Thrombocytopenic Disorders

Thrombocytopenia is a common clinical condition with a broad differential diagnosis, and identifying its etiology involves careful assessment of both clinical characteristics and the results of well-chosen laboratory tests. Thrombocytopenic disorders include numerous causes of decreased platelet production or increased platelet destruction and encompass conditions such as congenital thrombocytopenia, disseminated intravascular coagulation (DIC), heparin-induced thrombocytopenia (HIT), neonatal alloimmune thrombocytopenia (NAIT), thrombotic microangiopathies (TMAs), and primary immune thrombocytopenia, previously referred to as idiopathic thrombocytopenic purpura (ITP). Thrombocytopenic disorders can be life threatening, with increased bleeding or even thrombotic risk, depending on the underlying cause, and the clinical context (eg, an acutely ill, pregnant, or ambulatory patient) helps to determine which tests should be ordered and with what urgency. Initial and essential laboratory tests in all cases include a CBC and a peripheral blood smear, which can provide important clues about the etiology of the thrombocytopenia. Subsequent testing is guided by the clinical presentation and the results of initial laboratory tests and may involve chemistry, urine, hematology, coagulation, and antibody tests, among others.

Quick Answers for Clinicians

What is pseudothrombocytopenia?

Pseudothrombocytopenia is a spurious thrombocytopenia that most commonly occurs due to clumping of platelets when blood is collected in ethylenediaminetetraacetic acid (EDTA). This causes underestimation of platelet counts by automated analyzers. The problem can be resolved by peripheral smear review to identify the platelet clumping and manually estimate the true platelet count, or by recollection of a specimen in a different anticoagulant (such as sodium citrate), which allows accurate analyzer platelet counts to be obtained. The clinical significance is related to the risk of mistaking the pseudothrombocytopenia for true thrombocytopenia.

What platelet counts are typically associated with increased bleeding risk?

Bleeding risk usually does not occur until the platelet count falls below 50-100 x 10⁹/L. Major bleeding due to thrombocytopenia generally does not occur until the platelet count is <20 x 10⁹/L. If there is platelet dysfunction or if antiplatelet medications are present, bleeding can occur at higher platelet counts than these thresholds.

Are all thrombocytopenic disorders associated with increased bleeding risk?

No, certain disorders such as disseminated intravascular coagulation (DIC), thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP), and heparin-induced thrombocytopenia (HIT) are associated with increased thrombotic risk. Thrombocytopenia can result from a large number of underlying disorders, and close correlation with clinical and laboratory information is necessary for accurate diagnosis and assessment of bleeding or thrombotic risk.

Can primary immune thrombocytopenia be diagnosed by a specific laboratory test?

Primary immune thrombocytopenia, previously referred to as idiopathic thrombocytopenic purpura, is a diagnosis of exclusion. Patients with primary immune thrombocytopenia may demonstrate reduced platelet counts without an obvious underlying cause. Autoantibodies result in platelet destruction but also can suppress bone marrow platelet production. Diagnosis is generally based on clinical features, CBC, and evaluation of the peripheral blood smear to rule out other hematologic conditions.

Indications for Testing

Testing for thrombocytopenic disorders should be considered in patients with platelet counts <100-150 x 10⁹/L.

Laboratory Testing

Diagnosis

CBC and Peripheral Smear

The first step in a workup for a suspected thrombocytopenic disorder is to confirm the thrombocytopenia by repeating the CBC and/or performing peripheral smear review. In uncommon circumstances, the platelet count can be inaccurate (pseudothrombocytopenia) as a result of platelet clumping when blood is collected in ethylenediaminetetraacetic acid (EDTA). Platelet clumping can be seen on peripheral smear review. To obtain an accurate platelet count, a repeat CBC can be performed using an alternative anticoagulant, such as sodium citrate. The platelet count can also be estimated by expert peripheral smear review.

Once thrombocytopenia is confirmed, results should be considered in light of the clinical context (eg, newborn, pregnant, or asymptomatic patient; bleeding or thrombosis; other cytopenias; current medical conditions and medications), which provides essential clues as to the etiology.

The peripheral smear review can also provide clues. For example, the presence of schistocytes may indicate a microangiopathic process, such as DIC or thrombotic thrombocytopenic purpura (TTP), but is not a sensitive or specific finding for these disorders.

A workup for hemolysis and coagulation disorders may also be helpful during initial evaluation. Testing for DIC, an acquired condition that results in widespread clotting (particularly in small vessels) and consumption of coagulation factors and platelets, should be performed in all hospitalized patients with thrombocytopenia. Refer to the DIC ARUP Consult topic for additional information about testing for this condition.

Testing to Determine Etiology

Secondary testing should be performed based on the patient’s history and clinical presentation to identify the cause of the thrombocytopenia. Thrombocytopenic disorders are generally associated with either decreased platelet production or increased platelet destruction (either immune mediated or nonimmune mediated). The following table presents some potential causes of thrombocytopenia. For more information about testing for specific disorders, refer to the individual ARUP Consult topics linked to below.

Potential Causes of Thrombocytopenia by Category
Category^a	Cause	Comments
Increased platelet destruction (nonimmune mediated)	DIC	Acquired condition that results in widespread clotting in the bloodstream, consumption of coagulation factors and platelets, and activation of fibrinolysis Clinical symptoms can include both bleeding and clotting manifestations
Increased platelet destruction (nonimmune mediated)	Sepsis	Associated not only with an increase in platelet destruction and consumption but also with decreased platelet production
Decreased platelet production	Congenital disorder	Rare condition with varied causes and clinical characteristics Platelet size and severity and duration of bleeding tendency can help distinguish among the numerous forms Genetic testing may be helpful in some cases
	Bone marrow disorder	Examples: primary bone marrow or metastatic malignancy, ineffective or abnormal regulation of thrombopoiesis, vitamin deficiencies
	Chemical or toxin	Examples: chemotherapy or ionizing radiation, alcohol
	Infection	Examples: adenovirus, Epstein-Barr virus, HIV, or bacterial/protozoal infections
Increased platelet destruction (immune mediated)	Primary immune thrombocytopenia	May demonstrate reduced platelet count without obvious underlying cause Autoantibodies result in platelet destruction but also can suppress bone marrow platelet production Diagnosis generally based on clinical features, CBC, and blood smear; immune thrombocytopenia is a diagnosis of exclusion Can occur in combination with other immune cytopenias (Evans syndrome)
	Connective tissue or systemic autoimmune rheumatic disease	Examples: SLE, APS, RA Autoimmune diseases with associated autoimmune platelet destruction
	HIT	Highly prothrombotic condition of platelet activation caused by immune complexes containing heparin-platelet factor 4 antibodies that develop following heparin administration Platelet counts are often 50% lower than baseline; pretest probability can be assessed with 4Ts or another clinical scoring tool
	NAIT	Results from maternal alloantibodies that form in response to paternally inherited fetal platelet antigens Alloantibodies cross placenta and cause fetal platelet destruction
	Posttransfusion purpura	Associated with severe thrombocytopenia that manifests 5-14 days after platelet transfusion Both autoantibodies and alloantibodies play a role
	Drug induced	Associated drugs include sulfonamides, quinidines, heparin, adenosine diphosphate-receptor antagonists such as clopidogrel, glycoprotein IIb/IIIa inhibitors Drug-induced platelet destruction can occur due to a variety of immune mechanisms
	TMAs	Examples: TTP, HUS, aHUS, HELLP syndrome Thrombotic conditions associated with severe thrombocytopenia and microangiopathic RBC destruction
^aThrombocytopenia can also result from splenic sequestration due to splenomegaly and from dilution (eg, due to major surgery or transfusion). aHUS, atypical HUS; APS, antiphospholipid syndrome; HELLP, hemolysis, elevated liver function tests, and low platelet count; HUS, hemolytic uremic syndrome; RA, rheumatoid arthritis; RBC, red blood cell; SLE, systemic lupus erythematosus Sources: Smock, 2014; Hunt, 2014; Provan, 2019; Greinacher, 2016; Salter, 2016; Winkelhorst, 2017

The following table summarizes the typical test results seen in patients with DIC, TTP, and HIT. Refer to the associated ARUP Consult topics for more information about testing for these conditions.

Summary of Typical Test Results in DIC, TTP, and HIT
Disorder	CBC/Blood Smear	PT/aPTT/Fibrinogen Tests	Other Tests
DIC (fibrin clots)	Anemia Thrombocytopenia Schistocytes	Prolonged clotting times Decreased fibrinogen	Markedly elevated D-dimer
TTP (platelet-rich clots)	Anemia Thrombocytopenia Schistocytes (present in large numbers)	Normal or minimal abnormalities	ADAMTS-13 <5-10% of normal ADAMTS-13 antibodies in acquired form
HIT (platelet activation, then thrombin/fibrin formation)	Thrombocytopenia	Normal or minimal abnormalities in most cases, although some cases have more pronounced abnormalities	Strongly positive ELISA for heparin-platelet factor 4 antibodies Positive SRA
aPTT, activated partial thromboplastin time; ELISA, enzyme-linked immunosorbent assay; PT, prothrombin time; SRA, serotonin-release assay