May 302020
 

Jon-Emile S. Kenny MD [@heart_lung]

Knavery and flattery are blood relations.

-Abraham Lincoln

Background

SARS-CoV-2 is a positive-sense, single-stranded RNA virus with spiked surface glycoproteins  emanating from its viral envelope.  It is a member of the Coronaviridae family, similar to the first SARS [SARS-CoV] and the Middle East Respiratory Syndrome [MERS].  SARS-CoV-2 preferentially targets respiratory epithelium, entering host cells via angiotensin-converting enzyme 2 [ACE2]; a modus operandi comparable to the first SARS [SARS-CoV].  However, SARS-CoV-2 may also invade host cells via CD147.  Of interest, CD147 has also been identified as a red blood cell receptor for the parasite Plasmodium Falciparum and a vascular receptor for N. meningitidis.

Though much remains to be learned about COVID-19, the disease caused by SARS-CoV-2, the  virus itself is not inherently a procoagulant.  Accordingly, the coagulopathy associated with COVID-19 [CAC] is presumably of multifactorial genesis.  This brief synopsis is meant to lightly summarize basic pathophysiology, empirical evidence and therapeutic contemplations.

A Few Words on Hemostasis 

Primary hemostasis is the activation and deposition of platelets upon the subendothelial space.  Primarily, this is driven by GPIbα on the platelet surface binding to immobilized von Willebrand Factor [VWF] as well as GPVI binding to exposed collagen in the subendothelial layer following injury.  The ultimate result is platelet aggregation and plug formation.

Secondary hemostasis leads to fibrin mesh formation in response to tissue damage. It is the result of cascading serine proteases acting ultimately to activate prothrombin to thrombin.  Thrombin then converts fibrinogen to fibrin which cross-links into a reparative protein lattice.

Initiation of secondary hemostasis is traditionally parsed into the 1. the extrinsic and 2. ‘intrinsic’ or ‘contact’ pathways.  The extrinsic route begins with uncovered tissue factor [TF], a transmembrane protein present on fibroblasts and other extravascular tissues [though there are additional sources].  By contrast, the ‘intrinsic’ and the kallikrein–kinin system, collectively referred to as the ‘plasma contact system’, generate enzymatic activity on the surface of platelets, damaged cells, and invading pathogens.  In some ways, the contact system acts as a positive feedback loop for the coagulation cascade.

Virchow’s Triad in COVID-19

Obligatory in every review of thrombosis is a reminder of Virchow’s Triad: 1. venous stasis, 2. endothelial injury and 3. hypercoagulability.  All severely-ill patients in the intensive care unit are at risk for venous stasis from immobility.  The loss muscular contraction in the extremities [e.g. during walking, moving about] denies the venous valves pulsatile emptying and this enhances venous thrombosis upon valve cusps.

However, endothelial injury may also plague COVID-19 patients.  SARS-CoV2 binds to the endothelial cells via angiotensin 2 receptors – ostensibly a mechanism by which blood vessels are injured and thrombogenicity enhanced.  In other words, viral replication summons inflammatory cells, triggers endothelial apoptosis and exposes the prothrombotic underbelly of the microvasculature.  Further, inflammatory cytokines themselves can activate endothelial cells and advance endothelial injury.

Last and certainly not the least of Virchow’s infamous triad is hypercoagulability.  The processes by which the coagulation cascade is amplified in COVID-19 are plentiful and overlap with other inflammatory invectives in the ICU.  Typically, the ‘nexus’ of inflammation and secondary hemostasis lies with tissue factor.  A multitude of pathogen epitopes are recognized by toll-like receptors which, in turn effect tissue factor and stimulate the extrinsic pathway.  In other words, pathogen-associated molecular patterns [PAMPs] spark the coagulation cascade in sepsis and these processes have been generally coined ‘thrombo-inflammation’ or ‘immuno-thrombosis’.  But the contact pathway can also be stimulated by pathogens.  For example, polyphosphates from microbiological invaders activate factor XII in the contact pathway of coagulation.

In addition to direct stimulation of the coagulation cascade, COVID-19 may do so indirectly via activation of the complement system, elaboration of lupus anticoagulant and via hypoxemia itself. Recall that the complement cascade stimulates tissue factor and platelet activation.  Specifically, murine models of coronavirus infections [i.e. SARS and MERS], have demonstrated biochemical markers congruent with complement activation.  Further, lupus anticoagulant has been identified in SARS-CoV-2 infection and these antibodies can mediate thrombosis via inhibition of the activated protein C, antithrombin III pathways, fibrinolysis and upregulation of tissue factor activity despite prolonging the PT and aPTT.

Finally, and of particular interest in COVID-19, is that hypoxia itself accentuates both primary and secondary hemostasis!  Hypoxia induced thrombosis has been related to von Willebrand factor and GPIbα receptor interaction.  Of note, von Willebrand factor activity was elevated in a cohort of severely ill COVD-19 patients with clotting complications.  Lastly, stimulation of hypoxia inducible factors [i.e. HIFs] are known to potentiate the extrinsic pathway via tissue factor and inhibit the potent fibrinolytic tissue plasminogen activator [tPA].

SIC versus DIC

Given the ubiquity of Virchow’s Triad and the risk of dysregulated thrombogenesis in the ICU, it is unsurprising that COVID-19 patients are menaced by sepsis-induced coagulopathy [i.e. SIC] and, potentially, disseminated intravascular coagulation [i.e. DIC].  As outlined by the International Society for Thrombosis and Hemostasis [ISTH], the relationship between SIC and DIC is a continuum, with patients progressing through the former and then latter.  SIC is considered likely when a patient has at least 4 points on a scale made up of the SOFA score, prothrombin time and platelet count.  If SIC is present, then the patient is screened for DIC which includes points for fibrin degradation products [FDP] such as d-dimer as well as low fibrinogen scores.  Though the authors do explicate the controversial aspects of treating SIC or sepsis-associated DIC with anti-coagulation.

Evidence in COVID-19

Venous thromboembolism [VTE] is quite common in hospitalized patients, particularly in patients with severe systemic infection. In a retrospective observational study of roughly 19,000 pneumococcal pneumonia patients and 75,712 controls, the risk of developing DVT and PE in patients with pneumococcal pneumonia compared to controls was increased by 1.78 and 1.97-fold, respectively. Thus, it is unsurprising that the hyper-inflammatory state observed in severe COVID-19 is associated with a higher incidence of VTE.  As detailed below, the incidence of VTE is roughly 25% of patients hospitalized in the intensive care unit for COVID-19, even in those receiving anticoagulation with prophylactic doses.

However, there is a paucity of data in COVID-19 patients at this juncture.  There have been a handful of observational studies that describe the specific risk of VTE in those with COVID-19 in addition to case reports.  Klok and colleagues reported on 184 COVID-19 in the ICU.  They observed a high incidence of VTE despite the use of at least prophylactic anticoagulation; VTE was observed in 27% and 3.7% had arterial thromboses.  Age, prolongation of the prothrombin time >3 seconds or activated partial thromboplastin time >5 seconds were independent predictors of thromboses.  Cui and colleagues, similarly, found a 25% incidence of VTE in severe COVID-19 patients but in this report, no patients received prophylactic anticoagulation.

Poissy et al. observed an increased incidence of PE at 15 days in the ICU for COVID-19 patients; 91% of those who developed PE did so on standard dose VT prophylaxis. The PE frequency [roughly 21%] was higher than a cohort of ICU patients from the same time period the previous year [about 6%]; additionally, in 40 patients admitted to their ICU with influenza in 2019, the frequency of PE was 7.5%.

Helms and colleagues evaluated 150, critically-ill COVID‐19 patients all receiving prophylactic therapy for thromboembolism.  Notably, 43% had clinically relevant thrombotic complications which were mainly pulmonary emboli as well as clotting events on renal replacement and ECMO.  None developed overt DIC.  When propensity matched with non-COVID-19 ARDS patients, those with COVID-19 developed significantly more thrombotic complications, mainly pulmonary embolisms [11.7 vs. 2.1%, p < 0.008]. Of additional interest, coagulation parameters significantly differed between COVID and non-COVID ARDS groups: prothrombin time, antithrombin, fibrinogen and platelets were higher, whereas aPTT and D-dimers were significantly lower in COVID-19 patients.

Prophylactic Approach

First, the ISTH and American Society of Hematology [ASH] guidelines advise prophylactic low molecular weight heparin [LMWH] in all hospitalized COVID-19 patients without contraindications [e.g. active bleeding and platelet count less than 25].

In an oft-referenced investigation, Tang and colleagues retrospectively evaluated the effect of prophylactic low molecular weight heparin or heparin on outcome in severe COVID-19.  As the incidence of VTE is low in the Asian population, routine VTE prophylaxis is not frequently used. Nevertheless, 22% of the cohort received prophylactic dose anticoagulation.  In those with either SIC score of > 4 or a D-dimer elevated > 6 x upper limit of normal, there was decreased mortality when treated with prophylactic doses of enoxaparin or unfractionated heparin for 7 days.

Yet, given the aforementioned ‘breakthrough’ VTE whilst on prophylactic doses of heparin, some have vociferously advocated for ‘intermediate’ dose prophylaxis [e.g. enoxaparin 0.5 mg/kg b.i.d. or enoxaparin 1mg/kg once daily].  Indeed, using the Delphi method, a consensus document found about one-third of participants supported intermediate intensity dose, while roughly 5% favoured therapeutic dose anticoagulation.  The remaining majority supported using standard VTE prophylaxis dose for hospitalized patients with moderate to severe COVID-19 and lack of DIC. [see table 6].

Finally, recent retrospective data seems to support higher dose anticoagulation in mechanically-ventilated COVID-19 patients.  Treatment-dose, systemic anti-coagulation [AC] was associated with an in-hospital mortality of 29.1% compared to 62.7% in patients who did not receive AC.  Nevertheless, as noted by the authors, their report is limited by its observational nature, unobserved confounding, unknown indication for AC, indication bias amongst other inherent limitations to retrospective analyses.

Given the above and your clinical experience, please vote below!

Best,

 JE

Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org

 

 

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COVID-19 Associated Coagulopathy: a contentious conundrum