key: cord-0819376-s0akex11
authors: Levi, Marcel
title: COVID-19 coagulopathy vs disseminated intravascular coagulation
date: 2020-06-23
journal: Blood Adv
DOI: 10.1182/bloodadvances.2020002197
sha: 1dc91583ef35be08fd861dc5512e23bf043886ab
doc_id: 819376
cord_uid: s0akex11

nan

In this talk I will discuss the coagulation changes seen in patients with COVID-19 infection and discuss similarities and differences between this coagulopathy and the DIC usually seen in critically ill patients with severe infections. In addition I will briefly review common features but also distinct differences with thrombotic microangiopathies that can complicate infections. Also, the clinical relevance of the COVID-19-associated changes in coagulation, both in terms of its relationship with clinical outcome and its association with the occurrence of thromboembolic events will be discussed. Lastly, I will briefly review the current prophylactic and therapeutic strategies that are used in patients with COVID-19 infection and coagulation abnormalities.

The most striking coagulation test abnormality in severe COVID-19 patients is an abnormally high D-dimer level. [1] [2] [3] [4] In several series of patients with COVID-19, markedly increased Ddimer levels were observed in almost 50% of patients. Also, patients with D-dimer levels more than 6-fold the upper limit of normal were found to have an increased need for mechanical ventilation and a significantly higher risk of death. Another marker of inflammation and thrombotic risk is fibrinogen. Mean fibrinogen plasma concentration in COVID-19 patients are usually very high, which is likely due to an acute phase response. However, a swift drop in plasma fibrinogen to concentrations below <1.0 g/L was demonstrated in a small number of the most severe COVID-19 patients in China, shortly before they died. 3 Another coagulation abnormality that is seen in the most severe patients is a relatively mild thrombocytopenia. 5,6 Most of these patients have a platelet count between 100 and 150x10 9 /L and lower platelet counts are rarely (<5%) seen. In contrast to thrombocytopenia associated with other infections including viral disease and bacterial sepsis, a low platelet count in COVID-19 has not been significantly associated with an adverse outcome (although very low platelet counts can be an exception). The prothrombin time (PT) in patients with the most severe COVID-19 infection is only mildly prolonged (approximately 3 seconds), indicating near-normal levels of coagulation factors. 3, 7 Prolongation of the activated partial thromboplastin time (aPTT) is less clear and might be obscured by (very) high levels of factor VIII and fibrinogen that instead sometimes leads to shortening of the aPTT. Plasma levels of protease inhibitor such as protein C and antithrombin are slightly decreased, in particular in the non-surviving patients, but plasma concentrations seldom fall below 80% of normal values. 8

The question is whether these changes reflect disseminated intravascular coagulation (or DIC). The combination of increased D-dimer, thrombocytopenia, and prolonged global coagulation tests mimics the pattern seen in DIC. However, there seem to be distinct differences from DIC commonly seen in patients with sepsis, cancer, or other underlying conditions known to be associated with DIC. 9 First, in most cases with DIC complicating a serious systemic condition a more profound thrombocytopenia is observed. Also, these patients usually have much lower levels of coagulation factors (in particular factors II, V, VII and X) and severely decreased plasma concentrations of physiological anticoagulants, such as antithrombin and protein C. 10 One of the pathogenetic hallmarks of DIC is dysregulated thrombin generation, usually as a result of tissue factor expression on mononuclear and possibly endothelial cells induced by proinflammatory cytokines, most prominently interleukin (IL)-6. 11 Of note, IL-6 levels are 7 times higher in COVID-19 compared to patients with severe bacterial sepsis). 12 Whilst IL-6 and other pro-inflammatory cytokines were shown to be extremely elevated in severe COVID-19 infection there is not yet definitive proof of excessive thrombin generation in these patients. Observations with a thrombin generation test and assessment of markers for prothrombin to thrombin activation (F1+2) and thrombin-antithrombin complexes would be helpful in obtaining further insight into this issue. In view of the coagulation test results, most patients with COVID-19 would not reach a score sufficiently high to be diagnosed with overt DIC according to the DIC score of the International Society on Thrombosis and Haemostasis. 9 The clinical presentation of the COVID-19 coagulopathy is mostly prothrombotic, with a high incidence of overt venous (and possibly arterial) thromboembolism, and patients do not have many hemorrhagic complications, which is no surprise in the absence of a real consumption coagulopathy. 8, 13 Taken together it might be fair to conclude that the coagulopathy of COVID-19 should be classified as a specific form of prothrombotic intravascular coagulation which is distinctly different from DIC commonly seen in other conditions and may need new diagnostic criteria.

Some features of the coagulation changes in COVID-19 are also reminiscent of thrombotic microangiopathy. 14 Post-mortem histopathology reports indicate the presence of microvascular platelet-rich thrombi, in particular in the lung microvasculature, reminiscent of what is seen in cases of localised thrombotic microangiopathy. 15 Some other laboratory abnormalities in severe COVID-19 that are also often seen in patients with thrombotic microangiopathy are an increased LDH and a strikingly high ferritin level, in particular in patients with the most severe organ dysfunction. Thrombotic microangiopathy is a result of increased platelet adhesion to the vascular endothelium in association with platelet aggregation and activation causing consumptive thrombocytopenia. The resultant platelet thrombi in the microvasculature cause impaired organ function and classically contribute to complications such as renal insufficiency or neurological disease as well as microangiopathic hemolysis. Post-mortem histopathology, however, has not shown a lot of evidence for microvascular platelet-rich thrombi in other organs. 15 In addition, overt intravascular hemolysis and severe thrombocytopenia, as seen in typical cases of thrombocytopenic thrombotic purpura (TTP), is also not a clinical feature of COVID-19 infection. Taken together, there is evidence of a localised thrombotic microangiopathy as evidenced by microvascular thrombosis in COVID-19-affected lungs but there is no strong evidence for a systemic thrombotic microangiopathy.

One of the mechanisms that distinguishes a COVID-19 infection from other coagulopathies commonly seen in patients with severe infection is the direct infection and resulting injury of endothelial cells by the virus. 16 This results in a massive release of endothelial cell constituents, such as von Willebrand factor multimers, but also plasminogen activators. The release of both tissue-type plasminogen activator and urokinase-type plasminogen activator result in enhanced plasmin generation and may explain the excessively increased D-dimer levels. However, there may be other effects as well. Coronavirus infections seem to be associated with a typical activation of the fibrinolytic system. 17 Experiments in urokinase knock-out mice indicated that the urokinase-driven pathway was an important mediator of lethality. 18 A mechanism could be that plasmin-mediated effects on the metalloproteinase system may result in changes in extracellular matrix facilitating capillary leakage and pulmonary edema. There is a strong connection between bronchoalveolar coagulation and fibrinolysis and the pathogenesis of acute respiratory distress syndrome (ARDS), in which enhanced intrapulmonary fibrin deposition due to abnormal broncho-alveolar fibrin turnover is a crucial factor. 19 Measurement of coagulation and fibrinolysis factors in bronchoalveolar fluid have demonstrated that enhanced intrapulmonary thrombin generation, insufficiently balanced by physiological anticoagulant factors and endogenous fibrinolysis is mediating this pathogenetic pathway.

The coagulation changes associated with COVID-19 infection point in the direction of a hypercoagulable state that may at least cause an enhanced risk of thromboembolic complications. 8, 13 There are several reports of patients with COVID-19 infections with documented pulmonary embolism indicating that there may be a disproportionately high incidence of venous thromboembolism and possibly arterial thrombosis in COVID-19 patients. 13, 20, 21 In critically ill medical patients the incidence of thromboembolic complications ranges between 5-15%. The precise incidence of thromboembolic complications in COVID-19 patients is not known. It has been suggested that in some patients with a rapid respiratory deterioration pulmonary embolism may be involved but for practical reasons it is not always possible to perform adequate objective diagnostic testing, e.g. by CT-angiography. In a Chinese retrospective study in 449 patients that were admitted to hospital with severe COVID-19 infection mortality in patients with COVID-19-associated coagulopathy who received prophylactic heparin was 40% compared to 64% in patients not receiving anticoagulant treatment. In particular in patients with higher levels of D-dimer ( in particular more than 6 times the upper limit of normal) mortality was lower in heparin-treated patients. 8 There is evidence supporting the use of prophylactic dose low-molecular-weight (LMW) heparin as prophylaxis for venous thromboembolism in critically ill medical patients. 22 In view of the hypercoagulable state of severe COVID-19 patients and the possibly increased risk of thrombosis, we suggest that all patients with COVID-19 that are admitted to the hospital should receive this prophylactic treatment. It may be hypothesized that severe COVID-19 patients should receive higher dose thromboprophylaxis because of their hypercoagulable state and this should be further investigated in randomized controlled trials. Preliminary observations suggest that in patients with high D-dimer levels and a sudden deterioration of respiratory insufficiency pulmonary embolism should be part of the differential diagnosis. Preferably, this diagnosis should be confirmed by imaging, although this may not always be feasible. Alternatively, venous ultrasound of the legs can be helpful to identify lower extremity thrombosis. In those patients with a strong suspicion of pulmonary embolism in whom no objective diagnosis can be obtained, it may be considered to start therapeutic anticoagulation, in particular if there are no risk factors for bleeding. Of note, the incidence of hemorrhagic complications in COVID-19 patients, even those with severe coagulopathy, appear to be low.

In conclusion, severe COVID-19 infection is associated with coagulation abnormalities that include elements reminiscent of both DIC and thrombotic microangiopathy. However, this coronavirus infection seems to cause a specific coagulopathy that is more localised and distinctly different from 'classical' DIC or thrombotic microangiopathy syndromes. The specific coagulopathic features of this disease are likely relevant in view of the high incidence of thromboembolic complications in severely affected patients and may present an important point of impact for preventive or therapeutic management strategies to improve clinical outcome.

Marcel Levi has done the literature review and has written this paper

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis

Platelets in Coronavirus Disease

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

How I treat disseminated intravascular coagulation

Disseminated intravascular coagulation

Bidirectional relation between inflammation and coagulation

Elevated Interleukin-6 and Severe COVID-19: A Meta analysis

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Syndromes of thrombotic microangiopathy

Vander Heide RS. Pulmonary and cardiac pathologyin Covid-19:The first autopsy series from New Orleans

Endothelial cell infection and endotheliitis in COVID-19

Elevated plasma tissue-type plasminogen activator (t-PA) and soluble thrombomodulin in patients suffering from severe acute respiratory syndrome (SARS) as a possible index for prognosis and treatment strategy

Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury

Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome

Acute pulmonary embolism and COVID-19 pneumonia: a random association?

COVID-19 Complicated by Acute Pulmonary Embolism

Venous thromboembolism prophylaxis in critically ill patients

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