Table 2.
Primary ITP and inherited thrombocytopenia
| Primary ITP3,78 | WAS35,95,* | XLT96,97,* | BSS98,99,* | TAR100,101 | X-linked gray plt syndrome102,* | Gray plt syndrome103,* | Disorders of filamen A104 | MYH9-RD105,* | vWF type IIb106,* | Plt-type VWD107,* | RUNX1108,* heterozygous | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical characteristics | ||||||||||||
| Incidence | 1-6.4:100 000 | 1-4:1 million males | 1:10 million males | <1:1 million | 0.4:100 000 | Rare | Rare | Rare | Rare | Rare | Rare | Rare |
| Distinguishing features | Isolated thrombocytopenia with petechiae/bruising in a healthy-looking patient | Male with eczema, petechiae, and infections. | Isolated thrombocytopenia, very small plt, and possibly milk allergy–related GI bleeding. | Very large plt, falsely decreased number, and epistaxis (homozygous worse phenotype than heterozygous). | Missing radii, other skeletal abnormalities, spontaneous improvement of counts within first year of life. | Variable thrombocytopenia, “invisible” platelets missing α granules, myelofibrosis due to “leakage” of α granule contents (TGF-β and PDGF) into the marrow. | Variable: bleeding, CNS dysplasia, deafness, skeletal dysplasia. | Döhle bodies, genotype/phenotype correlation: May Hegglin anomaly, Fechtner syndrome, Ebstein anomaly, Sebastian syndrome, Alport syndrome, etc. | Variable plt count that falls dramatically with stress, plt clumping on smear; vWF type IIb 10-fold more common than plt-type vWF. | Mild thrombocytopenia with plt dysfunction, 50% risk of malignancy (2/3 leukemia, 1/3 solid tumors). | ||
| Diagnostic tests | CBC, peripheral blood smear. ↓↓plt: normal or increased in size. Normal RBCs and WBCs. Rule out other causes. |
Peripheral blood smear: small plt. Decreased number/function of T cells. ↓IgG, ↓IgM, ↑IgE, ↑IgA; genetic panel and WES. | Peripheral blood smear: small plt; genetic panel and WES. | Peripheral blood smear: giant plt. No platelet aggregation in response to ristocetin. Flow cytometry; genetic panel and WES. | XR forearm Fetal US (missing radii, ulna, humerus, tibia, etc.). If plt don’t normalize, they may deteriorate; genetic panel and WES. |
↓plt count, large-sized gray platelets. Hb electrophoresis: mild β-thalassemia–like phenotype (↓HbA2); genetic testing and WES. | ↓plt count, large-sized gray platelets. BM shows myelofibrosis; genetic testing and WES. | Clinical characteristics, radiologic studies, family history, X-linked inheritance; genetic testing and WES. | Macrothrombocytopenia, Döhle-like bodies. Hearing screen: sensorineural hearing loss; genetic testing and WES. | vWD panel: ↓VWF:RCo/VWF:Ag ratio; increased affinity of vWF to plt, aggregation with low-dose ristocetin, loss of high-molecular monomers with variable thrombocytopenia; genetic panel and WES. | Abnormal vWD panel: aggregation with low-dose ristocetin, with normal monomers; variable thrombocytopenia; genetic panel and WES. | CBC: mild thrombocytopenia. Plt aggregation: impaired to ADP; genetic testing and WES. |
| Molecular characteristics | None identified | Mutations of WAS gene on X chromosome | Mutation of GP1BA gene, resulting in lack of GP1b receptor. | Mutations in RBM8A gene. | Mutation in GATA1 gene | NBEAL2 or GFI1B mutation | FLNA gene mutations | Mutations in MYH9 gene | Mutations in vWF gene | GP1BA mutations | RUNX1 mutations | |
| Clinical approach | Standard first- and second-line treatment. | HSCT. Future: gene tx. | TPO-RA, splenectomy, HSCT. Future: gene tx. | Transfusions, desmopressin, antifibrinolytics. | Plt transfusions, antifibrinolytics until improvement. | HSCT | HSCT | Supportive | Usually not requiring treatment; plt transfusions and TPO-RAs, if needed. | Infuse vWF | Plt transfusions | Supportive care, plt transfusions for procedures and surgeries. |
↓ indicates a decrease in value; ↓↓ indicates a significant decrease in value; ↑ indicates an increase in value.
ADP, adenosine diphosphate; BM, bone marrow; CNS, central nervous system; GI, gastrointestinal; Hb, hemoglobin; HSCT, hematopoietic stem cell transplant; PDGF, platelet-derived growth factor; Plt/plt, platelets; RBC, red blood cells; RUNX1, RUNT-related transcription factor 1; TAR, thrombocytopenia absent radii syndrome; TGF, transforming growth factor; tx, therapy; US, ultrasound; vWD, von Willebrand disease; vWF, von Willebrand factor; VWF:RCo/VWF:Ag ratio, ratio of von Willebrand factor ristocetin cofactor activity/von Willebrand antigen; WAS, Wiskott-Aldrich syndrome; WBC, white blood cells; WES, whole-exome sequencing; XLT, X-linked thrombocytopenia; XR, X-ray.
In these diseases, a patient with a mild phenotype may go undiagnosed until screening is initiated upon a relative’s positive diagnosis.