Diagnostic considerations with inherited platelet disorder testing


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1. Identify complications with platelet disorders and populations at risk.
2. Define and identify the genetic pathology of platelet function disorders.
3. Define and identify the genetic pathology of inherited platelet disorders.
4. Discuss thalassemia pathology and the importance of genetic testing.

Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that can affect platelet number, platelet function, or both. Symptoms may include purpura, petechiae, prolonged bleeding from cuts, epistaxis, gum bleeding, excessive bleeding after surgery, hemoptysis, hematuria, and menorrhagia in women. Severe platelet disorders and those with clear syndromic associations can be evident in the newborn period and early childhood, while mild thrombocytopenia may remain undiagnosed until adulthood when it is detected incidentally on routine blood counts.

Misdiagnosis of platelet disorders can result in inappropriate therapies and inadequate surveillance for additional medical complications. The diagnosis of a suspected IPD may be difficult to establish based solely on functional studies, especially in patients with milder disorders, as these assays are often technically challenging and difficult to interpret, and typically require immediate testing on fresh patient platelets due to limited sample stability. Advances in genetic testing through next-generation sequencing (NGS) allow for identification of underlying genetic defects and for distinguishing inherited platelet disorder cases from acquired platelet disorders, including immune thrombocytopenia. Accurate diagnosis is essential in guiding medical management of bleeding and associated non-hematologic conditions, assisting with the identification of affected family members, and predicting genetic recurrence risk assessment.

While this review will focus primarily on hallmark platelet disorders, a summary table on gene-associated clinical phenotypes is also provided (Table 1).

Table 1. Gene-associated clinical phenotypes


Inherited platelet function disorders are typically associated with normal platelet counts and may be variable in severity. They are caused by defects in platelet adhesion, glycoprotein expression, receptor function, signaling pathways, aggregation, cytoskeleton proteins, secretion, or granular contents and abnormalities in procoagulant activity. It should be noted that abnormal platelet function may be acquired by use of medication or secondary to certain medical conditions; these should be accounted for in the differential diagnosis.

Disorders of platelet adhesion

Bernard-Soulier Syndrome (BSS) is a rare inherited bleeding disorder due to absence or dysfunction of the platelet glycoprotein receptor Ib/V/IX complex. Laboratory evaluation typically reveals mild to moderate thrombocytopenia, unusually large platelets, and abnormal platelet function with absent or markedly reduced aggregation response to ristocetin. Flow cytometric analysis demonstrates absence of GPIb (CD 42) on the platelet surface. GPIbα, GPIbβ and GPIX, encoded by the GP1BA, GP1BB and GP9 genes, are all required for efficient expression of the complex on the platelet surface, while absence of GPV does not appear to affect receptor expression or VWF binding.2 Most cases of BSS are inherited as an autosomal recessive genetic trait, but autosomal dominant variants have been reported.

Disorders of platelet aggregation

Glanzmann thrombasthenia (GT) is caused by an abnormality in the genes which encode glycoproteins IIb/IIIa, the glycoprotein IIb/IIIa receptor (also called the fibrinogen receptor). Absence or dysfunction of the fibrinogen receptor does not allow for normal coagulation and presents as a bleeding phenotype. Laboratory evaluation typically reveals normal platelet counts and morphology. Platelet aggregation is highly specific for GT, as platelet aggregation fails to occur with any agonist, except ristocetin, where the reaction is preserved.3 Flow cytometric analysis generally demonstrates decreased quantity or absence of GPIIb/IIIa on the platelet surface. Genetic analysis has shown autosomal recessive pathogenic variants in the ITGA2B or ITGB3.

Disorders of platelet secretion

Platelet activation involves the release of several cytoplasmic granules. When released, alpha granules, dense granules, and lysosomes secrete their contents to assist in the adhesion of segregation of platelets.

Gray platelet syndrome (GPS) is an alpha granule deficiency typically characterized by large platelets, mild to moderate thrombocytopenia, and bleeding caused by homozygous or compound heterozygous mutations in the NBEAL2.4 Platelet aggregation studies in these patients may only be moderately affected, confounding laboratory diagnosis. Platelet electron microscopy demonstrates absence of alpha granules. Patients with GPS can develop myelofibrosis and splenomegaly.5

Paris-Trousseau thrombocytopenia is a disorder that presents with mild bleeding tendency with variable thrombocytopenia, abnormal giant alpha-granules in platelets, and dysmegakaryopoiesis. The original description was in patients with deletions in 11q leading to Jacobsen syndrome. It was later recognized that the platelet phenotype is due to dysfunctional FLI1 and FLI1 homozygous mutations in absence of 11q, leading to the same phenotype.6

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder caused by mutations in one of ten different genes that lead to platelet dense granule deficiency. These mutations affect melanosome formation and cellular trafficking in other organs and also lead to oculocutaneous albinism, neutropenia, pulmonary fibrosis, and granulomatous colitis.7 Molecular confirmation of the particular subtype is important as the non-hematologic manifestations are part of some types and not others, and hence identification of the particular mutation is helpful in prognostication and establishing a plan for surveillance of end organ damage.8


Inherited thrombocytopenia is characterized by a reduction in platelet number with or without other associated non-hematologic conditions. From a diagnostic perspective, classification according to platelet size—small, normal, or large—can help guide the diagnostic process. Platelet size can be estimated through mean platelet volume (MPV), which is an automated measure available in most commercial blood counters, or through direct observation and measurement on a peripheral smear.9 Misdiagnosis of inherited thrombocytopenia as autoimmune thrombocytopenia (ITP) can result in inappropriate therapies and inadequate surveillance for additional medical complications. There are more than twenty-five different molecular defects described leading to inherited thrombocytopenia. Some, such as MYH9-related disorders (MYH9-RD), can affect up to one in 300,000 individuals, while others have been described only in one or two families.

Thrombocytopenia with large platelet size

The MYH9-related disorders encompass a group of macrothrombocytopenia with or without deafness, renal failure, cataracts, and transaminitis that can present with the pathognomonic finding of Döhle-like bodies within the cytoplasm of neutrophils. They were previously described as the May-Hegglin anomaly, Fechtner syndrome, Sebastian syndrome, and Epstein syndrome, yet they all result from autosomal dominant mutations in the cytoskeletal protein MYH9.10 The type of mutation and area of the protein affected correlates with the phenotype, both at the ultrastructural level (type of inclusions seen) and the clinical phenotype (type of end organ damage associated); hence, molecular characterization can be an important tool in prognostication and follow-up of the affected families.11

Thrombocytopenia with normal platelet size

Non-syndromic thrombocytopenias with increased risk of hematologic malignancy are associated with mutations in RUNX1, ANKRD26 and ETV6, which lead to thrombocytopenia with mild to moderate bleeding and no other syndromic associations.12-14 They all have a high risk of evolution to myeloid neoplasms (acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and chronic myelomonocytic leukemia), and in the case of ETV6, predisposition to acute lymphoblastic leukemia.12-14 RUNX1 germline mutations can present with decreased delta storage granules and more significant bleeding.15 Some abnormalities in platelet aggregation, platelet electron transmission electron microscopy, and surface glycoprotein expression have been described; however, they are not diagnostic and confirmation requires molecular techniques.16

Thrombocytopenia with small platelet size

Wiskott-Aldrich syndrome (WAS)-related disorders and X-linked thrombocytopenia affect males almost exclusively. They comprise a spectrum of disorders with a wide range of clinical manifestations. The specific phenotype may be related to the location and nature of the genetic variant as well as the amount of residual protein expression.17 Patients typically present with profound thrombocytopenia, eczema, and recurrent infections and are also predisposed to autoimmune disorders and lymphoma.18


Due to the heterogeneity of these disorders and the diversity of phenotypes, a careful history and physical examination should always be performed. A broad differential diagnosis should be considered, particularly in differentiating immune or acquired forms from inherited thrombocytopenia. Initial diagnostic evaluation includes a complete blood count with a peripheral smear, followed by assays to assess the coagulation cascade and platelet function. Advanced diagnostic techniques, including platelet aggregation studies or genetic evaluation, often require specialized referral centers.19

Treatment of inherited platelet disorders will vary depending on severity of disease. The scope and scale of treatment should be personalized for each patient. At a minimum, patient education and counseling is recommended following diagnosis. Patients should be made aware of primary self-care options if mild bleeding were to occur as well as exposure to drugs that may impact platelet function (that is, aspirin).

For more severe cases, desmopressin (DDAVP) or antifibrinolytics may be used to control mild bleeding episodes, while platelet transfusion remains a primary option to address severe bleeding or prepare patients for surgeries with a high bleeding risk, such a neurosurgery.20 In some instances, such as in patients with GT, alloimmunization to platelet antigens occurs, and hemostatic support has to be provided with activated clotting factor concentrates.

Bone marrow transplant has been successful in treating inherited platelet disorders in highly selected cases, particularly those that have associated bone marrow failure or immunodeficiency as an associated feature.21 However, due to the high associated transplant morbidity and mortality, transplant is not widely recommended.
Gene therapy and gene-editing technologies are promising options currently under investigation that could greatly benefit patients with IPDs in the future.18


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Juliana Perez Botero, MD, serves as an Associate Medical Director at BloodCenter of Wisconsin and Assistant Professor of Medicine at Medical College of Wisconsin. Dr. Perez Botero completed her training in Internal Medicine and Hematology and Oncology at the Mayo Clinic in Rochester, MN. She specializes in non-malignant hematologic disorders, including inherited and acquired bleeding and clotting disorders with a special focus on phenotype-genotype correlation in patients with familial platelet disorders.