • Ackermann M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      ]. In a study by Menter et al, five out of eleven patients showed evidence of microthrombi in lung autopsies [
      • Menter T.
      • et al.
      Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction.
      ], and another case series by Ackermann et al. showed widespread thrombosis with microangiopathy in the lung autopsies of seven COVID-19 patients[
      • Ackermann M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      ]. The authors compared these findings to those of severe influenza patients, and found that alveolar microthrombi were 9 times more prevalent in COVID-19 patients (p < 0.001) [
      • Ackermann M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      ]. Interestingly, one report from China described the presence of extensive microvascular thrombosis in extrapulmonary organs where coronavirus was not detected, suggesting that a mechanism beyond viral infection is operative[
      • Zhang T.
      • Sun L.X.
      • Feng R.E.
      Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019.
      ]. Tian et al provided evidence of microthrombi in pathological samples obtained from two asymptomatic patients who underwent lobectomies for lung adenocarcinoma, and were subsequently found to be positive for COVID-19 [
      • Tian S.
      • et al.
      Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer.
      ]. Pathological examinations revealed patchy inflammatory cellular infiltrate with focal areas of fibrin deposit, suggesting that a local hypercoagulable state in the pulmonary tissue may be an early occurrence. Furthermore, TMA may contribute to findings of unusual sites and presentations of thrombosis that have been described in several clinical reports (Table 3). COVID-19 induced chilblains eruption has been reported, where histopathology revealed microangiopathy thought to be induced by a robust interferon response to the virus [
      • Kolivras A.
      • et al.
      Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings.
      ]. Chilblain-like lesions have also been reported in otherwise asymptomatic adolescents[
      • Guarneri C.
      • et al.
      Silent COVID-19: what your skin can reveal.
      ]. Transient livedo reticularis has been reported in two patients and is believed to be secondary to coagulopathy[
      • Manalo I.F.
      • et al.
      A dermatologic manifestation of COVID-19: transient livedo reticularis.
      ]. Several reports have mentioned cases with bowel ischemia [
      • Varga Z.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ], limb or acral ischemia[
      • Zhang Y.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      ,
      • Zhang Y.
      • et al.
      Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia.
      ] and cutaneous ischemia[
      • Magro C.
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      ]. Whether the renal injury seen in COVID-19 is related to direct viral toxicity or endothelial/microvascular injury has not been established. One review of 26 autopsy reports did not find evidence of fibrinous material in the renal vasculature[
      • Su H.
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      ], while this was found in 3 out of 18 patients in another autopsy review[
      • Menter T.
      • et al.
      Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction.
      ].
      Table 3Demographic and clinical characteristics of reported cases of thrombi in unusual sites. An article written in Chinese could not be included in this table but has been cited in the main body of this review.
      Location (first author)AgeGenderThromboembolic eventPathologic findingsD-dimer (institution specific units)ComorbiditiesVTE prophylaxisTreatmentOutcome
      Switzerland

      (Varga et al)
      58FMesenteric ischemiaEndotheliitis in small intestine, lung, heart, kidney and liverUnknownDiabetes, hypertension, obesityUnknownSurgical removal of necrotic bowel, renal replacement therapyDeath
      Switzerland

      (Varga et al)
      69MMesenteric ischemiaEndotheliitis of submucosal vessels in small intestineUnknownHypertensionUnknownResection of small intestine, mechanical ventilationSurvived
      New York

      (Magro et al)
      32MPurpuric rash on buttocksThrombogenic vasculopathy with necrosis of epidermis and adnexa; complement depositsD-dimer 1024 ng/mL that peaked at 2090 ng/mL on day 19 (normal 0-229 ng/mL); INR 1.6-1.9; normal PTT and plateletsObstructive sleep apnea, anabolic steroid useUnknownHydroxychloroquine, azithromycin, remedesvir, mechanical ventilationNot mentioned
      New York

      (Magro et al)
      66FPurpuric rash on palms and solesSuperficial vascular ectasia with occlusive arterial thrombus; complement depositsD-dimer 7030 ng/mL; low platelets at 128 × 109/L on day 10; normal INR and PTTNoneYesHydroxychloroquine, prophylactic anticoagulation, renal replacement therapy and supportive careNot mentioned
      New York

      (Magro et al)
      40FLivedo racemosa on chest, arms and legsperivascular lymphocytic infiltrate in superficial dermis and deep seated small thrombi in rare venules; complement depositsD-dimer 1187 ng/mL; INR 1.4; normal platelet and PTTNoneUnknownMechanical ventilationNot mentioned
      Beijing, China (Zhang et al)69MLower limb, digital ischemia in hand and strokeNoneD-dimer >21.0 mg/L; PT 17 s, PTT 43.7 s, fibrinogen 4.15 g/L, FDP 85.5 mg/L all on admission to ICUHypertension, diabetes and prior strokeUnknownOseltamivir, intravenous immunoglobulin and mechanical ventilationNot mentioned
      Camden, New Jersey, USA84MRenal infarct in addition to stroke and pulmonary embolusNoneD-dimer 21.6 μg/mLHypertensionNo (Thromboembolism at presentation)LMWH infusion, mechanical thrombectomy, mechanical ventilationDeath
      LMWH = low-molecular-weight heparin.
      VTE = venous thromboembolism.

      3. Pathophysiology of COVID-19 coagulopathy: inflammatory thrombosis

      In addition to bedside evidence for a hypercoagulable state in COVID-19, laboratory tests have also been consistent with a prothrombotic milieu such as increased D-dimer, fibrinogen, factor VIII (FVIII), von Willebrand factor (vWF), decreased antithrombin, and TEG results [
      • Panigada M.
      • et al.
      Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis.
      ]. While critical illness is known to cause a hypercoagulable state due to immobilization, mechanical ventilation, central venous access devices, and nutritional deficiencies, COVID-19 appears to cause a hypercoagulable state through mechanisms unique to SARS-CoV-2 and centers around the cross-talk between thrombosis and inflammation [
      • Wang T.
      • et al.
      Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19.
      ,
      • Ranucci M.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      ].
      The causal, bi-directional relationship between inflammation and thrombosis is well established [
      • Jackson S.P.
      • Darbousset R.
      • Schoenwaelder S.M.
      Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms.
      ]. COVID-19 causes a profoundly pro-inflammatory state, as evident from multiple reports of high C-reactive protein, lactate dehydrogenase, ferritin, interleukin-6 and D-dimer levels [
      • Esmon C.T.
      Inflammation and thrombosis.
      ]. IL-6 and fibrinogen levels are shown to correlate with each other in COVID-19 patients, providing credence to the idea of inflammatory thrombosis [
      • Ranucci M.
      • et al.
      The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.
      ]. Researchers presently believe that the inciting event sparking the cycle of inflammation and thrombosis originates in the pulmonary alveoli, where SARS-CoV-2 enters the alveolar epithelium through the ACE2 receptor. Consequently, a severe inflammatory response is initiated that sets the stage for thrombosis through several mechanisms. We propose the following mechanisms as the central pathophysiological aspects of the inflammatory thrombosis caused by COVID-19, which we visually summarize in Fig. 1.
      Fig. 1
      Fig. 1Pathophysiology of the Hypercoagulable State in COVID-19. The current understanding of the pathophysiology of COVID-19 induced coagulopathy centers around the bidirectional cross-talk between inflammation (yellow arrows) and thrombosis (black arrows). COVID-19 leads to a severe inflammatory response that originates in the alveoli. Release of inflammatory cytokines leads to activation of epithelial cells, monocytes and macrophages. Direct infection of the endothelial cells through the ACE2 receptor also leads to endothelial activation and dysfunction, expression of TF, and platelet activation and increased levels of VWF and FVIII, all of which contribute to thrombin generation and fibrin clot formation. Thrombin, in turn, causes inflammation through its effect on platelets which promote NET formation in neutrophils. It also activates endothelium through the PAR receptor, which leads to release of C5A that further activates monocytes. These mechanisms are currently hypothetical based on existing findings in COVID-19 and previous understanding of the cross-talk between inflammation and thrombosis.
      ACE2: Angiotensin-converting enzyme 2. FVIII: Factor VIII. IL: Interleukin. NET: Neutrophil extracellular trap. TF: Tissue factor. TNF: Tumor necrosis factor. VWF: von Willebrand factor.

      3.1 Localized intravascular coagulopathy

      A report by Tang et al. described a high rate (71.4%) of COVID-19 patients meeting ISTH disseminated intravascular coagulopathy (DIC) criteria[
      • Tang N.
      • et al.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ]. However, clear evidence of overt clinical DIC in COVID-19 is lacking thus far. It is possible that the laboratory abnormalities noted are a reflection of a localized coagulopathy in the pulmonary vasculature, resulting from severe alveolar inflammation [
      • Fogarty H.
      • et al.
      COVID-19 coagulopathy in Caucasian patients.
      ,
      • Marongiu F.
      • Grandone E.
      • Barcellona D.
      Pulmonary thrombosis in 2019-nCoV pneumonia?.
      ]. Progression of this process to the systemic circulation may explain microthrombotic complications and ensuing multi-organ failure. In fact, Ciceri et al propose to label this entire pathophysiology as microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome or MicroCLOTS.[
      • Ciceri F.
      • et al.
      Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis.
      ] The group postulates that, in individuals predisposed to severe outcomes, initial viral damage occurring in the alveoli generates inflammation and local microvascular pulmonary thrombosis. This is followed by more generalized endothelial dysfunction and thrombo-inflammation in the microvasculature of the brain, kidneys and other organs leading to a hypercoagulable state and multiple organ failure.

      3.2 Inflammatory cytokines

      Excessive cytokine release is postulated to cause the severe illness noted in younger patients without pre-existing conditions. Higher serum levels of several inflammatory cytokines and chemokines have been associated with severe illness and death in multiple studies [
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Chen G.
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Qin C.
      • et al.
      Dysregulation of immune response in patients with COVID-19 in Wuhan.
      ,
      • Yang Y.
      • et al.
      Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome.
      ,
      • Gong J.
      • et al.
      Correlation analysis between disease severity and inflammation-related parameters in patients with COVID-19 pneumonia.
      ]. The cytokine profiles in patients with severe COVID-19 show increased production of IL-6, IL-7, TNF, and inflammatory chemokines such as CCL2, CCL3, and soluble IL-2 receptor, a profile similar to that seen in cytokine release syndromes, such as macrophage activation syndrome [
      • Merad M.
      • Martin J.C.
      Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.
      ]. Excessive cytokine release contributes to thrombosis through multiple mechanisms, including activation of monocytes, neutrophils, and the endothelium, all of which generates a prothrombotic state.

      3.3 Endothelial activation & dysfunction

      Varga and colleagues first reported endothelial dysfunction in multiple vascular beds on post mortem specimens obtained from three patients [
      • Varga Z.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ]. In case series of 7 patients by Ackerman et al, lung autopsies of COVID-19 patients showed severe endothelial injury with presence of intracellular virus, as well as widespread thrombosis with microangiopathy[
      • Ackermann M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      ]. Furthermore, significantly elevated levels of VWF and FVIII in COVID-19 patients are suggestive of endothelial activation in these patients[
      • Helms J.
      • et al.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      ,
      • Escher R.
      • Breakey N.
      • Lammle B.
      Severe COVID-19 infection associated with endothelial activation.
      ]. Endothelial activation or dysfunction with COVID-19 may occur through multiple mechanisms. This includes inflammatory cytokines generated in the pulmonary interstitium, the activation of the complement components in blood, or possibly, as a direct result of SARS-CoV-2 infection of endothelial cells through the ACE2 receptor[
      • Monteil V.
      • et al.
      Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.
      ]. Endotheliitis, in turn, is a major forerunner to thrombosis. The observation that male sex, obesity, hypertension, and diabetes are poor prognostic factors for severe disease with COVID-19 further supports this theory due to the presence of endothelial dysregulation at baseline in these patients[
      • Varga Z.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ]. Whether anti-phospholipid (aPL) antibodies contribute to endothelial dysfunction and activation in COVID-19 is unclear. Anticardiolipin antibodies, β2 glycoprotein antibodies and positive lupus anticoagulant have all been reported in a few sudies [
      • Helms J.
      • et al.
      High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      ,
      • Zhang Y.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      ,
      • Escher R.
      • Breakey N.
      • Lammle B.
      Severe COVID-19 infection associated with endothelial activation.
      ,

      Harzallah, I., A. Debliquis, and B. Drénou, Lupus anticoagulant is frequent in patients with covid-19, (in J Thromb Haemost).

      ]. The presence of aPL antibodies in the general population, especially in states of infection, is common[
      • Connell N.T.
      • Battinelli E.M.
      • Connors J.M.
      Coagulopathy of COVID-19 and antiphospholipid antibodies.
      ]. In addition, the contribution of IgA aPL antibodies, reported by Zhang et al, to thrombosis is controversial. Many lupus anti-coagulant assays are sensitive to C-reactive protein (CRP), and lead to false positive results in states where CRP is markedly elevated such as COVID-19[
      • Connell N.T.
      • Battinelli E.M.
      • Connors J.M.
      Coagulopathy of COVID-19 and antiphospholipid antibodies.
      ,
      • Schouwers S.M.
      • Delanghe J.R.
      • Devreese K.M.
      Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results?.
      ]. Thus, the clinical relevance of these findings is yet to be determined.

      3.4 Mononuclear phagocytes (MNPs)

      Monocytes and macrophages are theorized to play a crucial role in the inflammation and thrombosis seen in COVID-19. Liao et al demonstrated that MNPs account for 80% of the total bronchoalveolar fluid from patients with severe COVID-19 illness, compared to 60% and 40% in mild cases and healthy controls, respectively [
      • Liao M.
      • et al.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      ]. Furthermore, the composition of the cells was characterized by an abundance of inflammatory monocyte-derived macrophages in patients with severe disease. Bronchoalveolar fluid in severe patients is enriched with chemokines potently recruit monocytes [

      Zhou, Z.A.R., Lili and Zhang, Li and Zhong, Jiaxin and Xiao, Yan and Jia, Zhilong and Guo, Li and Yang, Jing and Wang, Chun and Jiang, Shuai and Yang, Donghong and Zhang, Guoliang and Li, Hongru and Chen, Fuhui and Xu, Yu and Chen, Mingwei and Gao, Overly exuberant innate immune response to SARS-CoV-2 infection. Cell Host & Microbe-D-20-00205.

      ]. COVID-19 patients requiring ICU hospitalization were noted to have a significant expansion of CD14+, CD16+ monocyte populations producing IL-6 in peripheral blood [
      • Merad M.
      • Martin J.C.
      Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.
      ,
      • Zhou Y.
      • et al.
      Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients.
      ,
      • Zhang D.
      • et al.
      COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome.
      ,
      • Wen W.
      • et al.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      ]. In another study, circulating monocytes were shown to have a sustained production of TNF-α and IL-6, a pattern that differs from bacterial or influenza sepsis [
      • Giamarellos-Bourboulis E.J.
      • et al.
      Complex Immune dysregulation in COVID-19 patients with severe respiratory failure.
      ]. Similarly, post-mortem analyses of COVID-19 positive patients revealed that lymphoid tissue macrophages infected with SARS-CoV-2 viral particles expressed IL-6. Further, the presence of IL-6+ macrophages was associated with severe depletion of lymphocytes from lymphoid tissue [
      • Chen Y.
      • et al.
      The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes.
      ]. These findings suggest that COVID-19 is associated with a clinical and laboratory picture similar to that of macrophage-activation syndrome (MAS). However, there distinguishing features present in COVID-19, such as higher fibrinogen levels and a less pronounced elevation in ferritin and liver dysfunction in comparison to that seen in classical MAS[
      • McGonagle D.
      • et al.
      The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease.
      ]. Presently, the exact mechanisms through which COVID-19 leads to activation of monocytes and macrophages remains unclear. However accumulating data suggests a role for MNPs in the generation of severe illness, including possibly the prothrombotic sequelae. This is not surprising given the understanding that activated monocytes rapidly upregulate tissue factor (TF) expression. This triggers the coagulation cascade resulting in production of thrombin which in turn leads to thrombus generation, platelet activation, and amplification of pro-inflammatory pathways, primarily through PAR signaling[
      • Foley J.H.
      • Conway E.M.
      Cross talk pathways between coagulation and inflammation.
      ].

      3.5 Neutrophil extracellular traps (NETs)

      While neutrophilia [
      • Wang D.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      ] and an elevated neutrophil-lymphocyte ratio (NLR) [
      • Liu J.
      • et al.
      Neutrophil-to-lymphocyte ratio predicts severe illness patients with 2019 novel coronavirus in the early stage.
      ] have been reported by numerous studies now as predictive of worse disease outcomes, the contribution of neutrophil extracellular traps in the pathophysiology of COVID-19 was reported only recently[
      • Zuo Y.
      • et al.
      Neutrophil extracellular traps in COVID-19.
      ]. NETs are implicated to portend pathogenicity in a wide variety of disorders including influenza-associated ARDS [
      • Porto B.N.
      • Stein R.T.
      Neutrophil extracellular traps in pulmonary diseases: too much of a good thing?.
      ] and thrombo-inflammation [
      • Frangou E.
      • et al.
      REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A).
      ,
      • Fuchs T.A.
      • et al.
      Extracellular DNA traps promote thrombosis.
      ]. Yu et al report elevated levels of serum NETs in hospitalized COVID-19 positive patients based on a finding of elevated cell-free DNA, myeloperoxidase-DNA and citrullinated histones in 50 patients with COVID-19. This was especially noted in hospitalized and mechanically ventilated patients [
      • Zuo Y.
      • et al.
      Neutrophil extracellular traps in COVID-19.
      ]. Moreover, they showed that sera obtained from these patients stimulated NET generation in control neutrophils. Taken together with literature linking NETs to pulmonary diseases and thrombo-inflammation, these data begin to implicate NETs as causative in organ damage, widespread thrombosis and mortality that is noted in COVID-19 infection. Finally, a recent manuscript by Barnes et al describes an abundance of neutrophil infiltration in pulmonary capillaries of three patients who succumbed to COVID-19 and suggests that aberrant activation of neutrophils and NET generation may underlie the cytokine storm and severe disease outcomes noted in this disease[
      • Barnes B.J.
      • et al.
      Targeting potential drivers of COVID-19: neutrophil extracellular traps.
      ].

      3.6 Complement-mediated microangiopathy

      Previous studies in animal models provide evidence for complement activation in serum and pulmonary tissue [
      • Jiang Y.
      • et al.
      Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.
      ,
      • Sun S.
      • et al.
      Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection.
      ]. A growing body of evidence suggests a major role for dysregulated complement activation in severe COVID-19[
      • Song W.-C.
      • FitzGerald G.A.
      COVID-19, microangiopathy, hemostatic activation, and complement.
      ]. Several reports of post-mortem examinations have demonstrated evidence of TMA, including hyaline thrombi in the small vessels of the lungs and other organs [
      • Yao X.H.
      • et al.
      A pathological report of three COVID-19 cases by minimally invasive autopsies.
      ,
      • Fox S.E.
      • et al.
      Pulmonary and cardiac pathology in covid-19: the first autopsy series from New Orleans.
      ]. One of those reports demonstrated lung and skin biopsy findings revealing a pauci-inflammatory thrombogenic vasculopathy with complement deposit. Researchers in China observed complement hyper-activation in COVID-19 patients, as well as significantly increased plasma C5a levels in severe cases[
      • Gao T.
      • et al.
      Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation.
      ]. Dysregulated complement system activation may be a major contributor to cytokine storm, particularly through the pro-inflammatory effects of anaphylatoxins C3a and C5a [
      • Zhang X.
      • et al.
      Regulation of Toll-like receptor–mediated inflammatory response by complement in vivo.
      ]. These effects are likely to become more detrimental in patients with a genetic predisposition for decreased complement regulation, and may contributed to findings of TMA and subsequent organ dysfunction.

      3.7 Dysregulated renin angiotensin system (RAS)

      Although dysfunction of RAS is known to play a significant role in ARDS in general [
      • Vrigkou E.
      • et al.
      The evolving role of the renin–angiotensin system in ARDS.
      ,
      • Zhang H.
      • Baker A.
      Recombinant human ACE2: acing out angiotensin II in ARDS therapy.
      ], this system is specifically important in COVID-19 infections for several reasons. The SARS-CoV2 uses its Spike (S) protein and fuses with the enzyme Angiotensin-Converting Enzyme 2 (ACE2) located on the cell membrane of human cells to gain entry into cells. ACE2 is homologous to ACE, which cleaves angiotensin I (ANGI) to generate ANGII. ANGII binds to the Angiotensin Type I Receptor (AT1R) that leads to vasoconstriction and an increase in blood pressure. The inactivation of ANGII by ACE2 results in vasodilation. Conversely, ANGII also negatively regulates ACE2 [
      • Zores F.
      • Rebeaud M.E.
      COVID and the Renin-Angiotensin System: Are Hypertension or Its Treatments Deleterious?.
      ], which is located on lung alveolar epithelial cells, renal tubular epithelial cells, enterocytes of the small intestine, endothelial cells, cardiomyocytes, fibroblasts and pericytes in the heart. SARS-CoV-2 has a high affinity for ACE2, and binding of the SARS-CoV-2 results in loss of ACE2 due to internalization of the virus and ACE2 shedding. This decrease in ACE2 leads to decreased degradation of ANGII resulting in excess ANGII binding to AT1R and increase lung injury [
      • Zores F.
      • Rebeaud M.E.
      COVID and the Renin-Angiotensin System: Are Hypertension or Its Treatments Deleterious?.
      ]. Finally, studies suggest that ANGII binding to AT1R may stimulate IL-6 release, further contributing to the cytokine storm syndrome that is typical of severe COVID-19 infection. Supporting this hypothesis is the evidence showing increased risk of severe disease in patients infected with SARS-CoV or influenza H7N5 that had higher ANGII levels [
      • Itoyama S.
      • et al.
      ACE1 polymorphism and progression of SARS.
      ,
      • Huang F.
      • et al.
      Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients.
      ]. Further, in recent studies on COVID-19 positive patients, viral load and lung injury directly correlated with plasma ANGII levels[
      • Liu Y.
      • et al.
      Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
      ]. In addition,COVID-19 appears to generate worse outcomes in patients with hypertension, cardiovascular disease and diabetes, all of which are associated with reduced baseline levels of ACE2 expression suggesting imbalance in ACE/ACE2 levels[
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Tikellis C.
      • Thomas M.C.
      Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease.
      ]. It has been shown that ANGII induces TF and plasminogen activator inhibitor 1 (PAI-1) expression by endothelial cells via AT1R, leading to a hypercoagulable state[
      • Vaughan D.E.
      • Lazos S.A.
      • Tong K.
      Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis.
      ,
      • Nakamura S.
      • et al.
      Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo.
      ]. Thus, it is likely these derangements in the RAS pathways, in addition to the multiple pathways described above, likely contribute to the hypercoaguable state of COVID-19, and the ensuing mortality and morbidity of the disease. Presently, rapid investigation into the molecular mechanisms involved is essential in order to gain a better understanding of the pathophysiology of the disease and to direct appropriate, timely therapeutic interventions.

      4. Impact of blood count abnormalities

      COVID-19 is associated with a significant effect on the hematological and hemostatic system. In this section we will review the available data on the common hematologic parameters and their prognostic significance. See Table 4 for a summary of the hematologic parameters from various studies.
      Table 4Summary of literature on the impact of common hematologic parameters on disease severity in COVID-19.
      LabLocation (reference)N (total, non-severe/severe)Non-severeSevereP value
      White blood cell count (×109/L)

      Median (IQR) or [SD]
      China (Guan, et.al NEJM)1099, 926/1744.9 (3.8–6.0)3.7 (3.0–6.2)NR
      Wuhan, China (Qin, et al. Clin Inf Disease)452, 166/2864.9 (3.7–6.1)5.6 (4.3–8.4)<0.001
      China (Wang et al. JAMA)138, 102/364.3 (3.3–5.4)
      ICU vs non-ICU.
      6.6 (3.6–9.8)
      ICU vs non-ICU.
      0.003
      Shangai, China (Wu, et al. Jama)201, 117/845.02 (3.37 –7.18)
      Without ARDS vs with ARDS.
      8.32 (5.07–11.20)
      Without ARDS vs with ARDS.
      <0.001
      Wuhan, China (Chen, et al. BMJ)247, 161/1135.0 (3.7–6.3)
      Survivors vs Non-Survivors.
      10.2 (6.2–13.6)
      Survivors vs Non-Survivors.
      NR
      Wuhan, China (Zhou, et.al)191, 137/545.2 (4.3–7.7)
      Survivors vs Non-Survivors.
      9.8 (6.9–13.9)
      Survivors vs Non-Survivors.
      <0.0001
      Absolute neutrophil count (×109/L)

      Median (IQR) or [SD]
      Wuhan, China (Qin, et al. Clin Inf Disease)452, 166/2863.2 (2.1–4.4)4.3 (2.9–7.0)<0.001
      China (Wang et al. JAMA)138, 102/362.7 (1.9–3.9)
      ICU vs non-ICU.
      4.6 (2.6–7.9)
      ICU vs non-ICU.
      <0.001
      Shangai, China (Wu, et al. Jama)201, 117/843.06 (2.03–5.56)
      Without ARDS vs with ARDS.
      7.04 (3.98–10.12)
      Without ARDS vs with ARDS.
      <0.001
      Wuhan, China (Chen, et al. BMJ)247, 161/1133.2 (2.4–4.5)
      Survivors vs Non-Survivors.
      9.0 (5.4–12.7)
      Survivors vs Non-Survivors.
      NR
      Absolute lymphocyte count (×109/L)

      Median (IQR) or [SD]
      China (Guan, et.al NEJM)1099, 926/1741.0 (0.8–1.4)0.8 (0.6–1.0)NR
      Wuhan, China (Qin, et al. Clin Inf Disease)452, 166/2861.0 (0.7–1.3)0.8 (0.6–1.1)<0.001
      China (Wang et al. JAMA)138, 102/360.9 (0.6–1.2)
      ICU vs non-ICU.
      0.8 (0.5–0.9)
      ICU vs non-ICU.
      0.03
      Shangai, China (Wu, et al. Jama)201, 117/841.08 (0.72–1.45)
      Without ARDS vs with ARDS.
      0.67 (0.49–0.99)
      Without ARDS vs with ARDS.
      <0.001
      Wuhan, China (Chen, et al. BMJ)247, 161/1131.0 (0.7–1.4)
      Survivors vs Non-Survivors.
      0.6 (0.4–0.7)
      Survivors vs Non-Survivors.
      NR
      Wuhan, China (Zhou, et.al)191, 137/541.1 (0.8–1.5)
      Survivors vs Non-Survivors.
      0.6 (0.5–0.8)
      Survivors vs Non-Survivors.
      <0.0001
      Neutrophil/lymphocyte ratio

      Median (IQR) or [SD]
      Beijing, China (Liu, et al. preprint)61, 44/172.2 (1.4–3.1)3.6 (2.5–5.4)0.003
      Wuhan, China (Qin, et al. Clin Inf Disease)452, 166/2863.2 (1.8–4.9)5.5 (3.3–10.0)<0.001
      China (Yang, et al. Int Immun)93, 69/244.8 [± 3.5]20.7 [± 24.1]<0.001
      Wuhan, China (Ma. et al.)37, 17/202.6 (1.8–3.5)
      Cancer patients.
      5.5 (3.6–6.5)
      Cancer patients.
      0.022
      Platelet count (×109/L)

      Median (IQR) or [SD]
      China (Guan, et.al NEJM)1099, 926/174172 (139–212)137 (99–179.5)NR
      China (Wang et al. JAMA)138, 102/36165 (125–188)
      ICU vs non-ICU.
      142 (119–202)
      ICU vs non-ICU.
      0.78
      Shangai, China (Wu, et al. Jama)201, 117/84178 (140.0–239.5)
      Without ARDS vs with ARDS.
      187 (124.5–252.5)
      Without ARDS vs with ARDS.
      0.73
      Wuhan, China (Chen, et al. BMJ)247, 161/113198 (160–256)
      Survivors vs Non-Survivors.
      156 (111.8–219.3)
      Survivors vs Non-Survivors.
      NR
      Wuhan, China (Zhou, et.al)191, 137/54220 (168–271)
      Survivors vs Non-Survivors.
      165.5 (107–229)
      Survivors vs Non-Survivors.
      <0.0001
      Hemoglobin (g/dL)

      Median (IQR) or [SD]
      China (Guan, et.al NEJM)1099, 926/17413.5 (12.0–14.8)12.8 (11.2–14.1)NR
      Wuhan, China (Chen, et al. BMJ)247, 161/11312.8 (11.8–13.8)
      Survivors vs Non-Survivors.
      12.8 (11.4–14.5)
      Survivors vs Non-Survivors.
      NR
      Wuhan, China (Zhou, et.al)191, 137/5412.8 (12.0–14.0)
      Survivors vs Non-Survivors.
      12.6 (11.5–13.8)
      Survivors vs Non-Survivors.
      0.3
      New York, USA (Goyal et al. NEJM)393, 263/13013.5 (12.4–14.8)
      Non-invasive vs invasive ventilation.
      13.7 (12.3–15.3)
      Non-invasive vs invasive ventilation.
      NR
      NR = not reached.
      a ICU vs non-ICU.
      b Without ARDS vs with ARDS.
      c Survivors vs Non-Survivors.
      d Non-invasive vs invasive ventilation.
      e Cancer patients.

      4.1 Neutrophil count

      Although initial studies from Wuhan reported leukopenia in hospitalized COVID-19 positive patients, [
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ], [
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ], subsequent reports showed a trend of higher neutrophil count in patients who required ICU admission (ANC 4.2 vs 2.6 × 109/L, p = 0.17) [
      • Fan B.E.
      • et al.
      Hematologic parameters in patients with COVID-19 infection.
      ]. Thus, patients requiring ICU care developed neutrophilia during the hospitalization, with a median peak Absolute Neutrophil Count (ANC) of 11.6 × 109/L, compared to 3.5 × 109/L in the non-ICU group (P value <0.001). Further, in a retrospective review of 25 patients who died with COVID-19 in Wuhan the neutrophil count trended up prior to death in 87.5% of patents with evaluable data [
      • Li X.
      • et al.
      Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.
      ].

      4.2 Lymphocyte count

      The lymphocyte count has gained much attention in COVID-19 patients and studies consistently report the presence of lymphopenia in this setting. In the report from China Medical Treatment Expert Group for COVID-19 83.2% had lymphocytopenia at hospital admission [
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ].
      Importantly, the lymphopenia is a consistent marker of poor prognosis. Thus, when comparing 109 patients who died in Wuhan versus 116 patients who recovered, the patients who died presented with a decreased lymphocyte count (0.63 vs 1.0 × 109/L) and decreased lymphocyte percentage [
      • Deng Y.
      • et al.
      Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study.
      ]. In a retrospective cohort study of 191 patients with 54 deaths, lymphocyte count was lowest at day 7 of illness onset in survivors and then improved, whereas severe lymphopenia was observed until death in non-survivors [
      • Zhou F.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ]. Wang et al. reported that non-survivors developed more severe lymphopenia over time [70]. Flow cytometry on peripheral blood lymphocytes of COVID-19 patients requiring ICU care showed significantly lower CD45+, CD3+, CD4+, CD8+, CD16+, and CD16/56+ counts, without an inversion of the CD4/CD8 ratio [
      • Fan B.E.
      • et al.
      Hematologic parameters in patients with COVID-19 infection.
      ].
      Interestingly, while the number of CD4+ and CD8+ T cells were reduced, both the proportion and number of B cells were not affected or even increased in most patients. Further, the producton of IFN-γ by CD4+ T cells and not CD8+ T cells or NK cells tended to be lower in severe cases. Finally, circulating CD8 + T cells contained high concentrations of cytotoxic granules including perforin and granulysin. All these data suggest a dysregulated immune system with overactivation of cytotoxic CD8 + T cells [
      • Xu Z.
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ].
      Potential mechanisms of lymphocytopenia may include direct infection of the lymphocytes by the virus, though the proportion of ACE2-positive lymphocytes is quite small. Lymphocytes express the coronavirus receptor Angiotensin converting enzyme (ACE2) and may be directly targeted [
      • Tan L.
      • et al.
      Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study.
      ,
      • Xu H.
      • et al.
      High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.
      ]. In a retrospective comparison of 42 patients with COVID-19 and hypertension, the 17 patients treated with an ACE inhibitor/ARB had absolute numbers of CD3+ and CD8+ T cells that were significantly higher than that in the non-ACEI/ARB group, but no difference in the CD4+ T cells [
      • Meng J.
      • et al.
      Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.
      ].

      4.3 Neutrophil to lymphocyte ratio

      NLR has been shown to have prognostic significance in septic shock, pancreatitis, pancreatic cancer, and bacteremia, amongst other diseases [
      • Zhou Y.
      • et al.
      Prognostic role of the neutrophil-to-lymphocyte ratio in pancreatic cancer: A meta-analysis containing 8252 patients.
      ]. An increasing neutrophil count in the setting of a lymphopenia appears to be a sensitive marker of early inflammation and physiologic stress[
      • Benschop R.J.
      • Rodriguez-Feuuerhahn M.
      • Schedlowski M.
      Catecholamine-induced leukocytosis: Early observations, current research, and future directions.
      ,
      • Onsrud M.
      • Thorsby E.
      Influence of in vivo hydrocortisone on some human blood lymphocyte subpopulations. I. Effect on natural killer cell activity.
      ,
      • Zahorec R.
      Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill.
      ]. In a study of 413 healthy volunteers the mean NLR was 1.65 (±1.96 SD: 0.78–3.53) [
      • Zahorec R.
      Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill.
      ].
      Several studies have shown a relationship between an elevated NLR and more severe COVID-19 infection. An increased NLR at presentation has a strong association with increased disease severity when compared to patients without severe disease at presentation. Moreover, when stratified by high NLR (>3.13) and age ≥ 50, 50% of the patients had severe illness. Similarly, in another analysis of 96 patients, Yang, et al. identified that 46.1% of non-severe patients with an NLR >3.3 and age >49.5 would transform into severe cases within a mean of 6.3 days.[
      • Yang A.-P.
      • et al.
      The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients.
      ] In a study of 301 patients, an NLR of 2.973 (AUC 0.7338, sensitivity 75.8%, specificity 66.8%) was associated with progression of disease [
      • Long L.
      • et al.
      Short-term Outcomes of Coronavirus Disease 2019 and Risk Factors for Progression.
      ]. Finally, a meta-analysis of 5 studies from China with 828 patients, NLR was found to increase significantly in patients with severe disease (standardized mean difference = 2.404, 95% CI - 0.98-3.82) [
      • Lagunas-Rangel F.A.
      Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis.
      ].
      Increased NLR was also associated with VTE with a mean NLR of 9.5 (5.9-13) in 33 patients who developed VTE versus 5 (3.5-7.9) in 165 patients without VTE [
      • Middeldorp S.
      • et al.
      Incidence of venous thromboembolism in hospitalized patients with COVID-19.
      ].

      4.4 Platelets

      Although a significant drop in platelet counts has not been a prominent feature of the disease, there are certain situations when the presence of severity thrombocytopenia is being recognized as a marker of worse outcomes. Thrombocytopenia was more pronounced in patients with severe infection with a mean platelet count of 137 × 109/L vs 172 × 109/L in non-severe patients. See Table 4 for the difference in platelet counts between patients with mild versus severe disease. In a retrospective review specifically investigating the relationship between thrombocytopenia and mortality of 1476 consecutive patients in Jinyintan Hospital, Wuhan, thrombocytopenia was reported in 20.7% of patients, using a cutoff of 125 × 109/l. 72.7% of non-survivors had <125 × 109/L platelets vs only 10.7% in survivors, p < 0.001[
      • Yang X.
      • et al.
      Thrombocytopenia and its association with mortality in patients with COVID-19.
      ]. 76 patients (5.1%) had a platelet nadir <50 × 109/L with a mortality rate of 92.1%. The mortality rate was 61.2% in the group of patients with a nadir platelet count between 50 and 100 × 109/L. Overall, the majority of patients appear to have a mild thrombocytopenia, which is more pronounced with severe infection.
      Presently, it is unclear if a decreased platelet count reflects a more severe DIC and increased consumption or a direct platelet-viral interaction [
      • Amgalan A.
      • Othman M.
      Exploring possible mechanisms for COVID-19 induced thrombocytopenia: Unanswered questions.
      ]. Multiple possible mechanisms are possible for viral infection induced thrombocytopenia. These include the development of autoantibodies and immune complexes mediating clearance; direct infection of hematopoietic stem/progenitor cells and the megakaryocytic lineage via CD13 or CD66a resulting in decreased production of platelets; and pathologic activation of the coagulation pathway and consumption of platelets[
      • Amgalan A.
      • Othman M.
      Exploring possible mechanisms for COVID-19 induced thrombocytopenia: Unanswered questions.
      ,
      • Goeijenbier M.
      • et al.
      Review: viral infections and mechanisms of thrombosis and bleeding†.
      ].

      4.5 Hemoglobin

      No significant abnormalities have been described regarding red blood cells and anemia. There has been a trend of worse anemia in patients with more severe disease, [
      • Fan B.E.
      • et al.
      Hematologic parameters in patients with COVID-19 infection.
      ] with a median hemoglobin (Hgb) of 13.2 g/dL in patients requiring ICU versus 14.2 g/dL in non ICU patients (p = 0.07), and the majority of patients presented with a normal Hgb count. Of 1099 patients with confirmed COVID-19 in China, the median Hgb was 13.5 g/dL in non-severe patients and 12.8 g/dL in severe patients[
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ]. However, this trend was not appreciated in a review of 393 patients who required or did not require invasive ventilation in New York City[
      • Goyal P.
      • et al.
      Clinical characteristics of covid-19 in New York City.
      ]. See Table 4 for a review of the median Hgb levels reported in the various studies.

      5. Management

      The first general rule in the management of coagulopathy is the treatment of the underlying cause. However, with COVID-19, treatments of the viral infection remain experimental at the current time. As such, until an effective treatment option is available, it is crucial to be able to appropriately manage the sequela of COVID-19-associated coagulopathy.

      5.1 Monitoring of laboratory parameters

      As a result of the crosstalk between inflammatory and thrombotic pathways, infections are almost always associated with a concomitant activation of the coagulation system, evidenced by elevation in the markers of an activated coagulation system. The D-dimer has been shown to be frequently elevated in patients with COVID-19 [
      • Zhou F.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Cui S.
      • et al.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Leonard-Lorant I.
      • et al.
      Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels.
      ,
      • Li T.
      • Lu H.
      • Zhang W.
      Clinical observation and management of COVID-19 patients.
      ,
      • Chen N.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ]. Increased fibrinogen, fibrin degradation products, prothrombin time (PT), activated partial thromboplastin time (aPTT), and shortened thrombin time (TT) have been described in patients with COVID-19 compared to healthy controls [
      • Han H.
      • et al.
      Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
      ,
      • Terpos E.
      • et al.
      Hematological findings and complications of COVID-19.
      ].

      5.1.1 D-Dimer

      Numerous studies in COVID-19 patients highlight the prognostic value of increased D-dimer (Table 5) [
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Tang N.
      • et al.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ,
      • Cui S.
      • et al.
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Fogarty H.
      • et al.
      COVID-19 coagulopathy in Caucasian patients.
      ,
      • Zhang L.
      • et al.
      D-dimer levels on admission to predict in-hospital mortality in patients with covid-19.
      ,
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ]. Accumulating data clearly suggests that an elevated D-dimer, and presence of coagulopathy, serve as prognostic indicators of worse morbidity and mortality in hospitalized patients with COVID-19. In general, the D-dimer is a marker of fibrin formation and degradation, and specifically of plasmin-catalyzed degradation of fibrin polymers and thus, in the case of COVID-19 infection, reflective of pathological activation of the hemostatic pathways. In this review, we describe D-dimer units as reported in the original studies. In the study by Lodigiani et al, the median D-dimer of survivors on admission was 353 ng/mL (μg/L), and trended to 529 ng/mL a week later, in comparison to 869 ng/mL and 1494 ng/mL for non-survivors, respectively [
      • Lodigiani C.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ]. Consistently, data by Tang et al shows that non-survivors of COVID-19 infection demonstrated higher D-dimer levels and platelet counts, lower fibrinogen and antithrombin levels, all highly suggestive of ongoing DIC [
      • Tang N.
      • et al.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ]. Monitoring hemostatic parameters such as platelet counts, coagulation assays, D-dimer and fibrinogen is common practice in critical care, especially in DIC [
      • Wada H.
      • et al.
      Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines.
      ,
      • Taylor Jr., F.B.
      • et al.
      Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation.
      ,
      • Levi M.
      • et al.
      Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology.
      ,
      • Di Nisio M.
      • et al.
      Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET).
      ], These data now provide evidence for the importance of these assessments especially in COVID-19 patients and offer crucial prognostic insights which will likely guide alterations in management.
      Table 5Summary of current literature evidence on the prognostic value of elevated D-dimer in COVID-19 across the globe.
      Location (first author)Sample sizeClinical settingD-dimer assay (reference range)D-dimer cut-off for risk assessmentOutcome of interestStatistics (sensitivity/specificity/odds ratio with p-value)Salient findings
      Wuhan, China (Zhou et al)191HospitalizedUnknown>1 μg/mLMortalityOR 18.42, 95% CI: 2.64-128.55; p = 0.0033D-dimer>1 μg/mL indicative of higher odds of death
      Wuhan, China

      (Yao et al)
      248HospitalizedImmunoturbidimetric assay (0-0.50 mg/L)>2.14 mg/LMortalitySe 88.2%/Sp 71.3%D-dimer elevated in 74.6% of inpatients. Median D-dimer 6.21 mg/L and 1.02 mg/L in non-survivors and survivors respectively, p = 0.000
      Wuhan, China (Zhang et al)343HospitalizedCS5100 automatic coagulation analyzer (0-0.5 μg/mL)>2 μg/mLMortalityHR 51.5, p < 0.001; adjusted HR 22.4 (for age, gender and comorbidity), p = 0.003D-dimer>2.0 μg/mL had higher incidence of mortality when compared to <2 (12/67 vs 1/267, P < 0.001)
      Wuhan, China (Tang et al)183HospitalizedSTA-R MAX coagulation analyzerN/A (continuous variable)MortalityN/AMedian D-dimer values were 2.12 μg/mL vs 0.61 μg/mL in the non-survivors and survivors respectively, p < 0.001. 71.4% of non-curvivors had DIC per ISTH criteria.
      Mainland China (Guan et al)1099HospitalizedNot mentionedN/A

      (continuous variable)
      Severe disease; Primary composite endpoint was admission to ICU/mechanical ventilation or deathN/A1) 59.6% of the severe cases presented with elevated D-dimer vs 43.2% of non-severe cases (p = 0.002).

      2) 69.4% of patients with the composite primary endpoint had elevated D-dimer vs. 44.2% of those without (P = 0.001).
      Wuhan, China (Huang et al)41HospitalizedNot mentionedN/A

      (continuous variable)
      ICU admissionN/AMedian D-dimer values were 2.4 vs 0.5 in the ICU patients and non-ICU patients respectively, p = 0.0042.
      Wuhan, China (Wang et al)138HospitalizedNot mentioned (0-500 mg/L)N/A

      (continuous variable)
      ICU admissionN/AMedian D-dimer values were 414 mg/L vs 166 mg/L, p < 0.001 in ICU cases and non-ICU cases respectively.
      Wuhan, China (Wu et al)201HospitalizedNot mentionedN/A

      (continuous variable)
      ARDS; mortalityARDS HR = 1.03, p < 0.001; mortality HR = 1.02, p = 0.002Higher D-dimer associated with progress to ARDS and mortality
      Milan, Italy (Lodigiani et al)388HospitalizedNot mentionedN/A

      (continuous variable)
      ICU; mortalityN/ATable 2 in this published study highlights the higher D-dimer values in non-survivors vs survivors and also in ICU patients vs general ward patients.
      Beijing, China (Cui et al)81ICUSucceeder SF8200 automatic coagulation analyzer>1.5 μg/mLVTESe 85%/Sp 88.5%/NPV 94.7%20/81 (25%) patients had VTE. 8/20 patients with VTE died. D-dimer values were 5.2 ± 3.0 vs 0.8 ± 1.2 μg/ml in the VTE group and non-VTE group respectively, P < 0.001.
      Strasbourg, France (Leonard-Lorant et al)106HospitalizedUnknown>2660 μg/LPulmonary embolismSe 100%/Sp 67%32/106 (30%) patients had a PE. Median D-dimer values were IQR 6110 ± 4905 versus 1920 ± 3674 μg/L in the PE and non-PE group respectively, p < 0.001
      The ASH expert panel recommends serial monitoring of platelet count, PT, aPTT, D-dimer, and fibrinogen in hospitalized COVID-19 patients. The panel suggests that since worsening of these parameters, specifically the D-dimer, indicates worsening illness, this predicts the need for aggressive critical care or experimental therapies. Likewise, improvement of these parameters along with stable or improving clinical condition may support the decision to step down on aggressive anticoagulation therapy [
      • Agnes Y.Y.
      • Lee J.M.C.
      • Kreuziger Lisa Baumann
      • Murphy Mike
      • Gernsheimer Terry
      • Lin Yulia
      COVID-19 and Coagulopathy: Frequently Asked Questions. [Webpage].
      ]. The ISTH provides similar recommendations [

      Thachil, J., et al., ISTH interim guidance on recognition and management of coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis. n/a(n/a).

      ]. On the other hand, blood product support can be considered in bleeding scenarios as with bleeding in DIC, although clinically overt bleeding is reportedly uncommon in the setting of COVID-19 [
      • Wada H.
      • et al.
      Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines.
      ,
      • Bikdeli B.
      • et al.
      COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up.
      ].
      For therapeutic monitoring of patients who are on anticoagulation with heparin products, anti-Xa monitoring is recommended over aPTT since the latter may be elevated in COVID-19. Furthermore, this allows for less frequent visits to the patient room.

      5.2 Anticoagulation

      5.2.1 Use of prophylactic or therapeutic dose anticoagulants

      As our understanding of the coagulopathy associated with COVID-19 evolves, the best approach to management continues to be explored. Given the paucity of data in the pathophysiology of this disorder, physicians globally are compelled to prepare guidelines for management of this hypercoagulable state based on the established understanding of crosstalk between inflammation and thrombosis. Thus, clinicians are using prophylactic, intermediate, or therapeutic doses of anticoagulation, based on coagulation parameters and the clinical scenario.
      Although the optimal dosing remains unclear the benefit of anticoagulation with heparin products (mostly LMWH at prophylactic doses) in COVID-19 patients was demonstrated by a study in China. [
      • Tang N.
      • et al.
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      ] Importantly, in the sub-group analysis, those with a sepsis-induced coagulopathy (SIC) score of greater than 3 (n = 97) had decreased 28-day mortality (40.0% vs 64.2%, P = 0.029), as did the 161 patients with D-dimer greater than 6 times the upper limited of normal (32.8% vs 52.4%, P = 0.017). Of concern, a Dutch study by Klok et al reported a 31% incidence of thrombotic complications that occurred despite the presence of at least prophylactic anticoagulation (with LMWH) in patients hospitalized for COVID-19 pneumonia [

      Klok, F., et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19, (in Thromb Res).

      ]. Consistently, another study, albeit smaller, done in France demonstrated the significant hypercoagulability that exists in COVID-19 patients. Here, Llitjos et al showed that all patients with severe COVID-19 who received prophylactic anticoagulation (n = 8) developed VTE, as did 56% of those who received therapeutic dose anticoagulation (n = 18) [
      • Llitjos J.F.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ].
      These findings make a strong argument for considering higher doses (intermediate or therapeutic) of anticoagulation in the management of patients with severe COVID-19, especially in the absence of obvious contraindications such as ongoing bleeding. However, they also bring to mind, the concern that anticoagulation in itself may be insufficient to prevent thrombotic complications. While we battle with these dilemmas, hemostasis experts outline and revise guidelines based on rapidly accumulating data, bearing in mind that there may exist pathophysiologic differences in COVID-19 induced coagulopathy. Below, we summarize the current guidelines and recommendations from different societies, as of the date this article is written, on the role of prophylactic and therapeutic anticoagulation in Table 6.
      Table 6Current guidelines and recommendations on prophylactic and therapeutic anticoagulation from different societies and institutions.
      Recommending sourceWhen to consider prophylactic dose anticoagulationWhen to consider therapeutic dose anticoagulation
      International Society of Thrombosis & HemostasisIn all patients with COVID-19 who are hospitalized, including non-critically ill, in the absence of contraindications (active bleeding and platelet count <25 × 109/L). PT and PTT abnormalities are not considered a contraindication [

      Thachil, J., et al., ISTH interim guidance on recognition and management of coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis. n/a(n/a).

      ].
      American Society of Hematology (Expert Panel)All hospitalized patients with COVID-19. LMWH or fondaparinux (suggested over UFH to reduce contact) in the absence of increased bleeding risk[
      • Kreuziger L.B.
      • et al.
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions. [Webpage].
      ].
      • Intubated patients who develop sudden clinical and laboratory findings consistent with PE, especially when chest X-ray and/or markers of inflammation are stable or improving
      • Patients with physical findings consistent with thrombosis, such as superficial thrombophlebitis, peripheral ischemia or cyanosis, thrombosis of dialysis filters, tubing or catheters, or retiform purpura
      • Patients with respiratory failure, particularly when D-dimer and/or fibrinogen levels are very high, in whom other causes are not identified (e.g., ARDS, fluid overload) [
        • Lee A.
        • et al.
        COVID-19 and Pulmonary Embolism: Frequently Asked Questions. [Webpage].
        ]
      Thrombosis UK
      • For CrCl >30 mL/min: Give LMWH or fondaparinux
      • For CrCl <30 mL/min or acute kidney injury: UFH 5000 units SC BD or TDS or dose-reduced LMWH
      • All completely immobilized patients would benefit from intermittent pneumatic compression in addition to pharmacological thromboprophylaxis
      • Mechanical thromboprophylaxis should be used alone if platelets <30 × 109/L or bleeding [
        • Hunt B.
        • Retter A.
        • McClintock C.
        Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19.
        ].
      National Institute for Public Health of the NetherlandsAll patients with (suspected) COVID-19 admitted to the hospital, irrespective of risk scores.
      • In patients with a D-dimer <1,000 μg/L on admission but a significant increase during hospital stay to levels above 2,000-4,000 μg/L, when imaging is not feasible, therapeutic-dose LMWH can be considered when the risk of bleeding is acceptable.


      • In patients with a strongly increased D-dimer on admission (e.g. 2,000-4,000 μg/L), D-dimer testing should be repeated within 24-48 h to detect further increases in which case imaging for DVT or PE, or empiric anticoagulation, should be considered [

        Oudkerk, M., et al., Diagnosis, prevention, and treatment of thromboembolic complications in covid-19: report of the National Institute for Public Health of the Netherlands. Radiology. 0(0): p. 201629.

        ].
      While all guidelines presently recommend intravenous or subcutaneous low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) for anticoagulation, another proposed approach has been the use of nebulized heparin for an enhanced localized anticoagulant effect in the pulmonary vasculature. Prior data demonstrated that nebulized heparin significantly reduces coagulation activation in the lungs of critically ill patients [
      • Dixon B.
      • et al.
      Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury.
      ]. However, as with so many other therapies, this approach is yet to be studied in the context of COVID-19.

      5.2.2 Drug Interactions with anticoagulants and antiplatelets

      Attention should be given to potential drug interactions between anticoagulants and experimental drugs for COVID-19. ISTH guidelines advice caution (although not avoidance) in patients on DOACs who are admitted with COVID-19 illness due to interactions with antiviral or any other investigational drugs. In a small study by Testa et al, DOAC patients treated with antiviral drugs showed an alarming increase in DOAC plasma levels [

      Testa, S., et al., Direct oral anticoagulant plasma levels striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents. The Cremona experience. Journal of Thrombosis and Haemostasis. n/a(n/a).

      ]. The effect of direct oral anticoagulants appears to be potentiated by atazanavir, lopinavir/ritonavir, hydroxychloroquine, and decreased by tocilizumab. Furthermore, apixaban may confer increased risk for QT prolongation when used with hydroxychloroquine. Atazanavir and lopinavir/ritonavir may decrease the active metabolite of clopidogrel and prasugrel. Among atazanavir, lopinavir/ritonavir, remdesivir, hydroxychloroquine, tocilizumab, and interferon beta, there has not been shown to be interactions with heparin products, fondaparinux, or argatroban. A list of drug interactions (collated by the University of Liverpool) can be found at http://covid19-druginteractions.org [
      • Liverpool Drug Interactions Group
      Interactions With Experimental COVID-19 Therapies.
      ].

      5.2.3 Duration of Anticoagulation

      Data on the optimal duration and method of anticoagulation for COVID-19 patients post-discharge is currently not available. Aspirin has been studied for extended VTE prophylaxis in low-risk orthopedic patients, and could be considered for COVID-19 VTE prophylaxis if the post-discharge criteria are met [
      • Anderson D.R.
      • et al.
      Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty.
      ]. The ASH expert panel recommends that any decision to use extended post-discharge thromboprophylaxis with anticoagulation or aspirin should consider the individual patient's VTE risk factors, such as reduced mobility, coagulopathy, and bleeding risk [
      • Kreuziger L.B.
      • et al.
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions. [Webpage].
      ]. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score has been used as a tool to identify patients who would benefit from extended-use prophylaxis with LMWH [
      • Spyropoulos A.C.
      • et al.
      Modified IMPROVE VTE risk score and elevated D-dimer identify a high venous thromboembolism risk in acutely Ill medical population for extended thromboprophylaxis.
      ]. Protocols suggest that patients hospitalized with COVID-19, especially those with an IMPROVE VTE score of >3, an elevated D-dimer level (>2× upper limit of normal), and 2 or more of the following characteristics: age >60, previous VTE, known thrombophilia, current cancer, should be strongly considered for extended thromboprophylaxis up to 39-45 days post-discharge either with prophylactic dose LMWH or rivaroxaban [
      • Spyropoulos A.C.
      • et al.
      Modified IMPROVE VTE risk score and elevated D-dimer identify a high venous thromboembolism risk in acutely Ill medical population for extended thromboprophylaxis.
      ,

      Cohoon, K.P., et al., Emergence of institutional antithrombotic protocols for coronavirus 2019. Research and Practice in Thrombosis and Haemostasis. n/a(n/a).

      ,
      • Hull R.D.
      • et al.
      Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial.
      ]. For patients who have been empirically started on therapeutic anticoagulation for suspected PE, the ASH panel recommends that they should remain anticoagulated for at least 3 months, regardless of results of future investigation studies. Furthermore, cases of confirmed VTE should be considered as “provoked” and treated for 3-6 months duration [
      • Kreuziger L.B.
      • et al.
      COVID-19 and VTE/Anticoagulation: Frequently Asked Questions. [Webpage].
      ].

      5.3 Antifibrinolytics

      There has been interest in the use of anti-fibrinolytics in the management of thrombosis and ARDS in the setting of COVID-19. Fibrin deposition in the alveolar spaces and lung parenchyma is a known observation in ARDS leading to worse respiratory outcomes [

      Whyte, C.S., et al., Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. Journal of Thrombosis and Haemostasis. n/a(n/a).

      ]. Although inhibiting thrombin generation with heparin agents may prevent further fibrin deposition, unlike the use of anti-fibrinolytics, it is not effective against pre-existing fibrin deposits. The use of tPA to treat ARDS in COVID-19 has been proposed, following a case series of 3 COVID-19 patients in whom tPA was associated with temporary improvement in respiratory parameters [
      • Moore H.B.
      • et al.
      Is there a role for tissue plasminogen activator (tPA) as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome (ARDS)?.
      ,
      • Wang J.
      • et al.
      Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series.
      ]. However, bleeding complications remain a major concern, and given the paucity of data, the use of anti-fibrinolytics is not yet a strong recommendation. An alternative, safer approach that may confer benefit in COVID-19 induced ARDS is the use of nebulized fibrinolytics. In 2019, a study on 60 patients with ARDS showed that use of nebulized streptokinase in patients with severe ARDS resulted in improvements in oxygenation and lung mechanics more rapidly than nebulized heparin [
      • Abdelaal Ahmed Mahmoud A.
      • et al.
      Streptokinase versus unfractionated heparin nebulization in patients with severe acute respiratory distress syndrome (ARDS): a randomized controlled trial with observational controls.
      ]. This approach would need further investigation in the COVID-19 setting.
      Another agent with fibrinolytic properties that has been considered is Nafamostat. Nafamostat is a synthetic serine protease inhibitor that has been used in Japan for treatment of DIC in pancreatitis for decades. Nafamostat possesses both anti-fibrinolytic activity as well as anti-viral activity, and has thus generated interested in being repurposed as a potential therapeutic agent for COVID-19 in ongoing studies [
      • Asakura H.
      • Ogawa H.
      Potential of heparin and nafamostat combination therapy for COVID-19.
      ].

      5.4 Future therapeutic targets and areas of research

      As previously highlighted, SARS-CoV-2 presents unique mechanisms of inducing coagulopathy. The limited data revealing a high incidence of thrombosis despite anticoagulation underscores the necessity for novel therapeutic approaches to prevent thrombotic complications and mortality [

      Klok, F., et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19, (in Thromb Res).

      ,
      • Llitjos J.F.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ]. We enlist below the main areas of research that are either being pursued or warrant further study, and provide a summary of ongoing observation and interventional trials in Table 6 and Table 7. These approaches remain theoretical or experimental, but offer insight into potential future strategies that bear promise.
      Table 7Summary of ongoing interventional trials using different anti-thrombotic agents in COVID-19 patients.
      Clinical TrialLocationStatusIntervention
      NCT04345848SwitzerlandRecruiting

      (200 patients)
      Low and high dose anticoagulation with UFH or LMWH
      NCT04354155

      (COVAC-TP)
      USANot yet recruiting

      (38 patients)
      Thromboprophylaxis with enoxaparin
      NCT04344756

      (CORIMUNO-COAG)
      FranceNot yet recruiting

      (808 patients)
      Tinxaparin or UFH for 14 days
      NCT 04357730USANot yet recruiting

      (60 patients)
      Fibrinolytic therapy to treat ARDS in COVID-19 patients
      NCT04362085CanadaNot yet recruiting

      (462 patients)
      Therapeutic LMWH or UFH versus standard of care
      NCT04360824USANot yet recruiting

      (170 patients)
      Standard versus intermediate dose enoxaparin
      NCT04367831

      (IMPROVE)
      USANot yet recruiting

      (100 patients)
      Intermediate to prophylactic dose anticoagulation
      NCT04363840

      (LEAD COVID-19)
      USANot yet recruiting

      (1080 patients)
      Aspirin 81 mg plus vitamin D
      NCT04373707

      (COVI-DOSE)
      FranceNot yet recruiting

      (602 patients)
      Weight adjusted versus fixed low dose LMWH for VTE
      NCT04354155

      (COVAC-TP)
      USANot yet recruiting

      (38 patients)
      Thromboprophylaxis with LMWH in children
      Interventional Clinical Trials presently listed on ClinicalTrials.gov.
      LMWH = low molecular weight heparin; UFH = unfractionated heparin.

      5.4.1 Inflammatory thrombosis

      As previously highlighted, the bidirectional cross-talk between inflammation and thrombosis, or “immuno-thrombosis”, is emerging as a major cornerstone of the prothrombotic complications of COVID-19. Experimental use of immunosuppressive agents can potentially set the brakes on this inflammatory process in COVID-19 patients and has been of interest [

      Thachil, J., et al., ISTH interim guidance on recognition and management of coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis. n/a(n/a).

      ].

      5.4.1.1 Complement pathway

      As previously mentioned, a growing body of evidence supports the role of complement hyper-activation contributing to severe COVID-19 [
      • Song W.-C.
      • FitzGerald G.A.
      COVID-19, microangiopathy, hemostatic activation, and complement.
      ]. These studies provide the basis for the suggestion that severe and fatal cases of COVID-19, that have findings consistent with excessive complement activation, may have an increased susceptibility to TMA due to a genetic predisposition to a pathogenic complement activation. Previous data showed that treatment with humanized anti-C5a antibody greatly ameliorated lung injury and inflammation in a monkey model of virus-induced acute lung injury (H7N9 virus) [
      • Wang R.
      • et al.
      The role of C5a in acute lung injury induced by highly pathogenic viral infections.
      ]. In fact, in the same study in China where elevated C5a levels were demonstrated in severe COVID-19, researchers also treated two severe cases with a recombinant C5a monoclonal antibody. Both patients showed significant improvement with resolved fever and increased oxygenation [
      • Gao T.
      • et al.
      Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation.
      ]. Thus, complement inhibition, with agents such as eculizumab, may also be a promising treatment for severe COVID-19 [
      • Campbell C.M.
      • Kahwash R.
      Will Complement Inhibition be the New Target in Treating COVID-19 Related Systemic Thrombosis?.
      ].

      5.4.1.2 Neutrophil extracellular traps

      Accumulating data show that neutrophils extracellular traps or NETs have the potential to propagate both inflammation and thrombosis. As highlighted above, NETs are postulated to play a role in COVID-19 associated immuno-thrombosis as well. This suggests a role for potentially targeting NETs to reduce the clinical severity of COVID-19. Barnes et al propose several mechanisms of either directly targeting the molecules that form NETs, or the process that leads to their formation[
      • Barnes B.J.
      • et al.
      Targeting potential drivers of COVID-19: neutrophil extracellular traps.
      ]. Anakinra targets IL1β, which enhances NET formation, and is currently being investigated in COVID-19 trials (ClinicalTrials.gov identifiers: NCT04324021, NCT04330638, NCT02735707) [
      • Barnes B.J.
      • et al.
      Targeting potential drivers of COVID-19: neutrophil extracellular traps.
      ].

      5.4.1.3 Inflammatory cytokines

      Tocilizumab, an interleukin-6 inhibitor, has been used in the setting of cytokine release syndrome in COVID-19, and recent pilot prospective data suggests a survival benefit when given early in the course of the disease [
      • Sciascia S.
      • et al.
      Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in severe patients with COVID-19.
      ]. While the impact of tocilizumab on thrombotic outcomes is unclear, it is possible that the survival benefit is secondary to reduced endothelial inflammation and microvascular thrombosis. Regardless, this warrants further investigation. In a small case series in China, the use of plasma exchange for the similar purpose of reducing cytokine storm was attempted with the suggestion of potential benefit [
      • Ma J.
      • et al.
      Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19.
      ]. Additionally, the use of non-anticoagulant heparin-like molecules has been proposed as a mechanism to attenuate the release of inflammatory cytokines. LMWH is known to possess anti-inflammatory properties, which could provide additional benefit in COVID19 patients subject to pro-inflammatory cytokines [
      • Guan W.J.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
      ,
      • Poterucha T.J.
      • Libby P.
      • Goldhaber S.Z.
      More than an anticoagulant: do heparins have direct anti-inflammatory effects?.
      ]. Specifically designed heparan sulfate oligosaccharides with neutralizing proinflammatory proteins and potential anti-viral effect are being investigated in managing COVID-19 [
      • Liu J.
      • et al.
      Using heparin molecules to manage COVID-2019.
      ].

      5.4.2 Natural anticoagulant pathways

      Since the pathogenesis of inflammation and sepsis-induced coagulopathy involves the generation of thrombin and the reduction of natural anticoagulant proteins, numerous studies have explored the benefit of using coagulation inhibitors such as antithrombin in these situations. Hayakawa et al demonstrated that AT treatment in sepsis-induced DIC may be associated with a reduced in-hospital all-cause mortality [
      • Hayakawa M.
      • et al.
      Antithrombin supplementation and mortality in sepsis-induced disseminated intravascular coagulation: a multicenter retrospective observational study.
      ]. Similarly a study be Kato et al suggested possible mortality benefit in septic patients with coagulopathy treated with recombinant thrombomodulin [
      • Kato T.
      • Matsuura K.
      Recombinant human soluble thrombomodulin improves mortality in patients with sepsis especially for severe coagulopathy: a retrospective study.
      ]. Although none of the studies with anticoagulants provide data as robust as the PROWESS trial studying activated protein C (APC), the benefit of using APC is offset with the increased risk for bleeding [
      • Bernard G.R.
      • et al.
      Efficacy and safety of recombinant human activated protein C for severe sepsis.
      ]. In general, these data provide fuel for considering experimental therapies that address physiologic anticoagulant pathways that are most likely inhibited or inactivated in COVID-19. To this end, a group in Austria has already registered a study with Clinicaltrials.gov to examine the thrombin generation potential of COVID-19 positive patients, with and without the addition of thrombomodulin (NCT04356144). The results from such studies may provide the foundation for interventional studies exploring anticoagulants such as recombinant thrombomodulin or antithrombin for the management of COVID-19 coagulopathy.

      5.5 COVID-19 in patients with bleeding disorders

      While we still do not understand how COVID-19 infection may affect people with bleeding disorders, we are aware that severe illness is usually associated with a coagulopathy that resembles DIC. Since some of the treatments used presently for management of bleeding disorders may also interfere with clotting assays, this information is vital to the management of the disease in patients who may receive these therapies.
      This is especially true of patients with hemophilia who are treated with emicizumab. The pharmaceutical company manufacturing emicizumab, Genetech, wasted no time in distributing guidelines and information to the physicians at hemophilia treatment centers and other healthcare professionals. Given in Table 8 is a summary of information they provided, which enlists the common coagulation assays that may be used to monitor patients with COVID-19 associated coagulopathy and if these assays are affected by emicizumab[
      • Thachil J.
      • et al.
      DOACs and ‘newer’ haemophilia therapies in COVID-19.
      ].
      Table 8Coagulation assays used to monitor COVID-19 positive patients that may be affected by emicizumab (adapted from Genetech).
      Analyte/assayAssay with interference with emicizumab?Alternatives
      aPTTYes (overestimate coagulation potential of emicizumab)For heparin monitoring: anti Xa assay
      PTYes (weak effect)No mitigation required (small effect)
      D-dimerNo
      Fibrinogen: Clauss methodNo
      Fibrinogen: derivedYes (weak effect)No mitigation required (small effect); or use Clauss method
      Protein C: chromogenicNo
      Protein C: aPTT-basedYes (overestimate coagulation potential of emicizumab)Chromogenic protein C assay
      Antithrombin activityNo
      Anti-Xa activityNo
      FVIII activity: aPTT basedYes (overestimate coagulation potential of emicizumab)Chromogenic FVIII assay (see below guidance)
      FVIII activity: chromogenic bovine reagentsNoDoes not detect emicizumab, but allows measurement of endogenous or infused FVIII activity
      FVIII activity: chromogenic human reagentsNoResponsive to emicizumab, but may overestimate clinical hemostatic potential of emicizumab
      For additional information on effects and interferences of emicizumab on coagulation assays, please refer to Adamkewicz et al. Thromb Haemost 2019;119:1084-1093.

      6. Conclusion

      The hypercoagulable state in COVID-19 is emerging as a major pathological occurrence with serious consequences in mortality and morbidity. It is clear that this derangement in the hemostatic pathways is unlike the one seen in other kinds of infection, sepsis, or ARDS. Strikingly, current reports indiciate clinical manifestations of both widespread microvascular as well as large vessel thrombosis. Of concern are the data suggesting that anticoagulation in itself may not be adequate in preventing these thrombotic events. Accumulating evidence supports the notion that the hypercoagulability of SARS-CoV-2 involves a unique mechanism of thrombo-inflammation triggered by viral infection, originating in the pulmonary vasculature. A better understanding of this pathophysiology will allow for the development of appropriate therapeutic modalities. Furthermore, the identification of biomarkers of thrombosis and severe illness can guide clinicians on early interventional strategies and focus healthcare resources towards the group of patients at risk for worse outcomes. The significant number of studies listed on ClinicalTrials.gov is very reassuring and physicians eagerly await the results of these investigations.

      Declaration of compering interest

      The authors report no conflicts of interest.

      Author contributions

      MA, AD, SK, YA, LN all contributed to the writing of the manuscript. MA illustrated the pathophysiology illustration. LN mentored and supervised the manuscript.

      Acknowledgements

      LN's work is supported by National Heart, Lung, and Blood Institute grants HL142647-01, HL121131-01, and U01 HL143402.

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