SARS-CoV-2 infection is associated with immune dysfunction, altered coagulation and tissue injury. The lung is the most severely injured organ by SARS-CoV-2, and this virus can harm many other organs, such as the heart, liver, kidney, brain and intestines. Most individuals with mild cases may recover fully without treatment, but those with severe cases definitively need intensive care unit(1).
The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Thrombosis is an important feature of patients with COVID-19; although thrombosis and bleeding are the coexisted features of coagulopathy, the dominant symptom is different depending on the causal virus(2).
The accurate diagnosis of COVID-19-associated coagulation/fibrinolytic abnormality is important due to morbidity and mortality. In order to make the optimal evaluation, this review includes information on clinical manifestations, laboratory evaluation in predicting the course of COVID-19 and for identifying patients at high risk, and anticoagulation in patients infected with SARS-CoV-2.
Clinical manifestations and laboratory evaluation
While most patients show only mild symptoms, a characteristic feature of COVID-19 is that a proportion of patients develop severe complications within a short time after infection, such as adult respiratory syndrome (ARDS), coagulopathy followed by organ failure and death, caused by an intense inflammatory response triggered by SARS-CoV-2 and/or in the context of secondary infections(3). Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate that the essence of coagulopathy is massive fibrin formation(2). The patients with COVID-19 are at high risk of thromboembolic complications, mainly affecting the venous, but also the arterial vascular system. Specifically, arterial thrombosis includes cerebral infarction, myocardial infarction and limb arterial thrombosis(4). Venous thromboembolism (VTE), a constituent of deep vein thrombosis (DVT) and pulmonary embolism (PE), has significant implications for the clinical outcome of COVID-19 patients. Hospitalized patients for COVID-19 – in particular those with a severe disease – are at an increased risk for VTE. The evolution of a systemic coagulopathy is indicative of poor prognosis(5).
Clinical and laboratory findings provide important information on the diagnosis of severe cases of COVID-19. Highly elevated D-dimer may be associated with DIC, thromboembolic complications and pulmonary embolism (PE), as well as with inflammatory conditions. VTE is a serious risk, particularly in severe disease. Patients hospitalized also demonstrate an increased risk of DVT.
The American Society of Hematology (ASH) guideline panel recommends for patients at low (unlikely) VTE risk the use of D-dimer test, as the initial test reduces the need for diagnostic imaging. For patients at high (likely) VTE risk, imaging is necessary. For pulmonary embolism (PE) diagnosis, ventilation-perfusion scanning and computed tomography pulmonary angiography are the most validated tests, whereas isolated or concurrent deep vein thrombosis (DVT) diagnosis uses ultrasonography(6). As a characteristic of VTE in COVID-19, PE can develop due to the arrival of DVT thrombus, but more often PE develops even without DVT. Pulmonary thrombosis is more frequent than PE, this microthrombotic pattern seems more specific for COVID-19(4).
Evaluating the usefulness of plasma D-dimer in providing guidance on whether or not to order imaging studies, a level of >2.66 mg/L was found to have a 100% sensitivity and a 67% specificity for the detection of PE by computed tomography pulmonary angiography(5), but its usefulness during pregnancy shows limitations. D-dimer levels increased progressively and significantly during normal pregnancy and peaked in the third trimester, in which D-dimer levels were above the conventional cut-off point (500 µg/L) in 99% of pregnant patients(7). However, a negative D-dimer test <500 µg/L has a significant negative predictive value, this test being used to rules out VTE. The presence of comorbidities, especially hypertension, can lead to a significantly higher risk of thrombotic complications in pregnant patients infected with SARS-CoV2(3).
High fibrinogen levels are associated with thrombosis during the early stages of COVID-19. In this disease, coagulation and fibrinolytic pathologies may change rapidly within a short period of time, and follow-up is required every 2-3 days(8). A significant reduction in clotting parameters, such as platelets (<50×109/L) or fibrinogen levels (<100 mg/dL), are most commonly associated with bleeding caused by DIC and sepsis(3).
In many of the COVID-19 patients, hemostatic abnormalities include mild thrombocytopenia (<100×109/L) on admission; the platelet count did not decrease to a level at which bleeding occurs(8).
Thrombocytopenia is often considered an indicator of sepsis mortality. Multiorgan failure is more likely in patients with sepsis if they develop coagulopathy. During disease progression, the platelet count was significantly lower (from 35 to 29×109/L) in patients with bleeding risk, and associated with mortality(8).
Two guidelines addressing coagulopathy in COVID-19 highlighted D-dimer elevation, thrombocytopenia and low fibrinogen as poor prognostic indicators of mortality risk. In pregnancy, low fibrinogen was the only coagulation parameter associated with a postpartum hemorrhage (PPH) severity, with a positive predictive value of 100% with fibrinogen <2 g/L(9).
Additional laboratory tests to be performed in COVID-19
Some COVID-19 patients had abnormal blood tests, such as lymphopenia, increased neutrophil to lymphocyte ratio, elevated C-reactive protein, upregulated lactose dehydrogenase, prolonged prothrombin time, increased aspartate aminotransferase, creatinine, creatine kinase, IL-6, or decrease in antithrombin activity. In contrast, the serum level of procalcitonin, a blood marker for bacterial infections, was normal in COVID-19 patients on hospital admission. The low absolute value of lymphocytes can be used as a reference indicator for diagnosis(1).
Activated partial thromboplastin time (APTT) testing in patients with COVID-19 provides useful information for monitoring unfractionated heparin (UFH). Heparin is often used during the treatment of COVID-19, and heparin-induced thrombocytopenia (HIT) is reported. This diagnosis should not be delayed, and the proactive measurement of HIT antibodies is needed(4).
A prolonged APTT, which is frequently considered indicative of a systemic coagulopathy, may be caused by a lupus anticoagulant(4,5,10). Similar to patients with severe COVID-19-associated coagulopathy, about 1% of antiphospholipid syndrome (APS) patients develop a severe life-threatening clinical condition, characterized by multiple thrombosis, involving mainly small vessels, which has been described as catastrophic APS (CAPS)(10,11). In both COVID-19-associated coagulopathy and CAPS, acute inflammatory response, cytokine storm and highly elevated ferritin levels occur. In patients with definite CAPS, along with a clinically aPL profile, aPL test results, usually in high titres, remain positive over long periods of time. In contrast, infection-induced aPL may be transient(10). The disease severity and the medications used in COVID-19 can affect lupus anticoagulant testing, and patients hospitalized with COVID-19 become transiently positive for aPL antibodies(12). The question of whether transient aPL positivity may contribute to the occurrence of thrombotic events needs further studies(5,10).
The care of pregnant patients with COVID-19 or suspected with pathogenic autoantibodies add further complexity with regard to antiphospholipid syndrome as a potentially life-threatening acquired thrombophilia.
Heparins are the anticoagulants of choice in the prevention of thrombotic complications for both pregnant and nonpregnant patients with COVID-19, in ambulatory and hospitalized patients, unless there are absolute or relative contraindications, such as active bleeding, severe thrombocytopenia, heparin-induced thrombocytopenia or an anticipated surgical procedure or delivery within 12 hours(13). When decided, thromboprophylaxis was achieved with preventive treatment once-daily with low-molecular-weight heparins (LMWHs), or with prophylactic twice-daily subcutaneous unfractionated heparin (UFH). Patients receiving low-molecular-weight heparins for VTE prophylaxis should have dose adjustments for obesity (BMI of 30 to 40 kg/m2) and renal function(14).
If no urgent procedures are anticipated, LMWHs are used. Compared with unfractionated heparin, the LMWHs have the advantage of a more predictable dose-response curve. Consequently, the LMWHs are administered in a fixed dose, based on total body weight, decreased risk of HIT and osteoporosis, and do not require tight regulation and monitoring, as indicated with UFH. In cases with renal insufficiency, obesity, or when iatrogenic overdose is a concern, antifactor Xa levels can be used to monitor LMWH. Ideally, the antifactor Xa level should be obtained 4 hours after the administration of the LMWH(15).
Taking into account the coagulopathy and interaction with acute-phase proteins, UFH monitoring must be done with an anti-Xa assay instead of the aPTT(14), when used intravenously, because the therapeutic efficacy occurs almost immediately, while the therapeutic efficacy is reached within 20-60 minutes when administered subcutaneously(15).
For postpartum women, the duration of thromboprophylaxis may vary from 2 to 6 weeks, depending on risk factors(16).
Following discharge from hospital, prolonged pharmacological VTE prophylaxis in the ambulatory setting is reasonable in patients with persistent immobility, high inflammatory activity and/or additional risk factors(5).
The dose, duration and the type of anticoagulation should be determined individually(16).
A sizeable proportion of thrombotic complications occurred despite thromboprophylaxis, controversy exists regarding the dose, timing, risk-benefit ratio and the duration of anticoagulation, clearly underlining the need of an optimized antithrombotic strategy(17,18).
A crucial consideration in patients with COVID-19 is that thrombotic complications also include immunothrombosis, which may not be prevented by the administration of anticoagulants(13). Proinflammatory cytokines are critically involved in abnormal clot formation and platelet hyperactivation also plays an important role in the downregulation of important physiological anticoagulant pathways(3).
Preventing thrombosis and delaying coagulopathy progression to DIC might improve outcomes in high-risk patients(19).
Patients infected with SARS-CoV-2 are at an increased risk of thrombosis due to their overcoagulation status, endothelial dysfunction, hypoxemia, pulmonary intravascular coagulation and thromboinflammation(17).
Common laboratory changes in COVID-19 coagulopathy include increased D-dimer concentrations and elevated fibrinogen. Less commonly, decreased fibrinogen and platelet count associated with prolongation of the prothrombin time may occur and suggest the diagnosis of disseminated intravascular coagulation(20)
The application of unfractionated heparin and LMWH inhibits thrombin activation, reduces inflammation and inhibits platelet aggregation, thereby preventing thrombosis and delaying coagulopathy progression to DIC in high-risk patients(21).
The identification of current practice patterns about prevention, diagnosis and treatment of coagulopathy in patients with COVID-19 has important implications(12).
In conclusion, coagulopathy is a non-negligible complication and a potentially important cause of death in patients with critical COVID-19. The dynamic monitoring of hematological and coagulation parameters might provide a reliable and convenient method for classifying and predicting the severity and outcomes of patients with COVID-19(21).