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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


There have been lots of publications about the thrombotic nature of the coronavirus, however the actual relationship between this thrombotic nature is not well understood. Data has shown that the role of COVID-19 and patients exhibiting a cytokine storm resulted in thrombotic complications.(1) Information on bleeding as a complication of COVID is limited however a study showed that up to 18% of patients admitted to the ICU had a major bleeding event. This included bleeding that occurs in a critical organ, or that is fatal, a hemoglobin level drop by 2 g/dL that requires a transfusion of two or more units of packed red cells.(2) The SARs-CoV-2 infection can result in activation of the coagulation cascade, fibrinolysis and in severe cases disseminated intravascular coagulation (DIC).(3)

 

Bleeding events

Bleeding event rate was 4.8%, which included 3.1% rate of noncritically ill patients and 7.6% rate in critically ill patients with a major bleeding rate of 2.3%.(4) The incidence of major bleeding occurs between the second and third week after admission. In contrast, the incidence of thrombosis occurs more frequently within the first week. There is an initial hyperinflammatory phase which results in elevated levels of acute phase reactants, but after that D-dimer levels and fibrinogen levels can fall and contribute to anticoagulant overdose. A study of 56 ICU patients with a major bleed found that fibrinogen levels decreased three to five days prior to the occurrence of bleeding and could be used as a marker to alert clinicians to the possibility of a bleed.(2)

 

Causes of Bleeding in COVID Patients

Patients who presented with thrombotic complications had a consistently elevated D-dimer, fibrinogen, CRP, ferritin and procalcitonin in contrast to patients with bleeding complication presented with higher procalcitonin and peak D-dimer as well as low platelet counts.(4) A review of 58 studies that included 6902 patients showed that thrombocytopenia was found in 22.9% of patients.(2) Older people who present with thrombocytopenia most commonly result in cerebral hemorrhage as a bleeding complication. Although rare (0.6 cases/100 patients) the mortality rate is 45.7%.(5)

Severe immune thrombocytopenia have also been seen as a result of SARs-COV-2. There has also been a correlation between COVID-19 and the development of disseminated intravascular coagulation (DIC).(1)

Bleeding complications have also been seen in some patients. Understanding the balance between coagulation and fibrinolysis will help when considering approaches to thrombosis prophylaxis as well as the possible utilization of fibrinolytic targeted therapies.(3) A study looked at 118 COVID 19 patients versus 30 normal healthy controls. Half of the COVID patients were on a ventilator, and a quarter breathed room air. It was found that patients on supplemental oxygen had higher levels of plasminogen activator inhibitor 1 (PAI-1) when compared to those breathing room air. PAI-1 is responsible for stabilizing clots. Patients with high level of tissue plasminogen activator (tPA) which is responsible for removing blood clots resulted in worse lung function, but high tPA was linked to death. Blood from 10 COVID patients with high tPA, were compared with 10 COVID patients with low tPA as well as 10 healthy volunteers. Results showed that plasma from COVID patients with high levels of tPA and PAI-1 correlated with worse respiratory status. Extremely high levels of tPA enhance spontaneous fibrinolysis and are signficantly associated with mortality. High levels of tPA could be a biomarker for a high bleeding risk and poor outcomes.(3)

Gastrointestinal bleeding has been demonstrated to be an increased risk in these patients. This may be the result of stress, critical illness or mechanical ventilation. Additionally, the virus may infect the endothelium of blood vessels and contribute to GI bleeding.(1) Adrenal insufficiency causes increased blood flow and reduced venous return which can contribute to both GI and retinal bleeding.(2) SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE-2) receptors, causing a decrease in their activity. This triggers an immune response and activates the renin-angiotensin-aldosterone axis, causing an increase in blood pressure and thus favoring endothelial dysfunction and bleeding.(6)

Due to the thrombotic nature of COVID-19, clinical practice guidelines recommend thromboprophylaxis with heparin. There has been no evidence to indicate a full dose of heparin in these patients unless thromboembolism is present or other indication for use such as AF, or a mechanical heart valve. Excess heparin may result in hemorrhage in soft tissue, muscle or the retroperitoneal space. It is important to be aware of this type of bleeding in patients on heparin.(2)

 

Conclusion:

SARS-CoV-2 infection is associated with inflammation and thrombosis. It has been shown that there are cases in which COVID-19 patients may present with a bleeding event. It is important to be aware of this and to use anticoagulation with caution to maintain a hemostatic balance.

 

 

REFERENCES:

  1. Mohamed M, Nassar M, Nso N, Alfishawy M. Massive gastrointestinal bleeding in a patient with COVID-19. Arab J Gastroenterol. 2021;22(2):177-179.
  2. Boira I, Esteban V, Vañes S, et al. (August 01, 2021) Major Bleeding Complications in COVID-19 Patients. Cureus 13(8): e16816.
  3. Zuo, Y., Warnock, M., Harbaugh, A. et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci Rep 11, 1580 (2021).
  4. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500.
  5. Altschul DJ, Unda SR, de La Garza Ramos R, et al.: Hemorrhagic presentations of COVID-19: Risk factors for mortality. Clin Neurol Neurosurg. 2020,
  6. Chan NC, Weitz JI: COVID-19 coagulopathy, thrombosis, and bleeding. Blood. 2020, 136:381-383.