Inherited thrombocytopenia diseases

Inherited thrombocytopenia diseases

Thrombocytopenia (combination of medical terms, “thrombocyte” [platelet] and “penia” [deficiency], based upon Greek “thrombos” [clot]; “kytos” [container, with modern meaning of cell]; and “penia” [poverty]) indicates reduced platelet count numbers.

Inherited thrombocytopenia diseases

Depending on its cause, thrombocytopenia can indicate increased risk of bleeding, thrombosis, and/or mortality. Thus, when faced with a thrombocytopenic patient, the clinician’s key question is: what isthe probable cause of the patient’s thrombocytopenia? The answer will point to the appropriate prognostic and therapeutic considerations.

Autosomal dominant thrombocytopenias

1. MYH 9 – related thrombocytopenia syndromes
These syndromes are caused by mutations in the MYH9 gene that encodes non – muscle myosin – heavy chain IIa and includes the May – Hegglin anomaly and other entities with associated clinical features such as nephritis, deafness and cataracts. The thrombocytopenia is mild to moderate with large or giant platelets and mild bleeding. Neutrophils have large blue cytoplasmic inclusions called D ö hle – like bodies which is non – muscle myosin heavy – chain IIA in the May – Hegglin variant

2. Mediterranean macrothrombocytopenia

This disorder is a relatively common mild form of macrothrombocytopenia in southern Europe and is without significant bleeding. The thrombocytopenia is identified incidentally during routine blood testing. This disorder is due to a mutation in GpIb α with impaired expression.

3. RUNX 1 – related mutations
These patients have mild bleeding but have a marked predisposition for acute leukemia and familial platelet dysfunction. They have mutations or deletions in hematopoietic transcription factor RUNX1.

4. Paris – Trousseau thrombocytopenia
Platelets are larger than normal in this disorder and are characterized by giant α – granules. It is associated with mutations involving transcription factor FLI – 1 and the bone marrow has increased immature megakaryocytes. Mental retardation, facial and cardiac abnormalities are associated features.

5. Gray platelet syndrome
This entity is characterized by reduced or absent α – granules in platelets that appear gray color on Wright – Giemsa stain. The defects are in granule formation and targeting of proteins to the granules. Some of these patients have macrothrombocytopenia.

6. Velocardiofacial/DiGeorge syndrome
These syndromes are caused by deletions in chromosome 22 and have only mild thrombocytopenia without significant bleeding. They are characterized by cardiac abnormalities, parathyroid and thymus insufficiencies, cognitive impairment, and, in some, facial abnormalities.

Autosomal recessive thrombocytopenias

1. Congenital amegakaryocytic thrombocytopenia
This entity is a severe thrombocytopenia (less than 10,000 platelet/ μ L) that presents in the newborn with absence of megakaryocytes in the bone marrow. Affected infants are identified within days to weeks of birth because of bleeding. Leukocyte and erythrocyte production is decreased leading to pancytopenia by the second decade. This disorder is caused by mutations in the thrombopoietin receptor c – Mpl.

2. Thrombocytopenia with absent radii (TAR)
Affected individuals have shortened or absent forearms bilaterally due to defects in radius development with severe thrombocytopenia at birth requiring platelet transfusion. Thrombocytopenia becomes less severe during the first year of life.

3. Bernard – Soulier syndrome This macrothrombocytopenia has marked platelet dysfunction with severe bleeding. The mutation is in the GpIb, which forms the binding site on platelets for vWF.

X – Linked disorders

1. Wiskott – Aldrich syndrome (WAS)

This syndrome affects males with moderate to severe microthrombocytopenia, immunodeficiency and eczema. WAS usually presents within the first year of life with bruising and bleeding and recurrent infections with eczema developing after the first year. The underlying defect is a mutation in the WAS protein (WASP) that links the cellular cytoskeleton with signal transduction pathways.


The thrombocytopenia often improves after splenectomy. Stem cell transplantation is curative. A large proportion of patients with mutations in WASP exhibit a milder form of X – linked thrombocytopenia. These patients have residual WASP and do not have significant eczema or immunodeficiency.

2. GATA – 1 mutation X – linked macrothrombocytopenia with dyserythropoiesis

This disorder has marked thrombocytopenia (10,000 – 40,000/ μ L) with bruising and severe bleeding, and a variable degree of anemia. It is caused by mutations in the hematopoietic transcription factor GATA – 1. The bone marrow is hyper-cellular with dysplastic features in the megakaryocytic and erythroid lineages.



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