COVID-19 associated coagulopathy: more questions than answers?

Severe COVID-19 infection is characterized by coagulopathy, with manifestations related to arterial and venous thrombosis. Often unrecognized, lethal complications may ensue, including stroke and acute coronary syndrome. COVID-19-associated coagulopathy (CAC) is similar to, yet distinctively different, from sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC). There are several reports of sudden, out-of-hospital deaths associated with COVID-19, possibly related to thrombotic events.^1,2   

The mechanism of coagulopathy in COVID-19

The sepsis syndrome leads to a massive release of cytokines, including IL-1β, IL-6, and tumor necrosis factor-α (TNFα), with activation of the complement system. Besides the profound inflammatory response, the coagulation cascade is also activated. Furthermore, there is an excess of plasminogen activator inhibitor (PAI-1), resulting in impaired fibrinolysis. All of this leads to clot formation in the microcirculation, leading to organ dysfunction. Typically, the prothrombin and activated partial thromboplastin times are prolonged with low platelet counts; the D-dimer levels are usually normal.

In contrast, CAC is characterized by increased D-dimer levels, with mild thrombocytopenia and minimal prolongation of the prothrombin and activated partial thromboplastin times. The D-dimer levels in COVID-19 may be five times higher than the upper limit of normal.³ In a Chinese study of 1099 patients during the early phase of the pandemic, elevated D-dimer levels were a common finding.⁴ Another study of 183 consecutive patients COVID-19 pneumonia revealed significantly higher mortality in patients with elevated D-dimer levels.⁵ This was corroborated by Zhou et al. who observed a several-fold increase in mortality on multivariable regression analysis among 191 patients who had elevated D-dimer levels (odds ratio:18·42; CI: 2·64-128·55; p=0·0033). The disproportionately high D-dimer levels in COVID-19 probably occur due to enhanced fibrinolytic activity in the lung, induced by the alveolar release of urokinase-type plasminogen activator (U-PA).⁶ Furthermore, viral entry into endothelial cells in the lung may trigger an upsurge of plasminogen activation. Fibrinogen levels may be high during the early phase of COVID-19, probably representing an acute phase response. The ACE-2 receptor in the lung normally maintains the anticoagulant activity of the endothelium; however, when the SARS-CoV-2 virus occupies the receptor, the anticoagulant activity is suppressed. Besides, the tissue factor coagulation pathway is activated, while the protein C mediated anticoagulant pathway is inhibited. Both these mechanisms may lead to an increased incidence of thrombosis within the lung. Autopsy findings have demonstrated widespread thrombosis and microangiopathy in patients with COVID-19 with extensive microthrombi formation in the alveolar capillaries.⁷

Secondary hemophagocytic lymphohistiocytosis  (HLH)

Infection with the SARS-COV-2 virus may lead to secondary HLH due to a massive release of proinflammatory cytokines from activated macrophages and lymphocytes. The activated macrophages and histiocytes cause phagocytosis of red blood cells, leucocytes, and platelets. Hyperferritinemia, one of the cardinal features of HLH if often seen in COVID-19, although the levels are usually lower.⁸ Secondary HLH must be considered when COVID-19 patients deteriorate acutely with unremitting fever, worsening hypoxia, cytopenia, high ferritin, and lactic dehydrogenase levels. Corticosteroids may have an important therapeutic role in this situation.⁹

Thrombotic microangiopathy

Increased levels of Von Willebrand factor (VWF) and factor VIII levels may occur in COVID-19.¹⁰ It is likely that the pathophysiology of severe COVID‐19 infection may be more similar to the phenotype of thrombotic microangiopathies (TMA), in contrast to sepsis‐induced coagulopathy and disseminated intravascular coagulation. The entry of the SARS-CoV-2 virus into endothelial cells may lead to the excessive release of VWF. The multimers of VWF bind to endothelial cells; platelets adhere to VWF resulting in thrombus formation. ADAMTS13 normally cleaves VWF multimers, thus preventing thrombosis. However, in thrombotic microangiopathy, ADAMTS13 levels are disproportionately low, leading to excessive thrombogenesis. A similar type of microangiopathy may occur in other viral infections, including dengue virus infection. 

How often do thrombotic complications occur in COVID-19? 

Klok et al. evaluated the incidence of acute pulmonary embolism, deep-vein thrombosis, acute ischemic stroke, acute myocardial infarction, and systemic arterial embolism among COVID-19 patients in a multicentric study from the Netherlands. The incidence of thrombotic complications was 31% (95% CI: 20–41). The most frequent complication was acute pulmonary embolism (81%); arterial thrombotic occurred in 3.7% of patients (95% CI: 0–8.2%). In this study, the incidence of thrombotic complications was high despite routine thromboprophylaxis with low molecular weight heparin.¹¹

Cui et al. investigated the incidence of venous thromboembolism in 81 patients with COVID-19 admitted to the ICU of Union Hospital in Wuhan, China. Twenty patients (25%) with severe disease developed deep vein thrombosis of the lower limbs. The authors observed that D-dimer levels had high sensitivity and specificity for the prediction of venous thrombosis.¹²

Among 150 patients admitted to 4 ICUs in France, 64 clinically significant thrombotic complications occurred, with pulmonary embolism (16.7%) being the most common. Thrombotic complications were significantly higher in COVID-related acute respiratory distress syndrome (ARDS) compared to non-COVID-related ARDS. It is interesting to note that thrombotic complications occurred although 70% of patients had received prophylactic and 30% of patients, therapeutic anticoagulation.¹³  

A single-center study from the UK corroborate these findings. Sixty-three patients with COVID-19 were included; patients received thromboprophylaxis with dalteparin based on body weight and renal function. Pulmonary embolism occurred in five patients, while two suffered acute myocardial infarction. There was a 27% (95% CI: 10–47%) cumulative incidence of venous thromboembolism and a 4% % (95% CI: 1–12%)  incidence of arterial thrombosis.¹⁴  These studies suggest that there may be a relatively higher incidence of thrombotic complications in COVID-19 compared to other critically ill patients. 

Anticoagulation in COVID-19

Considering the relatively high risk of thrombotic complications, the International Society on Thrombosis and Haemostatis (ISTH) and the American Society of Hematology (ASH) recommend that hospitalized COVID-19 patients should receive thromboprophylaxis. They suggest that therapeutic anticoagulation should be considered if indicated.^15,16 However, it remains unclear if hospitalized patients with severe COVID-19 who deteriorate with worsening hypoxia or hemodynamic instability should be treated empirically with therapeutic anticoagulation. This is particularly important because confirmatory imaging, including CT pulmonary angiogram, may not be feasible in clinically unstable patients, besides the increased risk of transmission of infection during patient transport. The duration of anticoagulant therapy is unknown; however, a prolonged prothrombotic state may occur in these patients. The need for anticoagulant therapy in non-hospitalized patients with restricted mobility and predilection for venous thrombosis also remains unanswered. 

Current recommendations 

The ISTH and ASH recommend that hospitalized patients with COVID-19 infection should receive prophylactic low-molecular weight heparin unless contraindicated (active bleeding or platelet count <25 x 109/L). Low-molecular weight heparin is preferred over unfractionated heparin to reduce patient contact. Fondaparinux is an alternative in case of heparin-induced thrombocytopenia. Mechanical thromboprophylaxis is recommended if pharmacological anticoagulation is contraindicated. The empirical use of therapeutic-level anticoagulation in seriously ill patients with COVID-19 is discouraged.^15,16  

Summary

• Thrombotic complications appear to be common in patients with severe COVID-19 infection; the incidence is higher compared to other critically ill patients
• COVID-19 associated coagulopathy has several distinctive features compared to sepsis-induced coagulopathy and disseminated intravascular coagulation; raised D-dimer levels is a common finding with a mild increase in the prothrombin and activated partial thromboplastin times; severe thrombocytopenia is uncommon
• Bleeding complications appear to be relatively uncommon in COVID-19
• The coagulation profile, including D-dimer levels, should be monitored in patients with severe COVID-19 once in 2–3 days
• There is a strong rationale for the use of prophylactic anticoagulation in all hospitalized patients with COVID-19
• Patients with severe COVID-19 may require higher-dose thromboprophylaxis considering their hypercoagulable state
• The question of empirical, therapeutic anticoagulation in patients who are deteriorating with worsening hypoxia or hemodynamic instability is contentious and requires an individualized approach

References

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2.         Beri A, Kotak K. Cardiac injury, Arrhythmia and Sudden death in a COVID-19 patient. Hear Case Rep. Published online May 13, 2020. doi:10.1016/j.hrcr.2020.05.001

3.         Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care. 2020;24(1):360. doi:10.1186/s13054-020-03077-0

4.         Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. Published online February 28, 2020. doi:10.1056/NEJMoa2002032

5.         Arachchillage DRJ, Laffan M. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(5):1233-1234. doi:10.1111/jth.14820

6.         Gralinski LE, Bankhead A, Jeng S, et al. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio. 2013;4(4). doi:10.1128/mBio.00271-13

7.         Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. Published online 2020:9.

8.         Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet Lond Engl. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0

9.         Horby P, Lim WS, Emberson J, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. Published online June 22, 2020:2020.06.22.20137273. doi:10.1101/2020.06.22.20137273

10.       Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098. doi:10.1007/s00134-020-06062-x

11.       Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-147. doi:10.1016/j.thromres.2020.04.013

12.       Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421-1424. doi:10.1111/jth.14830

13.       Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. Published online May 4, 2020:1-10. doi:10.1007/s00134-020-06062-x

14.       Thomas W, Varley J, Johnston A, et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-77. doi:10.1016/j.thromres.2020.04.028

15.       Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810

16.       COVID-19 and VTE-Anticoagulation – Hematology.org. Accessed July 28, 2020. https://www.hematology.org:443/covid-19/covid-19-and-vte-anticoagulation