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A Cerebrovascular Accident (CVA) or “Stroke”, is a medical emergency and is a result of interruption of blood supply to a part of the brain. The symptoms of stroke depend on the part of brain affected by the stroke. They could include trouble walking, speaking and understanding, paralysis or numbness of the face, arms, or legs.

A CVA could be ischemic (clot obstructing blood flow) or hemorrhagic (vessel rupturing and preventing blood flow).An ischemic stroke can be caused by thrombosis, embolism, systemic hypoperfusion as in shock, or cerebral venous thrombosis. Hemorrhagic strokes could be related to cerebral amyloid angiopathy, cerebral arteriovenous malformations and intracranial aneurysms.

Thrombotic (ischemic) strokes are the more common types of strokes. The occluding thrombus (clot) usually forms around atherosclerotic plaques. Thrombotic strokes can involve large vessels, when it is called large vessel disease or small vessels when it is called small vessel disease. The large vessels are Common and Internal carotid artery, vertebral artery and Circle of Willis. Examples of small arteries are branches of Circle of Willis and Middle Cerebral Artery.

Strokes and other Thrombotic Complications in COVID-19 Patients

Though strokes can occur at any age, they more commonly affect the older age groups. The risk of having a stroke more than doubles after the age of fifty five. In recent times, it is being observed that middle aged and younger patients, suffering from COVID-19 are presenting with symptoms of stroke.

Investigators from Mount Sinai Health System, in New York City, reported that the number of patients coming in with large vessel blockages in the brain, doubled during the last the three weeks of COVID-19 surge to more than thirty two. More than half of these were COVID-19 positive. On an average, COVID-19 stroke patients were fifteen years younger than the stroke patients without the virus. None of them had any of the traditional risk factors for stroke like diabetes, hypertension, obesity or heart diseases. A case series of five patients with large vessel stroke, in COVID-19 positive cases, has been published in the New England Journal of Medicine (April 28, 2020). The lead investigator, Thomas Oxley, reported that these five cases were seen over a two week period (March 23 to April 7, 2020) and all were under the age of fifty. This is a sevenfold increase over the norm. All these cases had only mild or no symptoms of COVID-19. Thomas Oxley reported that involvement of large vessels was more common than that of small vessels in these five patients. One patient in the case series died, one is still hospitalized, two are undergoing rehabilitation and one was discharged.

Thomas Jefferson University Hospitals at Philadelphia and NYU Langone Health in New York City, found that twelve of their patients treated for large blood vessel blockages in their brain during a three week period, had the SARS-CoV-2. Forty percent of them were less than fifty years old and had few or no risk factors. Researchers at Johns Hopkins Hospital, Baltimore, reported strokes in COVID-19 patients who were as young as in their thirties.

Recently, investigators in the Netherlands, found a 31% rate of thrombotic complications among 184 critical care patients with COVID-19 pneumonia. This series included patients with pulmonary embolism, deep vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism.

A recent analysis from a French group showed that the rate of thrombotic complications in 150 COVID-19 patients with Acute Respiratory Distress Syndrome (ARDS) was much higher (11.7%) than that observed in a historical control group of non-COVID 19 ARDS patients (2.1%) despite anticoagulation. Corrado Lodigiani et al reported in Thrombosis Research (published April 23, 2020) that venous and arterial thromboembolic strokes occurred in 8% of hospitalized patients and 50% of the thrombotic events were diagnosed within 24 hours of hospitalization. The thrombotic events included Venous Thromboembolism (VTE), Pulmonary Embolism (PE), Deep Vein Thrombosis ( DVT), Ischemic strokes, and Acute Coronary Syndrome (ACS), A total of 388 patients, requiring intensive care, were included in this study conducted at University Hospital in Milan, Italy.

Abnormalities of Coagulation in COVID-19 Patients

In a March 11 paper in Lancet, Dr Cao and colleagues reported that D-dimer levels over 1ug/L at admission predicted an 18 fold increase in the odds of death before discharge (Lancet 2020;395(10229).1054-1062).

The most common pattern of coagulopathy observed in hospitalized COVID-19 patients is elevations in fibrinogen and D-dimer levels. Some report a mild thrombocytopenia and increased D-dimer levels as the most consistent hemostatic abnormality. Whether the coagulation cascade is directly activated by the virus or it is the result of local or systemic inflammation, is not completely understood. There is a parallel rise in markers of inflammation like CRP, ferritin and IL-6. Zhou et al showed that the increase in IL-6 was discrepant with the elevations in D-dimer; IL-6 levels appeared to increase only 13 days after disease onset, whereas D-dimer levels were already 10-fold increased by that time.

The other laboratory abnormalities in COVID-19 patients are lymphopenia and increased LDH levels. The disturbances in hemostatic abnormalities are associated with a higher risk of requiring mechanical ventilation, ICU admission or death. Unlike the pattern seen in classic DIC from bacterial sepsis or trauma, the degree of aPTT elevation is often less than PT elevation in COVID-19 patients. The thrombocytopenia is also milder (platelet count around 100x10⁹) compared to patients with DIC. Some COVID-19 patients also develop DIC with serious infection.

A study conducted on 22 COVID-19 patients, admitted to the ICU of Padua University Hospital, Padua, Italy, by Luca Spiezia et al was recently published in the Journal of Thrombosis and Haemostasis (April 21, 2020). The controls were 44 healthy, age, sex, and body weight matched subjects. The coagulation profile of the study population showed a severe hypercoagulability rather than a consumptive coagulopathy (as in DIC). They concluded that the severe hypercoagulability is due to hyperfibrinogenemia. There is increased fibrin formation and polymerization that may predispose to thrombosis. Fibrin deposition in alveolar and interstitial lung spaces, in addition to thrombosis of microcirculation, may contribute to worsening of respiratory failure. In this regards anticoagulant therapy may improve prognosis in COVID-19 patients.

Anticoagulation Therapies for Hospitalized COVID-19 Patients

Hospitalized COVID-19 patients, who have acute medical illness like pneumonia, are at increased risk of VTE. Prophylactic anticoagulation reduces the risk of VTE in such patients. The WHO interim guidance statement recommends prophylactic daily dose of Low Molecular Weight Heparin (LMWH) or twice daily subcutaneous Unfractionated Heparin (UFH) in hospitalized patients. The International Society on Thrombosis and Haemostasis recently recommended that all hospitalized COVID-19 patients, even those not in the ICU, should get prophylactic-dose low molecular weight heparin (LMWH), unless they have contraindications (active bleeding and platelet count <25×10⁹/L). Since UFH needs time to achieve therapeutic aPTT and increased healthcare worker exposure for frequent blood draw, LMWHs may be preferred in patients who are unlikely to need procedures. In fact LMWH is preferred, unless there is a contraindication, such as acute kidney injury. All the same, in many ill patients with VTE, parental anticoagulation (e.g. UFH) is preferred as it may temporarily be withheld and has no known drug-drug interactions with investigational COVID-19 therapies. Heparin has potential benefits over other anticoagulants due to its anticoagulant (decreased coronary thrombi, pulmonary emboli, and microvascular ischemia), anti-inflammatory (decreased lung inflammation and improving oxygenation) and potentially anti-viral properties.

Mechanical VTE prophylaxis (intermittent pneumatic compression) should be used in immobilized patients and those who have contraindications for pharmacological prophylaxis. Direct Oral Anti Coagulants (DOAC) may be used for patients after discharge.

Conclusion

Since there is not much peer reviewed literature regarding the effect of COVID-19 on the coagulation profile, detailed guidelines cannot be formed regarding anticoagulation and monitoring of the coagulation profile. As more evidence accumulates about the devastating thrombotic complications of COVID-19 especially the strokes seen in the younger population, the general consensus is to start prophylactic anticoagulation on hospitalization, with some centers in favor of therapeutic anticoagulation.

References

1. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
2. Spiezia L, Radu C, Marchioro P. , et al. Peculiar whole blood rotation thromboelastometry (Rotem) profile in 40 sideropenic anaemia patients. Thromb Haemost 2008; 100 (06) 1106-1110
3. Sørensen B, Johansen P, Christiansen K, Woelke M, Ingerslev J. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost 2003; 1 (03) 551-5587

4. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; DOI: 10.1111/jth.14817.

5. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020. doi:10.1111/jth.14817

6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229):1054-1062. Doi: 10.1016/S0140-6736(20)30566-3.

7. Corrido Modigliani, Giacomo Lap chino, Luca Carazo, Maria Teresa Sandri, Stefano Barco. Venous and Arterial Thromboembolic Complications in COVID-19 Patients Admitted to an Academic Hospital in Milan, Italy. Thrombosis Research. Published April23, 2020.