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:

Overview

There is an association between severe COVID-19 infection and thrombocytopenia.

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 is defined by platelet count <150 x <math>10^9</math>/L on CBC.
• Classification of thrombocytopenia 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
• Most patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.
• Patients with platelet count between 30 and 50 x <math>10^9</math>/L rarely have purpura, but may have excessive bleeding with trauma.
• Patients with platelet count between 10 and 30 x <math>10^3</math>/L may have bleeding with minor trauma.
• Patients with platelet count less than 10 x <math>10^3</math>/L have increased risk for spontaneous bleeding, petechiae, and bruising.
• 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 increase in auto-antibodies and immune complexes.

• Decrease in circulating platelet due to lung injury which causes megakaryocyte fragmentation and decreases platelet production, because lung is a reservoir for megakaryocyte and hematopoieitic progenitor cells and has a role in platelet production.
• In addition, decrease in platelets may be due to activation of platelets that result in platelet aggregation and formation of micro-thrombus which increase platelet consumption.

Causes

The causes of thrombocytopenia in COVID-19 infection are:

• Attack on hematopoietic stem cells (HSCs)  
• Abnormal bone marrow microenvironment
• Decreased production of thrombopoietin (TPO)  
• Cellular immunity and cytokine storm  
• Lung damage  
• Increased platelet consumption
• Increased platelet clearance
• Drug-induced thrombocytopenia (antiviral drugs)

Differentiating Thrombocytopenia from other Diseases

The differential diagnosis to consider in thrombocytopenia include:

• Pseudothrombocytopenia  
• Splenomegaly
• Infections (Epstein-Barr virus, cytomegalovirus, hepatitis C, HIV, parvovirus B19, H pylori)
• Drugs (antibiotics, alcohol, chemotherapy, radiation)
• Folate deficiency or vitamin B12 deficiency
• Liver disease
• Bone marrow failure (such as aplastic anemia, Fanconi anemia, and Diamond-Blackfan anemia)
• Hematologic disorders (lymphoma, leukemia, myelodysplastic syndrome)
• Tumor infiltration of bone marrow
• 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)
• Posttransfusion purpura
• Autoimmune-related thrombocytopenia (such as systemic lupus erythematosus (SLE), common variable immunodeficiency (CVID), antiphospholipid antibody syndrome,thyroid disease)
• Mechanical destruction (such as cardiopulmonary bypass, intra-aortic balloon pump)  

Epidemiology and Demographics

• Thrombocytopenia is seen in 36% of 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 syndrome
• 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 compelete blood count (CBC).

• Thrombocytopenia is defined by platelet count <150 x <math>10^9</math>/L on CBC.
• Thrombocytopenia in patients with COVID-19 is usually moderate (>100× <math>10^9</math>/L), however in patients with multi-organ failure with ARDS or capillary leak syndrome platelet count is >50×<math>10^9</math>.

History and Symptoms

• Thrombocytopenia in patients with COVID-19 is usually moderate (>100× <math>10^9</math>/L), however in patients with multi-organ failure with ARDS or capillary leak syndrome platelet count is >50×<math>10^9</math>.
• Most patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.

• 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

• Thrombocytopenia in patients with COVID-19 is usually moderate (>100× <math>10^9</math>/L), however in patients with multi-organ failure with ARDS or capillary leak syndrome platelet count is >50×<math>10^9</math>.
• 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 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

• Compelete blood count (CBC): Thrombocytopenia is defined by platelet count <150 x <math>10^9</math>/L on CBC.
  • Thrombocytopenia in patients with COVID-19 is usually moderate (>100× <math>10^9</math>/L), however in patients with multi-organ failure with ARDS or capillary leak syndrome platelet count is >50×<math>10^9</math>.

• Peripheral blood smear:

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

There are no established measures for the secondary prevention of [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

References

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