Approach to the child with unexplained thrombocytopenia

INTRODUCTION — Thrombocytopenia, defined as a platelet count <150,000/microL, is clinically suspected when a child develops characteristic clinical symptoms, which include a petechial rash, easy bruising or bleeding, or mucosal hemorrhage. Depending on the degree of thrombocytopenia, it can present with bleeding symptoms or may be asymptomatic (eg, an incidental finding during routine evaluation or during laboratory investigations performed for other reasons). A common cause of thrombocytopenia in children is immune thrombocytopenia (ITP), defined by consensus as isolated thrombocytopenia (platelet count <100,000/microL) in the absence of an underlying condition [1].

Our approach to the evaluation of thrombocytopenia in children will be reviewed here. Other topic reviews with information relevant to the child with thrombocytopenia include the following:

●(See "Causes of thrombocytopenia in children".)

●(See "Neonatal thrombocytopenia: Etiology".)

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

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

●(See "Inherited platelet function disorders (IPFDs)".)

PLATELET COUNT AND BLEEDING RISK — Bleeding risk generally increases with a low platelet count. This is because circulating platelets fulfill many critical hemostatic functions, including adhesion to sites of vascular injury, secretion of mediators of hemostasis, activation of the coagulation cascade, and aggregation via fibrinogen binding (figure 1). (See "Platelet biology and mechanism of anti-platelet drugs", section on 'Overview of platelet function'.)

The normal platelet count for children ranges from approximately 150,000 to 450,000/microL [2]. In general, the risk of bleeding does not increase until the platelet count falls well below 100,000/microL, and significant spontaneous bleeding is not likely to occur until the platelet count falls below 20,000/microL. Surgical bleeding solely due to a decreased platelet count typically occurs only if the platelet count is <50,000/microL. If a patient with thrombocytopenia has bleeding that is out of proportion to the degree of thrombocytopenia, other potential causes of bleeding should be considered (eg, inherited functional platelet disorders, medications). (See "Inherited platelet function disorders (IPFDs)".)

The platelet lifespan ranges from 7 to 10 days, after which they are removed from the circulation by cells of the monocyte-macrophage system. Younger circulating platelets are generally larger and more hemostatically active. For example, at a platelet count of 20,000/microL, patients with immune thrombocytopenia (ITP) have a higher proportion of younger circulating platelets and, consequently, less severe bleeding symptoms than patients with a similar degree of thrombocytopenia due to a production defect such as bone marrow failure or malignancy. Thus, for a given platelet count, bleeding risk is generally higher in patients with thrombocytopenia due to impaired platelet production primarily due to an older circulating population of platelets. (See 'Reticulated platelets/immature platelet fraction' below.)

When thrombocytopenia is recognized or suspected, reasonable precautions to minimize bleeding risk should be implemented. This includes precautions to reduce the risk of traumatic injury, particularly head injury (eg, ensuring adult supervision during play; avoidance of contact and collision sports; and avoidance of other activities that pose high risk of head trauma with velocity such as trampolines or bounce houses or riding a bicycle, scooter, all-terrain vehicle, hoverboard, or similar vehicle without helmet). In addition, drugs that impair platelet function (eg, nonsteroidal antiinflammatory drugs) should be avoided. (See "Immune thrombocytopenia (ITP) in children: Initial management", section on 'General measures'.)

BLEEDING SYMPTOMS — Many children with mild or moderate thrombocytopenia may be asymptomatic, and thrombocytopenia may be first detected on a complete blood count (CBC) obtained for another reason. Patients with symptomatic thrombocytopenia generally present with cutaneous and/or mucosal bleeding (eg, easy bruising, petechiae, gingival bleeding, epistaxis). Some affected children with severe thrombocytopenia may have persistent, profuse bleeding from superficial cuts. In postmenarcheal females, thrombocytopenia may present with heavy menstrual bleeding or bleeding between periods. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Causes of heavy menstrual bleeding'.)

The pattern of bleeding differs between patients with thrombocytopenia and those with disorders of coagulation factors, such as hemophilia. Patients with thrombocytopenia are more likely to have bleeding after minor cuts and less likely to have deep bleeding into tissues, muscles, and joints or to have delayed bleeding. In patients with thrombocytopenia, posttraumatic or postoperative surgical bleeding usually responds to local measures. In addition, petechiae are a characteristic finding in patients with thrombocytopenia, whereas patients with coagulation disorders tend not to have petechiae. (See "Clinical manifestations and diagnosis of hemophilia".)

Cutaneous bleeding — Cutaneous bleeding is usually manifested as petechiae or superficial ecchymoses. Petechiae are small, red, flat, discrete lesions attributable to red cells which have extravasated from capillaries (picture 1). They often occur in crops in dependent areas, are nontender, and do not blanch under pressure. Petechiae that are confluent form a type of purpura that is not palpable (in contrast with the palpable purpura seen in vasculitic disorders). (See "Vasculitis in children: Evaluation overview".)

Ecchymoses and hematomas are larger areas of bleeding into the skin (picture 2). The affected area of the skin is initially red or purple due to the presence of extravasated blood and then evolves to green, orange, and yellow due to breakdown of heme pigment by skin macrophages. Ecchymotic lesions in patients with thrombocytopenia are usually small, multiple, and superficial. They may develop without trauma and in areas not usually prone to bruising such as the back or chest.

Mucosal bleeding — Mucosal bleeding is manifested as any of the following:

●Epistaxis

●Gingival bleeding

●Bullous hemorrhages on the buccal mucosa, known as "wet purpura" (picture 3)

●Gastrointestinal bleeding

●Genitourinary bleeding (eg, prolonged and/or heavy uterine bleeding)

Most thrombocytopenic patients with mucosal bleeding also have cutaneous bleeding.

In patients with thrombocytopenia, findings of "wet purpura" and mucosal bleeding are thought to indicate increased risk of subsequent potentially life-threatening hemorrhage [3]. However, thrombocytopenia-associated bleeding in children, particularly children with immune thrombocytopenia, is very heterogeneous and unpredictable [4]. Further validation of predictors for severe bleeding are needed in children with thrombocytopenia. To date, no factors have been identified that can accurately predict at the time of presentation whether a child will develop more serious bleeding.

Intracranial hemorrhage — Intracranial hemorrhage (ICH) is a rare but serious consequence of thrombocytopenia and is the most common cause of death in affected patients. When ICH occurs, it is often preceded by a history of head trauma. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Intracranial hemorrhage'.)

DIAGNOSTIC EVALUATION — The initial step in the evaluation of suspected thrombocytopenia in children is verification of a low platelet count. Once thrombocytopenia has been confirmed, the evaluation is focused on determining the underlying etiology so that directed therapeutic measures can be implemented. The evaluation includes a detailed history, complete physical examination, and laboratory testing.

Verification of thrombocytopenia — A platelet count that is inconsistent with the clinical presentation of the patient (such as a platelet count <20,000/microL in a patient with no petechiae or other abnormalities) should be confirmed before extensive evaluation is undertaken to ensure that the low platelet count is not due to artifact or laboratory error. This can be accomplished through repeating testing or, preferably, review of the peripheral blood smear by a qualified observer.

Spurious thrombocytopenia can be caused by improper collection, delayed processing, or inadequate anticoagulation of the blood sample, resulting in platelet clumps that are counted as leukocytes by automated cell counters. In addition, agglutination of platelets by ethylenediaminetetraacetic acid (EDTA)-dependent antibodies, which are normally present in 0.1 percent of adults, may cause a falsely low platelet count (referred to as pseudothrombocytopenia). EDTA exposes a normally concealed epitope on the platelet membrane, glycoprotein IIb/IIIa, which interacts with these antibodies, resulting in platelet clumping. Examination of the blood smear will demonstrate large clumps, often found on the edges of the blood film, of agglutinated platelets or adherent platelets surrounding neutrophils. The presence of pseudothrombocytopenia can also be confirmed by collecting a blood sample in a non-EDTA anticoagulant tube such as sodium citrate and confirming a normal platelet count.

History — The history should document the onset, frequency, and severity of present and past bleeding symptoms. The family history should be reviewed, focusing on family members with a history of bleeding or thrombocytopenia. Other components of the history may provide clues to the underlying etiology of thrombocytopenia (table 1). (See "Causes of thrombocytopenia in children".)

●Bleeding symptoms – Details of any present or past bleeding symptoms, including:

•Bruising with little or no trauma

•Prolonged bleeding from superficial cuts or wounds

•Epistaxis (including duration and frequency)

•Visible blood in the urine or stool

•Bleeding from the gums

•Unexpected bleeding with surgical or dental procedures

•Excessive hematoma formation with vaccinations

•Abnormal uterine bleeding in postmenarcheal girls

The duration and onset of any bleeding symptoms may help to determine whether the thrombocytopenia is acquired or congenital [5]. (See 'Bleeding symptoms' above.)

●Systemic symptoms – Systemic symptoms (fever, bone pain, appetite change, weight loss, and decreased energy) may suggest a systemic disease process, such as malignancy or autoimmune disorder. In patients with these symptoms, an expeditious evaluation should be performed because of the serious potential morbidity and mortality associated with these conditions.

●Previous blood counts – Previous blood counts (if available) should be reviewed. A prior history of thrombocytopenia suggests the possibility of a congenital or chronic disorder, while a past pattern of normal platelet counts points toward an acquired condition.

●Prodromal illness – Immune thrombocytopenia (ITP) has been associated with triggers such as viral infection and live virus vaccination (eg, measles-mumps-rubella). (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Preceding illness or vaccination'.)

A prodromal illness that includes abdominal pain and bloody diarrhea suggests the possibility of Shiga-toxin-associated hemolytic uremic syndrome (HUS). This disorder is caused by an enteric pathogen that produces Shiga toxin. HUS is characterized by hemolytic anemia, thrombocytopenia, and acute renal injury, usually developing 5 to 10 days after the onset of diarrhea. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

●Medication history – The patient's medications should be reviewed carefully because many drugs may lower the platelet count through either bone marrow suppression or antibody formation. Examples include chemotherapeutic agents, heparin, and certain antiseizure medications and antibiotics. (See "Drug-induced immune thrombocytopenia".)

●Underlying disease – The patient's medical history should be reviewed for any underlying disorders that may be associated with thrombocytopenia, including cancer, sepsis, congenital heart disease, autoimmune disorders including systemic lupus erythematosus (SLE), immune deficiency syndromes, liver disease, or hypersplenism (table 1).

●Family history – A family history of thrombocytopenia and/or mucosal bleeding suggests the possibility of an inherited thrombocytopenia syndrome. Most of these are rare syndromes. Review of the peripheral blood smear can be helpful if an inherited platelet disorder is suspected since these disorders are characterized based upon platelet size (table 2). (See 'Laboratory evaluation' below and "Inherited platelet function disorders (IPFDs)".)

●Travel – Malaria and Dengue fever should be considered in a child with fever, splenomegaly, and recent travel history to endemic areas.

●Dietary history – A child with a very restricted diet or malabsorptive disease may have a nutritional deficiency that causes the thrombocytopenia, such as iron, vitamin B12, or folate deficiency. Such deficiencies usually cause other abnormalities on the complete blood count (CBC). (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Physical examination — The extent of the bleeding should be evaluated and documented in detail. Bleeding into the skin is one of the most common findings in patients with thrombocytopenia and may include petechiae, nonpalpable purpura, and ecchymoses (see 'Cutaneous bleeding' above). Sites of bleeding should be noted, especially dependent parts of the body. Serial examinations can monitor the patient's clinical course by noting changes in the number of petechiae or bleeding pattern within involved areas. In hospitalized patients, careful examination for bleeding should be performed at the sites of indwelling catheters, drains and incisions, areas of previous trauma, and exit sites of venous access devices. The gingival and oral cavity should be examined carefully for evidence of bleeding.

Other components of the physical examination that may provide clues to the underlying cause of thrombocytopenia include:

●Constitution and growth – Short stature is a common finding in inherited bone marrow failure syndromes. Other congenital abnormalities can be present in inherited thrombocytopenia syndromes such as radial and thumb abnormalities (thrombocytopenia absent radius, Fanconi anemia), cleft palate (Jacobsen syndrome), and others. Clinodactyly, syndactyly, hip dysplasia, and radioulnar synostosis are other findings associated with specific inherited conditions. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)

●Neurologic findings – Neurologic symptoms and findings (confusion, headache, stroke, seizures) associated with thrombocytopenia can be seen in TTP, which is a medical emergency. (See "Diagnosis of immune TTP".)  

●Lymph nodes – Lymphadenopathy may be indicative of an underlying lymphoid malignancy with bone marrow infiltration, or a lymphoproliferative process such as autoimmune lymphoproliferative syndrome or hemophagocytic lymphohistiocytosis. Lymphadenopathy can also be seen with infectious causes of thrombocytopenia such as Bartonella henselae and Epstein-Barr virus infection. (See "Peripheral lymphadenopathy in children: Etiology", section on 'Uncommon but important causes'.)

●Head, eyes, ears, nose, and throat

•Hearing – Sensorineural deafness in association with macrothrombocytopenia (thrombocytopenia with large or giant platelets) suggests the possibility of an MYH9-related disease. These autosomal dominant diseases also feature varying degrees and combinations of nephritis, cataracts, and leukocyte inclusions. (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets' and 'Other tests' below.)

•Eyes and mouth – Cataracts are associated with MYH9-related disorders. Oral leukoplakia (white patches or plaques of the oral mucosa due to squamous epithelium hyperplasia) is one of the three main clinical manifestations characteristic of the bone marrow failure syndrome dyskeratosis congenita (table 3) [6,7]. (See "Inherited platelet function disorders (IPFDs)" and "Dyskeratosis congenita and other telomere biology disorders".)

●Abdomen – Splenomegaly, with or without hepatomegaly, from any cause can result in thrombocytopenia due to increased sequestration of the platelet mass. Important causes of splenomegaly include viral infections including Epstein-Barr virus, leukemia, lymphoma, portal vein thrombosis, and chronic liver disease with portal hypertension. (See "Approach to the child with an enlarged spleen".)

●Extremities – Joint swelling may be seen in patients with autoimmune disease such as SLE. In some cases of SLE, ITP or thrombotic thrombocytopenic purpura (TTP) may be the initial manifestation of this disorder. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Hematologic'.)

Skeletal abnormalities may be indicative of specific syndromes associated with thrombocytopenia. For example, absent radii may be seen in patients with thrombocytopenia-absent radius syndrome, fusion of the radius and ulna is seen in amegakaryocytic thrombocytopenia with radioulnar synostosis, and thumb abnormalities in patients with Fanconi anemia. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

●Skin – Cutaneous findings that may be associated with specific underlying causes of thrombocytopenia include eczema (Wiskott-Aldrich syndrome), pigmentary and nail dystrophic changes (dyskeratosis congenita), café-au-lait spots (Fanconi anemia (table 4)), and certain vascular tumors (Kasabach-Merritt syndrome). (See "Wiskott-Aldrich syndrome" and "Clinical manifestations and diagnosis of Fanconi anemia" and "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)".)

Laboratory evaluation — The laboratory evaluation of thrombocytopenia begins with a CBC, which includes the platelet count and mean platelet volume (MPV), and evaluation of the peripheral blood smear.

Complete blood count — In addition to measuring the platelet count, the CBC assesses for other cytopenias (anemia and leukopenia) and it estimates the MPV.

●Other cytopenias – The presence of anemia (not readily explained by bleeding), especially if accompanied by macrocytosis, could be suggestive of a marrow failure process or destructive process such as autoimmune or microangiopathic hemolytic anemia.

Leukopenia or abnormal white blood cell differential that is not explained by recent infectious illness (eg, mononucleosis or other viral illness) should prompt consideration of a hematologic malignancy. (See "Overview of common presenting signs and symptoms of childhood cancer", section on 'Blood count abnormalities'.)

●MPV – The normal range for MPV is 7 to 10 fL. Abnormal MPV may suggest a specific disorder or group of disorders (table 2):

•Mildly elevated or variable/unreportable MPV is consistent with a destructive etiology (eg, ITP). (See "Causes of thrombocytopenia in children", section on 'Platelet destruction' and "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

•An MPV that is well above the normal range suggests one of the macrothrombocytopenia syndromes (eg, Bernard-Soulier syndrome or MYH9-related disorders). (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets' and "Inherited platelet function disorders (IPFDs)".)

•A low MPV (3 to 5 fL) is almost exclusively seen in patients with Wiskott-Aldrich syndrome or X-linked thrombocytopenia. (See "Causes of thrombocytopenia in children", section on 'Small platelets' and "Wiskott-Aldrich syndrome".)

These abnormalities should be further evaluated by visual examination of the peripheral blood smear since both platelet counts and calculated MPV from automated cell counters can be inaccurate when platelet size is outside of the reference range [8]. The MPV can also be less reliable when the platelet count is very low (<10,000/microL).

Peripheral blood smear — When evaluating a patient with thrombocytopenia, the peripheral blood smear examination should include:

●Estimated platelet count

●Characterization of platelet size and morphology

●Presence of platelet clumping

●Whether there are associated white and/or red blood cell abnormalities

The following findings are suggestive of a specific etiology for thrombocytopenia.

●Platelet size

•Variably sized with some large platelets is suggestive of an ongoing platelet destructive process leading to the increased proportion of younger and larger platelets (eg, ITP, TTP, hypersplenism). (See "Causes of thrombocytopenia in children", section on 'Platelet destruction' and "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

•Uniformly large or giant platelets could suggest a congenital macrothrombocytopenia syndrome (picture 4). The MYH9-related diseases are variably associated with leukocyte inclusions (Dohle-like inclusions). Large platelets that lack alpha granules are seen in Gray platelet syndrome. (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets' and "Inherited platelet function disorders (IPFDs)".)

•Small platelets in the appropriate clinical setting (eg, male patient with eczema and immunodeficiency) suggest Wiskott-Aldrich syndrome. X-linked thrombocytopenia should be considered in a patient with microthrombocytopenia without these associated features. (See "Wiskott-Aldrich syndrome" and "Causes of thrombocytopenia in children", section on 'Small platelets'.)

●Circulating blast cells suggest a leukemic process (picture 5). Blast cells on the peripheral blood smear may be difficult to distinguish from atypical lymphocytes that are sometimes present in a postviral case of ITP (picture 6).

●Fragmented erythrocytes (schistocytes) (picture 7) suggest a microangiopathic process, such as HUS, atypical HUS, TTP, or disseminated intravascular coagulation. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Microangiopathic hemolytic anemia' and "Diagnosis of immune TTP", section on 'MAHA and thrombocytopenia' and "Disseminated intravascular coagulation in infants and children".)

●Spherocytes (picture 8) may suggest autoimmune hemolytic anemia coupled with autoimmune-mediated thrombocytopenia (Evans syndrome). In these patients, the direct antiglobulin test (also known as the Coombs test) is usually positive. Less commonly, autoimmune-mediated neutropenia may also occur. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evans syndrome'.)

Reticulated platelets/immature platelet fraction — Reticulated platelets (RP) are the youngest circulating platelets, analogous to the relationship between reticulocytes and mature red blood cells. RPs can be quantified by flow cytometry or with an automated measurement called the "immature platelet fraction" (IPF). IPF is not available on all automated blood cell counters, though it is increasingly available on newer models. Additional details about this testing are provided separately. (See "Automated complete blood count (CBC)", section on 'Reticulated platelets and immature platelet fraction (IPF)'.)

Comparison of the IPF with RPs, as measured by flow cytometry, has shown good correlation [9]. Measurement of RPs can be used to assess platelet turnover or thrombopoiesis in different types of thrombocytopenia [10].

The IPF has been used in the following clinical and research settings:

●To help distinguish between different causes of thrombocytopenia if the clinical picture is unclear [11,12]. The IPF is typically elevated in thrombocytopenia caused by peripheral consumption/destruction (eg, ITP), and it is usually normal in production defects such as bone marrow failure syndromes.

●To evaluate bleeding risk in ITP (lower IPF correlates with increased bleeding risk) [11].

●As a marker of platelet recovery in patients treated with chemotherapy or following stem cell transplantation [13,14].

Bone marrow examination — In most cases of isolated unexplained thrombocytopenia in children, bone marrow examination is not required in the initial evaluation unless there are clinical or laboratory features that suggest bone marrow infiltration or failure, as described above. (See 'Physical examination' above and 'Laboratory evaluation' above.)

Bone marrow examination is indicated in patients with any of the following findings, which are suggestive of either marrow infiltration with abnormal cells or marrow hypocellularity:

●Systemic symptoms (eg, fever, weight loss, night sweats, bone pain)

●Evidence of involvement of other blood cell lines (anemia, leukopenia, macrocytosis) in the absence of a clear alternative explanation

●Presence of blasts on peripheral blood smear

Bone marrow assessment may also be performed to evaluate chronic, stable thrombocytopenia that is not completely consistent with ITP. This is discussed separately. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Indications for bone marrow examination'.)

Other tests — In many cases, the cause of thrombocytopenia can be determined based on the history, physical examination, and initial laboratory testing (CBC and blood smear). For example, in an otherwise well-appearing child who presents with sudden-onset mucocutaneous bleeding without other systemic signs or symptoms and with laboratory confirmation of isolated thrombocytopenia, a provisional diagnosis of ITP can be made. The initial evaluation in this setting is summarized in the table and discussed in detail separately (table 5). (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Initial evaluation'.)

The following tests may be useful in determining the cause of thrombocytopenia if it remains uncertain after the initial evaluation. These tests are generally selected based upon suggestive clinical and laboratory findings.

●For patients with evidence of hemolytic anemia on the peripheral blood smear (eg, spherocytes, schistocytes, or polychromasia suggestive of reticulocytosis), the following tests are appropriate:

•The reticulocyte count can help confirm that the anemia is due to hemolysis, which is associated with an elevated reticulocyte count, rather than marrow failure or infiltration, which are associated with a low reticulocyte count

•A direct antiglobulin test (also known as the Coombs test) is obtained to detect an autoimmune hemolytic anemia (see "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Initial laboratory evaluation')

•Partial thromboplastin time (PTT), prothrombin time (PT), D-dimer, and fibrinogen levels are useful to diagnosis intravascular coagulation in a patient with schistocytes on the peripheral blood smear and/or vascular tumors on examination (see "Disseminated intravascular coagulation in infants and children")

•Other tests to evaluate for a microangiopathy include serum lactic dehydrogenase, creatinine, and ADAMTS13 activity (see "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Diagnosis' and "Causes of thrombocytopenia in children", section on 'Platelet activation and consumption')

●Patients with chronic thrombocytopenia or with features suggesting inherited bone marrow failure syndromes (eg, pancytopenia with short stature, café-au-lait spots, or other characteristic findings of Fanconi anemia (table 4)) should undergo specific testing for these disorders (in addition to a bone marrow biopsy, as described above). Genetic testing is available for many of the inherited bone marrow failure syndromes. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Evaluation'.)

●Patients with giant platelets and/or family history of thrombocytopenia should undergo testing for inherited platelet disorders, including MYH9-related disorder and Bernard-Soulier syndrome. Many of the inherited thrombocytopenias can be identified by genetic testing either with a targeted panel or single-gene testing if a particular diagnosis is suspected [15]. Additional details about these disorders are provided separately. (See "Inherited platelet function disorders (IPFDs)".)

SUMMARY AND RECOMMENDATIONS

●Definition – Thrombocytopenia is defined as a platelet count <150,000/microL. Spontaneous bleeding usually does not occur until the platelet count is <20,000/microL. (See 'Platelet count and bleeding risk' above.)

●Bleeding symptoms – Symptomatic patients generally present with cutaneous (petechiae, nonpalpable purpura, ecchymoses) and/or mucosal (epistaxis, gingival bleeding, bullous hemorrhage, menorrhagia) bleeding. Intracranial hemorrhage (ICH) is a rare but serious consequence of thrombocytopenia and is the most common cause of death in these patients. When ICH occurs, it is often preceded by a history of head trauma. (See 'Bleeding symptoms' above.)

●Diagnostic approach

•Verify the finding – The initial step in the evaluation of suspected thrombocytopenia in children is verification of the low platelet count. In particular, a platelet count that is inconsistent with the clinical picture (eg, a platelet count <20,000/microL in a patient with no petechiae or other bleeding symptoms) should be confirmed before extensive evaluation is undertaken to ensure that the low platelet count is not due to artifact, laboratory error, or pseudothrombocytopenia. (See 'Verification of thrombocytopenia' above.)

•History and physical examination – Once thrombocytopenia has been confirmed, the evaluation is focused on determining the underlying etiology (table 1). The evaluation starts with a detailed history and physical examination. One of the most common causes of thrombocytopenia in childhood is immune thrombocytopenia (ITP), which typically presents with the sudden appearance of a petechial rash in a previously healthy and otherwise well-appearing child. Thrombocytopenia associated with systemic symptoms and/or the presence of lymphadenopathy or hepatosplenomegaly should raise suspicion for malignancy or other proliferative process; patients with these signs or symptoms should be evaluated expeditiously. (See 'History' above and 'Physical examination' above and "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

•Laboratory evaluation – Laboratory evaluation of thrombocytopenia begins with a complete blood count (CBC) and evaluation of the peripheral blood smear. The blood smear must be carefully examined for estimation of platelet number, size, and morphology (table 2); presence of platelet clumping; and any associated white or red blood cell abnormalities. (See 'Complete blood count' above and 'Peripheral blood smear' above.)

Bone marrow examination is not routinely required for the initial evaluation in most cases of unexplained isolated thrombocytopenia in children. Bone marrow examination is indicated in patients with evidence of involvement of other blood cell lines (anemia, leukopenia, or peripheral blasts), systemic symptoms (eg, fever, weight loss, bone pain), abnormal physical examination findings (specifically, lymphadenopathy and/or organomegaly). (See 'Bone marrow examination' above.)

The findings of the initial evaluation inform the need for additional testing. (See 'Other tests' above.)

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