Managing COVID-19-Associated Coagulopathy in Hemophilia Patients

As the coronavirus disease 2019 (COVID-19) pandemic continues, with the super-contagious Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenging the sanitary control of the disease in many countries, research and medical communities are seeking understanding on how COVID-19 affects patients with chronic diseases. In addition, it is essential to assure that these patients receive proper treatment.

In the case of hemophilia, evidence suggests that the course of infection with SARS-CoV-2 is similar to that of the general population, but other challenges exist, particularly regarding treatment. “Rapid identification of the hemophilia status, undelayed and regular liaison with the hemophilia team, proper therapy with factor concentrates or alternative treatments appear instrumental to prevent hemophilia-related complications in this setting,” Hermans et al wrote in the journal Haemophilia.

COVID-19 has been associated with coagulopathy, which in turn can be responsible for pulmonary microvasculature thrombosis and systemic thromboembolic manifestations. The management of COVID-19-associated coagulopathy is likely to be more complex in patients with hemophilia or other bleeding disorders. In a review article published in Haemophilia, Pipe et al stated, “These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and hemostatic treatments.”

Identifying COVID‐19‐Associated Coagulopathy

The International Society on Thrombosis and Hemostasis, American Society of Hematology, and American College of Cardiology, among others, have been working on recommendations to recognize, monitor, and manage COVID‐19‐associated coagulopathy.

According to the summary provided by Pipe et al, to identify COVID‐19‐associated coagulopathy it is important to consider the following:

• Elevated fibrinogen, factor VIII (FVIII), von Willebrand factor (VWF), and D‐dimer levels with minimal changes in prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count in the early stages of infection are usually compatible with coagulopathy
  • Increased D‐dimer levels are the most significant change in coagulation parameters in COVID‐19‐infected patients – this occurs more frequently than alterations in other coagulation parameters
    • Elevated D‐dimer levels on admission are associated with increased mortality
    • Rising D‐dimer levels after admission precede multiorgan failure and overt disseminated intravascular coagulopathy (DIC); this was noted to start at 4 days after admission in nonsurvivors
    • Longer duration of hospital stay is associated with increasing D‐dimer levels and the development of sepsis physiology
  • Increasing interleukin-6 (IL‐6) levels directly stimulate increasing fibrinogen levels
  • A sudden marked decrease in plasma fibrinogen (to concentrations <1.0 g/L) suggestive of DIC with enhanced fibrinolysis has been observed shortly before death in a number of patients with COVID‐19 in China
  • A significant reduction in the platelet count, fibrinogen levels, or antithrombin levels, most frequently associated with DIC, have not been frequently described in patients with COVID‐19.

In addition, coagulopathy appears to be associated with the severity of illness and resultant thromboinflammation rather than the intrinsic viral activity. Bleeding manifestations are uncommon despite the coagulopathy (the overall and major bleeding rates are estimated to be approximately 5% and 2%, respectively)

Hence, the authors suggested that all patients admitted to the hospital should have their baseline coagulation parameters monitored. This includes PT, aPTT, fibrinogen, D‐dimer, and platelet count.

Balancing Bleeding Thrombotic Event Risk

The need to balance the increased risk of thrombotic events and bleeding is critical in hemophilia patients. This implies extra care with treatments such as emicizumab (Hemlibra^®), which is used to prevent hemorrhage.

“Observations from registration studies have shown a small number of cases displaying increased risk of thrombotic events and thrombotic microangiopathy, especially when combined with bypassing agents,” Urbaniak‐Kujda et al wrote in a letter to the editor in Haemophilia.

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Hence, when an additional prothrombotic factor such as COVID-19 is present, it may enhance prothrombotic activity. On the other hand, it has also been reported that patients receiving emicizumab may experience hemorrhagic episodes.

Urbaniak‐Kujda et al presented the case of a 70-year-old male patient with severe hemophilia A who developed severe COVID-19. Additionally, he suffered from hypertension and had a hepatitis C virus (HCV) infection in 2008 that was successfully treated.

At the time of admission, he was on emicizumab prophylaxis (3 mg/kg once weekly). He had no history of bleeding or thromboembolic events. Laboratory analysis confirmed SARS-CoV-2 infection on the day of admission.

The respiratory status of the patient deteriorated during hospitalization, ultimately requiring intubation and intensive care unit (ICU) admission. From this time on, the patient was administered prophylactic low‐molecular‐weight heparin (LMWH).

“As recommended by recent consensus guidelines, standard weight‐based prophylactic anticoagulation with LMWH should be offered as early as possible to prevent thrombotic events and organ damage in all patients with COVID‐19 infection requiring hospital admission, including the noncritically ill, unless contra‐indicated,” Pipe et al stated.

Conversely, direct oral anticoagulants should be avoided due to the risk of interactions with antiviral therapeutics.

The patient also received remdesivir for 5 days, dexamethasone, and convalescent plasma for COVID-19. Periodic administration of norepinephrine was required during the first 2 days in the ICU.

He was later diagnosed with ventilator‐associated bacterial pneumonia and secondary sepsis. He was treated for these conditions while maintaining the weekly dose of emicizumab. The dose of LMWH was increased to therapeutic levels and regular injections of plasma‐derived (pd) FVIII concentrate were administered.

The patient tested negative for COVID-19 after 19 days of hospitalization. On day 30, he was breathing independently, replacement therapy with pdFVIII was stopped, and he was continued on emicizumab prophylaxis. The patient was at home at the time of publication.

References

Pipe SW, Kaczmarek R, Srivastava A, Pierce GF, Makris M, Hermans C; Interim Guidance; Coagulation Products Safety, Supply and Access (CPSSA) Committee of the World Federation of Hemophilia. Management of COVID‐19‐associated coagulopathy in persons with haemophilia. Haemophilia. 2021;27(1):41-48. doi:10.1111/hae.14191

Urbaniak‐Kujda D, Biernat MM, Skalec T, Jacków‐Nowicka J, Windyga J, Wróbel T. Successful treatment of COVID‐19 in a patient with severe haemophilia A on emicizumab prophylaxis in the intensive care unit. Haemophilia. 2021;27(4):e567-e570. doi:10.1111/hae.14326

Hermans C, Lambert C, Sogorb A, Wittebole X, Belkhir L, Yombi JC. In-hospital management of persons with haemophilia and COVID-19: practical guidance. Haemophilia. 2020;26(5):768-772. doi:10.1111/hae.14045