COVID-19-associated thrombocytopenia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2]

Synonyms and keywords: Decrease in platelet count in COVID 19, effects of thrombocytopenia in COVID 19, thrombocytopenia complications of COVID 19

Overview

Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called SARS-CoV-2, which caused a respiratory illness outbreak that was first detected in Wuhan, China. Thrombocytopenia in COVID-19 infection is more common in patients with severe infection and it has been reported that thrombocytopenia upon admission for COVID-19 infection is associated with poor outcome and mortality. Thrombocytopenia is defined by platelet count <150 x <math>10^9</math>/L on complete blood count (CBC). The pathogenesis of thrombocytopenia in COVID-19 infection is due to several factors such as: infection of bone marrow, cytokine storm caused by the COVID-19 infection, increase in autoantibodies and immune complexes, lung injury which causes megakaryocyte fragmentation, and decrease in platelets which may be due to the activation of platelets that result in platelet aggregation.

Historical Perspective

• Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called SARS-CoV-2, which caused a respiratory illness outbreak that was first detected in Wuhan, China.

• On January 30, 2020, the outbreak was declared a Public Health Emergency of International Concern.
• On March 12, 2020, the COVID-19 outbreak was declared a pandemic by the World Health Organization (WHO).

Classification

• Thrombocytopenia in general is defined by platelet count <150 x <math>10^9</math>/L on complete blood count (CBC).
• Classification of thrombocytopenia in general by platelet count is:
  • Mild: between 70,000 and 150,000 x <math>10^9</math>/L
  • Severe: less than 20,000 x <math>10^9</math>/L
• In general:
  • Most thrombocytopenic patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.
  • Thrombocytopenic patients with platelet count between 30 and 50 x <math>10^9</math>/L rarely have purpura, but may have bleeding with trauma.
  • Thrombocytopenic patients with platelet count between 10 and 30 x <math>10^3</math>/L may have bleeding with minor trauma.
  • Thrombocytopenic patients with platelet count less than 10 x <math>10^3</math>/L have increased risk for spontaneous bleeding, petechiae, and bruising.
  • In thrombocytopenic patients, spontaneous bleeding, which is an emergency, usually occurs in patients with platelet counts less than 5 x <math>10^3</math>/L .

Pathophysiology

The pathogenesis of thrombocytopenia in COVID-19 infection is due to several factors:

• Decrease in primary platelet production due to infection of bone marrow cells by coronaviruses and inhibition of bone marrow growth, which lead to abnormal hematopoietic function.
• Decrease in platelets may also be due to a cytokine storm caused by the COVID-19 infection which results in the destruction of bone marrow progenitor cells.
• Increase in platelet destruction due to an increase in autoantibodies and immune complexes.
• Decrease in circulating platelet due to lung injury which causes megakaryocyte fragmentation and decreases platelet production, because the lung is a reservoir for megakaryocyte and hematopoietic progenitor cells and has a role in platelet production.
• In addition, a decrease in platelets may be due to the activation of platelets that result in platelet aggregation and formation of micro-thrombus which increase platelet consumption.

Summary of the mechanisms involved in thrombocytopenia in COVID-19 infection:

Causes

• Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called SARS-CoV-2 and is the cause of thrombocytopenia in COVID-19 infection.

Differentiating Thrombocytopenia from other Diseases

• Coronavirus disease 2019 (COVID-19) may cause thrombocytopenia. The differential diagnosis to consider for thrombocytopenia in general include:
  • Pseudothrombocytopenia  
  • Inherited thrombocytopenias (Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, and thrombocytopenia with absent radii)  
  • Immune thrombocytopenic purpura (ITP) and drug-induced ITP (such as quinine, NSAIDs, glycoprotein IIb/IIIa inhibitors)
  • Heparin-induced thrombocytopenia (HIT)
  • Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS)
  • Drug-induced TTP (such as mitomycin C, gemcitabine, oxaliplatin)
  • Disseminated intravascular coagulation (DIC)
  • Hematologic disorders (lymphoma, leukemia, myelodysplastic syndrome)
  • Post-transfusion purpura
  • Autoimmune-related thrombocytopenia (such as systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID), antiphospholipid antibody syndrome,thyroid disease)
  • Tumor infiltration of bone marrow
  • Bone marrow failure (such as aplastic anemia, fanconi anemia, and diamond-Blackfan anemia)
  • Liver disease
  • Splenomegaly
  • Infections (Epstein-Barr virus, cytomegalovirus, hepatitis C, HIV, parvovirus B19, H pylori)
  • Drugs (antibiotics, alcohol, chemotherapy, radiation)
  • Folate deficiency or vitamin B12 deficiency
  • Mechanical destruction (such as cardiopulmonary bypass, intra-aortic balloon pump)  

For detailed differential diagnosis of thrombocytopenia click here

Epidemiology and Demographics

• Thrombocytopenia is seen in 36.2% of all patients with COVID-19 infection.
• Thrombocytopenia is seen in 57.7% of patients with severe COVID-19 infection compared to 31.6 % of patients with non-severe infection.

Risk Factors

• Thrombocytopenia in COVID-19 infection is more common is patients with severe infection compared to patients with non-severe infection.

Screening

• It has been reported that thrombocytopenia upon admission for COVID-19 infection is associated with severe disease and mortality.
• However, there is insufficient evidence to recommend routine screening and monitoring of thrombocytopenia for predicting disease progression in patients with COVID-19 infection and further studies are required.

Natural History, Complications, and Prognosis

Natural History

• Thrombocytopenia is associated with an increased risk for severe COVID-19 infection (threefold).

Complications

• Complications of thrombocytopenia in patients with severe COVID-19 infection may include:
  • Disseminated intravascular coagulation (DIC)
  • Multiple organ dysfunction syndromes
  • Death

Prognosis

• It has been reported that thrombocytopenia upon admission for COVID-19 infection is independently and strongly associated with poor outcome and mortality.

Diagnosis

Diagnostic Study of Choice

• The diagnostic study of choice for thrombocytopenia is complete blood count (CBC).

• Thrombocytopenia in general is defined by platelet count <150 x <math>10^9</math>/L on CBC.
• The median platelet count in COVID-19 patients with thrombocytopenia is 137,500 and 172,000 x <math>10^9</math>/L in severe and non-severe infection, respectively.

History and Symptoms

• The median platelet count in COVID-19 patients with thrombocytopenia is 137,500 and 172,000 x <math>10^9</math>/L in severe and non-severe infection, respectively.
• In general, in thrombocytopenic patients, most patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.

• In general, in thrombocytopenic patients should be questioned about:
  • Bruising or petechiae
  • Bleeding (melena, epistaxis, menorrhagia, hematuria, prolonged bleeding after procedures, gingival bleeding and blood in sputum)  
  • Past medical history  
  • Family history
  • Medications history
  • Immunization history
  • Changes in vision
  • Rash
  • Fever
  • Recent travel
  • Transfusion history

Physical Examination

• The median platelet count in COVID-19 patients with thrombocytopenia is 137,500 and 172,000 x <math>10^9</math>/L in severe and non-severe infection, respectively.
• In general, in thrombocytopenic patients, most patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.
• The physical examination in patients with thrombocytopenia in general should include checking for:
  • Bleeding (epistaxis, bloody sputum, gingival bleeding, menorrhagia, heavy bleeding after invasive procedures or childbirth)
  • Unexplained bruising (petechiae, purpura, ecchymosis)
  • Hepatosplenomegaly
  • Abdominal tenderness
  • Urinary tract (check for hematuria)
  • Stool for occult blood (evaluation of gastrointestinal and rectal bleeding)  
  • Retinal hemorrhage on fundoscopic exam (evaluation of central nervous system bleeding)
  • Neurologic examination (check for intracranial bleeding)
  • Soft tissue or joint bleeding is not associated with thrombocytopenia and other coagulation disorders such as DIC should be checked.

Laboratory Findings

• Complete blood count (CBC): Thrombocytopenia in general is defined by platelet count <150 x <math>10^9</math>/L on CBC.
  • The median platelet count in COVID-19 patients with thrombocytopenia is 137,500 and 172,000 x <math>10^9</math>/L in severe and non-severe infection, respectively.

• Peripheral blood smear: Peripheral blood smear may be helpful if there is suspicion of other disorders that cause thrombocytopenia. However, there is insufficient evidence recommending routine peripheral blood smear in COVID-19 patients.
• Other laboratory testings (such as HIV, HCV testing, antibody testing, liver enzymes and liver function testing) are performed if there is suspicion of other disorders that cause thrombocytopenia.

Electrocardiogram

• There are no ECG findings associated with COVID-19-associated-thrombocytopenia.

X-ray

• There are no x-ray findings associated with COVID-19-associated-thrombocytopenia.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with COVID-19-associated-thrombocytopenia.

CT scan

• There are no CT scan findings associated with COVID-19-associated-thrombocytopenia.

MRI

• There are no MRI findings associated with COVID-19-associated-thrombocytopenia.

Other Imaging Findings

• There are no other imaging findings associated with COVID-19-associated-thrombocytopenia.

Other Diagnostic Studies

• There are no other diagnostic studies associated with COVID-19-associated-thrombocytopenia.
• However, bone marrow biopsy may be helpful if there is suspicion of other disorders that cause thrombocytopenia, but there is insufficient evidence recommending routine bone marrow biopsy in COVID-19 patients.

Treatment

Medical Therapy

The treatment options for thrombocytopenia in COVID-19 infection include:

• Rituximab
• Thrombopoietin receptor agonists (eltrombopag, avatrombopag, romiplostim)
• High-dose dexamethasone as an alternative to prednisone  
• Intravenous immunoglobulins (IVIG) (1 g/kg on 1 or 2 consecutive days or 0.4 g/kg per day for 5 days)
• Intravenous anti-D (50–75 mg/kg once) (consider potential triggering of DIC or hemolysis)
• Platelet growth factors in patients with bleeding, high risk for bleeding, unresponsive to prednisone (carefully evaluate due to the potential thrombotic events in corona-virus infection)
• Platelet transfusion in refractory visceral or cerebral meningeal hemorrhage

Surgery

• The mainstay of treatment for severe thrombocytopenia in COVID-19 infection is medical therapy.
• Surgery has not been reported to be indicated in thrombocytopenia in COVID-19 infection.

Primary Prevention

• There are no established measures for the primary prevention of thrombocytopenia in COVID-19 infection.

Secondary Prevention

• There are no established measures for the secondary prevention of thrombocytopenia in COVID-19 infection. However, it may include avoidance of antiviral medications.