Thrombocytopenia is a disorder of haematopoetic cells with predominant defects of platelets and it is defined as having a platelet count of less than 150,000 in mL of circulating blood, while the normal number of platelets ranges between 150,000 and 450,000 cells per mL of blood 1. Platelets are haemopoetic cells that play a primary role in haemostasis, interacting with subendothelium-bound von Willebrand factor (vWF) via the membrane glycoprotein complexes.
Platelet adhesion is the initial interaction in blood coagulation and control of bleeding. The estimated incidence of X-linked thrombocytopenia and Wiskott-Aldrich Syndrome is between 1 and 10 per million males worldwide 2. The prevalence of thrombocytopenia absent radius syndrome is estimated at 1:200,000-1:100,000 3. Causes of thrombocytopenia include decreased platelet production, increased platelet destruction, increased splenic sequestration, and dilution.
The major clinical signs and symptoms of thrombocytopenia may include the following:
- Easy or excessive bruising (“purpura”)
- Superficial bleeding into the skin (“petechiae”) (typically most evident on the lower legs)
- Scattered small ecchymosis at sites of minor trauma
- Prolonged bleeding
- Bleeding from gums or nose
- Blood in urine or stool
- Enlarged spleen
Thrombocytopenia usually presents in infancy or early childhood, most commonly with intensive and frequent mucosal bleeding, bloody diarrhea, intermittent petechiae and purpura, and recurrent bacterial and viral infections 4. At least 40% of affected individuals also develop one or more autoimmune conditions, including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver 1, 4.
Clinical expression of thrombocytopenia has broad spectrum of variations ranging from asymptomatic to life-threatening bleeding conditions. Various syndromes and diseases are associated with thrombocytopenia, including the following:
Wiskott-Aldrich syndrome caused by mutations in the WAS gene should be suspected in males affected with:
- Profound thrombocytopenia (<70,000 platelets/mL)
- Small platelet size (>2 SD below the mean)
- Recurrent bacterial or viral infection
- Autoimmune disorder
- Family history of one or more maternally related males with a WAS-related phenotype or disorder.
X-linked thrombocytopenia (XLT) also caused by mutations in the WAS gene 4 should be suspected in affected males with:
- Congenital thrombocytopenia (5,000-50,000 platelets/mL) 4
- Small platelet size
- Absence of other clinical findings of Wiskott-Aldrich syndrome
- Family history of one or more maternally related males with a WAS-related phenotype or disorder.
X-linked congenital neutropenia (XLN) also caused by mutation in the WAS gene 5 characterized with the following clinical features in affected males:
- Recurrent bacterial or viral infections
- Persistent neutropenia
- Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome TAR syndrome is thrombocytopenia-related disorder characterized by thrombocytopenia and absence of radius 6.
TAR syndrome is caused by mutations in RBM8A, encoding RNA regulatory protein. Diagnosis of TAR syndrome is established in a patient who has both of the following features:
- Bilateral absence of the radii with the presence of both thumbs
- Thrombocytopenia (usually <50,000 platelets/mL) 6.
Bernard Soulier syndrome (BSS) is an inherited platelet disorder characterized by mild to severe bleeding tendency, macrothrombocytopenia and absent ristocetin-induced platelet agglutination. BSS is caused by mutations in the GP1BA, GP1BB, or GP9 genes 7.
Glanzmann thrombasthenia platelet-type bleeding disorder is a congenital macrothrombocytopenia associated with platelet anisocytosis mildly increased bleeding tendency. Glanzmann thrombasthenia can be caused by mutations in the integrin-related genes ITGA2B or ITGB3 8.
Thrombocytopenia with beta-thalassemia is a hereditary thrombocytopenia caused by mutations in the GATA1 gene, encoding transcription factor GATA binding protein 9. The major clinical features of this thrombocytopenia subtype include variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis.
Additional thrombocytopenia-related conditions are caused by mutations in MYH9, encoding nonmuscular myosin heavy chain 9 protein:
Epstein syndrome is an autosomal dominant disorder characterized by thrombocytopenia, giant platelets, nephritis, and deafness 10.
Fechtner syndrome is an autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and Dohle-like body inclusions in peripheral blood leukocytes, with the additional features of nephritis, hearing loss, and eye abnormalities, mostly cataracts 10.
Sebastian syndrome is an autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusions in peripheral blood leukocytes 10.
May-Hegglin anomaly is an autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and Dohle-like body inclusions in peripheral blood leukocytes. About 25-50% of affected individuals have mild to moderate episodic bleeding 11.
Overview of thrombocytopenia-associated genes
|Chr. locus||Frequency of mutations||Associated/allelic disorders (OMIM)|
|9q34.2||AR||Thrombotic thrombocytopenic purpura, familial (274150)|
|10p12.1||AD||Thrombocytopenia 2 (188000)|
|7p15.3||AD||Thrombocytopenia 4 (612004)|
|Xp11.23||XLR||X-linked anemia (300835); Megakaryoblastic leukemia with or without Down syndrome(190685); Thrombocytopenia with beta-thalassemia (314050); Thrombocytopenia with or without dyserythropoietic anemia (300367)|
|17p13.2||AD, AR||Bernard-Soulier syndrome type A1 (231200); Bernard-Soulier syndrome type A2 (153670), von Willebrand disease platelet-type (177820); Nonarteritic anterior ischemic optic neuropathy (258660)|
|22q11.21||AR||Bernard-Soulier syndrome, type B/ Giant platelet disorder (231200)|
|3q21.3||AR||Bernard-Soulier syndrome type C (231200)|
|17q21.31||AD, AR||Bleeding disorder platelet-type 16 (187800); Glanzmann thrombasthenia (273800); Thrombocytopenia neonatal alloimmune (unknown)|
|17q21.32||AD, AR||Bleeding disorder platelet-type 16 (187800), Glanzmann thrombasthenia (273800); Posttransfusion purpura (unknown); Susceptibility to myocardial infarction (608446)|
|1p34.2||AD, AR, somatic||Myelofibrosis with myeloid metaplasia somatic (254450); Thrombocythemia 2 (601977), Thrombocytopenia, congenital amegakaryocytic (604498)|
|22q12.3||AD||Macrothrombocytopenia and progressive sensorineural deafness (600208); Epstein syndrome (153650); Fechtner syndrome (153640), May-Hegglin anomaly (155100), Sebastian syndrome (605249); Deafness autosomal dominant 17 (603622)|
|21q22.12||AD||Leukemia acute myeloid (601626); Platelet disorder with associated myeloid malignancy (601399)|
|Xp11.23||XLR||Thrombocytopenia X-linked (313900), Neutropenia severe congenital X-linked (300299); Wiskott-Aldrich syndrome (301000)|
Treatment of thrombocytopenia usually includes platelet transfusion used to provide an immediate platelet increase. Furthermore, treatment should be focused on the etiology of thrombocytopenia (e.g. discontinuation of the drug that caused the thrombocytopenia, treatment of the underlying infection, chemotherapy, and others). Hematopoietic cell transplantation (HCT) is the only known curative treatment. Topical steroids and antibiotics should be considered for infected eczema. Immunosuppressants should be used for autoimmune disease and granulocyte colony stimulating factor and appropriate antibiotics for neutropenia.
CENTOGENE offers sequencing and deletion/duplication analysis for the genes in the Thrombocytopenia panel (ADAMTS13, ANKRD26, CYCS, GATA1, GP1BA, GP1BB, GP9, ITGA2B, ITGB3, MASTL, MPL, MYH9, RUNX1, WAS).
The differential diagnosis of thrombocytopenia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Disseminated intravascular coagulation liver disease
- Thrombotic Thrombocytopenic Purpura (TTP)
- Drug-induced immune thrombocytopenia (alcohol, heparin, quinine/quinidine, sulfonamides)
- Acute leukemia, myelodysplastic syndrome or related malignancy
- Megaloblastic anemia.
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for thrombocytopenia using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Thrombocytopenia panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the thrombocytopenia panel, we further recommend continuing the bioinformatics analysis of the data with whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for thrombocytopenia testing:
- Individuals with a family history of thrombocytopenia and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling thrombocytopenia
- Individuals with a negative but suspected family history of thrombocytopenia, in order to perform proper genetic counseling.
Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having thrombocytopenia and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the thrombocytopenia and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.
More information on thrombocytopenia can be found in our genetic test catalogue.