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| Mechanisms of coagulation and thrombosis in COVID-19 |
Over the past eight months it has become increasingly clear that COVID-19 is characterized by hypercoagulation and thromboinflammation. The pathogen SARS-CoV-2 itself, the innate host immunity response, haemostatic factors, the Renin-Angiotensin-Aldosterone System (RAS/RAAS) and the complement system are wired up to evoke a procoagulant, thromboinflammatory state in COVID-19 affected patients. The mechanisms enhance thromboinflammation and reduce fibrinolysis (the breakdown of clots).
A few reports indicate that the hypercoagulant state in COVID-19 remains, in spite of thromboprophylaxis. In an early report, Deep Venous Thrombosis (DVT) was observed among non-Intensive Care Unit patients receiving thromboprophylaxis with either enoxaparin or fondaparinux (Incidence of deep vein thrombosis among non-ICU patients for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis 2020;18:2358-2363).
Another, more recent study reports ongoing activation of coagulation and fibrinolysis despite low therapeutic anticoagulation in COVID-19 patients. Hypofibrinolytic states (impairment of the breakdown of fibrin clots) occur, even in the presence of Low Molecular Weight Heparin (LMWH). It is hypothesized that low therapeutic anticoagulant therapies are insufficient to downregulate coagulation activation in COVID-19 (In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis 2020;18:2646-2653).
Keeping it simple: is it just the case that prophylaxis at hospital admission is too late?
One key factor, a major factor, might be explanatory for ongoing thromboinflammation, the occurrence of Deep Venous Thrombosis (even after hospital discharge) and hypercoagulation in spite of prophylaxis: time.
I hypothesize that the administration of thromboprophylaxis might be too late to curb already ongoing thrombotic activity in the vasculature, as thromboprophylaxis is received at the time of hospital admission, which is a main of 4 to 5 days after SARS-CoV-2 infection. If thromboinflammation occurs before or a few days from the onset of symptoms, thromboprophylaxis fails to break down fibrin accumulation and stabilized fibrin structures in the microvasculature. Markedly, a study involving 107 SARS-CoV-2 infected patients, chronic use of anticoagulation is associated with decreased thrombotic complications typical for COVID-19. Only 17 out of 107 chronically anticoagulated patients required Intensive Care (Chronic therapeutic anticoagulation is associated with decreased thrombotic complications in SARS-CoV-2 infection, Journal of Thrombosis and Haemostasis Vol. 18, Issue 10, October 2020, p2640-2645).
Nevertheless, questions on timing of thromboprophlaxis and therapeutic options for non-chronic anticoagulated COVID-19 remain to addressed. This is further complicated by a recent finding.
Pathogenesis of SARS-CoV-2: how this coronavirus impairs anticoagulation therapies
A recent finding is that the S-protein (spike) of SARS-CoV-2 binds heparin and heparan sulfate (Characterization of heparin and SARS-CoV-2 spike glycoprotein binding interactions, Antiviral Research Vol. 181, September 2020, 104873), which explains why heparin prophylaxis according to standard-dose LMWH or Unfractioned Heparin (UFH) is insufficient to reduce thrombotic activity in COVID-19 patients. The effect of nebulized heparin is under investigation.
A key role for hypoxia?
There are several topics to address. The timing and dose of anticoagulation therapies or thromboprophylaxis are essential, but mechanisms underlying thromboinflammation might offer insight into the presumed ongoing procoagulant state in COVID-19. Hypoxia and Hypoxia-inducible transcription factors (HIF) are a possible link between viral sepsis and thrombosis (Hypoxia and HIF activation as a possible link between sepsis and thrombosis, Thrombosis Journal 2019; 17: 16). The need for research of hypoxia as a trigger for thrombosis is expressed (Hypoxia- an overlooked trigger for thrombosis in COVID-19 and other critically ill patients, Journal of Thrombosis and Haemostasis, 29 July 2020; Incidence of Deep Vein Thrombosis among non-ICU Patients Hospitalized for COVID-19 Despite Pharmacological Prophylaxis: Response).
Making the shift towards more distinctive parameters to assess hypercoagulation: urokinase markers
Shifting towards distinctive parameters is recommended to provide more therapeutic targets. The urokinase pathway offers specific markers to assess the fibrinolytic state of a patient. PAP (plasmin-antiplasmin) and TAT (thrombin-antithrombin) as well as tPAI-C (tissue plasminogen activator-plasminogen activator inhibitor 1 complex) are the suggested specific markers to improve anticoagulation practice (Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant, Journal of Thrombosis and Haemostasis, 25 June 2020).
Noteworthy, an article published in ASH Blood from 1 May 1998 reviews the role of hypoxia in stimulating the urokinase-type plasminogen activator (uPAR) receptor, thereby enhancing cellular invasion (Hypoxia Stimulates Urokinase Receptor Expression Through a Heme Protein-Dependent Pathway, ASH Blood (1998) 91 (9):3300-3307).
