The novelty of COVID-19 is slowly fading as more studies are exploring the etiologies of this deadly virus. It is well known now that the mortality of this pathogen is rooted in hypoxemia due to the initiation and exacerbation of acute respiratory distress syndrome (ARDS). However, increasing amount of studies are suggesting an accompanying contribution of thromboembolic events [5,6]. Also, venous thromboembolism has been demonstrated on both microvascular and macrovascular scales in published post-partum studies in COVID-19 patients . The pathophysiology of this is still very much under investigation but various hypotheses have touched upon the possibility of the immuno-thrombotic phenomeno . McGonagle et al. suggests that the binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) ultimately leads to a generalized pulmonary hypercoagulable state due to activation of type II pneumocytes propagating an inflammatory cascade [8,9]. The subsequent cytokine storm leads to diffuse alveolar damage and immunostimulatory molecules invading microvasculature, thus leading to the phenomenon of immuno-thrombosis. A novel hypothesis by Hong-Long Ji et al. suggested that plasmin might be responsible for cleaving the furin sites of spike “S” proteins of SARS-CoV-2, which would then increase the infectivity of respiratory cells by the virus . This would suggest, in theory, that disease severity can be measured via plasmin, plasminogen, and D-dimer levels, thus opening the possibility of utilizing antiplasmin compounds as a potential mode of therapy .
Moreover, the case reports above highlight some of the pathological findings that might arise as a result of a direct COVID-19 infection. Based on the reported findings, it is appropriate to suggest that there is a direct or an indirect correlation between COVID-19 and the development of coagulopathies. Next, one of our seven patients suffered an ischemic brain stroke and developed a prothrombotic state secondary to COVID-19 infection. Whereas patients most placed on prophylactic thrombolytics achieved a positive outcome with reduced risk of thromboembolic complications. Although there are limited data available to inform clinical management surrounding prophylactic use of thrombolytics in COVID-19 patients, many hospitals began implementing it, due to the increased risk for venous and arterial thrombosis of large and small vessels . Therefore, understanding the pathophysiology, the coagulation cascade is a critical and fundamental part of appropriate therapeutic development and management for patients with COVID-19. The coagulation cascade is the physiological activation of a series of clotting factors that leads to secondary hemostasis, a physiological process that rapidly prevents and stops spontaneous bleeding at the site of injury. This pathway comprises of two independent paths, intrinsic and extrinsic, that converge at a common point known as the common pathway, which serves to ultimately convert fibrinogen to fibrin, a necessary clotting factor to stabilize the platelet plug formed during primary hemostasis in order stop bleeding.
In addition to the coagulation promoting factors that exist in the blood stream, there are also inhibitory substances which downregulate coagulation. For example, Protein C and S act to prevent coagulation, mainly by inactivating factors V and VIII, respectively. Moreover, thrombin (factor II), a procoagulant serves as a negative feedback by activating plasminogen to plasmin and stimulating the production of antithrombin (AT). Plasmin acts directly on the fibrin mesh and breaks it down. AT decreases the production of thrombin from prothrombin and decreases the amount of activated factor X.
Normal hemostasis strikes a balance between the pro-coagulant system (platelets and coagulation cascade) that is responsible for clot formation and the anticoagulant system, responsible for breaking down clots. If hemostatic dysregulation occurs due to a defect in one of these systems, then either thrombosis or excessive bleeding may occur especially in the perioperative or during critical illness period. Therefore, a balance between clot formation and fibrinolysis activation are essential to limiting detrimental extension of vessel clotting.
Many varieties of microorganisms have been shown to directly activate the blood coagulation system and component of the blood hemostatic systems involved in the immune response and immune system modulations. It has been hypothesized that the direct activation of coagulation is a beneficial response that aids in limiting pathogen dissemination, augmenting innate and adaptive immunity, and repair of damaged tissues. Generally, components of viral pathogens directly activate the coagulation cascade either by increased levels of clotting factors (e.g., factor VIII, factor XI), soluble tissue factor, and von Willebrand factor or a decrease levels of the anticoagulants, protein C, protein S, antithrombin, and tissue factor pathway inhibitor. Other markers that may indicate activation include increased thrombin generation, platelet activation, fibrin degradation and fibrinolysis (e.g., D-dimer and plasmin-a2-antiplasmin complexes). Although the main function of thrombin is to promote clot formation by activating platelets and by converting fibrinogen to fibrin, thrombin also exerts multiple cellular effects and can further augment inflammation via proteinase-activated receptors (PARs), principally PAR-1, the main thrombin receptor that mediates thrombin-induced platelet aggregation as well as the interplay between coagulation, inflammatory, and fibrotic responses. All of which are important aspects of the pathophysiology of fibroproliferative lung disease, such as seen in COVID-19.
Viral infections likely drove evolution to activate this coagulation cascade as a host defense mechanism in order to limit spread of the pathogen. Unfortunately, acute viral infections can also overstimulate this cascade during an immune response leading to multiple negative consequences such as micro-thrombosis, disseminated intravascular coagulation (DIC), subsequent hemorrhage, and ultimately multiorgan failure and mortality-- evidenced in severe COVID-19 pneumonia with raised d-dimer concentrations being a poor prognostic feature and DIC being commonplace in non-survivors.
Tissue factor (TF) plays a major role in the activation of the coagulation cascade during viral infection by several different mechanisms as observed in different viruses. Firstly, TF expression is increased in endothelial cells infected with human simplex virus (HSV) and Dengue virus . Secondly, Ebola virus infection induces TF expression in lymphoid macrophages and circulating blood cells, which is associated with Ebola associated hemorrhagic fever . Thirdly, the toll like receptor 3 (TLR3) - the host’s apparatus for recognizing viral DNA, induces TF expression in cultured endothelial cells and activates the coagulation system in mice. In a rhesus monkey model of Ebola virus hemorrhagic fever, direct inhibition TF expression was observed to reduce the cytokine storm and mortality - further evidence that TF plays such a pivotal role in viral activation of the coagulation cascade .
Following the inflammatory immuno-thrombosis model, Rico-Mesa et al. suggests the use of heparin not only as an anticoagulant but concurrently as an anti-inflammatory as well. This two-pronged approach shows promise in terms of halting the reciprocal relationship between coagulation and the immune system . Reducing thrombin generation, in theory, should lessen the intensity of the inflammatory response to COVID-19, and subsequently the resulting ARDS. A recent meta-analysis displayed that supplementing disease management with LMWH within 7 days of initial onset of the disease decreased the risk of 7-day mortality by 48% . By no means does this mean the end of COVID-19 but such studies and tested hypotheses seem to be pointing us in the right direction.
Furthermore, anticoagulation therapy has been used in our institutions due to the increased risk of thromboembolic events. Anticoagulation therapy is commonly prescribed to patients with conditions such as atrial fibrillation, deep vein thrombosis (DVT), hip or knee replacement surgery, ischemic stroke, myocardial infarction (MI), pulmonary embolism (PE), and unstable angina in an attempt to decrease the risk of thromboembolic events . Anticoagulation medications are also given to patients with extended hospitalization to prevent the risk of DVT and its concomitant progression to PE. Therapy is based on the comorbid condition and is targeted to prevent the progression of disease. However, the therapy is not without inherent risks, and each medication is unique in its adverse effects. Anticoagulation medications are divided into classes based on the target and mechanism of action .
There are 4 classes of anticoagulants:
- The indirect thrombin and Factor XA inhibitors (Heparins & Heparinoids)
- Vitamin K antagonists (Coumadin, 1,3 indandiones, and Tioclomarol)
- Direct thrombin inhibitors (Univalent & Bivalent)
- Direct factor XA inhibitors
Indirect thrombin and factor XA inhibitors
These medications include unfractionated heparin (Fragmin), low-molecular-weight heparins (Lovenox), and Fondaparinux (Arixtra). Heparin has a distinct mechanism of action where antithrombin III inhibits clotting factor proteases such as thrombin, factors IXA and XA, but it does so in a relatively slow manner. Heparin acts as a cofactor for the antithrombin-protease reaction where it binds to antithrombin III and accelerates the inhibition of those factors. Heparin is an injectable, rapidly acting anticoagulant, used to interfere with the formation of thrombi. The unfractionated and low molecular weight heparin (LMWH) are a mixture of straight chain sulfated mucopolysaccharides which are normally isolated from bovine lung or porcine intestinal mucosa. LMWH inhibits factor XA with high affinity but inhibits thrombin with a lesser affinity, while unfractionated heparin (UFH) inactivates thrombin and factor XA with the same affinity. LMWH has equal efficacy to UFH but has higher bioavailability with a longer half-life and less frequent dosing which is a common reason to replace UFH in clinical practice. Heparin levels can be monitored by performing the activated partial thromboplastin time (aPTT) assay which is a test for the intrinsic and common pathways of coagulation. When a patient is administered LMWH, the dosing is predictable in plasma levels and it is not necessary to measure LMWH blood levels. Heparin is used in DVT, PE, MI, and is the drug of choice during pregnancy. Adverse reactions include bleeding, hypersensitivity reactions, and the most dangerous being Heparin-induced thrombocytopenia (HIT). The risk of HIT is lower with LMWH than with heparin and minimal with fondaparinux4. Excessive anticoagulation is treated by discontinuing heparin, if bleeding occurs, protamine sulfate is administered.
Heparin Induced Thrombocytopenia (HIT)
When a patient is administered heparin, antibodies can recognize various complexes of heparin and platelet factor 4 (PF4) leading to the formation of a complex between the two. IgG binds to heparin/PF4 and forms an immune complex which can bind to the FC receptor on the surface of platelets leading to their activation, degranulation and aggregation . The activated platelets release more PF4 which can bind more heparin and lead to a vicious cycle causing thrombocytopenia and thrombosis. The treatment of choice for HIT is to discontinue heparin and administer a direct thrombin inhibitor such as argatroban or fondaparinux.
Vitamin K Antagonists
Vitamin K is involved in the coagulation cascade and it activates factors II, VII, IX, X, protein C, and protein S. Vitamin K antagonists such as warfarin (Coumadin) inhibit vitamin K epoxide reductase inhibiting the function of vitamin K, leading to inactivation of the clotting factors due to the lack of Y-carboxyglutamyl side chains. Anticoagulation with warfarin takes several hours as the coagulation factors involved have half-life’s ranging from 6- 60 hours, thus the anticoagulation effect becoming apparent within 24 hours of warfarin administration and peaking within 72 - 96 hours. In reciprocation, this also means that reversal of warfarin takes approximately 24 hours to become apparent. Warfarin also has a narrow therapeutic index, and it can have many drug-drug interactions so it must be regularly monitored. Monitoring warfarin is done by measuring the prothrombin time (PT) which tests the function of the extrinsic and common pathways in the coagulation cascade. Warfarin is used in the prevention and treatment of DVT and PE following an initial dose of heparin. Adverse effects of warfarin include hemorrhage and necrosis of the skin due to reduced activity of protein C. It is also contraindicated during pregnancy because it can cross the placenta and lead to hemorrhagic disorders and other birth defects in the fetus .
Direct thrombin inhibitors
Direct thrombin Inhibitors (DTIs) are a class of anticoagulants that directly inhibit thrombin and prolong clotting. They are mainly used in HIT and acute coronary syndrome. DTIs are classified as either univalent or bivalent according to the binding site on thrombin  The bivalent DTIs include bivalirudin (Angiomax), desirudin (Iprivask), and lepirudin (Refludan). They bind to the active as well as the exo-site 1 of thrombin. The Univalent medications include argatroban, dabigatran (Pradaxa), delagatran (Exanta), and ximelagatran (Exarta), and they only bind to the active site of thrombin. Bivalirudin is enzymatically eliminated and is safest to use in the presence of both hepatic and renal dysfunction . Lepirudin is metabolized mainly by the kidneys and the dose is adjusted in patients with renal dysfunction . Argatroban is mainly metabolized by the liver so it is not recommended in patients with hepatic dysfunction. It is used during percutaneous coronary intervention (PCI) in patients with or at risk of HIT . Dabigatran (also called dabigatran etexilate) is absorbed and converted to an active metabolite in the liver, it is used in the prevention of stroke in patients with non-valvular atrial fibrillation and routine laboratory monitoring is not recommended . Monitoring the therapeutic efficacy of DTIs is done via measuring aPTT but it is nonspecific as those agents are relatively new and there has been an increased focus on developing laboratory tests to measure DTI levels in the blood .
Direct factor XA inhibitors
Direct factor XA inhibitors include apixaban (Eliquis) and rivaroxaban (Xarelto). They are oral medications that have similar antithrombotic efficacy to warfarin and lower bleeding rates. They have a rapid onset of action, wider therapeutic window, fewer drug-drug interactions, and no monitoring requirements making them an ideal alternative to warfarin when used in the prevention and treatment of venous thromboembolism as well as pulmonary embolism.