Diagnostic approach to thrombocytopenia in adults

INTRODUCTION — Thrombocytopenia may be associated with a variety of conditions, with clinical presentations ranging from asymptomatic to life-threatening bleeding (eg, in immune thrombocytopenia [ITP]) or thrombosis (eg, in heparin-induced thrombocytopenia [HIT]).

Here we discuss our approach to the adult with unexpected thrombocytopenia. This approach can be used by the primary care physician and the consulting hematologist.

Separate topics discuss thrombocytopenia in other populations:

●Neonates – (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management".)

●Children – (See "Approach to the child with unexplained thrombocytopenia".)

●Pregnancy – (See "Thrombocytopenia in pregnancy".)

DEFINITIONS AND AREAS OF CONCERN

Severity of thrombocytopenia — Thrombocytopenia is defined as a platelet count below the lower limit of the reference range. Typically this is <150,000/microL (<150 x 10⁹/L) for adults. (See "Laboratory test reference ranges in adults", section on 'Platelet count'.)

Thrombocytopenia severity can be further subdivided by platelet count [1]:

●Mild – 100,000 to 149,000/microL

●Moderate – 50,000 to 99,000/microL

●Severe – <50,000/microL

However, these numbers must be interpreted (and the cutoffs may be adjusted) depending on the underlying disease. As an example, in immune thrombocytopenia (ITP) we consider a platelet count <30,000/microL to represent severe thrombocytopenia. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Thrombocytopenia'.)

Severe thrombocytopenia (platelet count <30,000 to 50,000/microL) confers a greater risk of bleeding and implies a greater likelihood for needing treatment, but the correlation between the platelet count and the risk of bleeding varies according to the underlying condition and may be unpredictable. (See 'When to worry about bleeding' below.)

Stability and variation in platelet counts

●Findings – Platelet counts are fairly stable over time in healthy individuals but vary between individuals. This is because total platelet mass, rather than platelet count, is regulated. (See "Megakaryocyte biology and platelet production", section on 'Control of platelet mass'.)

•A study of serial platelet counts in 3789 individuals found that <0.1 percent of the participants had variation in platelet count by >98,000/microL [2].

•A study from the United States involving >12,000 adults in the third National Health and Nutrition Examination Survey (NHANES) database found consistency in platelet counts across the general population with a tendency toward higher values in females, younger adults, and some people of color [3]. The reasons are not clear and may reflect higher rates of iron deficiency in these individuals (iron deficiency anemia can increase the platelet count); we do not endorse different platelet count ranges for different populations.

●Implications – The wide normal range between individuals and the narrow normal range within each individual have implications for evaluating any individual patient's platelet count:

•A small proportion of the healthy population (approximately 2.5 percent) will have a baseline platelet count <150,000/microL because platelet counts are normally distributed and reference ranges typically include two standard deviations above and below the mean.

•An individual can have a significant decrease in platelet count and still be within the 'normal' range and thus not be flagged as abnormal. As an example, a drop in platelet count from 400,000 to 200,000/microL is concerning, even though the value is still ≥150,000/microL. Such a reduction may be clinically significant and requires evaluation. At a minimum, the platelet count should be repeated.

•These issues highlight the importance of obtaining previous platelet counts to determine whether the count is stable or trending downward. (See 'Further questions to determine cause' below.)

When to worry about bleeding — Bleeding is a concern in patients with severe thrombocytopenia. (See 'Severity of thrombocytopenia' above.)

However, the correlation between platelet count and bleeding risk is relatively weak. In addition, platelet dysfunction and coagulation abnormalities play an important role in bleeding risk.

Clinical predictors of bleeding include prior bleeding episodes, the presence of wet purpura, and hematuria. Studies have documented increased bleeding risk in individuals with ITP who have oral purpura and in individuals with a hematologic malignancy who have hematuria [4,5]. (See 'Physical examination' below.)

The concept of a "safe" platelet count is imprecise, lacks evidence-based recommendations, and depends on the disorder and on the patient (even with the same disorder) [6]. The following may be used as guides but should not substitute for clinical judgment based on individual patient and disease factors:

●Surgical bleeding is generally not a concern with platelet counts >50,000/microL (>100,000/microL for some high-risk procedures such as neurosurgery or major cardiac or orthopedic surgery). Some procedures may be safely performed at lower platelet counts. Examples include certain dermatologic procedures, cataract surgery, and bone marrow aspiration and biopsy. The decision to proceed with a procedure also depends on the chronicity of the thrombocytopenia and the urgency of the procedure.

●Severe spontaneous bleeding is rare; it is most likely with platelet counts <20,000/microL, especially <10,000/microL. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Prevention of spontaneous bleeding'.)

●Bleeding risk in ITP may be slightly lower compared with other conditions for the same platelet count (eg, we are less concerned about bleeding in an individual with ITP and a platelet count of 30,000/microL than we are about bleeding in an individual with aplastic anemia and a platelet count of 30,000/microL).

Other factors may affect bleeding risk (eg, platelet dysfunction, coagulation abnormalities). Some inherited platelet function disorders are associated with thrombocytopenia and have bleeding out of proportion to the degree of thrombocytopenia due to platelet dysfunction. Similarly, patients with severe liver disease or disseminated intravascular coagulation (DIC) may have a greater risk of bleeding from impaired coagulation than from thrombocytopenia. (See "Inherited platelet function disorders (IPFDs)", section on 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)'.)

By contrast, most individuals with hemostatically normal platelets (as in ITP) do not have severe spontaneous bleeding even with low platelet counts. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Correlation of bleeding and thrombocytopenia'.)

When to worry about thrombosis — Rarely, patients with thrombocytopenia are at risk for thrombosis rather than, or in addition to, bleeding. Most of these disorders are rare, but they are important to consider because urgent treatment may be needed to prevent life-threatening thrombosis.

●Heparin-induced thrombocytopenia (HIT) – HIT is an uncommon complication of heparin exposure in which antibodies to a platelet factor 4 epitope induced by heparin can cause thrombocytopenia and platelet activation, leading to life-threatening venous and/or arterial thrombosis. This diagnosis should be considered in a patient recently exposed to heparin who develops thrombocytopenia, thrombosis, anaphylaxis, or skin reactions. Treatment involves immediate discontinuation of heparin and administration of a nonheparin anticoagulant. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

●Vaccine-induced immune thrombotic thrombocytopenia (VITT) – VITT is a rare syndrome that occurs after vaccination with a coronavirus disease 2019 (COVID-19) adenoviral vector vaccine (AstraZeneca or Janssen [JCOVDEN, Johnson & Johnson]). It resembles spontaneous HIT in that there is no prior heparin exposure, and it is associated with life-threatening venous and/or arterial thrombosis. Individuals with thrombosis and/or thrombocytopenia should be evaluated for recent administration of a COVID-19 vaccine within the preceding 5 to 30 days, and for which specific type of vaccine they received. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

●Antiphospholipid syndrome (APS) – APS can develop in individuals with systemic lupus erythematosus (SLE), other autoimmune conditions, infections, medications, cancer, or no underlying condition. Patients may have venous and/or arterial thrombosis. (See "Clinical manifestations of antiphospholipid syndrome" and "Management of antiphospholipid syndrome" and "Diagnosis of antiphospholipid syndrome", section on 'Other conditions associated with antiphospholipid antibodies'.)

●Disseminated intravascular coagulation (DIC) – Patients with DIC are at risk of bleeding or thrombosis, usually venous. DIC is commonly seen in acutely ill patients with sepsis or malignancy, but it can also be seen in a variety of other conditions (table 1). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

●Thrombotic microangiopathy (TMA) – TMAs such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced TMA (DITMA) are associated with small-vessel platelet-rich thrombi. These microthrombi can occur in any organ and can be life-threatening. Plasma exchange for TTP may be lifesaving. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Immune TTP: Initial treatment" and "Drug-induced thrombotic microangiopathy (DITMA)".)

●Paroxysmal nocturnal hemoglobinuria (PNH) – PNH is a rare condition caused by loss of glycosylphosphatidylinositol from cell membranes. Thrombosis often involves unusual locations such as intraabdominal or cerebral veins. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

●ITP with a concomitant thrombotic disorder – Certain conditions can occur in patients with ITP increasing their risk of thrombosis such as atrial fibrillation or recent or previous deep vein thrombosis. Thrombocytopenia is not protective against thrombosis, and anticoagulation is often indicated [7]. (See "Anticoagulation in individuals with thrombocytopenia".)

CATEGORIES OF CAUSES — Causes of thrombocytopenia can be grouped by mechanism, clinical setting (asymptomatic versus specific findings), or acuity/severity of illness. Experienced clinicians incorporate all of these perspectives when evaluating a patient with thrombocytopenia.

Organized by mechanism — Major mechanisms of thrombocytopenia include decreased platelet production, peripheral platelet destruction or consumption in thrombi, dilution from fluid resuscitation or massive transfusion, and sequestration (pooling) of platelets in the spleen. Some conditions cause thrombocytopenia by more than one of these mechanisms.

Decreased production — Platelet production depends on intact hematopoietic stem cell and megakaryocyte function in the bone marrow and thrombopoietin (TPO) production by the liver.

●Inherited platelet disorders – Inherited platelet disorders can affect platelet number, platelet function, or both. These include syndromic disorders with other manifestations as well as disorders with isolated thrombocytopenia. Details are discussed separately. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders' and "Inherited platelet function disorders (IPFDs)".)

Although these are lifelong disorders, they often are not diagnosed until adulthood, or they may be misdiagnosed as immune thrombocytopenia (ITP). This was illustrated in a database review from the McMaster ITP registry, which found that, of 295 individuals initially diagnosed with primary ITP, five were reclassified as having an inherited platelet disorder. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders' and "Inherited platelet function disorders (IPFDs)", section on 'Specific disorders'.)

●Bone marrow disorders – Platelets are produced in the bone marrow from megakaryocytes (picture 1); production can be increased up to eightfold during times of increased demand [8,9]. (See "Megakaryocyte biology and platelet production".)

Bone marrow disorders that impair platelet production often affect other blood cells and cause pancytopenia. Patients may present with bleeding, petechiae, or symptoms attributable to anemia (fatigue, shortness of breath) and/or infection.

Examples include:

•Deficiency of vitamin B12, folate, or copper

•Myelodysplastic syndromes (MDS)

•Hematologic malignancies

•Bone marrow infiltration by cancer cells

•Paroxysmal nocturnal hemoglobinuria (PNH) associated with reduced bone marrow function

•Aplastic anemia and other bone marrow failure syndromes

•Infections, including organisms that target the bone marrow and those that induce bone marrow suppressive cytokines

●Megakaryocyte loss – Isolated megakaryocyte loss can occasionally occur in response to a drug. Acquired amegakaryocytic thrombocytopenia is another possible rare cause in which autoantibodies to the TPO receptor on megakaryocytes can cause severe thrombocytopenia. Primary ITP is commonly associated with impaired platelet production due to antiplatelet autoantibodies that react with megakaryocytes. (See "Drug-induced immune thrombocytopenia" and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Pathogenesis'.)

●Liver disease – The liver produces thrombopoietin (TPO), and severe liver disease with impaired liver synthetic function can cause thrombocytopenia due to reduced TPO levels. (See "Megakaryocyte biology and platelet production", section on 'Control of platelet mass' and "Hemostatic abnormalities in patients with liver disease", section on 'Thrombocytopenia and platelet dysfunction'.)

Often in severe liver disease there is also a component of compensatory splenomegaly and hypersplenism (splenic sequestration of platelets). (See 'Redistribution/hypersplenism' below.)

Destruction/consumption — Platelets survive in the circulation for 8 to 10 days, after which they are removed by monocytes or macrophages of the reticuloendothelial system (eg, liver and spleen), perhaps as a result of programmed apoptosis or other pathways [10-12].

●Antibody-mediated – Accelerated destruction of platelets (and possibly megakaryocytes) can occur due to antibody-mediated clearance.

•Immune thrombocytopenia (ITP) – Antiplatelet autoantibodies occur in primary ITP and secondary ITP. There are numerous causes of secondary ITP (table 2). (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Pathogenesis'.)

The prevailing understanding of ITP mechanism involves antibody-mediated platelet destruction. However, antiplatelet antibodies are not always detected, and their testing is not clinically useful.

Combined cytopenias due to antibody-mediated destruction of more than one blood cell line can also occur; the term Evans syndrome refers to combined warm autoimmune hemolytic anemia (AIHA) and ITP. Autoimmune neutropenia can also occur in Evans syndrome. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)

•Drug-induced ITP – Antiplatelet autoantibodies can be induced by medications, vaccines, foods, and other substances (table 3). (See "Drug-induced immune thrombocytopenia", section on 'Mechanisms of DITP'.)

Commonly implicated medications include antibiotics (sulfonamides, ampicillin, piperacillin, vancomycin, rifampin) and older antiepileptic agents (eg, carbamazepine, phenytoin) [13]. Typically, thrombocytopenia develops within hours of drug exposure if the patient has been previously exposed to the drug, due to an anamnestic immune response, or within one to two weeks of daily exposure to a new drug. The thrombocytopenia typically resolves within five to seven days of drug discontinuation [14]. Specific treatment is rarely required.

•Post-transfusion purpura (PTP) – Antiplatelet alloantibodies can cause PTP, an extremely rare delayed transfusion reaction in which the antibodies destroy the recipient's own platelets lacking the target antigen. (See "Immunologic transfusion reactions", section on 'Post-transfusion purpura'.)

•Platelet refractoriness – Antiplatelet alloantibodies can lead to immune-mediated destruction of transfused platelets. (See "Refractoriness to platelet transfusion", section on 'Alloimmunization'.)

●DIC and TMAs – Platelet consumption also occurs within thrombi in disseminated intravascular coagulation (DIC) and thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). The table lists causes of DIC (table 1). (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

●CPB and ECMO – Intraarterial devices such as cardiopulmonary bypass (CPB) circuits, extracorporeal membrane oxygenation (ECMO) devices, and intraaortic balloon pumps (IABPs) are common causes of thrombocytopenia in hospitalized patients. Causes are multifactorial and include consumption and destruction within the circuit and others. (See "Postoperative complications among patients undergoing cardiac surgery", section on 'Bleeding' and "Extracorporeal life support in adults: Management of venovenous extracorporeal membrane oxygenation (V-V ECMO)", section on 'Thrombocytopenia' and "Intraaortic balloon pump counterpulsation", section on 'Other'.)

●Postoperative – Postoperative thrombocytopenia may occur if there is significant consumption of platelets during surgery or in wound healing. Dilutional thrombocytopenia may also contribute. This is generally a diagnosis of exclusion made when other causes of thrombocytopenia are absent and the platelet count gradually normalizes. (See 'Dilution' below.)

●Thrombosis – Large thromboses can consume platelets, causing transient thrombocytopenia. This typically occurs very early (within the first day or two) and is relatively mild, although more severe thrombocytopenia can occur. A series of four individuals with thrombocytopenia and an associated literature review documented platelet counts between 33,000 and 88,000/microL in the four with extensive venous thromboembolism (VTE) and platelet counts <150,000/microL in 10 percent of historical patients with a pulmonary embolus (mean platelet count, 293,000/microL) [15].

Dilution — In dilutional thrombocytopenia, excess volume of fluids or plasma lowers the platelet count.

●Fluid resuscitation or massive transfusion – Massive fluid resuscitation or massive transfusion without proportionate transfusion of platelets can cause thrombocytopenia. In massive transfusion, platelet counts are reduced in proportion to the number of red blood cell (RBC) units transfused in a 24-hour period [16,17]. If thrombocytopenia is mild, the patient can be observed until the platelet count recovers. If significant blood has been lost, platelet transfusions may be needed. Ratios of platelets to other products are discussed separately. (See "Use of blood products in the critically ill" and "Massive blood transfusion", section on 'Trauma'.)

●Postoperative – Postoperative thrombocytopenia may occur due to dilution, typically at around postoperative day 3. It is generally mild and may be due to fluid shifts as well as other mechanisms such as bleeding or platelet consumption. (See 'Destruction/consumption' above.)

●Gestational thrombocytopenia (GT) – GT is also due to a dilutional mechanism, as the plasma volume expands during pregnancy. The thrombocytopenia of GT is almost always mild and resolves after delivery. (See "Thrombocytopenia in pregnancy", section on 'Gestational thrombocytopenia (GT)'.)

Redistribution/hypersplenism — Approximately one-third of the platelet mass is found in the spleen, in equilibrium with the circulating platelet pool [18]. With splenomegaly, a greater fraction of the total platelet mass is sequestered in the spleen (up to 90 percent of the total platelet mass), resulting in a decreased circulating platelet count (figure 1) [18]. (See "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

Causes can include:

●Conditions that increase splenic size, such as lymphoproliferative disorders

●Conditions that cause splenic congestion through portal hypertension (eg, cirrhosis, alcoholic or nonalcoholic liver disease)

In a series of 354 patients with a presumptive diagnosis of nonalcoholic fatty liver disease, thrombocytopenia was seen in 29 percent [19]. (See "Hematologic complications of alcohol use" and "Alcoholic hepatitis: Clinical manifestations and diagnosis" and "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)

Thrombocytopenia from splenic pooling of platelets is typically mild to moderate (in the range of 60,000 to 100,000/microL). Severe thrombocytopenia or bleeding in the setting of splenomegaly should prompt investigation for other causes. (See 'Bleeding or other symptoms' below.)

In severe liver disease, platelets may also be decreased because of reduced thrombopoietin levels. (See 'Decreased production' above.)

Organized by acuity level — The pace of the evaluation and further testing of the thrombocytopenia depends on the acuity and severity of presentation, which can range from life-threatening to an incidental finding in an asymptomatic patient. The discussion below lists common causes of thrombocytopenia organized by acuity level.

Thrombocytopenic emergencies requiring immediate action — Certain presentations of thrombocytopenia are medical emergencies that require immediate action.

●Bleeding with severe thrombocytopenia (platelet count <50,000/microL)

●Urgently needed invasive procedure with severe thrombocytopenia

●Pregnancy with severe thrombocytopenia

●Suspected heparin-induced thrombocytopenia (HIT) or vaccine-induced immune thrombotic thrombocytopenia (VITT)

●Suspected post-transfusion purpura (PTP)

●Suspected thrombotic microangiopathy (TMA) such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced TMA (DITMA)

●Acute disseminated intravascular coagulation (DIC)

●Suspected acute leukemia, aplastic anemia, or other bone marrow failure syndrome

●Hemophagocytic lymphohistiocytosis (HLH)

An individual with expertise in these disorders, typically a hematologist, should be consulted immediately. They can assist with evaluation, diagnosis and management strategies, including platelet transfusions, other means of rapidly raising the platelet count, prevention of additional complications, and treatment of the underlying condition. (See 'Bleeding or other symptoms' below and 'Hematologist referral/consultation' below.)

Acutely ill/intensive care unit — Thrombocytopenia is common in acutely ill patients.

●Incidence – Thrombocytopenia is common in patients in the intensive care unit (ICU), especially those with the most severe illnesses. A 2011 systematic review found thrombocytopenia in 8 to 68 percent of ICU admissions and new-onset thrombocytopenia during the ICU stay in 13 to 44 percent [20].

●Likely causes – Sepsis (with or without DIC) and drug-induced thrombocytopenia are common causes. In a cohort of 329 medical and surgical ICU patients, sepsis was the most common cause of thrombocytopenia, with the following other causes (some individuals had more than one cause) [21]:

•Sepsis, all (48 percent)

•Sepsis with documented bacteremia (28 percent)

•Multiple causes (26 percent)

•Liver disease/hypersplenism (18 percent)

•Overt DIC (14 percent)

•Unknown cause (14 percent)

•Infection, other (11 percent)

•Primary hematologic disorder (9 percent)

•Medications, noncytotoxic (9 percent)

•Medications, cytotoxic (7 percent)

•Massive transfusion (7 percent)

•Other causes (7 percent)

•Excess alcohol use (5 percent)

Other studies have reported similar findings [1,20,22].

Thrombotic microangiopathies, acute leukemias, bone marrow failure syndromes, and hemophagocytic lymphohistiocytosis (HLH) are less common but critical diagnoses that cannot be missed. (See 'Thrombocytopenic emergencies requiring immediate action' above.)

●Heparin-induced thrombocytopenia (HIT) is an uncommon cause of thrombocytopenia in the ICU [23]. However, patients with an intermediate or high clinical suspicion of HIT should undergo HIT antibody testing. (See "Drug-induced immune thrombocytopenia" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Evaluation' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Postoperative patients and individuals with large thromboemboli can develop transient thrombocytopenia. (See 'Infection or fever' below and 'Postoperative or hospitalized' below.)

Evaluation is included in the figure (algorithm 1) and discussed below. (See 'Approach to evaluation' below.)

Postoperative or hospitalized

●Postoperative – A mild, transient decrease in platelet count due to dilution and/or consumption may occur following surgery. A more significant decrease (up to 50 percent) may occur following cardiopulmonary bypass surgery due to platelet consumption in the extracorporeal circuit. In both situations, the platelet count typically reaches a nadir 48 to 72 hours after surgery and then begins to recover. (See "Postoperative complications among patients undergoing cardiac surgery", section on 'Hematologic dysfunction'.)

●Hospitalized patients – Numerous causes of thrombopenia can occur in hospitalized patients, including medications, infections, sepsis, thrombotic microangiopathies, malignancies, and others. Common causes are discussed in more detail above. (See 'Thrombocytopenic emergencies requiring immediate action' above and 'Acutely ill/intensive care unit' above.)

A mild, transient fall in platelet count may occur with acute VTE due to platelet consumption in the thrombus [15]. The platelet count typically recovers shortly after initiation of anticoagulation. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

●Heparin-induced thrombocytopenia (HIT) – HIT is a special case of drug-induced thrombocytopenia in which antibodies against platelet factor 4/heparin complexes cause platelet activation, resulting in an increased risk of venous and arterial thrombosis.

Clinical features suggestive of HIT include new-onset thrombocytopenia in a patient exposed to heparin within the prior 5 to 10 days, a platelet count drop of more than 50 percent from baseline, venous or arterial thrombosis, necrotic skin lesions at sites of heparin injection, and acute systemic reactions after intravenous heparin administration. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Treatment involves immediate discontinuation of heparin and administration of a nonheparin anticoagulant. Evaluation for HIT and management of patients with a presumptive clinical diagnosis of HIT are discussed in detail separately. (See "Management of heparin-induced thrombocytopenia".)

Rare HIT-like disorders that are independent of heparin exposure have also been reported, including spontaneous HIT and COVID-19 VITT. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Terminology and HIT variants' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

Evaluating for other possible causes and closely watching the platelet count trend will usually reveal the correct diagnosis. (See 'Approach to evaluation' below.)

Infection or fever

●Infection – Virtually any type of infection can cause thrombocytopenia. The mechanism(s) may include immune-mediated platelet destruction, bone marrow suppression, and/or platelet consumption. (See 'Organized by mechanism' above.)

•Viral – Thrombocytopenia may occur with rubella, mumps, varicella, parvovirus, hepatitis C, and Epstein-Barr virus infections, among others. Thrombocytopenia may be an incidental finding that resolves spontaneously as the patient recovers; however, in some persistent infections, such as hepatitis C, thrombocytopenia may also persist. (See "Extrahepatic manifestations of hepatitis C virus infection".)

Thrombocytopenia has been reported with COVID-19. (See "COVID-19: Hypercoagulability", section on 'Coagulation abnormalities'.)

Any viral infection that causes severe hepatitis could cause thrombocytopenia related to liver failure because thrombopoietin is produced in the liver. (See 'Acutely ill/intensive care unit' above.)

Hepatitis B virus testing may be indicated before the administration of immunosuppressive medications such as rituximab to avoid viral reactivation. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'Rituximab'.)

Case reports have described thrombocytopenia in association with Zika virus infection [24,25]. (See "Zika virus infection: An overview".)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral infection seen in China and other countries in southeast Asia. The causative agent is a bunyavirus that appears to be carried by ticks. (See "Severe fever with thrombocytopenia syndrome virus".)

Other emerging viruses that may cause thrombocytopenia are listed separately. (See "Emerging viruses".)

•HIV – Human immunodeficiency virus (HIV) infection is a rare etiology of newly discovered thrombocytopenia. However, since thrombocytopenia may be the initial manifestation of HIV infection, it is appropriate to test for HIV as part of the evaluation of thrombocytopenia [26,27].

HIV can cause thrombocytopenia by several mechanisms, including direct toxicity to megakaryocytes, an ITP-like condition, and secondary opportunistic infections (eg, mycobacterium avium intracellulare). This subject is discussed in detail separately. (See "HIV-associated cytopenias", section on 'Thrombocytopenia'.)

•Bacterial infection/sepsis – Sepsis can cause thrombocytopenia by direct bone marrow suppression, which is usually accompanied by other cytopenias; as a component of disseminated intravascular coagulation (DIC), in which it is accompanied by coagulation abnormalities (eg, prolonged prothrombin time [PT], activated partial thromboplastin time [aPTT], low fibrinogen); from platelet consumption independent of DIC; or from increased destruction of platelets. Patients are generally acutely ill, and treatment is directed at the underlying infection. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Infection with Helicobacter pylori has also been associated with ITP. This may be suspected in patients with dyspepsia or symptoms of peptic ulcer disease. (See "Acute and chronic gastritis due to Helicobacter pylori" and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'H. pylori testing'.)

Thrombocytopenia is a common finding with other specific infections including:

-Leptospirosis (see "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis")

-Brucellosis (see "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis")

-Aanaplasmosis, and other tick-borne infections (see "Human ehrlichiosis and anaplasmosis" and "Borrelia miyamotoi infection")

•Intracellular parasites – Malaria and babesiosis can cause thrombocytopenia, typically accompanied by fever and hemolytic anemia; patients may present with mild illness or be acutely ill. The causative organisms may be seen within RBCs on review of the peripheral blood smear. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'Hematologic abnormalities' and "Babesiosis: Clinical manifestations and diagnosis", section on 'Infection due to B. microti'.)

●Fever – Various systemic illnesses can cause fever; an infection may or may not be identified, and it may be due to severe immunosuppression or it may be the trigger for a systemic condition that causes thrombocytopenia. Often other cytopenias are present.

•TMA – An acute episode of TTP, HUS, or other TMA may be "triggered" by another acute illness and therefore may occur suddenly and unexpectedly in patients hospitalized for other disorders, such as cardiac surgery or pancreatitis [28]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)

•Hematologic malignancy – Acute leukemia typically presents with leukocytosis and immature white blood cells (WBCs) in the peripheral blood; thrombocytopenia and anemia often accompany these changes, but thrombocytopenia is rarely seen in isolation. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

•Other cancer – Separate topic reviews discuss evaluation for cancer-associated DIC, bone marrow involvement, or DITMA. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Causes of DIC' and "Approach to the adult with pancytopenia" and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

•HLH – Hemophagocytic lymphohistiocytosis (HLH) can be triggered by immune dysregulation. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Bleeding or other symptoms — Patients who present with isolated thrombocytopenia and bleeding, manifested by petechiae, purpura, and mucosal bleeding (epistaxis, heavy menstrual bleeding), have a different diagnostic spectrum.

●Primary ITP or drug-induced thrombocytopenia – Individuals with bleeding who lack signs of systemic illness or other abnormalities of the complete blood count (CBC) are likely to have primary ITP or drug-induced thrombocytopenia. These diagnoses are made based on the appropriate history (drug exposure, bleeding, absence of other specific symptoms) and lack of other findings on physical examination. The only additional laboratory testing is for liver function tests, metabolic panel, HIV, and hepatitis C virus (HCV). (See 'Repeat CBC' below and 'Peripheral blood smear' below and 'Metabolic panel, liver function, HIV, and HCV testing' below.)

Testing for drug-dependent antibodies in potential drug-induced thrombocytopenia is discussed separately. (See "Drug-induced immune thrombocytopenia", section on 'Decide which drug(s) to stop'.)

●Systemic illnesses – Thrombocytopenia plus other symptoms suggests a broader range of potential diagnoses depending on the other symptom(s):

•Fever – (See 'Infection or fever' above.)

•Hepatosplenomegaly – Possible liver disease with hypersplenism, lymphoma. (See 'Redistribution/hypersplenism' above.)

•Neurologic findings – Possible TTP, HUS, DITMA, vitamin B12 deficiency, or copper deficiency. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Other considerations include stroke or central venous sinus thrombosis (CVT) due to antiphospholipid syndrome (APS), HIT, or VITT. (See 'When to worry about thrombosis' above.)

•Lymphadenopathy – Possible infection, lymphoma, other malignancy. (See 'Infection or fever' above and 'Redistribution/hypersplenism' above.)

•Joint involvement – Possible rheumatologic condition. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia' and "Hematologic complications of rheumatoid arthritis", section on 'High or low platelet count'.)

•Thrombosis – Possible antiphospholipid syndrome (APS), HIT, VITT, or paroxysmal nocturnal hemoglobinuria (PNH). (See 'When to worry about thrombosis' above.)

These individuals should have laboratory testing for the diagnoses suggested by these other symptoms. (See 'Other laboratory testing' below.)

Incidental finding of mild thrombocytopenia

●Common diagnoses – Common diagnoses for asymptomatic outpatients with mild thrombocytopenia (platelet count 100,000 to 149,000/microL) include:

•Normal variation

•ITP

•Occult liver disease

•HIV infection

•Hematologic malignancy including myelodysplastic syndrome (MDS)

Inherited platelet disorders, sometimes misdiagnosed as ITP, may also cause mild thrombocytopenia (table 4).

●Diet or altered gastrointestinal anatomy – Certain diets or altered gastrointestinal anatomy may cause vitamin B12, folate, or copper deficiency, which is associated with thrombocytopenia; the thrombocytopenia is typically mild, and there may be anemia and leukopenia.

•Vegan diet – A strict vegan diet and some vegetarian diets can cause vitamin B12 deficiency since vitamin B12 is only available from animal sources. Most individuals following these diets are aware of this and take a vitamin B12 supplement, but some individuals may not know this. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Inadequate dietary intake'.)

•Nutritional deficits – Folates come from plant sources and supplemented grains and other foods. A variety of dietary practices and gastrointestinal alterations can cause folate deficiency. This includes lack of adequate fresh vegetables, such as in diets of exclusively heavily cooked foods or exclusively alcohol. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Causes of folate deficiency'.)

•Zinc ingestion – Zinc ingestion can block copper absorption, leading to a myelodysplasia-like picture that resolves upon correction of copper deficiency. (See "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)

•Altered anatomy – Vitamin B12 deficiency can also occur when absorption is impaired, due to altered anatomy of the stomach (including bariatric surgery) or terminal ileum. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Food cobalamin malabsorption' and "Bariatric surgery: Postoperative nutritional management".)

●Alcohol – Alcohol can cause thrombocytopenia by direct toxicity to the bone marrow, nutrient deficiencies, or hypersplenism associated with alcoholic liver disease. Patients may be relatively asymptomatic or ill from cirrhosis. (See "Hematologic complications of alcohol use", section on 'Thrombocytopenia'.)

●Natural history – The natural history of asymptomatic, mild thrombocytopenia has been studied prospectively. Some individuals have resolution of thrombocytopenia, and others are later diagnosed with a causative condition, especially with longer follow-up.

•In a series of 217 apparently healthy individuals referred to a hematology center for incidentally discovered platelet counts between 100,000 and 150,000/microL who were evaluated after six months, 23 (11 percent) had normal platelet counts, two developed MDS, and one developed systemic lupus erythematosus (SLE) [29]. The remaining 191 (88 percent) had persistent platelet counts <150,000/microL without other disease becoming evident; after five years, most (64 percent) had spontaneous resolution or persistent mild thrombocytopenia without an associated condition, supporting a diagnosis of ITP or normal variation.

•In a case-control study involving 367 individuals with unexplained mild thrombocytopenia who were followed for many years, a hematologic malignancy developed in 7 percent by 15 years and 16 percent by 25 years [30]. The malignancies included MDS, myeloproliferative neoplasms, and lymphomas.

APPROACH TO EVALUATION

Assess severity — The initial step in evaluating a patient is to determine if there is a thrombocytopenic emergency requiring immediate action due to the risk of bleeding or thrombosis. (See 'Thrombocytopenic emergencies requiring immediate action' above.)

History

Initial questions and pace of the evaluation — When a patient presents with unexpected thrombocytopenia, we want to know:

●Is the thrombocytopenia real?

●Is the thrombocytopenia new?

●Are there other hematologic abnormalities?

●Are there potentially serious consequences of not starting disease-specific treatment quickly (eg, therapeutic plasma exchange [TPE] for thrombotic thrombocytopenic purpura)?

Confirmation that the thrombocytopenia is real (not a laboratory error or an in vitro artifact) is done by repeating the complete blood count (CBC) and reviewing the peripheral blood smear (or requesting review), especially if the platelet count does not make sense within the context of the clinical picture. (See 'Repeat CBC' below and 'Peripheral blood smear' below.)

●Diagnostic possibilities differ for new onset thrombocytopenia acquired in the hospital (algorithm 1) versus an outpatient.

●Any patient with unexplained thrombocytopenia should be evaluated by a hematologist to determine the cause and management. The urgency depends on the degree of thrombocytopenia, the time course, and the presence of bleeding or thrombosis. (See 'Hematologist referral/consultation' below.)

●A new reduction in platelet count is more concerning than a stable, mildly low count because it suggests the possibility of an evolving condition. (See 'Hematologist referral/consultation' below.)

●The blood smear can provide additional clues to the likely diagnoses. (See 'RBC and WBC abnormalities' below.)

Further questions to determine cause — A thorough history helps determine whether conditions are present that may explain thrombocytopenia. In an acutely ill patient who cannot provide a history, this information should be obtained from relatives, family members, caregivers, and/or other clinicians caring for the patient.

The history includes:

●Prior platelet counts – Helpful to determine the duration of thrombocytopenia and whether it is hereditary or acquired. A chronic, stable platelet count is less concerning than a new or decreasing count.

●Family history – A history of bleeding disorders and/or thrombocytopenia raises the possibility of a genetic condition. Thrombocytopenia in a relative may be useful, but a negative family history does not eliminate the possibility of an inherited disorder, as some individuals remain undiagnosed well into adulthood. Other elements of the family history may suggest a syndromic disorder. (See "Inherited platelet function disorders (IPFDs)", section on 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)'.)

●Bleeding history – Includes history of bleeding, petechiae, ecchymoses, epistaxis, gingival bleeding, hematemesis, melena, or heavy menstrual bleeding.

●Medication exposures – Includes new prescriptions, medications taken intermittently, over-the-counter medicines (aspirin, nonsteroidal antiinflammatory drugs), herbal remedies, vaccines, foods and beverages including quinine, and medicines prescribed for other family members or friends that the patient may have taken (table 3). Temporal relationship to new medications is relevant; special attention is paid to new medications or other substance exposures within the two weeks preceding a drop in platelet count.

For hospitalized patients, one must review the hospital chart, nursing notes, bedside flow sheets, and anesthesia records (algorithm 1). Heparin flushes may not be recorded, and some relevant medicines may also be contained in materials used in surgery (eg, vancomycin mixed into joint replacement cement) [31].

The timing of bleeding onset or first recognition of thrombocytopenia relative to medications should be explored in depth since it may focus attention on the most likely agent(s), especially in individuals receiving multiple medications.

Special attention should be paid to administration of heparin in hospitalized or recently discharged patients due to the possibility of HIT. This includes unfractionated or low molecular weight heparin (LMWH; enoxaparin, dalteparin, tinzaparin, nadroparin), and heparin flushes in vascular access lines or during surgery. Ingestion of quinine in over-the-counter products and beverages (table 5) should be addressed due to the association of quinine exposure with thrombocytopenia, although this has become much less common.

●Infectious exposures – Includes viral, bacterial, rickettsial, or live virus vaccination; recent travel to an area endemic for malaria, dengue virus, leptospirosis, meningococcemia, rat-bite fever, rickettsial infections, hantavirus, and viral hemorrhagic fevers (Ebola, Lassa fever); and risk factors for HIV infection [32,33].

●Dietary practices – Practices that could cause nutrient deficiencies include veganism (can cause vitamin B12 deficiency), vegetarianism, and zinc ingestion (can cause copper deficiency).

●Other medical conditions – Includes hematologic disorders, rheumatologic diseases, bariatric surgery or poor nutritional status, blood product transfusion or organ transplantation [34].

Physical examination

Skin and other sites of bleeding — Skin bleeding is common and may include petechiae, purpura, or frank mucosal bleeding (table 6). Petechiae and purpura differ from small telangiectasias, angiomas, and vasculitic purpura (picture 2).

●Petechiae – Petechiae are pinhead-sized, red, flat, discrete lesions often occurring in crops (picture 3 and picture 4). Petechiae are caused by red blood cell (RBC) extravasation from capillaries; they are asymptomatic, nontender, nonpalpable, and do not blanch under pressure. They are most dense in dependent areas where the hydrostatic pressure on the small superficial vessels is greatest, including the feet and ankles in ambulatory patients and the presacral area in bedridden patients. Petechiae are not found on the soles of the feet, where the vessels are protected by the strong subcutaneous tissue.

●Purpura – Purpura refers to purplish discoloration of the skin caused by confluent petechiae. Dry purpura is purpura in skin; wet purpura is on mucosal surfaces, such as panel B in the picture (picture 3).

•Wet purpura may be considered a prognostic sign for potentially more serious hemorrhage. (See 'When to worry about bleeding' above.)

•Palpable purpura is not typical of thrombocytopenia and suggests an underlying vascular or inflammatory disorder. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

●Ecchymoses – Ecchymoses (bruises) are nontender areas of bleeding into the skin, usually with multiple colors due to extravasated blood (red, purple) and breakdown products of heme pigment (green, orange, yellow). Ecchymotic lesions characteristically are small, multiple, and superficial. They may develop without noticeable trauma and do not spread into deeper tissues.

It can be helpful to document the extent of skin lesions (mark with a pen) to identify new lesions and/or expansion of existing lesions, which may signify persistent or worsening thrombocytopenia or may raise additional concerns about increased bleeding risk.

Other sites of bleeding such as occult blood in the stool or hematuria require appropriate evaluation and treatment, regardless of the cause of thrombocytopenia. (See "Evaluation of occult gastrointestinal bleeding".)

Liver, spleen, lymph nodes — The liver and spleen should be examined for tenderness and enlargement. Splenomegaly can be a sign of liver disease, lymphoma, or other hematologic condition; splenomegaly of any etiology may cause mild thrombocytopenia. (See "Splenomegaly and other splenic disorders in adults".)

Lymphadenopathy in a patient with thrombocytopenia may suggest infection, lymphoma, or other malignancy.

●Focal, tender lymph node enlargement is typical of localized bacterial infection. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Localized lymphadenopathy'.)

●Generalized lymphadenopathy may be associated with acute HIV infection, in which it is typically nontender and involves axillary, cervical, and occipital nodes. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Adenopathy'.)

●Lymphadenopathy may be associated with other infectious, malignant, autoimmune, and inflammatory conditions. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Generalized'.)

Thrombosis — Signs of thrombosis may also suggest a different spectrum of potential causes of thrombocytopenia. (See 'When to worry about thrombosis' above.)

Laboratory testing — The urgency of laboratory testing depends on the level of acuity and possible diagnoses. For all patients, review of the CBC and peripheral blood smear are essential.

Repeat CBC — A platelet count that does not make sense within the context of the clinical findings should be repeated before extensive evaluation is undertaken. The timing of repeat CBC depends on the severity of thrombocytopenia and whether there is bleeding.

●Immediate retesting – For patients with bleeding or severe thrombocytopenia (platelet count <50,000/microL), retesting should be performed immediately (algorithm 1).

●Retest one to two weeks – For asymptomatic patients with no bleeding or comorbidities and moderate thrombocytopenia (platelet count 50,000 to 100,000/microL), testing may be repeated in one to two weeks, provided the patient is advised to report immediately any changes in clinical status or bleeding during this interval.

●Retest one or more months – For outpatients with isolated mild thrombocytopenia (platelet count 100,000 to 149,000/microL), testing may be repeated in one or more months. In a small percentage of individuals, the platelet count will normalize with observation only. An exception is if a patient recently started on a new medication, or with new clinical findings or other abnormalities on the CBC, in whom mild thrombocytopenia may signify an evolving disorder.

Other cytopenias on the initial or repeat CBC raise concerns for additional diagnoses:

●Anemia – Anemia may accompany thrombocytopenia if thrombocytopenia has caused chronic gastrointestinal bleeding resulting in iron deficiency. Combined anemia and thrombocytopenia also raise the possibility of systemic disorders affecting the bone marrow or vasculature. (See 'Decreased production' above and 'Destruction/consumption' above.)

•Sepsis with disseminated intravascular coagulation (DIC)

•Thrombotic microangiopathies (TMAs)

•Autoimmune disorders such as Evans syndrome

•Deficiency of folate, vitamin B12, or copper

•Infection

•Myelodysplastic syndromes (MDS), leukemia, or bone marrow infiltrative disorders

●Leukocytosis – Combined leukocytosis and thrombocytopenia raise the possibility of infection, chronic inflammation, and malignancy.

●Pancytopenia – Combined leukopenia, anemia, and thrombocytopenia has a large differential diagnosis that is discussed in detail separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Peripheral blood smear — Review of the peripheral blood smear is used to exclude pseudothrombocytopenia due to platelet clumping and to evaluate morphologic abnormalities of blood cells that could be useful in determining the cause of thrombocytopenia. (See 'Pseudothrombocytopenia' below and 'RBC and WBC abnormalities' below.)

Examples of additional clues from the blood smear include:

●Giant platelets (picture 5) may suggest an inherited platelet function disorder; these may be counted as RBCs by some automated counters. (See "Inherited platelet function disorders (IPFDs)", section on 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)'.)

●Fragmented RBCs are characteristic of TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Anemia, leukopenia, and/or leukocytosis generally suggest a more serious diagnosis than isolated thrombocytopenia (eg, hematologic malignancy). (See "Evaluation of the peripheral blood smear", section on 'Worrisome findings'.)

Pseudothrombocytopenia — Pseudothrombocytopenia (low platelet count due to laboratory artifact) is evaluated by review of the blood smear and/or repeating the CBC using a non-ethylenediaminetetraacetic acid (EDTA) anticoagulant.

●Incompletely mixed or inadequately anticoagulated samples may form a clot that traps platelets in the collection tube and prevents them from being counted.

●In approximately 0.1 percent of individuals, the EDTA anticoagulant in the collection tube can induce platelet clumps (picture 6) or platelet rosettes around white blood cells (WBCs). These may be counted by automated counters as leukocytes rather than platelets. The mechanism is "naturally occurring" platelet autoantibodies directed against a concealed (or cryptic) epitope on platelet membrane glycoprotein (GP) IIb/IIIa that becomes exposed by EDTA-induced dissociation of GPIIb/IIIa [35-42].

If platelet clumping is observed, the platelet count is repeated using a collection tube containing heparin or sodium citrate as an anticoagulant. Alternatively, fresh, nonanticoagulated blood can be pipetted directly into platelet-counting diluent fluid.

RBC and WBC abnormalities — Abnormal RBC and WBC morphologies may suggest a specific condition. (See "Evaluation of the peripheral blood smear".)

●Schistocytes (picture 7) – Suggest a microangiopathic process (DIC, thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], drug-induced TMA [DITMA]). (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Nucleated RBCs (picture 8) and/or Howell-Jolly bodies (picture 9) – May be seen post-splenectomy or occasionally in patients with poor splenic function. (See "Splenomegaly and other splenic disorders in adults", section on 'Peripheral blood smear'.)

●Spherocytes (picture 10 and picture 11) – Suggest immune-mediated hemolytic anemia or hereditary spherocytosis. (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Hereditary spherocytosis".)

●Leukoerythroblastic findings (picture 12) – Teardrop cells (picture 13), nucleated RBCs, or immature granulocytes suggest an infiltrative process in the bone marrow. (See "Evaluation of bone marrow aspirate smears".)

●Leukocytosis – Suggests infection, especially with a predominance of bands (left shift) and/or toxic granulations (picture 14). (See "Approach to the patient with neutrophilia".)

●Immature WBCs (eg, myeloblasts) (picture 15) or dysplastic WBCs (picture 16) – Suggest leukemia or myelodysplasia. (See "Evaluation of the peripheral blood smear", section on 'Blasts or tumor cells'.)

●Multi-lobed/hypersegmented neutrophils – Neutrophils with >5 lobes (picture 17) suggest a megaloblastic process due to deficiency of vitamin B12, folate, or copper. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'CBC and blood smear'.)

Metabolic panel, liver function, HIV, and HCV testing — All patients with thrombocytopenia should have a metabolic panel and liver function testing (hepatic enzymes, coagulation testing, albumin) to evaluate for occult liver disease.

Thrombocytopenia has been identified as an important "indicator condition" for HIV infection [26]. Outpatients with thrombocytopenia of unknown causes and individuals with a new diagnosis of immune thrombocytopenia (ITP) should have HIV testing if not done recently. HIV testing may also be reasonable for other individuals. (See "HIV-associated cytopenias", section on 'Thrombocytopenia due to HIV or ITP' and "Screening and diagnostic testing for HIV infection".)

Thrombocytopenia may also be seen with hepatitis C virus (HCV) infection; testing is appropriate for outpatients with new thrombocytopenia if not done recently. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

Other laboratory testing

●Asymptomatic – Patients with isolated mild thrombocytopenia (platelet count 100,000 to 149,000/microL) who have a negative history for other concerning diagnoses, negative HIV and HCV testing, and an otherwise normal blood smear may be monitored without additional laboratory testing.

Thrombocytopenia may resolve or other findings may develop that point to a specific diagnosis. Regular platelet counts (eg, once per year) have been suggested [30]; the frequency of follow-up is individualized.

●Other symptoms or examination findings – Additional testing may be warranted, such as the following:

•Fever or other signs of infection should be evaluated with testing for DIC and sepsis (coagulation studies including prothrombin time [PT], activated partial thromboplastin time [aPTT], and fibrinogen; cultures). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Evaluation and management of suspected sepsis and septic shock in adults".)

•Symptoms or findings of systemic autoimmune disorders (systemic lupus erythematosus [SLE], antiphospholipid syndrome [APS]) may prompt testing for antinuclear antibodies or antiphospholipid antibodies, respectively. We do not test for these in patients with isolated thrombocytopenia and no signs or symptoms suggestive of SLE or APS. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'When to suspect SLE' and "Diagnosis of antiphospholipid syndrome", section on 'When to suspect the diagnosis'.)

•Findings of liver disease should prompt measurements of hepatic enzymes, tests of liver synthetic function (albumin, coagulation testing). (See "Overview of liver biochemical tests" and "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)" and "Hemostatic abnormalities in patients with liver disease", section on 'Laboratory abnormalities'.)

•Thrombosis should prompt consideration of a new malignancy, DIC, heparin-induced thrombocytopenia (HIT) and related syndromes, and APS. Depending on the site of thrombosis and other hematologic findings, paroxysmal nocturnal hemoglobinuria (PNH) may also be a consideration. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Diagnosis of antiphospholipid syndrome" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria" and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

•Microangiopathic changes on the peripheral smear should prompt coagulation testing, lactate dehydrogenase (LDH), and creatinine to evaluate for DIC, TTP, or HUS, with subsequent evaluation based on the results. (See 'Peripheral blood smear' above and "Diagnostic approach to anemia in adults" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

The possibility of rare yet life-threatening conditions should also be considered; some of these cause other cytopenias [43,44]. The hematologist consultant can advise on the likelihood of these conditions and the appropriate laboratory testing.

●HIT

●TTP or other TMA

●Drug-induced immune thrombocytopenia (DITP)

●Post-transfusion purpura (PTP)

●Primary ITP

●Acute leukemia

●Hemophagocytic lymphohistiocytosis (HLH)

●Aplastic anemia

Making a final diagnosis — For some patients, the cause of thrombocytopenia will be revealed by the above evaluation, or the thrombocytopenia will be transient and resolve. Two of the most common diagnoses, drug-induced thrombocytopenia and ITP, are diagnoses of exclusion.

●Drug-induced – If no cause of thrombocytopenia is identified by the above evaluation, any medications implicated in drug-induced thrombocytopenia (table 3) should be discontinued and/or replaced with an alternative [45]. If there are multiple likely medications, they can be stopped simultaneously or sequentially based on the likelihood of causing thrombocytopenia. The consultant can assist with this determination. (See 'Hematologist referral/consultation' below.)

●ITP – A presumptive diagnosis of ITP is made when the history, physical examination, and laboratory data do not suggest an alternative diagnosis. In a patient with incidentally discovered asymptomatic thrombocytopenia and a probable diagnosis of ITP, no further evaluation beyond the routine history, physical examination, CBC, review of the peripheral blood smear, metabolic panel, liver function tests, and testing for HIV and HCV infection is necessary. Antiplatelet antibody studies are not routinely done, and imaging studies are reserved for evaluation of suspected lymphadenopathy, splenomegaly on physical examination, or infection. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Preliminary evaluation'.)

Bone marrow evaluation is not required to diagnose ITP in all individuals, but bone marrow examination may be indicated for patients with other unexplained cytopenias (anemia, leukopenia), dysplasia on the peripheral blood smear, or other unexpected hematologic findings. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Additional testing in selected patients'.)

Response to ITP therapies, if indicated, supports the diagnosis of ITP. The platelet count should be monitored to determine the trend. The interval of retesting depends on the severity of thrombocytopenia and other clinical findings. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Overview of decision-making'.)

Referral to a hematologist to confirm the diagnosis is appropriate for any new hematologic diagnosis including ITP. (See 'Hematologist referral/consultation' below.)

Additional considerations

Hematologist referral/consultation — Referral to a hematologist is appropriate to confirm any new diagnosis of a thrombocytopenic condition or to determine the cause of any unexplained thrombocytopenia. The urgency of referral depends on the degree of thrombocytopenia and other abnormalities, and the stability of the findings.

In hospitalized patients, some conditions are medical emergencies that require immediate action (algorithm 1). Immediate hematologist involvement in diagnosis and management is appropriate for:

●Suspected TTP, HUS, or other TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Suspected HIT. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

●Suspected acute leukemia, aplastic anemia, or other bone marrow failure syndrome. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

●After adenoviral vectored vaccine administration. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

The hematologist can also assist in diagnosis and management of patients with severe thrombocytopenia (platelet count <50,000/microL) who have serious bleeding or require an urgent invasive procedure, and in pregnant individuals with severe thrombocytopenia, regardless of the cause.

Bone marrow evaluation — Bone marrow aspirate and biopsy is not required in all patients with thrombocytopenia. However, it may be helpful if the cause of thrombocytopenia is unclear or if a primary hematologic disorder is suspected, especially if other cell lines are affected. An exception is a clinical picture consistent with vitamin B12, folate, or copper deficiency, which can first be evaluated by laboratory testing. (See 'Other laboratory testing' above.)

The following bone marrow findings may be helpful:

●Normal or increased megakaryocytes suggest that the thrombocytopenia is due, at least in part, to a condition associated with platelet destruction such as ITP or DITP. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Additional testing in selected patients' and "Drug-induced immune thrombocytopenia", section on 'Mechanisms of DITP'.)

●Decreased megakaryocyte numbers, along with overall decreased or absent cellularity (picture 18 and picture 19), is consistent with decreased bone marrow production of platelets, as in aplastic anemia. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

●In rare cases, severe reduction or absence of megakaryocytes with no other abnormalities may occur. This finding is most often reported in patients with SLE and may be due to an autoantibody directed against the thrombopoietin (TPO) receptor or may be T cell-mediated. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia' and "Biology and physiology of thrombopoietin", section on 'Thrombocytopenia due to anti-thrombopoietin antibodies'.)

●Megaloblastic changes in the RBC and granulocytic series suggest deficiency of vitamin B12, folate, or copper (picture 20), while dysplastic changes suggest MDS or copper deficiency (picture 21 and picture 22). (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Bone marrow (generally not indicated)' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●Granulomata, increased reticulin or collagen fibrosis (picture 23 and picture 24), or infiltration with malignant cells (picture 25) establishes the diagnosis of bone marrow invasion, especially when a leukoerythroblastic blood picture is also present. (See "Evaluation of the peripheral blood smear", section on 'Leukoerythroblastic smear'.)

GENERAL MANAGEMENT PRINCIPLES — While awaiting a specific diagnosis or waiting for treatment to become effective, some general management principles apply to all patients with thrombocytopenia.

●Treat the underlying cause – Thrombocytopenia is often a symptom of an underlying disorder. Treatments, if needed, are directed at the underlying cause. Management of specific thrombocytopenic disorders once the diagnosis is made is discussed in separate topic reviews listed above. (See 'Categories of causes' above.)

●Platelet transfusions as a temporizing measure – Urgent management of critical bleeding with severe thrombocytopenia requires immediate platelet transfusion, regardless of the underlying cause. Platelet transfusion will transiently increase the platelet count and may be used as a temporizing measure to treat bleeding (or reduce the risk of bleeding if the platelet count is <10,000/microL [or higher in selected cases with especially high bleeding risk]). (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion'.)

●Activity restrictions – Patients who are otherwise healthy and have no petechiae or purpura may not require activity restrictions.

Individuals with severe thrombocytopenia (<50,000/microL) generally should not participate in extreme, high-impact athletics such as boxing, rugby, and martial arts. However, no restrictions are necessary for usual activities or low-impact exercise.

●Anticoagulant and antiplatelet medications – The clinical indications and risks associated with discontinuation are balanced against the bleeding risk associated with the degree of thrombocytopenia and of continuing the medication [7]. Input from the consulting specialist who prescribed the medication and/or the hematologist may be sought. Anticoagulation with thrombocytopenia is presented separately. (See "Anticoagulation in individuals with thrombocytopenia".)

Thrombocytopenia by itself does not protect against venous or arterial thrombosis, and appropriate use of thromboprophylaxis or anticoagulants should not be withheld from a patient with mild to moderate thrombocytopenia (>50,000/microL) if indicated. For patients with more severe thrombocytopenia, decisions are made on a case-by-case basis regarding the risks of bleeding and benefits of anticoagulation.

●Over-the-counter remedies – Patients should be educated about which nonprescription remedies interfere with platelet function, including aspirin, nonsteroidal antiinflammatory drugs, and possibly ginkgo biloba. In general, these are avoided unless there is a specific indication for which equivalent alternatives are lacking. (See "Clinical use of ginkgo biloba".)

●Safe platelet count for invasive procedures – Most platelet count thresholds for invasive procedures are based on weak observational evidence at best. In general, procedures with a greater risk of bleeding are performed at higher platelet counts. While there is some flexibility in individual circumstances, anesthesiologists and surgeons performing these procedures will have the last word. General guidelines are presented separately. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Preparation for an invasive procedure'.)

Optimal methods for raising the platelet count in preparation for an invasive procedure depend on the underlying condition. A glucocorticoid or intravenous immune globulin (IVIG) are used for presumptive immune thrombocytopenia (ITP); platelet transfusion is used for myelodysplastic syndrome (MDS). Individuals with impaired platelet function may require platelet transfusions despite adequate platelet counts, depending on the procedure. Attention should also be paid to correcting coagulation abnormalities if present.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immune thrombocytopenia (ITP) and other platelet disorders".)

SUMMARY AND RECOMMENDATIONS

●Definition – Thrombocytopenia (platelet count <150,000/microL [<150 x 10⁹/L]) can be mild, moderate, or severe. We are most concerned about spontaneous bleeding with platelet counts <10,000/microL and surgical bleeding with counts <50,000/microL. Rarely, there is a risk of thrombosis rather than, or in addition to, bleeding. (See 'Definitions and areas of concern' above.)

●Causes – Potential causes of thrombocytopenia differ depending on mechanism and clinical setting. (See 'Organized by mechanism' above and 'Organized by acuity level' above.)

•Emergencies – These include severe thrombocytopenia with major bleeding or risks of clotting; the latter include heparin-induced thrombocytopenia (HIT), thrombotic microangiopathies (TMAs; thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], drug-induced TMA [DITMA]). Other emergencies are acute leukemia or bone marrow failure with severe pancytopenia. The hematologist can facilitate life-saving interventions. (See 'Thrombocytopenic emergencies requiring immediate action' above.)

•Acutely ill – Common causes of new-onset thrombocytopenia in the intensive care unit (ICU) include sepsis, disseminated intravascular coagulation (DIC) (table 1), and drug-induced thrombocytopenia (table 3). Patients can have more than one cause. (See 'Acutely ill/intensive care unit' above.)

•Fever, hospitalized, or postoperative – In patients with fever, causes include infection, sepsis, and DIC. Hospitalized patients may also have drug-induced thrombocytopenia, HIT, secondary immune thrombocytopenia (ITP) (table 2), liver disease, malignancy, TMA, antiphospholipid syndrome (APS), or paroxysmal nocturnal hemoglobinuria (PNH). (See 'Infection or fever' above and 'Postoperative or hospitalized' above.)

•Bleeding and/or isolated thrombocytopenia – Causes include drug-induced thrombocytopenia (table 3) or primary ITP. Postoperative thrombocytopenia or dilutional thrombocytopenia are common transient causes. (See 'Bleeding or other symptoms' above.)

•Asymptomatic outpatient – Common causes of mild thrombocytopenia include normal variation, ITP, occult liver disease, HIV infection, nutrient deficiencies (vitamin B12, folate, copper), or myelodysplastic syndrome (MDS). Hereditary platelet disorders (sometimes misdiagnosed as ITP) may also occur (table 4). (See 'Incidental finding of mild thrombocytopenia' above.)

●Evaluation – Repeat the complete blood count (CBC) and review the peripheral blood smear, obtain prior platelet counts if available, and assess for other hematologic abnormalities. The pace of the evaluation depends on clinical severity. (See 'Organized by acuity level' above and 'Initial questions and pace of the evaluation' above.)

•History and examination – Review prior platelet counts, family history, bleeding, medications (table 3), remedies (table 5), infectious exposures, dietary practices, and medical conditions. Examine for bleeding, lymphadenopathy, hepatosplenomegaly, and thrombosis. (See 'Further questions to determine cause' above and 'Physical examination' above.)

•Laboratory testing – Review the CBC and peripheral blood smear. Adults with new thrombocytopenia should have HIV and hepatitis C virus (HCV) testing. Some findings suggest a potentially life-threatening condition (algorithm 1). Additional laboratory testing may be warranted in patients with other findings. (See 'Laboratory testing' above.)

•Diagnosis – Testing may reveal the diagnosis; drug-induced thrombocytopenia and ITP are diagnoses of exclusion. (See 'Making a final diagnosis' above.)

●Referral and bone marrow – Hematologist consultation is appropriate to confirm a new hematologic diagnosis or if the cause of thrombocytopenia is unclear, especially when urgent intervention is needed. Bone marrow evaluation may be helpful if the cause is unclear or a bone marrow disorder is suspected. (See 'Additional considerations' above.)

●Management – Management depends on the underlying diagnosis. Platelet transfusions may be temporizing if indicated to treat or prevent bleeding. Avoidance of medications that interfere with hemostasis and correction of coagulation abnormalities may be warranted. Invasive procedures require close coordination with anesthesiologists and surgeons. (See 'General management principles' above and "Platelet transfusion: Indications, ordering, and associated risks".)

●Other populations – (See "Neonatal thrombocytopenia: Etiology" and "Causes of thrombocytopenia in children" and "Thrombocytopenia in pregnancy".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James N George, MD, who contributed to earlier versions of this topic review.