COVID-19-associated thrombocytopenia
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
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 is 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, decrease in platelets 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.[1][2]
- 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).[3]
- Classification of thrombocytopenia in general by platelet count is:[4]
- 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:[4]
- 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:[5][6][7][8][9][10]
- 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:[5]
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:[11]
- 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.[12]
- Thrombocytopeniais seen in 57.7% of patients with severe COVID-19 infection compared to 31.6 % of patients with non-severe infection.[12]
Risk Factors
- Thrombocytopenia in COVID-19 infection is more common is patients with severe infection compared to patients with non-severe infection.[12]
Screening
- It has been reported that thrombocytopenia upon admission for COVID-19 infection is associated with severe disease and mortality.[13]
- 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.[14]
Natural History, Complications, and Prognosis
Natural History
- Thrombocytopenia is associated with an increased risk for severe COVID-19 infection (threefold).[15]
Complications
- Complications of thrombocytopenia in patients with severe COVID-19 infection may include:[14]
Prognosis
- It has been reported that thrombocytopenia upon admission for COVID-19 infection is independently and strongly associated with poor outcome and mortality.[13]
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.[3]
- 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.[12]
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.[12]
- In general, in thrombocytopenic patients, most patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.[4]
- In general, in thrombocytopenic patients should be questioned about:[3][4]
- 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.[12]
- In general, in thrombocytopenic patients, most patients are asymptomatic if the platelet count is 50,000 x <math>10^9</math>/L or greater.[4]
- The physical examination in patients with thrombocytopenia in general should include checking for:[3]
- Bleeding (epistaxis, bloody sputum, gingival bleeding, menorrhagia, heavy bleeding after invasive procedures or childbirth)[16][17]
- Unexplained bruising (petechiae, purpura, ecchymosis)
- Hepatosplenomegaly
- Abdominal tenderness
- Urinary tract (check for hematuria)[18]
- Stool for occult blood (evaluation of gastrointestinal and rectal bleeding)
- Retinal hemorrhage on fundoscopic exam (evaluation of central nervous system bleeding)[18]
- Neurologic examination (check for intracranial bleeding)[18]
- Soft tissue or joint bleeding is not associated with thrombocytopenia and other coagulation disorders such as DIC should be checked.[17][18]
Laboratory Findings
- Complete blood count (CBC): Thrombocytopenia in general is defined by platelet count <150 x <math>10^9</math>/L on CBC.[3]
- 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.[12]
- 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:[19]
- 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.
References
- ↑ https://www.cdc.gov/coronavirus/2019-ncov/about/index.html. Missing or empty
|title=(help) - ↑ Lu, Jian; Cui, Jie; Qian, Zhaohui; Wang, Yirong; Zhang, Hong; Duan, Yuange; Wu, Xinkai; Yao, Xinmin; Song, Yuhe; Li, Xiang; Wu, Changcheng; Tang, Xiaolu (2020). "On the origin and continuing evolution of SARS-CoV-2". National Science Review. doi:10.1093/nsr/nwaa036. ISSN 2095-5138.
- ↑ 3.0 3.1 3.2 3.3 3.4 Greenberg EM (2017). "Thrombocytopenia: A Destruction of Platelets". J Infus Nurs. 40 (1): 41–50. doi:10.1097/NAN.0000000000000204. PMID 28030481.
- ↑ 4.0 4.1 4.2 4.3 4.4 Gauer RL, Braun MM (2012). "Thrombocytopenia". Am Fam Physician. 85 (6): 612–22. PMID 22534274.
- ↑ 5.0 5.1 Xu P, Zhou Q, Xu J (2020). "Mechanism of thrombocytopenia in COVID-19 patients". Ann Hematol. 99 (6): 1205–1208. doi:10.1007/s00277-020-04019-0. PMC 7156897 Check
|pmc=value (help). PMID 32296910 Check|pmid=value (help). - ↑ Yang M, Ng MH, Li CK (2005). "Thrombocytopenia in patients with severe acute respiratory syndrome (review)". Hematology. 10 (2): 101–5. doi:10.1080/10245330400026170. PMID 16019455.
- ↑ Yeager CL, Ashmun RA, Williams RK, Cardellichio CB, Shapiro LH, Look AT; et al. (1992). "Human aminopeptidase N is a receptor for human coronavirus 229E". Nature. 357 (6377): 420–2. doi:10.1038/357420a0. PMC 7095410 Check
|pmc=value (help). PMID 1350662. - ↑ Nardi M, Tomlinson S, Greco MA, Karpatkin S (2001). "Complement-independent, peroxide-induced antibody lysis of platelets in HIV-1-related immune thrombocytopenia". Cell. 106 (5): 551–61. doi:10.1016/s0092-8674(01)00477-9. PMID 11551503.
- ↑ Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM; et al. (2017). "The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors". Nature. 544 (7648): 105–109. doi:10.1038/nature21706. PMC 5663284. PMID 28329764.
- ↑ Liu X, Zhang R, He G (2020). "Hematological findings in coronavirus disease 2019: indications of progression of disease". Ann Hematol. doi:10.1007/s00277-020-04103-5. PMC 7266734 Check
|pmc=value (help). PMID 32495027 Check|pmid=value (help). - ↑ Lee EJ, Lee AI (2016). "Thrombocytopenia". Prim Care. 43 (4): 543–557. doi:10.1016/j.pop.2016.07.008. PMID 27866576.
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX; et al. (2020). "Clinical Characteristics of Coronavirus Disease 2019 in China". N Engl J Med. 382 (18): 1708–1720. doi:10.1056/NEJMoa2002032. PMC 7092819 Check
|pmc=value (help). PMID 32109013 Check|pmid=value (help). - ↑ 13.0 13.1 Maquet J, Lafaurie M, Sommet A, Moulis G, Covid-Clinic-Toul investigators group. Alvarez M; et al. (2020). "Thrombocytopenia is independently associated with poor outcome in patients hospitalized for COVID-19". Br J Haematol. doi:10.1111/bjh.16950. PMID 32557535 Check
|pmid=value (help). - ↑ 14.0 14.1 Zhang Y, Zeng X, Jiao Y, Li Z, Liu Q, Ye J; et al. (2020). "Mechanisms involved in the development of thrombocytopenia in patients with COVID-19". Thromb Res. 193: 110–115. doi:10.1016/j.thromres.2020.06.008. PMC 7274097 Check
|pmc=value (help). PMID 32535232 Check|pmid=value (help). - ↑ Lippi G, Plebani M, Henry BM (2020). "Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis". Clin Chim Acta. 506: 145–148. doi:10.1016/j.cca.2020.03.022. PMC 7102663 Check
|pmc=value (help). PMID 32178975 Check|pmid=value (help). - ↑ Ghoshal K, Bhattacharyya M (2014). "Overview of platelet physiology: its hemostatic and nonhemostatic role in disease pathogenesis". ScientificWorldJournal. 2014: 781857. doi:10.1155/2014/781857. PMC 3960550. PMID 24729754.
- ↑ 17.0 17.1 Stasi R (2012). "How to approach thrombocytopenia". Hematology Am Soc Hematol Educ Program. 2012: 191–7. doi:10.1182/asheducation-2012.1.191. PMID 23233580.
- ↑ 18.0 18.1 18.2 18.3 Sekhon SS, Roy V (2006). "Thrombocytopenia in adults: A practical approach to evaluation and management". South Med J. 99 (5): 491–8, quiz 499-500, 533. doi:10.1097/01.smj.0000209275.75045.d4. PMID 16711312.
- ↑ Lorenzo-Villalba N, Zulfiqar AA, Auburtin M, Schuhmacher MH, Meyer A, Maouche Y; et al. (2020). "Thrombocytopenia in the Course of COVID-19 Infection". Eur J Case Rep Intern Med. 7 (6): 001702. doi:10.12890/2020_001702. PMC 7279909 Check
|pmc=value (help). PMID 32523922 Check|pmid=value (help).