(Location of Table 1)
Discussion:
Respiratory disorders have been reported as the main complication of COVID-19. However, there are reports that documented many other symptoms like cerebrovascular events especially secondary to an increase in risk of coagulopathy (10). This study describes two previously healthy men with COVID-19 that presented with ischemic stroke due to large vessel occlusion due to MTFHR gene mutations. To our knowledge these are the first two cases describing MTFHR gene mutations in the setting of hypercoagulability and sequential thromboembolic events in COVID-19 infection. The relative ratio of strokes in the young with age under 45 years old has been increasing over the past few decades (11). Hematologic and vasculopathic etiologies accounts for 44% of strokes in young patients (12). The most common causes in this age group are nonatherosclerotic, more often as a consequence of cardio embolism or arterial dissection (13). Inflammation-driven hypercoagulable and vasculopathic state secondary to a recent infection is an independent risk factor for stroke (odds ratio 3.4–14.5), mostly respiratory in origin (14-15). It has been reported that higher incidence of ischemic stroke is common with other respiratory viruses like Influenza and also with other coronaviruses (16) and recent data suggests COVID-19 confers a greater risk of stroke than influenza (17). Now it is well documented that COVID-19 can lead to hypercoagulable state that results in venous and arterial thromboembolism (10, 18). Our patients were found to have elevated serum homocysteine, possibly contributing to their hypercoagulable states. Typically, a level 60 µmol/L is considered severely elevated (19). The elevated serum homocysteine which is the result of MTHFR gene polymorphisms as in case of MTHFR C677T could lead to decreased enzyme activity and therefore to an elevation of serum homocysteine leve and in turn to thromboembolic events (9). It is controversial whether ischemic stroke is directly related to MTFHR mutation or not. In a recent study in Tunisian adults, it is confirmed that C677T and A1298C MTFHR variants are important risk factors for arterial ischemic strokes (20). In a meta-analysis by Shan Kang et al MTHFR A1298C genetic polymorphism was associated with increased risk of ischemic strokes (21). Acute cerebrovascular disease was reported to occur 1.4% of COVID-19 patients. The most common manifestation in 87.4% of these patients was with acute ischemic stroke (22). Mao et al reported 5.7% of patients with severe COVID-19 infection developed cerebrovascular disease later in the course of illness (23). More recently, emergent large LVO has been reported in patients with COVID-19. Shingo Kihira et al suggested that COVID-19 is related to LVO rather than small vessel occlusion. In their study of 329 participants, 71 patients (21.6%) developed LVO (24). Likewise, in our cases carotid occlusion took place in previously healthy young adults. Several studies have found an association between hyperhomocysteinemia and NAION (25-26). Different mechanisms have been suggested to play role. In our case, coagulation disorders could be in play (27). The high coagulopathic complications in our cases could be related to high levels of homocysteine along with MTHFR gene mutism that might have remained silent in the absence of COVID-19. This highlights the importance of thrombophilia assessment in COVID-19 patients with sequential events concerning for recurrent thromboembolism.
Conclusion:
We presented two cases of previously healthy young men with COVID-19 infection who developed acute ischemic stroke due to large vessel occlusion followed by secondary events concerning for a further thromboembolic event. Both these patients were found to have hyperhomocysteinemia along with a MTFHR gene mutation. Hypercoagulable state as a result of COVID-19 could have exacerbated the underlying silent coagulopathy in these patients. We suggest that performing an extensive thrombophilia screen is indicated in COVID-19 patients without conventional vascular risk factors who present with recurrent events concerning for thromboembolism.
List of abbreviations:
NAION: Nonarthritic anterior ischemic optic neuropathy
ATN: Acute tubular necrosis
LVO: Large vessel occlusion
RT-PCR: Real-time reverse-transcriptase– polymerase-chain-reaction
DSA: Digital subtraction angiography
ICA: Internal carotid artery
MTFHR: Methylenetetrahydrofolate reductase
rTPA: Recombinant tissue plasminogen activator
MCA: Middle cerebral artery
ACA: Anterior cerebral artery
RAPD: Relative afferent pupillary defect
AKI: Acute kidney injury
NIHSS: National Institutes of Health Stroke Scale
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Table 1. Clinical Characteristics of Two Young Patients Presenting with LVO Stroke .