Common Name |
Gene(s) and Locus |
Affected Component |
Inheritance |
Pathogenesis |
Laboratory Features |
Clinical Features |
Diseases Affecting PLT Granules |
ARC syndrome |
VPS33B (15q26), VIPAS39 (14q34) |
α-granule |
Autosomal recessive |
Impaired intracellular lysosomal sorting and trafficking |
Abnormally large PLTs deficient in α-granules, defective PLT aggregation (ADP) |
Bleeding, arthrogryposis, renal tubular dysfunction, cholestasis, facial dysmorphism, ichthyosis, cerebral malformations, sensorineural deafness, death in first years of life |
GFI1B-related syndrome |
GFI1B (9q34) |
α-granule |
Autosomal dominant |
Defect in megakaryocyte development |
Normal PLTs coexist with α-granule–deficient ones, decreased PLT aggregation with collagen |
Bleeding |
GATA1-related syndrome |
GATA1 (Xp11) |
α-granule |
X-linked |
Defect in α-granule production and/or distribution |
Not all PLTs affected, can be linked with trisomy 21 |
Bleeding, dyserthropoiesis, β-thalassemia–like |
Gray PLT syndrome |
NBEAL2 (3p21) |
α-granule |
Autosomal recessive |
Defect in formation of α-granules |
Large PLTs deficient in α-granules |
Bleeding, splenomegaly, myelofibrosis |
Chédiak-Higashi syndrome |
LYST (1q42.3) |
Dense granule |
Autosomal recessive |
Defective lysosomal trafficking regulator protein with disordered intracellular trafficking |
Giant inclusion bodies in leukocytes and PLT dense-granule deficiency |
Bleeding, oculocutaneous albinism, pyogenic infections, peripheral neuropathy, accelerated terminal disease with malignant lymphoma |
Hermansky-Pudlak syndrome |
HPS1 (10q24.2), AP3B1 (5q14.1), HSP3 (3q24), HSP4 (22q12.1), HPS5 (11p15.1), HPS6 (10q24.32), DTNBP1 (6p22.3), BLOC1S3 (19q13.32), PLDN (15q21.1) |
Lysosome-related organelle complexes including dense granule |
Autosomal recessive |
Abnormal biogenesis of lysosome-related organelle complexes |
Absent dense PLT granules; prolonged bleeding time; impaired aggregation with collagen, thrombin, epinephrine, and adenosine diphosphate (ADP) |
Multisystem disease with oculocutaneous albinism, bleeding diathesis, neutropenia, and abnormal lysosomal ceroid storage; pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency may develop |
Paris-Trousseau thrombocytopenia |
Fli-1 (11q23) |
α-granule |
Unknown, isolated cases |
Dysmegakaryopoiesis with formation of giant α-granules |
Variable thrombocytopenia, increased mean PLT volume, giant α-granules, micromegakaryocytes |
Mild bleeding tendency, dysmorphic facies, intellectual and developmental disabilities |
Quebec PLT disorder |
PLAU (10q22.2) |
PLAU; α-granule |
Autosomal dominant |
Excessive PLAU causing intragranular plasmin generation and degradation of α-granule components on PLT secretion |
Markedly increased PLT content of PLAU with normal or slightly increased plasma PLAU and normal urine PLAU; mild thrombocytopenia; normal closure time on PFA-100 |
Delayed-onset postsurgical bleeding, severe trauma-induced bleeding, muscle and joint bleeds, spontaneous hematuria, poor wound healing |
Diseases Affecting PLT Cytoskeletal Components |
MYH9-related disorders (May-Hegglin anomaly, Fechtner syndrome, Epstein syndrome, Sebastian syndrome) |
MYH9 (22q12.3) |
Nonmuscle MYH |
Autosomal dominant |
Defective PLT shape change, renal tubular dysfunction, cochlear dysfunction |
Macrothromocytopenia; Döhle body–like inclusions in leukocytes; prolonged bleeding time; defective PLT aggregation in response to ADP, collagen, and epinephrine; proteinuria; microscopic hematuria |
Variable phenotype with mucocutaneous bleeding, nephritis, sensorineural hearing loss, and cataracts |
WAS |
WAS (Xp11.23) |
WASP |
X-linked recessive |
Abnormal signaling and movement of actin filaments |
Thrombocytopenia, small PLTs, prolonged bleeding time, lymphopenia, increased IgA levels, elevated ESR and CRP |
Mucocutaneous bleeding, eczema, recurrent infections, vasculitis, hemolytic anemia, iron-deficiency anemia, bloody diarrhea |
Diseases Affecting PLT Metabolic and Signaling Pathways |
PLA2 deficiency |
PLA2G4A (1q31.1) |
Cytosolic PLA2 |
Unknown |
Defective PLT aggregation resulting from impaired synthesis of arachidonic acid from membrane phospholipids; decreased formation of prostaglandins, TXA2, and prostacyclin |
Impaired PLT aggregation and degranulation induced by ADP or collagen, normalized by arachidonic acid; markedly reduced plasma levels of thromboxane B2, 12-HETE, and leukotriene B4 |
Multifocal stenosis and ulceration of the small intestine |
TXAS1deficiency |
TBXAS1 (7q34) |
TXA2 synthase |
Autosomal dominant |
Impaired conversion of prostaglandin H2 to TBXA2, resulting in defective PLT aggregation |
Defective PLT aggregation with arachidonic acid; decreased plasma TBXB2 and malondialdehyde; increased levels of prostaglandins, particularly prostaglandin D2 |
Mucocutaneous bleeding, including petechiae, easy bruising, epistaxis, hematuria, and gastrointestinal bleeding; bleeding after dental extractions; symptoms can occur shortly after birth |
PTGS1deficiency |
PTGS1 (9q33.2) |
PTGS1 (COX1, PGHS1) |
Autosomal dominant |
Decreased synthesis of PGG2 and prostaglandin H2 from arachidonic acid, impaired formation of TXA2 and prostacyclin with defective PLT aggregation |
Moderate thrombocytopenia, mildly prolonged bleeding time, defective second-wave PLT aggregation with release reaction restored with added PGG2 |
Easy bruising, spontaneous hematomas, menorrhagia, epistaxis, hemarthroses, postsurgical bleeding, gastrointestinal bleeding |
Albright hereditary osteodystrophy |
GNAS (20q13.32) |
Maternal loss of function of the Gsα isoform of the GNAS gene |
Autosomal dominant |
Reduced Gsα protein activity |
Decreased cAMP formation on Gαs-receptor activation, hypocalcemia, hyperphosphatemia |
Short stature, obesity, round face, mental disability, brachydactyly, ectopic ossification, pseudohypoparathyroidism |
Leukocyte adhesion deficiency, type III |
FERMT3 (11q13.1) |
Integrin-activating proteins |
Autosomal recessive |
Defective in situ activation of leukocytes and PLT integrins with impaired PLT aggregation and leukocyte function |
Leukocytosis; defective neutrophil chemotaxis, activation, and adhesion with normal expression of CD11/CD18; impaired PLT aggregation to all agonists; normal PLT count and morphology |
Severe recurrent nonpurulent bacterial infections (skin infections, omphalitis, sepsis), moderate to severe bleeding diathesis beginning in infancy or early childhood, poor wound healing, anemia, hepatosplenomegaly, osteopetrosis-like radiologic signs |
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