119 Inherited Platelet Disorders Flashcards
Caused by abnormalities in either integrin αIIb (ITGA2B) or β3 (ITGB3), resulting in a profound defect in platelet aggregation and secondary defects in platelet adhesion, secretion, and coagulant activity
Glanzmann thrombasthenia (GT)
Loss of the platelet GPIb/IX/V complex because of recessive variants in GP1BA, GP1BB, or GP9, characterized by giant platelets, thrombocytopenia, and a defect in platelet adhesion to VWF
Bernard-Soulier syndrome (BSS)
The genetic defects may exist in only the genes encoding GPIb or GPIX
Glanzmann Thrombasthenia (GT) classification
- Type I: less than 5% residual αIIbβ3
- Type II: 5% to 20% αIIbβ3
- Variant-type: more than 20% αIIbβ3 but with a qualitative defect preventing function
Approximately 75% of GT patients are type I, 15% have type II, and 10% have variant GT
A correlation between bleeding severity and GT subtype could not be made
Six features contribute to the hemorrhagic diathesis in BS:
- Thrombocytopenia
- Abnormal platelet interactions with vWF
- Abnormal platelet interactions with thrombin
- Abnormal platelet coagulant activity
- Abnormal platelet interactions with P-selectin
- Abnormal platelet interactions with leukocyte integrin αMβ2
Thrombocytopenia is found in nearly all patients, ranging from about 20 × 109/L to nearly normal levels.
The most common symptom in BS
Epistaxis
Also known as LAD-1 variant or LAD-3, caused by recessive variants in FERMT3 (fermitrin family, member 3), coding for the KINDLIN3 protein
Characterized by a hemorrhagic diathesis in combination with a variable predisposition to infections and inflammation without pus formation, poor wound healing, delayed umbilical cord stump detachment, and variable osteopetrosis
FERMT3-Related Functional Thrombasthenia
Rare dominant platelet disorder caused by gain-of-function variants in GPIbα
Defect results in hyperresponsive platelets, patients present with mild to moderate bleeding symptoms, variably enlarged platelets and variable degrees of thrombocytopenia
Platelet-type von Willebrand Disease (PT-VWD)
PT-VWD and VWD-2B share several platelet phenotypes such as an enhanced binding between VWF to GPIb and thrombocytopenia caused by combined defects in platelet production and survival
Enhanced platelet aggregation in response to low concentrations of ristocetin is not corrected by normal plasma. (In type II von Willebrand disease, this abnormality is corrected by normal plasma.)
Caused by rare dominant gain-of-function variants in VWF has enhanced affinity for GPIbα
Von Willebrand disease type 2B (VWD-2B)
PT-VWD and VWD-2B share several platelet phenotypes such as an enhanced binding between VWF to GPIb and thrombocytopenia caused by combined defects in platelet production and survival
Three mechanisms proposed to explain thrombocytopenia in PT-VWD
- Ectopic platelet release in the marrow
- Formation of larger but less (pro)platelets
- Formation of GPIb-VWF positive platelets that are rapidly released from the circulation
The most characteristic laboratory finding in PT-VWD
Enhanced platelet aggregation in response to low concentrations of ristocetin or botrocetin
Possible mechanisms that could explain the thrombocytopenia in VWD2B
- Electron microscopy showed their platelets are larger, with the presence of giant platelets and platelet agglutinates
- In vitro megakaryopoiesis studies using hematopoietic stem cells showed a reduction in proplatelet formation from enlarged swellings and MK with a disorganized demarcation membrane system and abnormal granule distribution
- Platelets from VWD2B patients have a greater response at low ristocetin concentrations
Examples of δ-Storage Pool Deficiency
- Hermansky-Pudlak syndrome
- Chédiak-Higashi syndrome
- Wiskott-Aldrich syndrome
- Others (less frequently)
Characterized by variable oculocutaneous albinism and a bleeding diathesis, and in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency
Defects in the biogenesis of lysosome-related organelles (LRO) form the basis of HPS, including melanosomes in melanocytes, platelet δ granules, and Weibel-Palade bodies in endothelial cells
Patients with δ-SPD as part of the HPS may have severe, or even lethal, hemorrhage
Hermansky-Pudlak syndrome (HPS)
Essential criteria for diagnosis of HPS
- Tyrosinase-positive oculocutaneous albinism
- Delta-storage pool deficiency (δ-SPD) in platelets
Characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency caused by platelet δ-SPD
Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, a life-threatening, hyperinflammatory condition
Chediak-Higashi syndrome
A heterogeneous bleeding disorder characterized by selective deficiency of α granules and their contents, in combination with thrombocytopenia and large platelets
Some patients with GPS also present with splenomegaly and myelofibrosis
Recessive variants in NBEAL2 were found as the cause
Gray platelet syndrome (GPS)
α-Granule membranes form abnormal vesicular structures rather than granules.
May be diagnosed by measuring platelet factor 4 (PF4) and/or β-thromboglobulin in platelets.
Caused by recessive variants in VPS33B and VIPAS39 (or VPS16B), which form a complex, and in the absence of either, platelets lack α granules and the granule-specific membrane protein P-selectin
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome
A rare genetic disorder of lymphocyte cytotoxicity associated with variants in the genes encoding perforin or proteins important for vesicular trafficking and exocytosis
Flow cytometric analyses of platelets, who have recessive STXBP2 (or MUNC18-2) variants, revealed that thrombin-induced secretion from both α and δ granules is impaired
Familial hemophagocytic lymphohistiocytosis (FHLH)
A very rare mild bleeding disorder characterized by an isolated defect in procoagulant activity in platelets and other blood cells, caused by a lack of phosphatidylserine (PS) exposure after activation
Caused by recessive variants in ANO6, which encodes a phospholipid scramblase protein, TMEM16F
Scott syndrome
Bleeding is not primarily mucocutaneous, in contrast to other qualitative platelet disorders
- Serum prothrombin time is abnormal.
- Assays for platelet factor 3 are abnormal.
An inherited disorder characterized at birth by severe thrombocytopenia with reduced megakaryocytes, which evolves into marrow aplasia during childhood
Congenital amegakaryocytic thrombocytopenia (CAMT)
The most common cause of CAMT
Recessive variants in MPL, the gene encoding for the receptor of thrombopoietin (THPO)
Characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia that develops within the first few weeks to months of life but typically improves with age
Have δ-SPD with impaired platelet aggregation and secretion
Thrombocytopenia absent radius (TAR) syndrome
A variant of Jacobsen syndrome, is a rare autosomal dominant disorder characterized by mental retardation, congenital macrothrombocytopenia, giant α granules in a subpopulation (∼15%) of circulating platelets, and dysmegakaryopoiesis in association with deletion of the distal part of either the maternally or paternally derived chromosome 11q23.3–24
Paris-Trousseau (PT) syndrome
Characterized by macrothrombocytopenia and Döhle-like leukocyte inclusions, and some patients also present with chronic kidney disease and nonsyndromic sensory-neural deafness
MYH9-related disorders
Platelet disorder characterized by microthrombocytopenia, which may be life threatening in some patients because of GI hemorrhage or intracranial hemorrhage. Also has recurrent infections, and eczema
Platelets are normal in number, but platelet formation is abnormal, and platelet survival is decreased.
Wiskott-Aldrich syndrome (WAS)
X-linked disorder
Mutations of a Wiskott-Aldrich syndrome protein (WASP) occur in many, but not all, patients with the Wiskott-Aldrich syndrome and X-linked thrombocytopenia.
Autosomal dominant bleeding disorder associated with reduced platelet counts and decreased α-granule proteins as a result of increased plasmin-mediated degradation of these proteins.
The excessive plasmin generation results from increased MK expression of u-PA because of a direct tandem duplication of the u-PA gene (PLAU).
Quebec Platelet Disorder (PLAU)
Developed to identify patients who are likely to have VWD but can be applied in all bleeding disorders
Generates a numerical score from the bleeding history
ISTH-Bleeding Assessment Tool
Dietary culprits that can affect platelet function
- Alcohol
- Caffeine
- Garlic
- Onion
- Ginger
- Herbal supplements
