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Congenital Thrombocytopenia
Introduction
Inherited thrombocytopenia was once considered a rare disease, but more recent studies using next-generation sequencing (NGS) and genome-wide association studies suggest that the prevalence of inherited or familial thrombocytopenia may be much higher than originally appreciated and that some individuals who were previously thought to have immune thrombocytopenia (ITP) may, in fact, have a defect in platelet or megakaryocyte development. Further characterization and investigation of individuals and families will most certainly lead to expansion of the number of disorders and modify phenotypes. This will allow us to further improve management and avoid incorrect diagnosis and treatment of individuals who present for the first time to a clinician with a low platelet count.
Diagnosis
Patients with congenital thrombocytopenia may present with mild-to-moderate mucocutaneous bleeding (epistaxis, petechiae and bruising, gastrointestinal [GI] or genitourinary tract bleeding) ( Table 93.1 ). Severe bleeding is rarer but is possible depending on the degree of thrombocytopenia and whether or not there is associated platelet dysfunction. Some disorders may have associated physical or laboratory characteristics that suggest the diagnosis and so a thorough history, physical examination, and evaluation of the peripheral smear may guide the remainder of the diagnostic evaluation and limit unnecessary testing. A few well-characterized inherited thrombocytopenias have clinically available genetic testing that allows for complete evaluation of the entire family of an affected individual even in the absence of thrombocytopenia in other family members.
Table 93.1
Inherited Thrombocytopenias Classified by Platelet Size
| Inherited Condition | Gene (Location) | Inheritance | Key Features |
|---|---|---|---|
| Microthrombocytic | |||
| Wiskott–Aldrich syndrome/X-linked thrombocytopenia | WAS (Xp11) | X-linked | Thrombocytopenia, eczema, severe immunodeficiency, small platelets |
| Congenital autosomal recessive small-platelet thrombocytopenia | FYB (5p13.1) | AR | Thrombocytopenia with small platelets |
| Normothrombocytic | |||
| Congenital amegakaryocytic thrombocytopenia | MPL (1p34) | AR | Hypomegakaryocytic thrombocytopenia with eventual development of bone marrow failure |
| Thrombocytopenia with absent radii | RBM8A (1q21.1) | AR | Thrombocytopenia that improves with age, limb anomalies (but relatively normal thumbs) |
| Amegakaryocytic thrombocytopenia with radio/ulnar synostosis | HOXA11 (7p15) MECOM (3q26.2) |
AD | Severe thrombocytopenia that improves with age, skeletal abnormalities (radio/ulnar synostosis, clinodactyly, syndactyly, hip dysplasia), hearing loss |
| Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) | RUNX1 (21q22) | AD | Thrombocytopenia, myelodysplasia or even AML, platelet dysfunction |
| Paris-Trousseau/Jacobsen syndrome | FLI1 (11q23.3–24.2) | AR | Thrombocytopenia with large granules; may have associated cardiac anomalies, mental retardation, abnormal facies |
| Familial thrombocytopenia 2 | ANKRD26 (10p12.1) | AD | Mild-to-moderate thrombocytopenia with mild bleeding symptoms |
| Macrothrombocytopenic | |||
| Bernard–Soulier syndrome (BSS) | GPIbα (17), GPIbβ (22), GPIX (3) | AR | Platelet dysfunction with large platelets |
| Velocardiofacial syndrome | 22q11 | AD | Cardiac anomalies, cleft palate, hypocalcemia, thymic aplasia, and typical facies. BSS-like thrombocytopenia ±autoimmune |
| Benign Mediterranean macrothrombocytopenia | GPIb/IX/V; ITGB3 | AD | May represent as heterozygous BSS mutations |
| Platelet type von Willebrand disease | GPIbα (17) | AD | Decreased high-molecular-weight VWF multimers with thrombocytopenia because of increased platelet affinity for VWF |
| MYH9-related disease | MHY9 (22q11.2) | AD | Large platelets, leukocyte inclusions may have sensorineural hearing loss, cataracts, glomerulonephritis, or renal failure |
| Gray platelet syndrome | N BEAL2 (3p21.31) , GFI1B (9q34.13) | AD, AR | Large, pale platelets with absence of α granules |
| GATA-1 mutation of X-linked thrombocytopenia with thalassemia (GATA-1) | GATA1 (Xp11.23) | X-linked | Thrombocytopenia with variable anemia |
| ACTN1-related thrombocytopenia | ACTN1 (14q24.1) | AD | Macrothrombocytopenia |
| TUBB1-related thrombocytopenia | TUBB1 (20q13.1) | AD | Macrothrombocytopenia |
| FLNA-related thrombocytopenia | FLNA (Xq28) | X-linked | |
| TRPM7 | TRPM7 (15q21.2) | AD | Atrial fibrillation and macrothrombocytopenia in one family |
Differential Diagnosis
Initial evaluation must include a careful personal and family history with particular attention to ethnicity and consanguinity, bleeding history, including onset of bleeding and prior hemostatic challenges (surgery or trauma), and associated medical complications seen in the inherited disorders, including hearing loss, renal disease, cataracts, pigment changes, eczema, skeletal abnormalities, cardiac anomalies, frequent infections, or hematologic malignancy. As the most likely causes of thrombocytopenia are acquired (ITP or drug-induced thrombocytopenia), the onset of bleeding is as important as a careful evaluation of any current or recent medication exposures. Careful evaluation of the peripheral smear and physical examination to evaluate for hepato/splenomegaly or lymphadenopathy may suggest myeloproliferative, myelophthisic, or aplastic bone marrow disease that could account for the low platelet count. Inherited disorders should be suspected in any patient with long-standing, refractory thrombocytopenia; particularly if associated with any of the medial complications discussed above. In patients with mild thrombocytopenia, consideration should also be given to the diagnosis of congenital thrombocytopenia, particularly if there are no prior blood counts with normal platelet counts. The advent of NGS has led the identification of several forms of familial thrombocytopenia with predisposition to malignancy and therefore establishing a molecular diagnosis, whenever possible, may have important implications for other family members and may help inform risk prediction. Targeted therapies for some of the inherited thrombocytopenias, particularly those with associated other medical complications, are being developed, as are gene therapies. Some of the more severe disorders, such as Wiskott–Aldrich syndrome (WAS) or Bernard–Soulier Syndrome, may benefit from bone marrow transplant in the appropriate setting.
Management
Many patients with congenital thrombocytopenia have mild-to-moderately low platelet counts and therefore have no or moderate bleeding. Treatment may be necessary in the setting of trauma or surgical intervention (including dental procedures) and consists of supportive therapy: physical tamponade, local/topical glue or fibrin products, DDAVP, or antifibrinolytics. In disorders with more severe bleeding phenotype or in settings of significant bleeding, platelet transfusion may be necessary to control bleeding. Management of specific disorders is detailed below. For a few disorders with severe thrombocytopenia such as MYH9-related disease (MYH9-RD) and WAS, treatment with the novel thrombopoietin (TPO) receptor agonists has been tried with varying success.
Congenital Thrombocytopenias
There are multiple ways to organize the inherited thrombocytopenias, including by manner of inheritance, by size of platelets, or by pathologic defect. Clinically, size of platelets is a useful differentiation schema as it allows for the easy subcategorization of patients into useful groups that can then be systematically evaluated.
Disorders With Small Platelets (Microthrombocytopenia)
Wiskott–Aldrich Syndrome and X-Linked Thrombocytopenia
WAS and X-linked thrombocytopenia (XLT) are rare congenital thrombocytopenias caused by mutations in the WAS gene that encodes WASp, which plays an important role in signal transduction from cell surface receptors to the actin cytoskeleton. These patients usually have significantly small platelets (mean platelet volume [MPV] 3.5–5 fL) and may have associated immune dysfunction, resulting in eczema, frequent infections, or autoimmune disease. Recent reports have suggested that platelet size may be more variable than originally thought, and some patients with documented WAS mutations may have somewhat higher MPV. There is an increased risk of lymphoma and solid tumors in adolescents and young adults (particularly those with significant immunodeficiency). Mutations with essentially no protein expression result in the more severe WAS: immunodeficiency, autoimmunity, microthrombocytopenia, and eczema. Mutations with single amino acid substitutions and more normal levels of protein expression tend to result in isolated thrombocytopenia (XLT). Thorough evaluation of patient with small platelets includes sequencing of the WAS gene and evaluation of WASp levels and interrogation of the immune system. Splenectomy has been used in the past to improve platelet counts; however, asplenia in the setting of underlying immunodeficiency is a concern and thus should not be done without careful consideration. Management focuses on control of bleeding in the acute setting and monthly IVIG and vigilance regarding infections. Platelet transfusion can be used to control more significant hemorrhage. Thrombopoietin receptor agonists have been used to improve platelet counts in patients with XLT and ITP associated with WAS with varying success. Patients with more severe disease are more often offered with hematopoietic stem cell (HSC) transplant, and outcomes have been generally good.
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