COVID-19-associated coagulopathy

Haemostatic changes are seen in patients with severe coronavirus disease 2019 (COVID‐19) infection and their possible causes. There is a crosstalk between inflammation and coagulation resulting in high levels of acute‐phase proteins, very high levels of D‐dimers, and absence of disseminated intravascular coagulation seen in patients with severe COVID‐19. There appears to be high rates of venous thromboembolism and also, what has been poorly described before in acute lung injury, a high rate of pulmonary immunothrombosis (thrombosis secondary to inflammation).¹

COVID-19-associated coagulopathy

• There are marked increases in coagulation proteins in patients with severe coronavirus disease 2019 (COVID‐19) infection, consistent with a profound acute‐phase response.
• D‐dimer levels are extremely high and reflect activation of fibrinolysis systemically and also in the lungs.
• Disseminated intravascular coagulation is rarely seen in severe COVID‐19 infection outside of preterminal multiorgan failure.
• Thrombosis rates appear high due to venous thromboembolism and pulmonary immunothrombosis.

Blood Clotting in COVID-19 patients

According to new studies, most patients hospitalized because they have COVID-19 pneumonia have an unusual pattern of lab test abnormalities that have not been seen with prior infections. The abnormalities include elevated blood biomarkers for substances that signify high levels of inflammation and clotting activity called “thrombo-inflammation.” Patients with a high levels of thrombo-inflammation have the highest risk of death from COVID-19.

“In patients with high levels of thrombo-inflammation, we believe that tiny clots forming in the inflamed lungs may contribute to respiratory failure and the need for intensive care and ventilator use,” said co-author Prof. Levi, Consultant Physician at University College London Hospitals in London.

Prof. Hunt, Consultant at Guy's and St. Thomas' Hospitals in London, continued, “What is particularly interesting is that the use of blood thinning medications improved survival in those with thrombo-inflammation.³

Studies from China have shown increased D-dimers (0.5 mg/L or higher) in 46–63% of patients with COVID-19. Elevation in D-dimers was associated with higher rates of intensive care unit admission, development of ARDS (Acute respiratory distress syndrome) and mortality. One study found a D-dimer cut-off value of 1.5 μg/mL had 85% sensitivity and 88.5% specificity for VTE prediction in patients with COVID-19. However, the use of a D-dimer alone for risk stratification is not very useful for the following reasons: (1) elevated D-dimer levels are not specific for the diagnosis of VTE and (2) if only a high D-dimer level is relied on for diagnosis, it will unnecessarily increase the utilization of computed tomography pulmonary angiography (CTPA) without much benefit. Moreover, CTPA may worsen kidney function as a result of contrast use in critically ill patients.⁴

Imaging studies can help yield a definitive diagnosis of VTE. Studies have shown the usefulness of compression ultrasonography and CTPA. One study from Italy showed 16 (36%) out of 44 patients had VTE on imaging, and ten (33%) out of 30 patients had a pulmonary embolism on CTPA. More than 50% of VTE events were diagnosed within the first 24 h of hospital admission, highlighting the significance of early diagnosis and treatment in patients with COVID-19.⁵

Coagulopathy in COVID-19 as compared to DIC

DIC is recognized as a syndrome that complicates a variety of diseases and conditions with systemic activation of coagulation leading to thrombotic obstruction of small and less commonly medium-sized blood vessels. Unlike microangiopathies and COVID-19-associated coagulopathy, bleeding can dominate the clinical phenotype of DIC. In addition to activation of coagulation proteins, tissue factor and vascular endothelial cells, DIC is associated with activation of the fibrinolytic system, reduced endothelial cell surface proteases (Antithrombin, Protein C) and thrombocytopenia. The most common causes of DIC are severe infection, sepsis, major trauma, malignancy (acute or chronic DIC), complications of pregnancy, toxin exposures, severe allergic reactions and immunologic reactions (e.g. blood product transfusion).⁶

The laboratory features of DIC vary widely depending on the stage encountered. In early DIC, there is compensated activation of the hemostatic system, however with progression to decompensated hemostatic activation, characteristic findings are observed. These include thrombocytopenia, increased PT and PTT, elevated fibrinogen degradation products and decreased protease inhibition. Fibrinogen levels vary, however, in advanced stages of DIC fibrinogen levels decrease. VWF and factor VIII levels are typically increased from endothelial cell activation, but historically they are not elevated to the degree currently being observed in COVID-19-associated coagulopathy.⁶

Guidelines on Management of Coagulopathy in COVID-19

Clinical experience in COVID‐19 suggests there are anticoagulation failures in patients already receiving prophylactic anticoagulation. In a recently published study, despite systematic thromboprophylaxis, 31% of the 184 patients in critical care units with COVID‐19 developed thrombotic complications. In an update of this cohort, the cumulative incidence of arterial and venous thromboembolism was 49% (95% confidence interval, 41‐57). There is marked increase in the incidence of venous thromboembolism (VTE) in patients requiring intensive care unit (ICU) care that exceed similarly cared for ICU patients without COVID‐19, including comparison to past influenza patients. This could be due to several reasons:

• (a)

  COVID‐19‐specific coagulation changes with extensive coagulation activation for whichprophylactic dosing may be insufficient
• (b)

  Thromboembolism had already developed before starting anticoagulation
• (c)

  Inadequate dosing (high body mass index or inaccurate dosing).^6,7

In the setting of critically ill patients requiring mechanical ventilation, immobilization can occur from deep sedation and muscle paralysis. Also, the use of high‐pressure ventilation settings resulting in high intrathoracic pressure may impair pulmonary perfusion. Significant controversy has developed regarding an empiric increase in the dose of heparin, especially in the following situations

1. (a)

   Worsening of the clinical picture manifest as increasing oxygen requirements, which may bedue to pulmonary microthrombi.
2. (b)

   Suspicion of pulmonary thromboembolism based on abrupt development of hypoxemia, newtachycardia, and right heart strain seen on echocardiogram. Heightened suspicion should bemaintained in ALL patients;
3. (c)

   Need for ICU care and ventilatory support as the cumulative incidence of VTE in ICU patients has been found to be higher than those not requiring ICU care^6,7

Conclusion

An acquired syndrome known as COVID-19-associated coagulopathy has emerged and proven itself to be common, multifactorial with involvement of the venous, arterial and microcirculatory systems and distinct from other viral illnesses. As the world continues to learn more about COVID-19, emerging data reveals that hospitalized patients with COVID-19 have an increased risk for blood clots.⁸