Causes of thrombocytopenia in children

INTRODUCTION — Thrombocytopenia is defined as a platelet count of <150,000/microL. It is clinically suspected when there is a history of easy bruising or bleeding, or it may present as an incidental finding during routine evaluation or during investigations performed for other reasons.

Causes of thrombocytopenia in children will be reviewed here. Causes of neonatal thrombocytopenia differ somewhat and are reviewed separately. (See "Neonatal thrombocytopenia: Etiology".)

The approach to evaluating a child with unexplained thrombocytopenia and/or bleeding symptoms and the details of specific causes of thrombocytopenia (eg, immune thrombocytopenia, leukemia, aplastic anemia) are discussed in separate topic reviews:

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

●(See "Approach to the child with bleeding symptoms".)

●(See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

●(See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

CLASSIFICATION — A variety of schemes have been used in classifying the causes of thrombocytopenia, including categorization based on:

●Platelet size – Large (mean platelet volume [MPV] >11 fL), normal (MPV 7 to 11 fL), and small (MPV <7 fL)

●Mode of acquisition – Acquired or inherited

●Mechanism – Increased destruction (including sequestration and pooling of platelets), dilutional, or decreased production of platelets

●Degree of the thrombocytopenia – Mild to moderate thrombocytopenia (>20,000/microL) or severe thrombocytopenia (<20,000/microL)

This topic review will primarily use a categorization based on mechanism of thrombocytopenias (table 1). Classification by platelet size is also clinically useful, especially for differentiating the various inherited platelet disorder syndromes (table 2). Historical platelet counts (if available) and detailed family history can be helpful to distinguish inherited and acquired thrombocytopenias.

PLATELET DESTRUCTION — The destructive mechanisms resulting in thrombocytopenia in children include:

●Immune-mediated destruction

●Platelet activation and consumption

●Mechanical platelet destruction

●Platelet sequestration and trapping

Immune-mediated causes — Immune-mediated processes are among the most common causes of thrombocytopenia. Autoantibodies, drug-dependent antibodies, or alloantibodies mediate platelet destruction through interaction with platelet membrane antigens or by forming immune complexes, which can bind to reticuloendothelial cell Fc receptors, leading to platelet clearance from the circulation. The most common immune-mediated thrombocytopenia in children is immune thrombocytopenia (ITP).

In neonates, alloimmune thrombocytopenia is an important cause of thrombocytopenia that requires prompt recognition as it can be associated with intracranial hemorrhage. Neonatal alloimmune thrombocytopenia is discussed separately. (See "Neonatal immune-mediated thrombocytopenia".)

Immune thrombocytopenia — ITP is the most common acquired cause of thrombocytopenia in children. It can present at any age; peak incidence in childhood is between two and five years. Affected children may be asymptomatic but usually present with the sudden appearance of bruising and/or bleeding. ITP follows an antecedent viral illness in approximately one-half of cases; however, often no trigger is identified. Affected children are otherwise healthy appearing. The clinical manifestations, diagnosis, and management of ITP in children are discussed in detail separately. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Initial treatment of immune thrombocytopenia (ITP) in adults".)

There is a small increased risk of developing ITP following live virus immunization, especially the measles, mumps, and rubella vaccine. In addition, vaccine-associated thrombocytopenia has been described as a rare side effect of the adenoviral coronavirus disease 2019 (COVID-19) vaccines. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Preceding illness or vaccination' and "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Adverse effects' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

Infrequently, other autoimmune-mediated cytopenias (most commonly, autoimmune hemolytic anemia) present coincidentally or sequentially with thrombocytopenia, a condition known as Evans syndrome [1]. ITP can also manifest as part of a systemic autoimmune or immune dysregulation disorder (secondary ITP). Secondary ITP can be highly refractory to standard ITP treatments but generally responds well to treatment of the primary disorder. It is especially important to consider an underlying immune disorder in children with Evans syndrome, as there is a high frequency of immune disorders in this population (up to 65 percent) [2]. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evans syndrome'.)

Examples of autoimmune disorders that can present with or develop ITP include (but are not limited to):

●Antiphospholipid antibody syndrome (see "Clinical manifestations of antiphospholipid syndrome")

●Systemic lupus erythematosus (see "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Hematologic' and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Laboratory findings')

●Crohn disease (see "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents")

●Autoimmune hepatitis (see "Overview of autoimmune hepatitis")

●Autoimmune thyroid disease (see "Acquired hypothyroidism in childhood and adolescence", section on 'Autoimmune thyroiditis')

Immune deficiency and/or dysregulation syndromes can also trigger ITP. Examples include (but are not limited to) [3]:

●Autoimmune lymphoproliferative syndrome (see "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis")

●Common variable immunodeficiency (see "Common variable immunodeficiency in children")

●CTLA-4 deficiency (see "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease')

●DiGeorge syndrome (see "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis")

●Wiskott-Aldrich syndrome (WAS) (see "Wiskott-Aldrich syndrome")

Drug-induced thrombocytopenia — Drug-induced thrombocytopenia is typically caused by drug-dependent antibodies formed against a new antigen on the platelet surface created by drug binding to a platelet surface protein. Heparin-induced thrombocytopenia, which can be associated with severe thrombosis, is due to the formation of antibodies against a heparin-platelet factor 4 complex. This results in platelet activation leading to consumption of platelets and formation of thrombi. This condition is more common in adult patients and is relatively rare in children [4,5]. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Unfractionated heparin'.)

Other drugs that have been implicated in immune-mediated thrombocytopenia include valproic acid, quinine, quinidine, trimethoprim-sulfamethoxazole, and vancomycin [6]. (See "Drug-induced immune thrombocytopenia".)

Platelet activation and consumption — Thrombocytopenia due to platelet activation and consumption occurs in the following conditions:

●Microangiopathic disorders – Microangiopathic disorders include disseminated intravascular coagulation and the thrombotic microangiopathies (TMAs, which include Shiga toxin-mediated hemolytic uremic syndrome [ST-HUS], compliment-mediated hemolytic uremic syndrome [CM-HUS], and thrombotic thrombocytopenic purpura [TTP]). In these disorders, thrombocytopenia occurs as a result of platelet activation, aggregation, and consumption. TMAs are characterized by abundant schistocytes on the peripheral smear (picture 1), anemia, neurologic changes (in TTP), and renal insufficiency (in ST-HUS and CM-HUS). In these conditions, the formation of microthrombi results in red cell shearing and end-organ damage. (See "Disseminated intravascular coagulation in infants and children" and "Overview of hemolytic uremic syndrome in children" and "Diagnosis of immune TTP".)

Hereditary TTP (Upshaw-Schulman syndrome) is a rare disorder due to a congenital absence of ADAMTS13, whereas acquired TTP results from antibody formation against ADAMTS13. In hereditary TTP, thrombocytopenia tends to be sporadic, occurring in acute episodes, usually with illness; hence, this disorder should be considered when mostly normal platelet counts are interspersed with transient, recurrent thrombocytopenia [7]. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)

Rapid recognition of microangiopathic disorders is important as these represent a class of disorders with high morbidity and mortality, and prompt initiation of the correct management is essential. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

●Major surgery or trauma – Thrombocytopenia is a common finding after major surgery or trauma. Low platelet counts in this setting result from acute blood loss, hemodilution, and consumption of platelets in maintaining hemostasis. The degree of thrombocytopenia is generally mild to moderate (50,000 to 100,000/microL). This is essentially a "normal" finding, and evaluation for other causes thrombocytopenia is generally not necessary if there are no signs of overt bleeding. Patients should be monitored to ensure platelet counts recover back to normal levels. Platelet transfusions in this setting should be reserved for patients with bleeding. The platelet count nadir typically occurs between one to four days after surgery, and counts usually increase back to baseline levels within one week to 10 days [8,9]. Additional evaluation may be warranted if the degree and/or duration of thrombocytopenia is atypical (platelet count <20,000/microL or thrombocytopenia that persists beyond two weeks).

●Kasabach-Merritt phenomenon – A more localized manifestation of coagulation activation and platelet trapping accounts for the thrombocytopenia found in individuals with Kasabach-Merritt phenomenon, which is a complication of kaposiform hemangioendotheliomas and tufted hemangiomas. (See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)".)

In other vascular anomalies, patients can develop a localized intravascular coagulopathy which will similarly result in thrombocytopenia.

Mechanical destruction — The use of extracorporeal therapies, such as extracorporeal membrane oxygenation, cardiopulmonary bypass, hemodialysis, and apheresis, is associated with mechanical destruction of platelets, which may result in thrombocytopenia and bleeding [10]. (See "Extracorporeal life support in adults in the intensive care unit: Overview", section on 'Complications' and "Extracorporeal life support in adults: Management of venovenous extracorporeal membrane oxygenation (V-V ECMO)", section on 'Thrombocytopenia'.)

Sequestration and trapping — Sequestration and trapping of platelets occurs in hypersplenia and rare forms of von Willebrand disease (VWD).

●Hypersplenism – Normally, approximately one-third of the platelet pool is sequestered in the spleen. In patients with hypersplenism, a greater proportion of platelets are sequestered, reducing the number of circulating platelets and often leading to thrombocytopenia. Leukopenia and anemia may also accompany a low platelet count. The platelet count in hypersplenism rarely falls below 50,000/microL. (See "Approach to the child with an enlarged spleen".)

●VWD – Type 2B VWD and platelet-type VWD (also called "pseudo-VWD") may be associated with thrombocytopenia. In patients with these disorders, increased binding between larger von Willebrand factor multimers and platelets leads to the formation of small platelet aggregates, which are cleared from the circulation, resulting in a lower platelet count. The platelet aggregates may appear similar to large or giant platelets and can result in high mean platelet volume measurements by automated counters. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Summary of VWD types'.)

DILUTIONAL — Thrombocytopenia can result from dilution in the setting of massive transfusions, defined roughly as 40 mL/kg of red blood cells (RBCs) within 24 hours in pediatric patients. (See "Massive blood transfusion", section on 'Definitions and jargon'.)

Pediatric patients rarely require massive transfusions, but they are occasionally required in patients with severe traumatic injuries and those undergoing surgical procedures with high bleeding risk. Massive transfusions can cause electrolyte abnormalities, hemodilution, and volume overload. They are associated with high risk of morbidity and mortality. Patients receiving large volumes of transfused RBCs can be expected to develop some degree of dilutional thrombocytopenia. This can be overcome by activation of a massive transfusion protocol which empirically provides platelet support (usually in a 1:1:1 ratio of platelets, fresh frozen plasma, and RBCs) or the use of whole blood. One concern over the use of whole blood, however, is the potential impact of whole blood storage on platelet function [11]. (See "Massive blood transfusion", section on 'Approach to volume and blood replacement'.)

IMPAIRED PLATELET PRODUCTION — Decreased production of platelets may be due to:

●Suppression (ie, infection)

●Bone marrow infiltration

●Failure or a defect in megakaryocyte development and differentiation (nutritional deficiencies and inherited platelet disorders)

Infection — Thrombocytopenia due to infections (independent of disseminated intravascular coagulation) is usually caused by bone marrow suppression [12-14]. In some cases, the low platelet count also can be due in part to an immune-mediated process.

Infection-associated thrombocytopenia can occur with many different pathogens; infectious agents that are commonly implicated include Epstein-Barr virus, cytomegalovirus, parvovirus, and rickettsia. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Overview of cytomegalovirus infections in children" and "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

In patients with COVID-19, thrombocytopenia can be seen during the acute infection or as a postinfectious immune-mediated complication. (See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Thrombocytopenia is a common finding in HIV-infected patients. The mechanisms underlying HIV-related thrombocytopenia are complex and involve both immune-mediated platelet destruction and impaired production. (See "HIV-associated cytopenias", section on 'General concepts'.)

Thrombocytopenia is a common finding in patients with bacterial sepsis. In this setting, thrombocytopenia is often multifactorial with components of marrow suppression, consumption due to disseminated intravascular coagulation and inflammatory response, and/or drug-induced. (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'.)

Data on time to recovery of a normal platelet count from most commonly acquired infections are sparse, but in the otherwise healthy child, the thrombocytopenia is transient, with recovery within a period of weeks.

Nutritional deficiencies — The following nutritional deficiencies have been associated with thrombocytopenia:

●Folate and vitamin B12 deficiencies can impair bone marrow production, resulting in single cytopenias or pancytopenia [15].

●Iron deficiency, which has been reported to cause both thrombocytosis and thrombocytopenia, appears to impair a late stage of thrombopoiesis [16]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

Bone marrow failure or infiltration — Pancytopenia is the combination of anemia, leukopenia (low white cell count), and thrombocytopenia. Its presence suggests general bone marrow dysfunction (due to infection, aplastic anemia, chemotherapeutic agents, or radiation) or infiltrative disease (leukemia, lymphoma, fibrosis, hemophagocytic lymphohistiocytosis). (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Patients with pancytopenia, especially with systemic signs and symptoms (eg, fever, weight loss, or decreased energy), should undergo prompt evaluation for a serious disorder, such as leukemia or aplastic anemia, that may require urgent intervention. The assessment usually includes bone marrow examination. (See "Approach to the child with unexplained thrombocytopenia", section on 'Bone marrow examination'.)

Inherited platelet disorders — Thrombocytopenia may be a presenting finding in certain rare inherited diseases, some of which also feature impaired platelet function (table 3) [17-21]. These conditions should be considered in patients with "refractory immune thrombocytopenia (ITP)," a family history of thrombocytopenia or leukemia, or if platelet counts have been low on numerous occasions throughout the child's life.

Although less common than acquired causes of thrombocytopenia, inherited thrombocytopenias are an important consideration in children who present with isolated thrombocytopenia. Many of these syndromes are associated with other abnormalities (eg, immunodeficiency, renal disease, sensorineural hearing loss, risk of malignancy). Accurate diagnosis is also important for genetic counseling and to avoid inappropriate interventions (eg, splenectomy for presumed ITP). Historical platelet counts from children and their parents and ascertainment of the duration of bleeding symptoms, as well as identification of associated findings on history or physical, can help distinguish between inherited and acquired causes.

Most inherited platelet disorders arise from genetic defects of the megakaryocyte lineage that result in dysregulated thrombopoiesis. The number of genetic variants that have been reported to be associated with thrombocytopenia is large and growing [22].

The following sections outline some of the more common genetic syndromes associated with thrombocytopenia according to platelet size (table 2). Additional information regarding inherited platelet disorders is presented separately. (See "Inherited platelet function disorders (IPFDs)".)

Small platelets — Wiskott-Aldrich syndrome (WAS) and the related disorder, X-linked thrombocytopenia (XLT), are characterized by small platelets:

●WAS – WAS is of particular importance to the pediatric health care provider because of its association with serious infections due to immune deficiency beginning in infancy or early childhood. WAS is an X-linked recessive disorder in which patients have moderate to severe thrombocytopenia with small platelets (3 to 5 fL, as compared with normal platelet size of 7 to 10 fL), severe eczema, immunodeficiency, and predisposition to malignancy. WAS can also cause ITP secondary to related immune dysregulation, so normal or large platelet size in an otherwise consistent clinical picture should not dissuade the clinician from testing for WAS. The diagnosis can be confirmed by genetic testing. (See "Wiskott-Aldrich syndrome".)

●XLT – XLT, also due to a mutation in the WAS gene, presents as isolated microthrombocytopenia. Unlike WAS, XLT is not associated with eczema, recurrent infections, or predisposition to cancer. It is often difficult to differentiate WAS from XLT in young children. This determination should not be made until after the age of two years as clinical manifestations can evolve. The clinical phenotype can also vary within a family. Testing for the WAS protein levels can be helpful in that an absence of protein infers a more severe phenotype [23]. (See "Wiskott-Aldrich syndrome", section on 'X-linked thrombocytopenia'.)

XLT is distinct from "XLT with dyserythropoiesis," which is caused by mutations in the GATA1 gene and is characterized by large rather than small platelets, as discussed below. (See 'Large or giant platelets' below.)

●Other causes – Thrombocytopenia with small platelet size has also been reported in individuals with variants in the FYB, PTPRI, and ARPCIB genes.

Normal-sized platelets — Causes of inherited platelet disorders associated with thrombocytopenia and normal-sized platelets include inherited bone marrow syndromes, thrombocytopenia with absent radii (TAR) syndrome, amegakaryocytic thrombocytopenia with radioulnar synostosis (ATRUS), and familial platelet disorder with predisposition to myeloid malignancy.

●Inherited bone marrow failure syndromes – Patients with inherited bone marrow syndromes (eg, Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia [CAMT]) may present with isolated thrombocytopenia early in life. Other features of these syndromes include:

•Fanconi anemia – Macrocytic anemia, short stature, hyper- or hypopigmented skin lesions, thumb and/or radial abnormalities (table 4). (See "Clinical manifestations and diagnosis of Fanconi anemia".)

•Dyskeratosis congenita – Abnormal skin pigmentation, dystrophic nails, oral leukoplakia (table 5). (See "Dyskeratosis congenita and other telomere biology disorders".)

•Shwachman-Diamond syndrome – Neutropenia, macrocytic anemia, exocrine pancreatic dysfunction, bony abnormalities, including thoracic dystrophy with short stature. (See "Shwachman-Diamond syndrome".)

•Congenital amegakaryocytic thrombocytopenia (CAMT) – CAMT presents in the newborn period with isolated severe thrombocytopenia and bleeding into the skin, mucous membranes, or gastrointestinal tract. Pancytopenia develops later in childhood. CAMT is not associated with skeletal abnormalities, which differentiates it from other inherited bone marrow failure syndromes, TAR, and ATRUS. CAMT is caused by mutations in MPL, which encodes the thrombopoietin receptor [24]. Bone marrow examination reveals absent or decreased megakaryocytes. The diagnosis can be confirmed by genetic testing. The only curative option is allogeneic hematopoietic cell transplantation (HCT) [25].

●TAR syndrome – TAR syndrome is associated with radial agenesis, as well as other upper and lower limb defects. Approximately half of affected individuals have associated cow's milk intolerance. Bone marrow examination usually shows absent or markedly decreased megakaryocytes with normal erythroid and myeloid maturation. It is caused by variants in the RBM8A gene. Affected patients usually require frequent platelet transfusions in early infancy but then show spontaneous improvement in the platelet count throughout childhood.

●ATRUS – ATRUS is characterized by moderate to severe thrombocytopenia present at birth accompanied by proximal fusion of the radius and ulna, leading to impaired forearm pronation and supination. Additional features include clinodactyly, syndactyly, hip dysplasia, and sensorineural hearing loss. Initially, bone marrow examination shows normal cellularity with decreased megakaryocytes but may progress to hypocellularity and pancytopenia. It is caused by variants in the HOX11 gene. In contrast to TAR syndrome, the thrombocytopenia persists with age.

●Other inherited thrombocytopenias predisposing to hematologic malignancy – Thrombocytopenia 2, thrombocytopenia 5, and familial platelet disorder with associated myeloid malignancy (FPDMM) are autosomal dominant disorders characterized by decreased platelet counts and predisposition to hematologic malignancies [18,20,26]. They are caused by germline mutations in the ANKRD26, ETV6, and RUNX1 genes, respectively. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial platelet disorder with propensity to myeloid malignancies (FPD)'.)

Large or giant platelets — The rare giant platelet disorders are characterized by low platelet counts and giant platelets (macrothrombocytopenia). Platelets are significantly larger than in ITP (>12.4 fL and mean platelet diameter >3.3 micron), with some larger than red cells (picture 2) [27]. Because of their large size, platelets may not be recognized by the laboratory particle counter, which may result in a falsely low reported platelet count and inaccurate calculation of the mean platelet volume.

●Bernard-Soulier syndrome – The Bernard-Soulier syndrome (BSS) is an autosomal recessive disorder characterized by mild thrombocytopenia, giant platelets (mean diameter of 5 to 6 microns), marked platelet dysfunction, and, often, severe bleeding. The bleeding may be disproportionately severe relative to the degree of thrombocytopenia. This is explained by dysfunction or absence of the platelet glycoprotein (GP) Ib-IX-V, the platelet receptor for von Willebrand factor. Symptoms include easy bruising and severe hemorrhage at the time of injury or surgery. Bone marrow evaluation often shows a hypercellular marrow despite peripheral thrombocytopenia. If suspected, the diagnosis can be confirmed by platelet aggregation testing showing a lack of response to ristocetin, flow cytometry for the GP Ib-IX-V glycoprotein, or genetic testing for the responsible mutations in the GPIBA, GIPBB, and GPIX genes. (See "Inherited platelet function disorders (IPFDs)", section on 'Bernard-Soulier syndrome'.)

The heterozygous carrier state for BSS can be associated with macrothrombocytopenia with mild or no clinical symptoms and normal platelet function [28,29]. It is seen primarily in the Mediterranean region but also in other areas. This mild form of BSS is similar to the macrothrombocytopenia seen in DiGeorge syndrome. The chromosomal region affected in DiGeorge syndrome (22q11) encompasses the gene for one of the four subunits of the (GP) Ib-IX-V complex [30]. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●MYH9-related disorders – Mutations of the nonmuscle myosin heavy chain gene, MYH9, result in hereditary macrothrombocytopenia. These were previously described as four distinct disorders (May-Hegglin anomaly and Fechtner, Epstein, and Sebastian syndromes) but are now considered together as the spectrum of MYH9-related disorders [31]. They are characterized by macrothrombocytopenia, variable appearance of leukocyte inclusions, and other abnormalities, including sensorineural hearing loss, cataracts, and nephritis [32,33]. The risk for extra-hematologic manifestations (nephropathy and deafness) is correlated with the specific MYH9 mutation [34]. Lack of a relevant family history does not rule out the disorder, because approximately one-third of mutations are sporadic. MYH9-related disorders are discussed separately. (See "Inherited platelet function disorders (IPFDs)", section on 'MYH9-related disease'.)

●Paris-Trousseau syndrome – Paris-Trousseau syndrome is a rare condition with mild to moderate thrombocytopenia and large platelets with giant alpha granules. Depending on the size of the underlying genetic lesion (involving the FLI1 gene on chromosome 11q23), intellectual disability; head and face dysmorphisms; and cardiac, renal, and gastrointestinal defects can also be present. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '11q24.1 deletion syndrome (Jacobsen syndrome)'.)

●Gray platelet syndrome – Gray platelet syndrome is a rare autosomal recessive disorder characterized by moderate thrombocytopenia, mild to moderate bleeding tendency, and marked decrease or absence of platelet alpha granules. The platelets are enlarged, but not giant, and have a gray appearance on peripheral blood smears. Many patients with gray platelet syndrome develop stable myelofibrosis associated with progressive thrombocytopenia. (See "Inherited platelet function disorders (IPFDs)", section on 'Gray platelet syndrome'.)

●XLT with dyserythropoiesis – X-linked disorders of thrombocytopenia and dyserythropoiesis are due to GATA1 mutations on the X chromosome. They are characterized by severely defective maturation of megakaryocytes, alpha granule deficiency, abnormalities of the cytoplasmic membrane, mild dyserythropoiesis, and red cell hemolysis [35,36]. They should be suspected in boys with inherited thrombocytopenia, abnormal red cell morphology, and a hypercellular bone marrow. Patients with the GATA1 Arg216 mutation also have a thalassemic phenotype with associated microcytosis [36]. These conditions have been variably termed "XLT with thalassemia," "XLT with dyserythropoiesis," or "X-linked gray platelet syndrome" [37].

●Autosomal dominant deafness with thrombocytopenia – Autosomal dominant deafness with thrombocytopenia is caused by mutation in the DIAPH1 gene. It is characterized by sensorineural hearing loss within the first decade of life, mild to moderate thrombocytopenia, and large platelets. Functional studies have demonstrated altered platelet cytoskeletal regulation and proplatelet formation [38].

●Sitosterolemia – Sitosterolemia (alternatively termed "phytosterolemia") is an autosomal recessive metabolic condition caused by mutations in the ABCG8 or ABCG5 genes. It is characterized by hyperabsorption of cholesterol and plant sterols from the intestine. Typical features include very high plasma cholesterol levels, tendon and tuberous xanthomas, and atherosclerotic complications (ie, premature coronary artery disease). Hematologic abnormalities, including stomatocytosis and macrothrombocytopenia, have been described in some patients with this disorder, particularly in patients of Mediterranean descent. The hematologic findings in these patients appear to be due to abnormal lipid content in red blood cell and platelet membranes caused by extremely high plasma levels of phytosterols from high dietary consumption of olive oil.

●ACTN1-related macrothrombocytopenia – ACTN1-related macrothrombocytopenia is an autosomal dominant form of macrothrombocytopenia. Affected patients usually have no or only mild bleeding tendency. Laboratory studies show decreased numbers of large platelets and anisocytosis (ie, a broad distribution of platelet size), but in vitro functional platelet testing is typically normal. This disorder is also characterized by an elevated immature platelet fraction and can be confused with ITP [39].

SUMMARY AND RECOMMENDATIONS

●Definition – Thrombocytopenia is defined as a platelet count <150,000/microL. It is clinically suspected when there is a history of easy bruising or bleeding, or it may present as an incidental finding during routine evaluation or during laboratory investigations performed for other reasons. (See 'Introduction' above.)

●Classification schemas – Causes of thrombocytopenia can be classified according to (see 'Classification' above):

•Mechanism – Increased destruction (including sequestration and pooling of platelets), dilutional, or decreased production (table 1). (See 'Platelet destruction' above and 'Impaired platelet production' above.)

•Platelet size – Large (mean platelet volume [MPV] >11 fL), normal (MPV 7 to 11 fL), and small (MPV <7 fL). This classification schema is especially useful when platelet sizes are extreme. Large or giant platelets suggest immune-mediated thrombocytopenia or one of the giant platelet disorders, while very small platelets are almost exclusively found in Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT) (table 2).

•Mode of acquisition – Acquired or inherited.

•Degree of the thrombocytopenia – Mild to moderate thrombocytopenia (>20,000/microL) or severe thrombocytopenia (<20,000/microL).

●Causes of platelet destruction – Destructive mechanisms include (table 1) (see 'Platelet destruction' above):

•Immune-mediated destruction (eg, immune thrombocytopenia [ITP]) (see 'Immune thrombocytopenia' above)

•Drug-induced thrombocytopenia (see 'Drug-induced thrombocytopenia' above)

•Platelet activation and consumption, including (see 'Platelet activation and consumption' above):

-Disseminated intravascular coagulation and the thrombotic microangiopathies (thrombotic thrombocytopenic purpura [TTP], Shiga toxin-mediated hemolytic uremic syndrome [ST-HUS], and complement-mediated hemolytic uremic syndrome [CM-HUS])

-Major surgery or trauma

-Kasabach-Merritt phenomenon

•Mechanical platelet destruction (use of extracorporeal therapies, such as extracorporeal membrane oxygenation and cardiopulmonary bypass) (see 'Mechanical destruction' above)

•Platelet sequestration and trapping (eg, due to hypersplenism) (see 'Sequestration and trapping' above)

●Dilutional – Thrombocytopenia in the setting of massive red cell transfusions. (See 'Dilutional' above.)

●Causes of impaired platelet production – Decreased production of platelets may be due to bone marrow infiltration, suppression, or failure or a defect in megakaryocyte development and differentiation. Causes include (table 1) (see 'Impaired platelet production' above):

•Infection (see 'Infection' above)

•Nutritional deficiencies (see 'Nutritional deficiencies' above)

•Leukemia, lymphoma, or other bone marrow-infiltrating disease (see 'Bone marrow failure or infiltration' above)

•Acquired or inherited aplastic anemia or other bone marrow failure syndrome (see 'Bone marrow failure or infiltration' above)

•Genetic disorders (table 2) (see 'Inherited platelet disorders' above)

●Genetic causes – Thrombocytopenia may be a presenting finding in certain rare inherited diseases, some (table 1) of which also feature impaired platelet function (table 2 and table 3). These conditions should be considered in patients with "refractory ITP," a family history of thrombocytopenia or leukemia, or if platelet counts have been low on numerous occasions throughout the child's life. Accurate diagnosis is important for genetic counseling to avoid inappropriate interventions (eg, splenectomy for presumed ITP) and because many of these syndromes are associated with other abnormalities (eg, immunodeficiency, renal disease, sensorineural hearing loss, risk of malignancy). Historical platelet counts from children and their parents and ascertainment of the duration of bleeding symptoms can help distinguish between inherited and acquired causes. (See 'Inherited platelet disorders' above and "Approach to the child with unexplained thrombocytopenia", section on 'Diagnostic evaluation'.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Donald Yee, MD, and Jenny Despotovic DO, MS, who contributed to earlier versions of this topic review.