Micro- and macrothrombosis as key complications of COVID-19
As a COVID-19 infection is often associated with coagulopathy, Dr. Anna Falanga systematically described the pathogenesis of COVID-19 associated hypercoagulation and vascular complications. The severe inflammatory state secondary to the infection can lead to a profound derangement of the haemostatic system and needs to be managed carefully. Therefore, Falanga also described an algorithm for the management of coagulopathy in COVID-19 patients based on simple laboratory markers.
In addition to the pneumonia that often comes with a COVID-19 infection, the cardiovascular system is also affected by the viral infection and causes an increased risk of clinical complications such as myocarditis, acute myocardial infarction, heart failure, cerebrovascular events and venous thromboembolisms. As such, coagulopathy is common in patients with COVID-19 and the most common pattern of coagulopathy observed in these patients includes elevations in D-dimer and fibrinogen levels, which correlate with a parallel rise in markers of inflammation (e.g. CRP and IL-6). As recently reviewed, there is a clear association between markers of thrombosis and haemostasis and clinical outcomes in patients with elevated D-dimer levels are associated with more severe COVID-19 infections and intensive care unit hospitalisations.
Pathogenesis of COVID-19 associated hypercoagulation and vascular complications
The severe inflammatory state secondary to the COVID-19 infection leads to a profound derangement of the haemostatic system, not to mention other relevant contributing factors such as immobilisation, hospitalisation and individual cardiovascular risk factors. First of all, in the most critical cases of a SARS-CoV-2 infection, an excessive and aberrant hyper-inflammatory host immune response is induced that is associated with a so-called ‘cytokine storm’. In addition to shock and tissue damage in the heart, liver, and kidneys and a massive infiltration of neutrophils and macrophages into the lungs, these inflammatory cytokines can also activate blood clotting. The activation of the vascular endothelium, platelets and leukocytes results in dysregulated thrombin generation that occurs both systemically and locally in the lungs of patients with severe pneumonia, causing the deposition of fibrin with subsequent tissue damage and microangiopathic pathology. Secondly, SARS-CoV-2 uses the angiotensin converting enzyme receptor (ACE2) expressed by pneumocytes of the epithelial alveolar lining to infect host cells, thus causing lung injury. The ACE2 receptor is also widely expressed on endothelial cells, which cross multiple organs and can potentially explain the multi-organ lesions observed after a SARS-CoV-2 infection. The recruitment of immune cells can cause systemic endothelial dysfunction that, at its turn, is a main determinant of microvascular dysfunction by moving the vascular balance towards greater vasoconstriction with subsequent organ ischemia and inflammation wit associated tissue oedema and a pro-coagulant state.
From a clinical perspective, the extent of the derangement in coagulation parameters in patients affected by severe COVID-19 pneumonia has been associated with a poor prognosis. In these patients, low molecular weight heparin (LMWH) at doses registered for the prevention of venous thromboembolism (VTE), has been shown to be associated with a reduced risk of death and is currently recommended by the World Health Organisation. Data on the incidence of VTE in COVID-19 range from 0% to about 8% in general wards, and from 16% to 35% in the intensive care unit setting, often despite adequate LMWH prophylaxis. Finally, post-mortem analyses of a series of COVID-19 cases from Northern Italy indicated that platelet-fibrin thrombi were detected in 33 out of 38 patients that died from COVID-19. The presence of these platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy and should be one of the main targets of therapy.
Algorithm for the management of coagulopathy in COVID-19 based on simple laboratory markers
Coagulation markers suggested to be checked at hospital admission are D-dimers, the prothrombin time and serum fibrinogen. For the management of coagulopathy in COVID-19 positive patients, a prophylactic dose of LMWH should be considered in all patients, including the non-critically ill. The only exception to this rule are patients with active bleeding and a platelet count below 25 x 109/L or those patients with severe renal impairment. As always, treating the underlying condition is paramount. Bleeding is infrequent in COVID-19 patients, despite abnormal coagulation parameters. Supportive care with blood component transfusion should not be given on the basis of laboratory results and should be reserved for patients with active bleeding, requiring an invasive procedure or otherwise at high risk for bleeding complications. Traditional risk factors for bleeding also apply to COVID-19 patients. In patients who are not bleeding, replacement might worsen disseminated thrombosis. In patients who actively bleed, platelets should be transfused if the platelet count is < 50 x 109/L, plasma (4 units) should be administered if the INR is above 1.8 and fibrinogen concentrate (4 grams) or cryoprecipitation should be offered if the fibrinogen level is < 1.5 g/L. For patients with severe coagulopathy and bleeding, 4F-PCC (e.g. 25 units/kg) should be considered instead of plasma because of the lower volume that has to be administered. The haemostatic effectiveness of tranexamic acid is unknown.
Conclusions
In patients with COVID-19, the coagulopathy features support the occurrence of hypercoagulability together with a severe inflammatory state. This hypercoagulability is caused by different mechanisms, predominantly by the innate immune response but a direct effect of SARS-CoV-2 on the endothelium can also play an important role. A better understanding of COVID-19 related thrombotic risk will help to optimize diagnostic strategies and guide the design and conduction of randomised controlled trials on thrombosis prevention.
Reference
Falanga A. Micro- and macrothrombosis - key complications of COVID-19. Presented at EHA 2020; Oral presentation pq283-1.
