Approach to the adult with unexplained thrombocytopenia
- James N George, MD
James N George, MD
- Professor of Medicine
- University of Oklahoma Health Sciences Center
- Donald M Arnold, MD, MSc
Donald M Arnold, MD, MSc
- Associate Professor, Department of Medicine
- McMaster University
Thrombocytopenia may be associated with a variety of conditions, with associated risks that may range from life-threatening bleeding or thrombosis (eg, in heparin-induced thrombocytopenia [HIT]) to no risk at all. At the time of initial presentation, the cause may be unclear and the direction of the platelet count trend may not be known. The clinician is faced with distinguishing among many possible causes of thrombocytopenia and determining the risks of bleeding, thrombosis, and other potential complications.
Here we discuss our approach to the adult patient with unexpected thrombocytopenia, divided according to clinical presentation (eg, asymptomatic, associated with another condition, acutely ill hospitalized patient). This approach can be used by the primary care physician and the consulting hematologist. Thrombocytopenia in neonates and children, and thrombocytopenia during pregnancy are discussed separately. (See "Causes of neonatal thrombocytopenia" and "Causes of thrombocytopenia in children" and "Thrombocytopenia in pregnancy".)
DEFINITIONS AND AREAS OF CONCERN
What is a low platelet count — Thrombocytopenia is defined as a platelet count below the lower limit of normal (ie, <150,000/microL [150 x 109/L] for adults). Degrees of thrombocytopenia can be further subdivided into mild (platelet count 100,000 to 150,000/microL), moderate (50,000 to 99,000/microL), and severe (<50,000/microL) . Severe thrombocytopenia confers a greater risk of bleeding, but the correlation between platelet count and bleeding risk varies according to the underlying condition and may be unpredictable. (See 'When to worry about bleeding' below.)
The normal adult platelet count range is 150,000 to 450,000/microL, with mean values of 266,000 and 237,000/microL in females and males, respectively . Within that broad normal range, adult women have slightly higher platelet counts than men, younger people have higher platelet counts than older people, and non-Hispanic Blacks have higher platelet counts than Whites . Despite the wide variation of platelet counts within the population, there is little variation of the platelet count in a given individual over time. As an example, a study of serial platelet counts in 3789 individuals found that the platelet count range for an individual was relatively narrow; differences in platelet count greater than 98,000/microL occurred in less than 0.1 percent of participants . Interestingly, there was a modest seasonal variation, with platelet counts approximately 5000/microL higher in the fall/winter versus the spring/summer. This wide normal range, narrow individual range, and continuous distribution have implications for evaluating any individual patient's platelet count:
●A small proportion of the population (approximately 2.5 percent) will have a baseline platelet count lower than 150,000/microL, because normal values are typically determined based on the 95% confidence intervals around the mean.
- Williamson DR, Albert M, Heels-Ansdell D, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest 2013; 144:1207.
- Buckley MF, James JW, Brown DE, et al. A novel approach to the assessment of variations in the human platelet count. Thromb Haemost 2000; 83:480.
- Segal JB, Moliterno AR. Platelet counts differ by sex, ethnicity, and age in the United States. Ann Epidemiol 2006; 16:123.
- van Bladel ER, Laarhoven AG, van der Heijden LB, et al. Functional platelet defects in children with severe chronic ITP as tested with 2 novel assays applicable for low platelet counts. Blood 2014; 123:1556.
- Wessels P, Heyns AD, Pieters H, et al. An improved method for the quantification of the in vivo kinetics of a representative population of 111In-labelled human platelets. Eur J Nucl Med 1985; 10:522.
- Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest 1969; 48:963.
- Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128:1173.
- Dowling MR, Josefsson EC, Henley KJ, et al. Platelet senescence is regulated by an internal timer, not damage inflicted by hits. Blood 2010; 116:1776.
- Leslie SD, Toy PT. Laboratory hemostatic abnormalities in massively transfused patients given red blood cells and crystalloid. Am J Clin Pathol 1991; 96:770.
- Counts RB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma patients. Ann Surg 1979; 190:91.
- Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of "hypersplenic" thrombocytopenia. J Clin Invest 1966; 45:645.
- Sheikh MY, Raoufi R, Atla PR, et al. Prevalence of cirrhosis in patients with thrombocytopenia who receive bone marrow biopsy. Saudi J Gastroenterol 2012; 18:257.
- Mendes FD, Suzuki A, Sanderson SO, et al. Prevalence and indicators of portal hypertension in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012; 10:1028.
- Watson JC, Hadler SC, Dykewicz CA, et al. Measles, mumps, and rubella--vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1998; 47:1.
- Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr 2010; 156:623.
- Karimi O, Goorhuis A, Schinkel J, et al. Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet 2016; 387:939.
- Zammarchi L, Stella G, Mantella A, et al. Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications. J Clin Virol 2015; 63:32.
- Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117:4190.
- George JN, Vesely SK, Woolf SH. Conflicts of interest and clinical recommendations: comparison of two concurrent clinical practice guidelines for primary immune thrombocytopenia developed by different methods. Am J Med Qual 2014; 29:53.
- Rousan TA, Aldoss IT, Cowley BD Jr, et al. Recurrent acute thrombocytopenia in the hospitalized patient: sepsis, DIC, HIT, or antibiotic-induced thrombocytopenia. Am J Hematol 2010; 85:71.
- Azuno Y, Yaga K, Sasayama T, Kimoto K. Thrombocytopenia induced by Jui, a traditional Chinese herbal medicine. Lancet 1999; 354:304.
- Ohmori T, Nishii K, Hagihara A, et al. Acute thrombocytopenia induced by jui, a traditional herbal medicine. J Thromb Haemost 2004; 2:1479.
- Arnold J, Ouwehand WH, Smith GA, Cohen H. A young woman with petechiae. Lancet 1998; 352:618.
- Achterbergh R, Vermeer HJ, Curtis BR, et al. Thrombocytopenia in a nutshell. Lancet 2012; 379:776.
- Swisher KK, Doan JT, Vesely SK, et al. Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports. Haematologica 2007; 92:936.
- Fishman AD, Hoffman A, Volterra F, et al. Intracaval and intracardiac metastatic nonseminomatous germ cell tumor: a rare cause of hemolytic anemia and thrombocytopenia. Cancer Invest 2002; 20:996.
- Stasi R, Amadori S, Osborn J, et al. Long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia. PLoS Med 2006; 3:e24.
- Hui P, Cook DJ, Lim W, et al. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest 2011; 139:271.
- Strauss R, Wehler M, Mehler K, et al. Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 2002; 30:1765.
- Vanderschueren S, De Weerdt A, Malbrain M, et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med 2000; 28:1871.
- Arnold DM, Lim W. A rational approach to the diagnosis and management of thrombocytopenia in the hospitalized patient. Semin Hematol 2011; 48:251.
- Greinacher A, Selleng S. How I evaluate and treat thrombocytopenia in the intensive care unit patient. Blood 2016; 128:3032.
- Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010; 116:2127.
- Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Crit Care Clin 2011; 27:805.
- O'Donnell E, Shepherd C, Neff A. Immune thrombocytopenia from vancomycin in orthopedic cement. Am J Hematol 2007; 82:1122.
- Ladhani S, Khatri P, El-Bashir H, Shingadia D. Imported malaria is a major cause of thrombocytopenia in children presenting to the emergency department in east London. Br J Haematol 2005; 129:707.
- Patel U, Gandhi G, Friedman S, Niranjan S. Thrombocytopenia in malaria. J Natl Med Assoc 2004; 96:1212.
- West KA, Anderson DR, McAlister VC, et al. Alloimmune thrombocytopenia after organ transplantation. N Engl J Med 1999; 341:1504.
- Savage RA. Pseudoleukocytosis due to EDTA-induced platelet clumping. Am J Clin Pathol 1984; 81:317.
- Payne BA, Pierre RV. Pseudothrombocytopenia: a laboratory artifact with potentially serious consequences. Mayo Clin Proc 1984; 59:123.
- Pegels JG, Bruynes EC, Engelfriet CP, von dem Borne AE. Pseudothrombocytopenia: an immunologic study on platelet antibodies dependent on ethylene diamine tetra-acetate. Blood 1982; 59:157.
- Garcia Suarez J, Calero MA, Ricard MP, et al. EDTA-dependent pseudothrombocytopenia in ambulatory patients: clinical characteristics and role of new automated cell-counting in its detection. Am J Hematol 1992; 39:146.
- Vicari A, Banfi G, Bonini PA. EDTA-dependent pseudothrombocytopaenia: a 12-month epidemiological study. Scand J Clin Lab Invest 1988; 48:537.
- Bartels PC, Schoorl M, Lombarts AJ. Screening for EDTA-dependent deviations in platelet counts and abnormalities in platelet distribution histograms in pseudothrombocytopenia. Scand J Clin Lab Invest 1997; 57:629.
- Fiorin F, Steffan A, Pradella P, et al. IgG platelet antibodies in EDTA-dependent pseudothrombocytopenia bind to platelet membrane glycoprotein IIb. Am J Clin Pathol 1998; 110:178.
- Cesca C, Ben-Ezra J, Riley RS. Platelet satellitism as presenting finding in mantle cell lymphoma. A case report. Am J Clin Pathol 2001; 115:567.
- Montague N, Blackwelder P, Alsayegh H, et al. Platelet satellitism and dual surface immunoglobulin light-chain expression in circulating splenic marginal zone lymphoma cells. Ann Diagn Pathol 2013; 17:117.
- Bobba RK, Doll DC. Platelet satellitism as a cause of spurious thrombocytopenia. Blood 2012; 119:4100.
- Bizzaro N, Goldschmeding R, von dem Borne AE. Platelet satellitism is Fc gamma RIII (CD16) receptor-mediated. Am J Clin Pathol 1995; 103:740.
- Podda GM, Pugliano M, Femia EA, et al. The platelet count in EDTA-anticoagulated blood from patients with thrombocytopenia may be underestimated when measured in routine laboratories. Am J Hematol 2012; 87:727.
- DEFINITIONS AND AREAS OF CONCERN
- What is a low platelet count
- When to worry about bleeding
- When to worry about thrombosis
- CAUSES OF THROMBOCYTOPENIA
- OVERVIEW OF OUR APPROACH
- Thrombocytopenic emergencies requiring immediate action
- Initial questions and pace of the evaluation
- Asymptomatic, incidental finding, mild thrombocytopenia
- Thrombocytopenia with bleeding or other symptoms
- Acutely ill/intensive care unit
- PHYSICAL EXAMINATION
- Skin and other sites of bleeding
- Liver, spleen, lymph nodes
- LABORATORY TESTING
- Repeat CBC
- Peripheral blood smear
- - Pseudothrombocytopenia
- - RBC and WBC abnormalities
- HIV and HCV testing
- Other laboratory testing
- ADDITIONAL EVALUATION
- Hematologist referral/consultation
- Bone marrow evaluation
- GENERAL MANAGEMENT PRINCIPLES
- SUMMARY AND RECOMMENDATIONS