Coagulopathy in patients with COVID-19
Coagulation abnormalities and thrombosis in patients with COVID-19
The comment article by Levi et al. in The Lancet Haematology describes characteristics of coagulopathy in patients with COVID-19, discusses the incidence of thromboembolic events and gives recommendations for the management of coagulopathy in patients with severe COVID-19.
Coagulation abnormalities in COVID-19
Many patients with severe COVID-19 present with coagulation abnormalities and a substantial portion of patients develops venous and arterial thromboembolic complications [1,2]. Patients with COVID-19 and coagulopathy often present with an increased D-dimer concentration, a prolongation of prothrombin time, and a modest decrease in platelet count.
Several observational studies have shown an elevated D-dimer concentration in patients with COVID-19. Elevated D-dimer (>0.5 mg/L) was found in 260 (46%) of 560 patients with COVID-19 patients . In another study in 183 COVID-19 patients, a mean D-dimer concentration of 2.12 mg/L (range 0.77-5.27) was observed in non-survivors, compared with a concentration of 0.61 mg/L (0.35-1.29) in survivors . Patients admitted to the ICU had higher median D-dimer concentrations (2.4 mg/L, IQR 0.6-14.4), compared to patients who received no ICU care (0.5 mg/L, 0.3-0.8) . A D-dimer concentration >1 mg/L on admission led to an 18-times higher mortality risk (95%CI 2.6-128.6, P=0.0033) .
A mild prolongation of prothrombin time was observed in patients with severe COVID-19 who died (15.6 s, range 14.4-16.3), compared to patients who survived (13.6s, 13.0-14.3) . When prothrombin time is expressed as international normalized ratio (INR), these small changes might go undetected.
70-95% Of patients with severe COVID-19 present with mild thrombocytopenia (platelet count of <150×10^9 cells/L). However only ~5% of patients show a platelet count <100×10^9 cells/L [3,5]. It is noteworthy that thrombocytopenia in COVID-19 is not considered as an important predictor of disease progression or adverse outcome [2,5].
The combination of elevated D-dimer concentration, prolongation of prothrombin time and thrombocytopenia is suggestive of disseminated intravascular coagulation (DIC). However, the pattern of the low-grade DIC seen in COVID-19 is different from DIC seen in sepsis . In fact, most COVID-19 patients do not have DIC according to the DIC score of the International Society on Thrombosis and Hemostasis [2,4].
Other laboratory findings in patients with COVID-19 that might be relevant for coagulopathy include increased lactate dehydrogenase (LDH), and high ferritin concentrations in some patients . Mean fibrinogen concentrations are at the upper limits of normal. However, a sudden drop in plasma fibrinogen concentrations to <1.0 g/L has been observed shorty before death . Post-mortem findings showed platelet-rich thrombotic depositions in small vessels.
Thrombotic risk in COVID-19
The coagulation abnormalities found in patients with severe COVID-19 suggest the presence of a hypercoagulable state. Presence of a hypercoagulable state, together with immobilization and vascular damage, might increase the risk of thromboembolic complications. Initial cohort studies in patients with COVID-19 have shown a high incidence of thromboembolic complications .
A retrospective study in 449 hospitalized patients with COVID-19-associated coagulopathy showed lower mortality in patients with coagulopathy who received prophylactic heparin, compared to patients not receiving anticoagulant treatment (40 of 99 patients (40%) vs. 224 of 350 patients (64%), P=0.029) in a subgroup of patients with a high sepsis-induced coagulopathy score . However, these results need to be treated with caution, as conclusions in this study were drawn from multiple post-hoc and subgroup analysis, and patients were not randomized to receive heparin treatment. A prospective, randomized controlled trial is needed to investigate the effectiveness of anticoagulant treatment in patients with COVID-19-associated coagulopathy.
Therapeutic management of coagulopathy in patients with severe COVID-19
Levi and colleagues suggest a diagnostic approach with repeated assessment of D-dimer, prothrombin time and platelet counts, every 2-3 days. Furthermore, the authors suggest that all hospitalized patients with COVID-19 should receive prophylactic treatment with low molecular weight heparin (LMWH) in the absence of medical contraindications. If LMWH is not available, unfractionated heparin or fondaparinux can be considered. However, treatment with unfractionated heparin requires more frequent injections, and it is unclear whether fondaparinux has the postulated anti-inflammatory benefits of heparin. Patients with severe COVID-19 might require a higher-dose thromboprophylaxis than is generally given because of their hypercoagulable state. This will be investigated in several multicenter, randomized, controlled trials.
Venous thromboembolism should be part of the differential diagnosis in patients with high D-dimer concentrations and a sudden respiratory deterioration. This should be confirmed by imaging (CT angiography or ultrasound of the venous system of the lower extremities). If diagnostic testing is not possible in patients with a strong suspicion of pulmonary embolism, therapeutic anticoagulation could be considered, particularly in the absence of contraindications and risk factors for bleeding. Other therapeutic interventions (such as administration of other anticoagulants or anti-inflammatory drugs, or plasma exchange) are experimental and should only be considered in a controlled clinical trial setting.