INTRODUCTION — 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. This approach can be used by the primary care physician and the consulting hematologist. Thrombocytopenia in neonates, children, and during pregnancy are discussed separately. (See "Neonatal thrombocytopenia: Etiology" 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) [1]. However, these numbers must be interpreted in the context of the underlying disease, and higher or lower values may be expected for certain conditions (eg, in the setting of immune thrombocytopenia [ITP], we consider a platelet count <30,000/microL to represent severe thrombocytopenia). Severe thrombocytopenia (platelet count below a threshold of approximately 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.)
A study from the United States involving over 12,000 adults in the Third National Health and Nutrition Examination Survey (NHANES) database found the following [2]:
●Platelet counts ranged from 150,000 to 450,000/microL, with mean values of 266,000 and 237,000/microL in females and males, respectively.
●Platelet counts were slightly higher in women than men.
●Platelet counts were slightly higher in younger people than older people.
●Platelet counts were higher in non-Hispanic Black individuals compared with White individuals.
Despite the wide variation of platelet counts within the population, platelet counts among healthy individuals remain relatively stable 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 [3].
The 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 platelet count is normally distributed in the population and references ranges typically include two standard deviations above and below the mean, which represents 95 percent of the normal population.
●An individual can have a significant decrease in platelet count and still be within the 'normal' range and thus not be flagged as abnormal (eg, 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 (if available) to determine whether the count is stable or trending downward. A recent fall in the platelet count by 50 percent, even if still in the normal range, may herald severe clinical problems, and requires active follow-up. (See 'Overview of our approach' below.)
When to worry about bleeding — Bleeding is a concern in patients with severe thrombocytopenia; however, the correlation between platelet count and bleeding risk is uncertain. Clinical predictors of bleeding include prior bleeding episodes and the presence of wet purpura and possibly hematuria. In a retrospective review that described six patients with ITP who developed severe or life-threatening bleeding, all six had preceding oral purpura and four of the six had hematuria [4]. In a study that aggregated daily bleeding assessment data from three randomized controlled trials of patients with thrombocytopenia in the setting of hematologic malignancy, hematuria was significantly associated with the development of more severe bleeding [5] (eg, in mucosal membranes). (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 generally may be 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.
●Severe spontaneous bleeding is rare; it is most likely with platelet counts <20,000/microL, especially <10,000/microL.
●Bleeding risk in ITP may be slightly less than that in 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).
It is also important to consider other factors that may affect bleeding risk (eg, platelet function defects, coagulation abnormalities). When present, these factors may contribute to bleeding risk and may be more concerning than the low platelet count.
The role of platelet function in bleeding risk is illustrated by the rare inherited disorder Bernard-Soulier syndrome (BSS), characterized by thrombocytopenia and impaired platelet function in which bleeding is out of proportion to the degree of thrombocytopenia. Similarly, patients with severe liver disease or disseminated intravascular coagulation may have a greater risk of bleeding from coagulation defects than from the thrombocytopenia.
In contrast, most individuals with hemostatically normal platelets (eg, as seen in ITP) do not have severe spontaneous bleeding even with very 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. While most of the implicated disorders are rare, it is important to consider them because urgent treatment may be needed to prevent life-threatening thrombotic events.
Examples include the following:
●Heparin-induced thrombocytopenia – A small percentage of patients exposed to heparin (<5 percent) will develop heparin-induced thrombocytopenia (HIT) 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 non-heparin anticoagulant. A discussion of non-heparin anticoagulants and evidence to support their use is presented separately. (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 coronavirus disease 2019 (COVID-19) adenoviral vector vaccines (AstraZeneca and Janssen [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. Evaluation and emergency treatment are discussed separately. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)
●Antiphospholipid syndrome – The antiphospholipid syndrome (APS) can develop in individuals with systemic lupus erythematosus, other medical conditions (eg, infection, medications, cancer), or in individuals without an underlying condition. Patients may have venous and/or arterial thrombosis. Treatment involves anticoagulation or aspirin, and treatment of any underlying condition, as discussed in detail separately. (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 – Patients with disseminated intravascular coagulation (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). Treatment of the underlying condition is paramount. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Thrombotic microangiopathy – Thrombotic microangiopathies (TMAs) such as 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 life-saving and should be initiated immediately when TTP is suspected. (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 – Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition caused by loss of glycosyl phosphatidylinositol from cell membranes. Thrombosis (often involving unusual locations such as intraabdominal or cerebral veins) can occur, along with hemolytic anemia and/or bone marrow failure. Treatment depends on the degree of cytopenias and the presence of thrombosis. (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. Management of anticoagulation in that population can be challenging; however, it is important to note that the low platelet count is not protective against thrombosis, and anticoagulation is often indicated [7]. This subject is discussed in more detail separately. (See "Anticoagulation in individuals with thrombocytopenia".)
PATHOPHYSIOLOGY — The major pathophysiologic mechanisms of thrombocytopenia include decreased platelet production in the bone marrow; peripheral platelet destruction by antibodies; consumption in thrombi; dilution from fluid resuscitation or massive transfusion; and sequestration (pooling) of platelets in the spleen in individuals with portal hypertension and/or splenomegaly. These mechanisms are illustrated by the following examples:
●Decreased platelet production – Platelet production depends on intact hematopoietic stem cell function in the bone marrow and thrombopoietin (TPO) production by the liver.
•Bone marrow disorders – Platelets are produced in the bone marrow from megakaryocytes (picture 1), which are derived from multipotent hematopoietic progenitor cells. Each megakaryocyte produces an estimated 1000 to 5000 platelets. The rate of platelet production is 35,000 to 50,000 platelets per microL of blood daily at steady state; production can be increased up to eightfold during times of increased demand [8,9]. (See "Megakaryocyte biology and the production of platelets".)
Typically, bone marrow disorders that impair platelet production (eg, nutrient deficiencies, myelodysplastic syndromes, aplastic anemia) also reduce production of other blood cells (ie, red blood cells [RBC] and white blood cells [WBC]), causing pancytopenia. Patients may present with symptoms of thrombocytopenia (eg, bleeding, petechiae) or symptoms attributable to anemia and/or leukopenia (eg, fatigue/shortness of breath, infection).
Isolated megakaryocyte loss can also occasionally occur (eg, in response to a drug). In addition, primary immune thrombocytopenia (ITP) is commonly associated with impaired platelet production due to anti-platelet autoantibodies that also react with megakaryocytes. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Pathogenesis'.)
•Liver disease – The liver is the site of TPO production, and liver disease can cause thrombocytopenia due to reduced TPO levels when liver synthetic function is significantly impaired. (See "Megakaryocyte biology and the production of platelets", section on 'Regulation of platelet production' 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) as discussed below.
●Platelet 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 [10,11]. There may also be a contribution by Ashwell Morell receptors in the liver that recognize alterations in the glycan pattern on the surface of platelets [12]. Accelerated destruction of platelets (and possibly megakaryocytes) can occur due to antibody-mediated clearance. Anti-platelet antibodies occur in primary ITP and also in secondary ITP (ie, in the context of another autoimmune syndrome such as systemic lupus erythematosus). They can also be induced by some medications and ingested substances (eg, quinine). (See "Drug-induced immune thrombocytopenia", section on 'Mechanisms of DITP'.)
Combined cytopenias due to antibody-mediated destruction of more than one blood cell line can also occur; the term Evans syndrome is used to refer to combined warm autoimmune hemolytic anemia (AIHA) and ITP. Autoimmune neutropenia can also occur in this setting. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)
Platelet consumption also occurs within thrombi in disseminated intravascular coagulation (DIC) and thrombotic microangiopathies such as thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
●Dilution – An additional mechanism of thrombocytopenia is dilutional thrombocytopenia, as occurs in the setting of massive fluid resuscitation or massive transfusion without proportionate transfusion of platelets. Platelet counts are reduced in proportion to the number of RBC units transfused in a 24-hour period [13,14]. 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'.)
●Redistribution/hypersplenism – In individuals with normal splenic function, approximately one-third of the platelet mass is found in the spleen, in equilibrium with the circulating platelet pool [15]. Conditions that increase splenic size and/or cause splenic congestion through portal hypertension (eg, cirrhosis, alcoholic liver disease) can decrease the platelet count without altering the total platelet mass in the body (figure 1) [15]. Severe thrombocytopenia or bleeding in the setting of splenomegaly should prompt the clinician to investigate for other causes. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)
CAUSES OF THROMBOCYTOPENIA — The potential causes of thrombocytopenia differ depending on the clinical setting in which it occurs. Individuals presenting with asymptomatic, isolated thrombocytopenia are more likely to have immune thrombocytopenia (ITP); whereas acutely ill, hospitalized patients who develop thrombocytopenia are more likely to have platelet consumption, dilution, bone marrow suppression from sepsis/infection, or drug-induced thrombocytopenia. In between these extremes are autoimmune disorders, nutrient deficiencies, thrombotic microangiopathies, or infections, which may have a range of presentations depending on the severity of the underlying condition.
Causes of thrombocytopenia are presented in the table (table 2) and in the following list, ordered from the least likely to be symptomatic to the most acutely ill. However, the patient's clinical status cannot be used to exclude or confirm a diagnosis, as many of these causes can have a variable clinical presentation.
●Pregnancy – Most pregnant women have normal platelet counts. Approximately 5 to 10 percent develop incidental thrombocytopenia during pregnancy, also termed gestational thrombocytopenia. Gestational thrombocytopenia (also called physiologic thrombocytopenia of pregnancy) is mild, asymptomatic, occurs during late gestation, and resolves spontaneously after delivery. There is no associated risk of bleeding or fetal thrombocytopenia. Any change from routine obstetrical care is discouraged. (See "Thrombocytopenia in pregnancy", section on 'Gestational thrombocytopenia (GT)'.)
By contrast, if the platelet count is less than 70,000 to 80,000/microL, evaluation for alternative explanations of thrombocytopenia such as ITP should be performed. (See 'Overview of our approach' below.)
Severe thrombocytopenia, or thrombocytopenia accompanied by other findings during pregnancy (eg, renal insufficiency, hypertension, microangiopathic hemolytic anemia) should prompt an evaluation for more serious disorders such as the hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, preeclampsia, or thrombotic thrombocytopenic purpura (TTP). (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Thrombocytopenia in pregnancy", section on 'Preeclampsia with severe features/HELLP (PE/HELLP)' and "Thrombocytopenia in pregnancy", section on 'List of causes'.)
●Chronic liver disease or hypersplenism – Isolated thrombocytopenia may be the initial manifestation of chronic liver disease with portal hypertension and congestive splenomegaly (hypersplenism). Thrombocytopenia is usually mild to moderate (eg, in the range of 60,000 to 100,000/microL), and the spleen is often palpably enlarged. Up to 90 percent of platelets may be pooled within the splenic circulation in patients with chronic liver disease and hypersplenism, compared with approximately one-third of platelets in individuals without hypersplenism [15]. In severe liver disease, platelets may lower because of reduced thrombopoietin (TPO) levels. The frequency of thrombocytopenia in a series of 354 patients with a presumptive diagnosis of nonalcoholic fatty liver disease was 29 percent [16]. (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".)
●Immune thrombocytopenia – Immune thrombocytopenia (ITP) is a common cause of moderate to severe thrombocytopenia in an otherwise asymptomatic adult. Other cell lines are unaffected (ie, ITP does not cause anemia or leukopenia). The prevailing understanding of the mechanism of ITP is antibody-mediated platelet destruction. However, anti-platelet antibodies are not always detected, and their testing is not clinically useful. A presumptive diagnosis of ITP is made when the history, physical examination, and laboratory data do not suggest an alternative diagnosis. Only a complete blood count (CBC) and review of the peripheral blood smear are required; however, other testing may be useful to eliminate secondary causes of ITP (eg, HIV and hepatitis C testing) or other non-immune causes of thrombocytopenia (eg, liver enzymes for possible hepatic impairment). (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)
●Congenital platelet disorders – Some congenital platelet disorders associated with thrombocytopenia are discovered incidentally. Several may be associated with very large platelets on the peripheral blood smear (eg, MYH-9 related disease, Bernard-Soulier syndrome, Gray platelet syndrome), but not all cause macrothrombocytopenia. Although these are rare and often diagnosed in childhood, diagnosis in adulthood is possible. Many patients with congenital thrombocytopenia are initially mistakenly diagnosed as having ITP. This was illustrated in a database review from the McMaster ITP registry, which found that 35 of 614 adults with thrombocytopenia (approximately 6 percent) had an inherited syndrome [17]. 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 "Congenital and acquired disorders of platelet function".)
Other inherited syndromes associated with thrombocytopenia include Wiskott-Aldrich syndrome, thrombocytopenia absent radius (TAR) syndrome, Alport syndrome (also associated with hereditary nephritis and hearing loss), and a small subset of patients with von Willebrand disease [18]. These conditions are often associated with other clinical findings that may only be appreciated once the unifying diagnosis is considered. However, not all inherited thrombocytopenias are associated with syndromic features. Although these conditions are often diagnosed in childhood, an adult presentation is possible. (See "Wiskott-Aldrich syndrome" and "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)" and "Causes of thrombocytopenia in children", section on 'Normal-sized platelets' and "Congenital and acquired disorders of platelet function".)
●Infection – Thrombocytopenia can occur with a variety of infections. The mechanism(s) may include immune-mediated platelet destruction, bone marrow suppression, or platelet consumption.
•Viral – Thrombocytopenia may occur after a number of viral infections (eg, rubella, mumps, varicella, parvovirus, hepatitis C, and Epstein-Barr virus). 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 coronavirus disease 2019 (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' below.)
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'.)
The measles-mumps-rubella vaccine has been associated with thrombocytopenia; this association is very rare (ie, <1 in 30,000 for vaccination versus 1 in 3000 for rubella infection) [19,20]. (See "Measles, mumps, and rubella immunization in adults".)
Case reports have described thrombocytopenia in association with Zika virus infection [21,22]. (See "Zika virus infection: An overview".)
•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 [23,24].
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 PT, 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 immune thrombocytopenia. 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, brucellosis, anaplasmosis, and other tick-borne infections. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "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 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'.)
●Medications
•Drug-induced immune thrombocytopenia – Virtually any medication can cause thrombocytopenia by the occurrence of drug-dependent, platelet-reactive antibodies, but certain agents are more commonly implicated [25]. Examples include antibiotics (eg, sulfonamides, ampicillin, piperacillin, vancomycin, rifampin); older antiepileptic agents (eg, carbamazepine, phenytoin), and quinine (table 3 and table 4). Typically, thrombocytopenia develops within hours of drug exposure if the patient has been previously exposed to the drug, 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 [26]. Specific treatment is rarely required. A list of implicated drugs is available at www.ouhsc.edu/platelets; a more comprehensive discussion of drug-induced thrombocytopenia is presented separately. (See "Drug-induced immune thrombocytopenia".)
Vaccine-associated immune thrombocytopenia (ITP) has been classically described in children in the six weeks following administration of the MMR vaccine. As noted directly below, vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported with certain COVID-19 vaccines.
•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 >50 percent from baseline; venous or arterial thrombosis; necrotic skin lesions at sites of heparin injection; and acute systemic reactions after intravenous heparin administration. Treatment involves immediate discontinuation of heparin and administration of a non-heparin anticoagulant. Evaluation for HIT and management of patients with a presumptive clinical diagnosis of HIT are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "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 vaccine-induced immune thrombotic thrombocytopenia (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)".)
•Drug-induced thrombocytopenia (non-immune) – Some drugs, such as daptomycin, linezolid, and valproic acid, can cause mild or moderate isolated thrombocytopenia by dose-dependent suppression of platelet production.
•Drug-induced thrombotic microangiopathy – Drug-induced thrombotic microangiopathy (DITMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia; some cases may be associated with acute renal failure and/or fever. DITMA is divided into immune and dose-dependent mechanisms. Quinine, which can be obtained over the counter for leg cramps, is a classic cause of immune-mediated DITMA. Several cancer therapies, calcineurin inhibitors, and drugs of abuse can cause toxicity-mediated DITMA. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
•Bone marrow suppression by cytotoxic chemotherapy or radiation therapy – Cytotoxic chemotherapy agents and radiation therapy induce a predictable, dose-dependent myelosuppression that typically affects all blood cell lines (table 5). Lower doses may produce no changes or only mild/transient cytopenias, whereas higher doses can cause severe cytopenias in all cell lines. While the recovery of blood cell counts following discontinuation is also predictable, occasional patients with underlying bone marrow disorders may have a slower platelet count rise after discontinuation.
●Over-the-counter remedies, supplements, foods, and beverages – Thrombocytopenia has been reported after ingestion of quinine-containing beverages (eg, tonic water, bitter lemon) (table 4), as well as numerous herbal preparations [27,28], foods [29,30], and over-the-counter medicines. A thorough history may reveal a dietary cause of thrombocytopenia in some patients. This issue is discussed separately. (See "Drug-induced immune thrombocytopenia".)
●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'.)
●Malignancy – Cancer can cause thrombocytopenia as a component of chronic DIC, bone marrow infiltration, or thrombotic microangiopathy. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Causes of DIC' and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)
●Nutrient deficiencies – Deficiency of nutrients required for hematopoiesis (eg, folate, vitamin B12) typically causes mild pancytopenia, but isolated thrombocytopenia may be seen. Patients may be asymptomatic or affected by symptoms of anemia and/or neurologic findings. These deficiencies can develop in the setting of certain dietary practices (eg, poor nutrition, veganism, excessive zinc ingestion), by an autoimmune mechanism, or following bariatric or other gastrointestinal surgeries if supplementation is inadequate. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Copper deficiency myeloneuropathy", section on 'Hematologic' and "Bariatric surgery: Postoperative nutritional management".)
●Thrombotic microangiopathy (TMA) – TMAs such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and drug-induced TMA (DITMA) are rare in adults, but must be considered in any adult with microangiopathic hemolytic anemia and thrombocytopenia. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
Patients with TTP, HUS, or DITMA rarely present with the full pentad of clinical features (microangiopathic hemolytic anemia, thrombocytopenia, neurologic findings, renal insufficiency, fever) that were common in the era before effective treatment. The combination of thrombocytopenia and microangiopathic hemolytic anemia is sufficient to raise concern about the possibility of TMA. Acute kidney injury supports the diagnosis of HUS or complement-mediated TMA rather than TTP.
An acute episode of TTP or HUS may also 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 [31]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
●Bone marrow disorders – Several primary hematologic disorders cause thrombocytopenia; however, these disorders typically cause other abnormalities of the CBC (eg, pancytopenia, leukocytosis). Suspicion of any of these conditions should prompt hematologist involvement and bone marrow evaluation. (See 'Additional evaluation' below.)
•Myelodysplastic syndromes cause varying degrees of thrombocytopenia in roughly one-quarter of patients, but isolated thrombocytopenia is rare. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Complete blood count'.)
•Bone marrow failure syndromes can cause thrombocytopenia, almost always accompanied by other cytopenias. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)
•Acute leukemia typically presents with leukocytosis and immature 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".)
•Paroxysmal nocturnal hemoglobinuria (PNH) can present with bone marrow failure, including thrombocytopenia and thrombosis. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)
●Rheumatologic/autoimmune disorders – Systemic lupus erythematosus (SLE) is associated with secondary ITP in one-quarter to one-half of individuals. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia'.)
The antiphospholipid syndrome (APS) is an autoantibody-mediated syndrome characterized by venous or arterial thrombosis and/or pregnancy morbidity; stroke and other neurologic complications may occur. Mild to moderate thrombocytopenia due to secondary ITP is often present (See "Clinical manifestations of antiphospholipid syndrome".)
Thrombocytopenia may be seen in rheumatoid arthritis and may be accompanied by splenomegaly (eg, Felty syndrome). (See "Hematologic complications of rheumatoid arthritis", section on 'Neutropenia'.)
●Other causes – Additional rare causes of thrombocytopenia include vascular conditions associated with platelet destruction (eg, giant capillary hemangioma, large aortic aneurysms, cardiopulmonary bypass, intraaortic balloon pumps) (table 1) [32]. Post-transfusion purpura is a rare form of immune-mediated platelet destruction following transfusion of platelet-containing blood products. (See "Immunologic transfusion reactions", section on 'Post-transfusion purpura'.)
OVERVIEW OF OUR APPROACH — Our approach to the patient with newly-discovered, unexplained thrombocytopenia involves confirmation of the finding by repeating the complete blood count (CBC) and reviewing the peripheral blood smear, obtaining prior platelet counts if available, and assessing other hematologic abnormalities. The pace of the subsequent evaluation and further testing depends on the clinical presentation, which can range from asymptomatic to acutely ill (table 6).
Thrombocytopenic emergencies requiring immediate action — Certain presentations of thrombocytopenia are medical emergencies that require immediate action. These include:
●Bleeding in the setting of severe thrombocytopenia (ie, platelet count <50,000/microL)
●Urgently needed invasive procedure with severe thrombocytopenia
●Pregnancy with severe thrombocytopenia
●Suspected heparin-induced thrombocytopenia (HIT), vaccine-induced immune thrombotic thrombocytopenia (VITT), or post-transfusion purpura
●Suspected thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced thrombotic microangiopathy (DITMA)
●Suspected acute leukemia, aplastic anemia, or other bone marrow failure syndrome
The consulting hematologist can assist with patient evaluation, diagnosis and management strategies, including platelet transfusions, other means of rapidly raising the platelet count (eg, glucocorticoids and intravenous immune globulin for ITP, plasma exchange for TTP), prevention of additional complications (eg, thrombosis), and treatment of the underlying condition. (See 'Thrombocytopenia with bleeding or other symptoms' below and 'Hematologist referral/consultation' below.)
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?
Confirmation that the thrombocytopenia is real (eg, not a laboratory error or an in vitro artifact) is done by repeating the 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.)
A new reduction in platelet count is more concerning than a stable, mildly low count because it suggests the possibility of an evolving condition. Prior platelet counts are helpful in this regard, if available, and the platelet count should be monitored to determine the trend going forward, with the interval dependent on the severity of thrombocytopenia and other clinical findings. Temporal relationship to new medications (prescription and over-the-counter) and/or vaccinations is also relevant. (See 'History' below and 'Repeat CBC' below.)
Additional clues can also be identified from the blood smear (eg, giant platelets, which are read by the automated counter as red blood cells because of their size; or fragmented red blood cells, which are characteristic of thrombotic microangiopathy). Other hematologic abnormalities (eg, anemia, leukopenia, leukocytosis) generally suggest a more serious diagnosis than isolated thrombocytopenia. (See 'Repeat CBC' below and 'Peripheral blood smear' below.)
Any patient with unexplained thrombocytopenia should be evaluated by a hematologist to determine the cause and appropriate management; the urgency depends on the degree of thrombocytopenia and other findings. (See 'Hematologist referral/consultation' below.)
Asymptomatic, incidental finding, mild thrombocytopenia — Common diagnoses for asymptomatic outpatients with mild thrombocytopenia (platelet count between 100,000 and 150,000/microL) include mild forms of immune thrombocytopenia (ITP), occult liver disease, HIV infection, and myelodysplastic syndromes. Congenital thrombocytopenic conditions, sometimes misdiagnosed as ITP, may also cause mild thrombocytopenia. (See 'Causes of thrombocytopenia' above.)
In a patient with incidentally discovered asymptomatic thrombocytopenia and a probable diagnosis of ITP, no further evaluation beyond the routine history, physical examination, CBC, and review of the peripheral blood smear, and testing for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection is necessary. (See 'History' below and 'Physical examination' below and 'Laboratory testing' below and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Preliminary evaluation'.)
Referral to a hematologist to confirm the diagnosis is appropriate. Anti-platelet antibody studies are not routinely done and imaging studies, and bone marrow aspiration and biopsy are not necessary unless other abnormalities are present. (See 'Hematologist referral/consultation' below.)
The natural history of asymptomatic, mild thrombocytopenia was studied prospectively in 217 apparently healthy individuals referred to a hematology center for incidentally discovered platelet counts between 100,000 and 150,000/microL [33]. At six months of observation, 23 (11 percent) had normal platelet counts, two developed a myelodysplastic syndrome (refractory anemia), and one developed systemic lupus erythematosus. The remaining 191 individuals (88 percent) had persistent platelet counts <150,000/microL during this period without other signs of disease becoming evident; after five years, most (64 percent) had spontaneous resolution or persistent mild thrombocytopenia without development of an associated condition, supporting a diagnosis of ITP or normal variation.
Thrombocytopenia with bleeding or other symptoms — Patients who present with isolated thrombocytopenia and bleeding, manifested by petechiae, purpura, and mucosal bleeding (eg, epistaxis, heavy menstrual bleeding), have a different diagnostic spectrum.
●Individuals with bleeding who lack signs of systemic illness or other abnormalities of the complete blood count are likely to have drug-induced thrombocytopenia or primary ITP. These diagnoses are made based on the appropriate history (eg, drug exposure, bleeding, absence of other specific symptoms) and lack of other findings on physical examination. No additional laboratory testing is needed, with the exception of HIV and HCV testing. (See 'Repeat CBC' below and 'Peripheral blood smear' below and 'HIV and HCV testing' below.)
●The role of 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'.)
●Individuals with thrombocytopenia and other symptoms have a broader range of potential diagnoses. Specific diagnoses to consider depend on the other clinical findings. As examples:
•Fever – Possible infection, sepsis, disseminated intravascular coagulation (DIC)
•Hepatosplenomegaly – Possible liver disease with hypersplenism, lymphoma
•Neurologic findings – Possible TTP, HUS, DITMA, vitamin B12 deficiency, or copper deficiency
•Lymphadenopathy – Possible infection, lymphoma, other malignancy
•Thrombosis – Possible HIT, antiphospholipid syndrome (APS), or paroxysmal nocturnal hemoglobinuria (PNH)
These individuals should have additional laboratory evaluation directed at the diagnoses suggested by these other symptoms. (See 'Other laboratory testing' below.)
Acutely ill/intensive care unit — Thrombocytopenia is common in acutely ill patients.
A 2011 systematic review of thrombocytopenia in the ICU reported thrombocytopenia in 8 to 68 percent at the time of ICU admission and new onset thrombocytopenia during the ICU stay in 13 to 44 percent [34]. Thrombocytopenia was correlated with high-severity illness, sepsis, and organ dysfunction.
Predictors of developing thrombocytopenia in a cohort of 145 patients in a medical ICU included disseminated intravascular coagulation (DIC), cardiopulmonary resuscitation, and organ failure at admission [35]. In another randomized trial that enrolled medical and surgical ICU patients who had platelet count levels >75,000/microL at baseline, predictors of thrombocytopenia included a higher APACHE II score (calculator 1), surgical diagnosis, liver dysfunction, receipt of inotropes or vasopressors in the preceding three days, renal replacement therapy in the preceding three days, and development of HIT [1].
The most common cause of new-onset thrombocytopenia in a cohort of 329 medical and surgical ICU patients was sepsis, accounting for one-half of the cases [36]. More than one cause of thrombocytopenia was found in 26 percent. The frequency of specific causes of thrombocytopenia included the following:
●Sepsis, all (48 percent)
●Sepsis with documented bacteremia (28 percent)
●Liver disease/hypersplenism (18 percent)
●Overt DIC (14 percent)
●Unknown cause (14 percent)
●Infection, other (11 percent)
●Primary hematologic disorder (9 percent)
●Medications, non-cytotoxic (9 percent)
●Medications, cytotoxic (7 percent)
●Massive transfusion (7 percent)
●Other causes (7 percent)
●Excess alcohol use (5 percent)
Based on this spectrum of findings, we obtain laboratory testing for DIC, sepsis, and liver disease using coagulation studies, liver function tests, and cultures of blood and body fluids in critically ill patients with thrombocytopenia. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Hemostatic abnormalities in patients with liver disease".)
It is also important to evaluate the possibility of rare yet life-threatening conditions such as heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), drug-induced immune thrombocytopenia (DITP), post-transfusion purpura (PTP), primary immune thrombocytopenia (ITP), and acute leukemia [37,38]. Bone marrow evaluation is appropriate if thrombocytopenia is severe and other cell lines are abnormal.
For patients with moderate to severe thrombocytopenia, a thorough review of medications that were started or administered in the two weeks prior to development of thrombocytopenia should be undertaken. If DITP is suspected, the potentially implicated medication(s) should be discontinued, with close monitoring of platelet count recovery [39]. HIT is an uncommon cause of thrombocytopenia in the intensive care unit [40]. However, patients with a 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)".)
Adverse patient outcomes generally correlate with the severity of thrombocytopenia. In one study, adjusted hazard ratios for bleeding with mild, moderate, and severe thrombocytopenia were 1.96, 3.52, and 3.54, respectively [1]. Moderate and severe (but not mild) thrombocytopenia also correlated with an increased length of ICU stay and ICU death [1].
Additional diagnostic considerations in acutely ill patients with pancytopenia (ie, leukopenia, anemia, and thrombocytopenia), such as hemophagocytic lymphohistiocytosis (HLH), are presented separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)
HISTORY — A thorough patient history should be done to determine whether other conditions are present that may explain thrombocytopenia. In an acutely ill patient who cannot provide a history, this information should be obtained from family members and/or other clinicians caring for the patient.
A helpful history includes the following:
●Prior platelet counts, if available, because a stable platelet count is less concerning than a new or decreasing count.
●Family history of bleeding disorders and/or thrombocytopenia. Importantly, however, the absence of a positive family history does not eliminate the possibility of an inherited disorder, as some individuals remain undiagnosed with familial platelet disorders well into adulthood. (See 'Causes of thrombocytopenia' above.)
●History of bleeding (eg, petechiae, ecchymoses, epistaxis, gingival bleeding, hematemesis, melena, heavy menstrual bleeding).
●Medication exposures – It is important to include new prescriptions, medications that are only taken intermittently, over-the-counter medicines (eg, aspirin, nonsteroidal anti-inflammatory drugs), herbal remedies, vaccines, and medicines prescribed for other family members or friends that the patient may have taken (table 3).
Ingestion of quinine-containing beverages should be addressed specifically, due to the strong association of quinine exposure with thrombocytopenia (table 4). For hospitalized patients, one must review the hospital chart, nursing notes, bedside flow sheets, and anesthesia records. Relevant medicines may also be contained in materials used in surgery (eg, vancomycin mixed into joint replacement cement) [41]. The timing of onset of clinical bleeding or first recognition of the thrombocytopenia with use of 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 (LMW) heparin (eg, enoxaparin, dalteparin, tinzaparin, nadroparin), and heparin flushes in vascular access lines or exposure during surgery. In contrast, we are not aware of an association of thrombocytopenia with target-specific anticoagulants (eg, direct thrombin inhibitors, factor Xa inhibitors).
●Infectious exposures, including recent infections (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 (eg, Ebola, Lassa fever); and risk factors for HIV infection [42,43].
●Dietary practices that could cause nutrient deficiencies (eg, veganism, vegetarianism, zinc ingestion).
●Other medical conditions, including hematologic disorders; rheumatologic diseases; bariatric surgery or poor nutritional status; blood product transfusion or organ transplantation [44].
PHYSICAL EXAMINATION — The physical examination should focus on signs of bleeding, and the presence of lymphadenopathy or hepatosplenomegaly, which may be signs of an underlying condition responsible for the thrombocytopenia. Signs of thrombosis may also suggest a different spectrum of potential causes of thrombocytopenia. (See 'When to worry about thrombosis' above.)
Skin and other sites of bleeding — Bleeding into the skin is one of the most common findings in thrombocytopenia. Of note, thrombocytopenic bleeding differs from the bleeding seen in individuals with coagulation abnormalities (table 7). Patients with bleeding due to thrombocytopenia may have petechiae, purpura, or frank mucosal bleeding.
●Petechiae – Petechiae are pinhead sized, red, flat, discrete lesions often occurring in crops in dependent areas (picture 2 and picture 3). Petechiae are caused by red blood cell extravasation from capillaries; they are asymptomatic, nontender, non-palpable, and do not blanch under pressure. They are most dense in dependent areas where the hydrostatic pressure on the small superficial vessels is greatest (eg, feet and ankles in ambulatory patients; presacral area in bedridden patients). Petechiae are not found on the sole of the foot, where the vessels are protected by the strong subcutaneous tissue. Petechiae and other lesions should be noted, especially in the dependent parts of the body.
●Purpura – Purpura refers to purplish discoloration of the skin caused by confluent petechiae. Dry purpura refers to purpura in skin; wet purpura refers to mucosal purpura, in frame B of the picture (picture 2). It is generally thought that wet purpura may be a prognostic sign for potentially more serious hemorrhage. 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 associated with multiple colors due to the presence of 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.
Of note, petechiae and purpura differ from small telangiectasias, angiomas, and vasculitic purpura (picture 4).
It can be helpful to document the extent of skin lesions (eg, mark with a pen) to identify new lesions and/or expansion of existing lesions, which may signify persistent or worsening thrombocytopenia, or raise additional concerns about increased bleeding risk.
Other sites of bleeding (eg, occult blood in the stool, 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 "Evaluation of 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'.)
LABORATORY TESTING — Review of the complete blood count (CBC) and peripheral blood smear are essential in a patient with unexpected thrombocytopenia. Platelet clumping suggests the possibility of pseudothrombocytopenia.
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.
●For symptomatic patients (eg, signs of bleeding) or those with severe thrombocytopenia (ie, <50,000/microL), such retesting should be performed immediately.
●For asymptomatic patients (eg, non-bleeding, no associated comorbidities) with moderate thrombocytopenia (ie, 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.
●For outpatients with isolated mild thrombocytopenia (ie, 100,000 to 149,000/microL), testing may be repeated in one or more months, as a small percent of these patients will develop a normal platelet count with observation only. An exception is a patient recently started on a new medication, new clinical findings, or other abnormalities on the CBC, because mild thrombocytopenia may be a sign of an evolving disorder (eg, drug-induced or heparin-induced thrombocytopenia, drug-induced thrombotic microangiopathy).
●Combined anemia and thrombocytopenia may occur if there has been longstanding bleeding (eg, gastrointestinal). Combined anemia and thrombocytopenia also raises the possibility of systemic disorders.
•Sepsis with disseminated intravascular coagulation (DIC)
•TTP, HUS, or DITMA
•Autoimmune disorders (eg, Evans syndrome)
•Nutrient deficiencies (eg, folate, vitamin B12, copper)
•Infections
•Bone marrow disorders (eg, myelodysplastic syndromes, leukemia, bone marrow infiltration by malignancy)
●Combined leukocytosis and thrombocytopenia raise the possibility of infection, chronic inflammation, and malignancy.
●Combined leukopenia, anemia, and thrombocytopenia (ie, pancytopenia) is discussed in detail separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)
Peripheral blood smear — Review of the peripheral blood smear is used to exclude pseudothrombocytopenia (eg, falsely low platelet count due to platelet clumping) and to evaluate morphologic abnormalities of blood cells that could be useful in determining the cause of thrombocytopenia.
As an example, giant platelets (picture 5) may suggest a congenital platelet disorder (eg, MYH-9-related disorders, Bernard Soulier syndrome [BSS]); these may be counted as red blood cells by some automated counters. (See "Congenital and acquired disorders of platelet function".)
Pseudothrombocytopenia — The possibility of pseudothrombocytopenia (ie, falsely low platelet count) should be eliminated before any further evaluation is undertaken. Pseudothrombocytopenia can occur in a number of settings, all of which can be identified by review of the peripheral blood smear and/or repeating the CBC using a non-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, exposure of patient samples to 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 epitope on platelet membrane glycoprotein (GP) IIb/IIIa that becomes exposed by EDTA-induced dissociation of GPIIb/IIIa [45-52].
If platelet clumping is observed, the platelet count is repeated using heparin or sodium citrate as an anticoagulant in the collection tube. If citrate is used, the platelet count should be corrected for dilution caused by the amount of citrate solution; no such correction is needed for heparin. Alternatively, fresh, non-anticoagulated 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".)
Examples include the following:
●Schistocytes (picture 7) suggest a microangiopathic process (eg, DIC, TTP, HUS, DITMA).
●Nucleated RBCs (picture 8), and Howell-Jolly bodies (picture 9), may be seen post-splenectomy or occasionally in patients with poor splenic function.
●Spherocytes (picture 10 and picture 11) suggest immune-mediated hemolytic anemia or hereditary spherocytosis.
●Leukoerythroblastic findings (picture 12), teardrop cells (picture 13), nucleated RBCs, or immature granulocytes suggest an infiltrative process in the bone marrow.
●Leukocytosis with a predominance of bands (left shift) and/or toxic granulations suggests infection (picture 14).
●Immature WBCs (eg, myeloblasts) (picture 15) or dysplastic WBCs (picture 16) suggest leukemia or myelodysplasia.
●Multi-lobed/hypersegmented neutrophils (ie, >5 lobes) (picture 17) suggest a megaloblastic process (eg, B12/folate/copper deficiency).
HIV and HCV testing — Thrombocytopenia has been identified as an important "indicator condition" for HIV infection [23]. Thus, adults with new thrombocytopenia should have HIV testing if not done recently. (See "Screening and diagnostic testing for HIV infection".)
Thrombocytopenia may also be seen with hepatitis C virus (HCV) infection; testing is appropriate for adults with thrombocytopenia if not done recently. (See "Screening and diagnosis of chronic hepatitis C virus infection".)
Other laboratory testing — Aside from the testing mentioned above (CBC, review of peripheral smear, HIV and HCV testing), no additional laboratory testing is absolutely required in a patient with isolated thrombocytopenia. However, additional testing may be warranted in patients with other findings.
Examples of findings that may trigger other laboratory testing include the following:
●Symptoms or findings of systemic autoimmune disorders (eg, systemic lupus erythematosus [SLE], anti-phospholipid syndrome [APS]) may prompt testing for anti-nuclear antibodies or anti-phospholipid antibodies, respectively. We do not test for these in patients with isolated thrombocytopenia and no signs or symptoms suggestive of SLE or APS.
●Findings of liver disease should prompt measurements of hepatic enzymes and possibly tests of liver synthetic function (eg, albumin, coagulation testing), depending on the severity of the liver disease. (See "Liver biochemical tests that detect injury to hepatocytes" and "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)".)
●Thrombosis should prompt consideration of 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. Testing for these conditions is discussed separately. (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 (eg, PT, aPTT, fibrinogen) and measurement of serum lactate dehydrogenase (LDH) and renal function 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)".)
ADDITIONAL EVALUATION
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. Immediate hematologist involvement in diagnosis and management is appropriate for the following:
●Suspected thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●Suspected heparin-induced thrombocytopenia (HIT). (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
●Suspected COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT). (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)
●Suspected hematologic malignancy (eg, 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".)
The consulting hematologist can also assist in diagnosis and management of patients with severe thrombocytopenia (ie, platelet count <50,000/microL) who have serious bleeding or require an urgent invasive procedure, and in pregnant women with severe thrombocytopenia, regardless of the cause.
Bone marrow evaluation — Bone marrow evaluation (aspirate and biopsy) is not required in all patients with thrombocytopenia. However, it may be helpful in some patients if the cause of thrombocytopenia is unclear, or if a primary hematologic disorder is suspected. A possible exception may be a clinical picture consistent with a nutrient deficiency in which a bone marrow would only be needed if a deficiency could not be documented, or if the hematologic findings did not resolve upon nutrient repletion.
The following bone marrow findings may be helpful:
●Normal or increased numbers of megakaryocytes suggests that the thrombocytopenia is due, at least in part, to a condition associated with platelet destruction (eg, ITP, drug-induced immune thrombocytopenia). (See "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 (also called acquired amegakaryocytic thrombocytopenia or acquired pure megakaryocytic aplasia) may occur. This finding is most often reported in patients with SLE, and is typically due to an autoantibody directed against the thrombopoietin receptor. (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 a nutrient deficiency (eg, vitamin B12, folate, copper) (picture 20), while dysplastic changes suggest a myelodysplastic disorder (picture 21 and picture 22). (See "Clinical manifestations and diagnosis 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 — Management of specific thrombocytopenic disorders (ie, once the diagnosis is made) is discussed in separate topic reviews. However, there are some general management principles that apply to all patients with thrombocytopenia regardless of the cause, and for which questions may arise before a diagnosis has been established.
●Activity restrictions – Patients who are otherwise healthy and have no manifestations of petechiae or purpura may not require activity restrictions.
Individual considerations apply to participation in certain activities. As an example, individuals with severe thrombocytopenia (<50,000/microL) generally should not participate in extreme athletics such as boxing, rugby, and martial arts. However, no restrictions are necessary for usual activities or low-impact exercise.
●Anticoagulant and anti-platelet medications – For anticoagulant and anti-platelet medications, the clinical indications and risks associated with discontinuation (eg, thrombosis) are balanced against the bleeding risk associated with the degree of thrombocytopenia and of continuing the anticoagulant and/or anti-platelet medication [7]. Input from the consulting specialist who prescribed the medication and/or the hematologist may be sought. A discussion of anticoagulation in adults with thrombocytopenia is presented separately. (See "Anticoagulation in individuals with thrombocytopenia".)
It is also important to note that 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 (eg, >50,000/microL) if it is indicated (eg, postoperatively). 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 non-prescription remedies interfere with platelet function (eg, aspirin, nonsteroidal anti-inflammatory drugs, ginkgo biloba). In general, these agents 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. A listing of general guidelines used for different procedures is 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 (eg, corticosteroids or intravenous immune globulin (IVIG) for presumptive ITP; platelet transfusion for myelodysplastic syndromes). These approaches are discussed in detail in separate topic reviews.
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.
●Emergency management of bleeding – Urgent management of critical bleeding in the setting of severe thrombocytopenia requires immediate platelet transfusion, regardless of the underlying cause. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Actively bleeding patient'.)
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 (ie, platelet count <150,000/microL [150 x 109/L]) may be associated with a variety of conditions, with associated risks that range from life-threatening to none. We are most concerned about spontaneous bleeding with counts <10,000/microL, and surgical bleeding with counts <50,000/microL. Rarely, thrombocytopenia is associated with a risk of thrombosis rather than, or in addition to, bleeding. (See 'Definitions and areas of concern' above.)
●Causes – The potential causes of thrombocytopenia differ depending on the clinical setting in which it occurs (table 6). (See 'Causes of thrombocytopenia' above and 'Overview of our approach' above.)
•Severe thrombocytopenia with bleeding and certain causes of thrombocytopenia (suspected heparin-induced thrombocytopenia [HIT], thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], drug-induced thrombotic microangiopathy [DITMA], or bone marrow failure syndrome with severe pancytopenia) are medical emergencies that require immediate action. (See 'Thrombocytopenic emergencies requiring immediate action' above.)
•In asymptomatic outpatients with thrombocytopenia, common diagnoses include immune thrombocytopenia (ITP), occult liver disease, HIV infection, and myelodysplastic syndromes. Congenital thrombocytopenias (sometimes misdiagnosed as ITP) may also occur (table 2). (See 'Asymptomatic, incidental finding, mild thrombocytopenia' above.)
•In patients with bleeding who lack signs of systemic illness or other abnormalities of the complete blood count (CBC), drug-induced immune thrombocytopenia (table 3) or primary ITP are likely diagnoses. (See 'Thrombocytopenia with bleeding or other symptoms' above.)
•In patients with other clinical findings, causes of thrombocytopenia include infection, sepsis, disseminated intravascular coagulation (DIC), drug-induced thrombocytopenia, HIT, liver disease, lymphoma, other malignancies, nutrient deficiencies (vitamin B12, folate, copper), TTP or HUS, antiphospholipid syndrome (APS), and paroxysmal nocturnal hemoglobinuria (PNH). (See 'Thrombocytopenia with bleeding or other symptoms' above.)
•In acutely ill patients, common causes of new-onset thrombocytopenia include sepsis, DIC, and drug-induced thrombocytopenia (table 1). Many patients in the intensive care unit with thrombocytopenia have more than one cause. (See 'Acutely ill/intensive care unit' above.)
●Evaluation – We confirm thrombocytopenia by repeating the CBC and reviewing the peripheral blood smear; obtain prior platelet counts, if available, and assess other hematologic abnormalities. The pace of the subsequent evaluation, further testing, and hematologist consultation depends on the clinical presentation, which can range from asymptomatic to acutely ill. (See 'Overview of our approach' above and 'Initial questions and pace of the evaluation' above.)
•History and examination – The history should focus on prior platelet counts, family history, bleeding, medications (table 3), over-the-counter remedies (table 4), infectious exposures, dietary practices, and other medical conditions (eg, hematologic disorders, rheumatologic conditions, surgery, transfusion). The physical examination should evaluate bleeding, lymphadenopathy, hepatosplenomegaly, thrombosis, and organ involvement. (See 'History' above and 'Physical examination' above.)
•Laboratory testing – No additional laboratory testing besides the CBC and peripheral blood smear is absolutely required in a patient with isolated thrombocytopenia. Adults with new thrombocytopenia should have HIV and HCV testing if not done recently. Additional laboratory testing may be warranted in patients with other findings. (See 'Laboratory testing' above.)
●Referral – Hematologist consultation is appropriate to confirm a new diagnosis or if the cause of thrombocytopenia is unclear. The urgency of referral depends on the degree of thrombocytopenia and other abnormalities, and the stability of the findings. In hospitalized patients, early hematology involvement is appropriate for individuals with suspected TTP, HUS, HIT, and some hematologic malignancies (eg, acute leukemia). (See 'Hematologist referral/consultation' above.)
●Bone marrow – Bone marrow evaluation is not required in all patients with thrombocytopenia; however, it may be helpful in some patients if the cause of thrombocytopenia is unclear, or if a primary hematologic disorder is suspected. (See 'Bone marrow evaluation' above.)
●Management – Management of patients with thrombocytopenia depends on the underlying diagnosis. General principles that apply to all patients include a review of medications that may interfere with normal hemostasis and a decision regarding whether they should be continued, coordination with anesthesiologists and surgeons before invasive procedures, and correction of coagulation abnormalities. Activity restrictions are often not needed. (See 'General management principles' above and "Platelet transfusion: Indications, ordering, and associated risks".)
●Other populations – Thrombocytopenia in neonates and children, and thrombocytopenia during pregnancy are discussed separately. (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 an earlier version of this topic review.
