A 35-year-old male patient with a medical history of well-controlled hypertension and diabetes mellitus presented to the emergency room with left sided weakness when he woke up from sleep that progressed to paralysis of the left side of his body. The symptoms started 12 hours prior to his arrival. The patient also reported feeling shortness of breath for the last few days. He denied any recent sick contact, headache, photophobia, recreational drug use, and family history of note. His medications included metformin and hydrochlorothiazide. Vitals signs were temperature 97.6°F, blood pressure 153/117 mmHg, heart rate of 117 beats/min, and oxygen saturation of 91% on nonrebreather mask. His finger stick glucose was 98 mg/dl. Physical examination revealed alert, oriented male in mild respiratory distress. Pupillary examination revealed anisocoria. Lungs were clear to auscultation except bibasilar crackles, and heart sounds were normal. On neurological examination, the patient had hemiplegia of the left side of the body but had good strength on the right side of the body. Abdomen was soft without any organomegaly. Initial labs revealed mild leukocytosis (white blood cell [WBC] of 11.0 k/μl), with normal hemoglobin, electrolytes, and renal function. D-dimers were elevated at 1088 ng/ml. His initial international normalized ratio (INR) was 1.06, prothrombin time (PT) was 12.5 seconds, and partial thromboplastin time (PTT) was 30.7 seconds. He was also noted to have an elevated lactate dehydrogenase (LDH) level at 254 unit/L and elevated C-reactive protein at 17.2 mg/L. The patient tested positive for SARS-CoV-2 RNA via polymerase chain reaction testing. Chest X-ray revealed bilateral pulmonary opacities. Computed tomography (CT) of the head showed no evidence of acute intracranial hemorrhage or injury. CT angiogram of the brain revealed abrupt occlusion of the right M2 middle cerebral artery (MCA) inferior branch with lack of visible perfusion in the posterior inferior right MCA territory. Subsequent CT head showed interval development of a large acute right MCA distribution territorial infarct, with findings suspicious for thrombus involving a branch of the right M2 segment. The patient was diagnosed with acute right MCA stroke in the setting of COVID-19 infection. Since he was not a candidate for tissue plasminogen activator (tPA) due to the late presentation, he was given aspirin and high-intensity statin. He also received conservative management for COVID-19 pneumonia. After 48 hours of stroke symptoms, he was initiated on low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis. His oxygenation and hemodynamic parameters started to improve. His D-dimer and LDH started to trend down. He was later discharged to rehabilitation center for physical therapy.
According to observational data, the incidence of thromboembolic disorder such as pulmonary embolism (PE) in COVID-19 infection ranges from 1.5%-9%. (1-3) Similarly, the incidence of asymptomatic deep venous thrombosis (DVT) in hospitalized patients with COVID infection ranges from 18%-20%. (1-3) Cerebrovascular accident was observed in 1%-6% of the population with COVID infection. More younger patients (median age 58 years) developed thromboembolic events in COVID infection with male gender predisposition. (1-3)
SARS-CoV-2 virus enters the cell via angiotensin-converting 2 receptors, which are expressed on the vascular endothelial cells. Both in vitro and autopsy studies have shown evidence of the invasion of vasculature by the virus. Autopsy studies have demonstrated the presence of intracellular virus and severe endothelial injury in the form of endotheliitis and apoptotic bodies in the vascular architecture of many organs including lungs, kidneys, and intestines. Dysregulated and uncontrolled host responses lead to the release of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α. IL-6 is a major cytokine that is implicated in the pathogenesis of coagulopathy.(1) It triggers the activation of tissue factor expression and increased platelet and fibrinogen production. Tissue factor then triggers activation of factor Xa, factor VIIa, and thrombin production. These microthrombi are stabilized by neutrophils via release of neutrophil extracellular traps (NETs). Degradation of tissue factor antagonist by neutrophil elastases leads to further immobilization of these microthrombi.(2)
Diagnostic algorithm of COVID-19–related thromboembolism.
It is noteworthy that IL-6 levels are considerably higher in critically ill COVID-19 patients compared with similarly ill patients due to bacterial pneumonia. IL-1 and TNF-a have also been implicated in COVID-19–related coagulopathy due to their role in the suppression of endogenous anticoagulant pathways. In addition, SARS-CoV-2 also leads to disruption of the balance between the plasmin and urokinase pathway, which causes fibrin accumulation. Hypoxia is another significant symptom of COVID-19 infection and a potent stimulator of thrombosis. The resulting inflammatory cascade can lead to both microvascular and macrovascular thrombosis.
In addition to the inflammatory response, pathogens including SARS-CoV-2 can also lead to the activation of complement. Complement activation products have been detected on the circulating red blood cells in COVID-19 patients. As the illness progresses, dysregulation of the complement activation pathway can occur, which can further potentiate tissue damage. In patients with severe COVID-19 illness, overactivation of the complement pathways can also occur. Together with a prothrombotic state and cytokine release syndrome, overactivated complement cascade can lead to widespread organ damage and clinical deterioration of these patients.
Differentiating COVID-19–induced coagulopathy from disseminated intravascular coagulation (DIC) often can be challenging. Significant elevations in D-dimers can be seen with both conditions, and a higher level is frequently encountered in critically ill COVID-19 patients.
Fibrin split products (FSPs), which are one of the International Society of Thrombosis and Hemostasis (ISTH) criteria to diagnosis overt DIC, is often normal in milder COVID-19 illness. Levels of FSP can, however, be elevated in critically ill patients and have been associated with poor outcomes. Fibrinogen levels are often elevated in most patients with COVID-19 illness. In contrast, fibrinogen levels are low in patients with DIC. Similarly, PT and activated PTT (aPTT) is often normal in COVID-19 patients but is frequently elevated in DIC. Between PT and PTT, only PT prolongation is seen with the progression of COVID-19 illness.
Thrombocytopenia, which is another common finding in DIC and in critically ill septic patients, is uncommon in COVID-19 patients with only 5% of patients with platelet counts of <100 x 109/L. Thrombocytopenia, however, is common in patients with fatal COVID-19 and is seen in half of such cases. Nonetheless, progressive thrombocytopenia should prompt the workup for alternative etiologies such as bacterial superinfections and adverse drug reactions. (3)
Thromboelastogram (TEG) is another test designed to assess clot formation and dissolution. In a study evaluating incidence of a hypercoagulable state based on TEG and its association with thrombotic events noted that the hypercoagulable state was not associated with thrombotic events. Similarly, there was no association between hypercoagulable state and inflammatory markers, and coagulation markers and use of thromboprophylaxis. (4)
Like in any other illness, evaluation for a thrombotic state should start with a detailed history, physical examination, and results of laboratory tests for hemostasis. Patients with clinical suspicion for DVT should undergo further evaluation with venous Doppler or compression ultrasound examination. Similarly, PE should be considered if the patient is hypotensive or has unexplained hypoxia. Diagnosis relies on definitive imaging, as patients with COVID-19 can be hypoxic and present with signs of PE such as high D-dimers and right ventricular strain even in the absence of PE. Studies have shown that COVID-19 patients can have high incidence of thromboembolic events, especially when they have elevated hypercoagulability markers. Similarly, studies have shown the association between worsening coagulation markers and the development of cytokine storm and multiorgan failure.
Other macrovascular thrombotic conditions, such as myocardial injury or infarction, stroke, abdominal and thoracic aortic thrombosis, acute limb ischemia, and mesenteric ischemia, have also been reported in COVID-19 patients. Although stroke, aortic thrombosis, and acute limb ischemia can be diagnosed with a detailed physical examination and confirmed with diagnostic imaging, the diagnosis of other conditions can be particularly challenging in COVID-19 patients. For example, cardiac markers can be elevated in severe COVID-19 illness due to cytokine storm and hypoxic injury and not necessarily due to direct plaque rupture. Furthermore, typical chest pain is often absent in COVID-19 patients with acute coronary syndrome. Electrocardiogram (ECG) is often helpful as it can show ST elevation, whereas in those with equivocal symptoms and nonspecific EKG changes can benefit from echocardiogram and serial ECG monitoring. Mesenteric ischemia is uncommon, but it is another disease entity that can present with nonspecific findings such as abdominal pain, vomiting, or diarrhea. A routine CT with contrast could easily miss this diagnosis; especially early in the disease, and a dedicated CT angiography of mesenteric vessels is often needed for diagnosis. (5)
Society guidelines have recommended prophylactic anticoagulation in all patients hospitalized with COVID-19 barring any contraindications. Mechanical prophylaxis has been recommended in patients with contraindications to chemical prophylaxis.
The American Society of Hematology (ASH) recommends using prophylactic-intensity over intermediate intensity or therapeutic-intensity anticoagulation in patients with COVID-19 without confirmed or suspected thromboembolic disease. Regarding specific anticoagulants for thromboprophylaxis, the American College of Chest Physicians (ACCP) guidelines recommend using standard dose LMWH or fondaparinux over unfractionated heparin (UFH) or direct oral anticoagulant therapy (DOAC; Table 3-1).
TABLE 3-1Anticoagulation Strategies in COVID-19 Patients ||Download (.pdf) TABLE 3-1 Anticoagulation Strategies in COVID-19 Patients
| ||Prevention ||Treatment |
|Aspirin ||No role to prevent VTE, may have role in preventing stroke and MI ||First-line drug for stroke and MI, no role in VTE |
|Low molecular-weight-heparin ||Preferred for VTE prophylaxis, less interactions, less staff exposure ||Preferred for VTE treatment, less interactions, less staff exposure |
|Unfractionated heparin ||May be used in ARDS patients (critically ill), not preferred ||May be used in ARDS patients (critically ill), not preferred |
|DOACs ||Can be used, but with caution due to drug-drug interaction ||Can be used, but with caution due to drug-drug interaction |
|Parenteral thrombolytics ||No role ||Utilized for highly suspected/diagnosed cases with hemodynamic instability |
|Catheter-directed thrombolytics ||No role ||Utilized for highly suspected/diagnosed cases with hemodynamic instability |
ASH and IISTH also favor LMWH therapy for thromboprophylaxis. Due to lack of data regarding benefits of extended prophylaxis after hospital discharge, ACCP has only recommended in-patient prophylaxis. For patients diagnosed with PE or proximal DVT, ACCP has favored LMWH over UFH to limit need for staff exposure and over DOAC due to their concern for drug interaction. ASH recommends either LMWH or UFH over DOAC therapy in these patients. ACCP also recommends a 20%-30% higher dose of LMWH for COVID-19 patients who develop recurrent VTE despite appropriate weight-adjusted LMWH dosing. Antiplatelet therapy (e.g., aspirin) is likely inferior to anticoagulants for VTE prophylaxis in COVID-19 patients, but it has a definite role in the setting of stroke and MI.
Systemic thrombolysis is recommended by ACCP for VTE patients with hypotension (defined as systolic blood pressure of <90 mm Hg) or in those without hypotension who have progressive cardiopulmonary deterioration due to PE and have low risk for bleeding. (6)
In patients with acute limb ischemia, aortic thrombosis or mesenteric ischemia, a surgical or interventional radiology consultation is often required in addition to systemic anticoagulation. If there are signs of massive or high-risk PE with hemodynamic instability, a bedside echocardiogram followed by thrombolytic therapy is preferred. In case of refractory circulatory collapse or cardiac arrest, extracorporeal membrane oxygenation (ECMO) is an option of treatment, along with surgical embolectomy or catheter-directed treatment.
Management of stroke is similar to non-COVID patients with stroke, with IV alteplase therapy for patients without contraindications who are diagnosed within 3 hours of onset of symptoms or a select subgroup of patients presenting within 4.5 hours. Similarly, COVID-19 patients with ST elevation myocardial infarction (STEMI) are treated similar to non-COVID patients with STEMI. (1-5)
In a small series of patients with COVID infection receiving mechanical ventilation, systemic tPA (25 mg over 2 hours followed by another 25 mg over the subsequent 22 hours) was used. It showed improvement in ventilatory parameters, but the effect of this intervention on long-term outcomes is not known yet. (1-3) A second case series depicted the effect of aerosolized freeze-dried plasminogen in moderate to severe critically ill COVID-19 patients. The study reported great improvement in oxygenation and ventilatory parameters. (1-3) Although there have been many studies in this regard, the long-term role of thrombolytics is not clear.
ISTH and ASH are the only societies that recommend monitoring coagulation parameters such as D-dimer, PT, PTT, fibrinogen levels, and platelet count for risk stratification and for potential use of experimental therapies. ISTH recommends monitoring in all COVID-19 patients including those who are outpatients. ISTH also provides an algorithm based on these markers to assess which outpatients would benefit from inpatient therapy.
These markers include platelet count <100 x 109, fibrinogen level of <2.0 gm/L, three- to fourfold rise in D-dimer, and prolongation of PT. ISTH also recommends further evaluation of COVID-19 inpatients who have D-dimer levels of greater than six times above normal.
The Centers for Disease Control and Prevention (CDC) has stated that there is insufficient data to recommend for or against using these markers to guide management decisions. None of the societies have recommended daily use of these markers to guide anticoagulation dosing intensity. (6)