Journal of Neurology and Neuroscience

Keywords

Coagulopathy; COVID-19; Ischemic stroke; SARS-CoV-2.

Introduction

Coronavirus disease (COVID-19) is a disease caused by SARS-CoV-2 which represents the causative agent of a potentially fatal disease that is of great global public health concern. Previous outbreaks of corona viruses (CoVs) include the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome (MERS)-CoV which have been previously characterized as agents that are a great public health threat. Early reports predicted the onset of a potential Coronavirus outbreak given the estimate of a reproduction number for the 2019 Novel Coronavirus (COVID-19) deemed to be significantly larger than 1 (ranges from 2.24 to 3.58) [1], later it was proven to be more aggressive and so declared a pandemic by WHO in February 2020. Presently above 6 million people have been affected by this virus across the world and the number seems to be going up relentlessly with every passing day.

Literature Review

Clinically, the disease is characterized by fever, dyspnea, dry cough, and fatigue. Upper�respiratory tract symptoms are not prominent, but diarrhea was reported by some patients. Pulmonary imaging has shown multiple ground glass and infiltrative shadows in both lungs. Severe cases have been shown to develop acute respiratory distress syndrome (ARDS) and septic shock. Severe cases may also develop myocarditis, cardiac arrhythmia and acute kidney injury. As the information about clinical manifestation is increasing, new treatment strategies and measures are being carried out. Earlier in this year FA Klok et al. published their data of 184 ICU COVID-19 patients, presenting mainly with upper respiratory symptoms and pneumonia. Despite the fact that all their patients were on thromboprophylaxis they encountered a cumulative incidence of thrombotic events in 31% cases (mainly venous), of which venous thrombo-embolism was seen in 27% cases. Arterial thrombotic events were reported in 3.7% patients and pulmonary embolism was the most frequent [2].

COVID-19 and coagulation disorders

As a matter of fact clinical spectrum of COVID-19, its manifestations, complications and long term outcome is yet to be elucidated completely. As the pandemic is still in progression with a hazy picture and potential treatments are on the way, we sought to explore the available literature about thrombotic events. Some assistance might be achieved from severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) which inflicted the recent past.

Preliminary reports on COVID-19 pandemic outcomes have shown that infected patients commonly develop thrombocytopenia (36.2%) and may have elevated D-dimer (43.2%) , while these rates are even higher in patients with severe COVID-19 disease (57.7% and 59.6%, respectively) [3]. Emerging data indicate that patients with COID-19 infection are at a risk of developing disseminated intravascular coagulation (DIC) especially with Increased D-dimer and fibrin degradation product levels, and prolonged prothrombin time, which may indicate poor prognostication [4]. However Pangada et al. in their Italian cohort established that their COVID-19 serious patients also showed up hypercoagulable state but some of the observed features were different than usual DIC, so they claim it is disturbed coagulation hemostasis secondary to sepsis rather than DIC [5]. Furthermore, reduced platelet counts and low fibrinogen clotting activities, which are pathognomonic characteristics of DIC, were shown to be normal or even increased in their data and so it did not support DIC. Cumulatively their results delineated that patients with COVID-19 may develop a state of hypercoagulability as projected by the thromboelstography parameters, increased factor VIII, von Willebrand factor and fibrinogen [5].

However, in either case DIC or not, COVID-19 patients develop hypercoagulable state and anticoagulation is warranted for a better outcome [6].

So far we have seen patients developing deep venous thrombosis, pulmonary embolism and strokes, as pointed by targeted literature review. Exact mechanism might not be validated yet but above mentioned pathogenesis seem to play a pivotal role as indicated by a stroke series of COVID-19 patients, stating that most plausible mechanism of early cerebrovascular accidents could be hypercoagulability leading to macro and micro thrombi formation in the vessels [7].

Thrombogenesis in COVID 19

Supposedly, coagulation and inflammation are highly integrated, delicately balanced biological systems with extensive cross talk can respond to injury and invasion caused by pathogens. Dysregulation of any one component in these systems can affect the entire balance, resulting in varying degrees of inflammation and thrombosis. Hence, inflammatory conditions deliberately invoke prothrombotic state.

Tissue factor (TF) is positioned at the nexus of coagulation and inflammation, providing a trigger for initiation of the host response to injury or invasion by pathogens. TF is exposed to the blood, sustained through the release of proinflammatory cytokines, chemokines, and inflammatory/ procoagulant micro particles (MPs). It triggers the generation of factor VIIa, factor Xa, and thrombin (IIa) which activate platelets. Certain more sequence of events trigger release of P-selectin (CD62), von Willebrand Factor (VWF), platelet factor 4 (PF4), and CD40 ligand which further promotes thrombosis [8]. Moreover, in COVID-19 patients such prothrombotic conditions are slightly more potent than usual bacterial/ viral infection, as depicted by Activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA) model [9].

Another theory states hyperfibrgenmia, resulting from inflammation is the fuel to the cascade of hypercoagulable state.

Complexity of COVID-19 dilemma is revealing day by day in fragments. Many reports now have finally suggested that it’s a thromboembolic phenomenon rather than only pneumonia. Few more have claimed that there are microthrombi in the lung microvasculature causing these symptoms. Ventilator settings, especially demands of high FiO2 peculiarly fit into this understanding. As denoted by an Italian group of scientists who conducted autopsy on the dead COVID -19 patients and found the features of the exudative and proliferative phases of Diffuse Alveolar Disease (DAD), comprising of capillary congestion, necrosis of pneumocytes, hyaline membrane, interstitial edema, pneumocyte hyperplasia, reactive atypia and platelet-fibrin thrombi. The main relevant finding was the presence of plateletfibrin thrombi in small arterial vessels which plugs into the clinical context of coagulopathy in COVID-19 patients [10].

Role of vessels injury in thrombogenesis

COVID-19 infects the host by targeting the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs including the lung, heart, kidney and intestine. ACE2 receptors are also expressed by endothelial cells. Whether vascular derangements in COVID-19 are due to direct endothelial cell involvement by the virus was unclear, however interestingly COVID-19 can directly infect engineered human blood vessel in vitro [11]. Varga Z et al. did electron microscopic evaluation of pulmonary endothelium of COVID-19 patients and demonstrated the presence of viral elements within endothelial cells along with accumulation of inflammatory cells suggesting that COVID-19 infection facilitates the induction of endothelitis in several organs as a consequence of direct viral endocytosis and could explain the systemic impaired circulatory function in different vascular beds and their clinical sequelae [12]. Although these electron microscopic findings were noticed in microvasculature, in stroke mainly large vessels are involved. There might be histopathologic variation amongst pulmonary and cerebral vasculature.

The endothelium prevents clotting by providing an antithrombotic surface by the expression of tissue factor inhibitor, thrombomodulin and by the production of tissue-type plasminogen activator that promotes fibrinolysis and maintained by heparansulphate replete in the matrix surrounding the cells. Endothelial dysfunction refers to a systemic condition while it loses its physiological properties, including the tendency to promote vasodilation, fibrinolysis, and anti-aggregation [13].

Several studies indicated the elevated von Willebrand factor levels, which may be taken as surrogate marker of endothelial dysfunction in COVID-19 [5]. So, endothelial damage is there, whether caused directly by virus itself or by resulting inflammatory cascades that is another debate. Hence endothelial injury contributes to Virchow's triad, described as three broad categories of hypercoagulability, hemodynamic changes (stasis, turbulence) and endothelial dysfunction, leading to thrombotic events.

Stroke in COVID-19

In a Chinese cohort from Wuhan, china, researchers found 58.9% patients displayed neurological manifestation during their course of COVID-19 illness, out of which 5.7% had cerebrovascular event [14]. Most neurologic manifestations occurred earlier in the illness period (the median time to hospital admission was 1-2 days). In fact, 2 patients presented with stroke and next day developed fever and other symptoms of SARS-CoV-2. Thrombotic events like stroke were identified to manifest averagely after 12 days of COVID-19 symptom onset according to another observation [15]. Elevated levels of CRP and D-dimer invariably indicate a high inflammatory state at the time of stroke onset and abnormalities with the coagulation cascade supposedly play an epic role in the pathophysiology of stroke in the setting of COVID-19 infection.

All the stroke cases in a stroke series had high Fibrinogen, dimers and ferritin but normal platelet count. Stroke involved only large vessels surprisingly and all the strokes were of high NIHSS. Severities of pneumonia or respiratory symptoms were not directly correlated with stroke [16]. Many of the case series have indicated occurrence of stroke in young people and in patients without a risk factor. Coagulopathy and vascular endothelial dysfunction have been proposed as complications of COVID-19 [17], which qualifies for the most plausible explanation for the stroke in COVID-19 patients.

Why large vessel stroke in COVID-19 patients?

With time, the understanding of clinical manifestations of COVID-19 is increasing. Based on various analytical observations and studies it can certainly be established that Novel Corona virus contains characteristic of thrombogenesis through various proposed mechanisms (as explained above). Stroke is one of the major manifestation and in almost all the cases it is invariably large vessel stroke. While peeping through the history, in 2004 large-vessel stroke was reported in association with SARS-CoV-1 outbreak in Singapore as well [18]. Various hypotheses were suggested to explain the apparent link between viruses and cerebrovascular accidents. Virus-induced inflammation of the vessel wall is believed to be responsible for stroke associated with chicken pox and herpes zoster [19] as they belong to same family as SARS-CoV-2, so it was supposed to cause strokes by same mechanism.

As the blood vessels do contain ACE 2 receptors which are deliberate target of COVID 19, the reason for the affinity to the vessels is quite clear. Whether virus directly affects the large arteries or it modulates through the cascade of thrombogenesis and endothelial injury is an unanswered query as yet, however it was discovered by Electron microscopic studies by Varga Z et al. that endothelium tissue contained viral inclusion bodies in a peritubular space and viral particles of SARS-CoV-2 (COVID 19) in endothelial cells of the glomerular capillary loops [12]. Similarly targeting of large cerebral arteries directly by virus is a possibility. Virus may invade cerebral arteries in a fashion it does to glomerular vascular bed and proceed with inflammation to trigger procoagulant environment leading to stroke.

Furthermore, Sardu C et al. elaboratedthat endothelial dysfunction is a major determinant of COVID-19 manifestations. The SARS-CoV-2 coronavirus accesses host cells via the binding of its spike glycoprotein to ACE2 receptors, sialic acid receptor, transmembrane serine protease 2 (TMPRSS2), and extracellular matrix metalloproteinase inducer (CD147); whereas catepsin B and L also participate in virus entry. All of these factors are expressed on endothelial cell surface. All of the drugs proposed as a potential therapeutic strategy to treat COVID-19 patients have been shown to improve endothelial function, including tocilizumab, colchicine, chloroquine/ hydroxychloroquine, azithromycin, and famotidine [20]. Question raises here, why the large vessels and not small vessels? This might be due to variability of receptors or target biochemical proteins in cerebral circulation which help anchoring the virus stronger in large vessels rather than small vessels. But it has to be proven yet.

Almost all the strokes described in literature seem to be embolic in nature. Especially while the mechanism of thrombogenesis by COVID-19 has been well established and it has been shown to involve almost all the systems of the body, one can conclude that strokes ensued by this mechanism are embolic pathologically. Inflammation and hypercoagubility cross talk as described in above references, which along with endothelial damage triggers thrombosis. As speed of blood flow is enormously higher in large arteries so turbulence and worsening of endothelial injury, effective enough to trigger thrombosis happens here mainly. Hence it completes the Virchow’s triad in large vessels. As a consequence thrombogenesis is primarily found in large arteries supplying to brain, at sites of branching where there is more turbulence as per hemodynamics of the flow [13]. This turbulence against the walls of the large arteries (internal and external carotid arteries, vertebral and basilar) which along with local platelet activation, endothelial cell injury, accumulation of lipid-laden macrophages and inflammatory cells, tissue factor expression and distortion of the otherwise smooth arterial wall promote coagulation [21]. As a consequence alterations in the arterial surface and loss of the endothelial cell protection trigger fibrin deposition and platelet-fibrin formation. Embolization of thrombus leads to downstream occlusion and stroke. Embolic phenomenon occurs mainly in large arteries and thrombus particles travel with blood flow and are trapped in tapering part of large blood vessel before reaching to small vessel.

In a stroke series in COVID -19 patient’s five out of six patients had positive Lupus anticoagulant and some contained anticardiolipin antibodies as well. It has been observed in many cohorts that thromboembolic phenomenon in COVID -19 patients is associated with antiphospholipid antibodies, which raises the possibility that COVID-19 activates antibodies related to Antiphospholipid antibody syndrome [22]. By and large, it is commonly noticed that most of the time strokes caused by antiphospholipid Ab syndrome (APLA) are large vessels strokes as indicated by Trimble M et al. in their large series on prevalence of APLA in patients of stroke and transient ischemic attack, proposing that most likely mechanism is large vessel occlusion, however vasculitis can be a second rare possibility [23]. Consequently this can be one of the rationale for the fact that we encounter large vessel stroke most of the time in COVID -19 patients.

Cardiac involvement in COVID-19 infection is not an ambiguity any more. Manifestations of acute myocardial injury, cardiac failure, myocarditis, arrhythmias, myocardial infarction and intra-cardiac thrombus formation are well alerted by many cohorts [24].

Arrhythmias or myocardial infarction leading to clot formation in left ventricleand contemporarily giving origin to acardioembolic stroke seems a plausible mechanism in this context. Owing to their large size, cardiac emboli flow to the intracranial vessels in most cases and cause massive, superficial, single large or multiple infarctsin the brain [25]. As many a times large emboli from heart obliterate the major cerebral blood vessel causing a massive stroke which in fact happened to many of COVID-19 patients and sufficiently explains the presumable mechanism of large vessel stroke.

Discussion and Conclusion

SARS-CoV-2 or COVID-19 has caused a global pandemic which has so far affected around 6 million people worldwide and this has been found to cause systemic thrombosis in addition to the various respiratory and other multisystem manifestations. Various pathological mechanism of thrombosis have been proposed including inflammatory cascade, inflammation and thrombosis cross talk phenomenon, endothelial dysfunction, endothelitis, arteritis and flare up of antiphospholipid antibodies with some certainty. Majority of strokes caused by COVID-19 involve large vessel showing to likely mechanisms of Virchow’s triad more proficient in large vessels, high affinity of virus to certain receptors or biochemical proteins in large arteries, escalated antiphospholipid antibodies or a cardiac source. As the information about COVID-19 is evolving by every passing day, we may be able to confirm soon the actually working mechanism.

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