119 Inherited Platelet Disorders

Question 1

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

Answer 1

Glanzmann thrombasthenia (GT)

Question 2

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

Answer 2

Bernard-Soulier syndrome (BSS)

The genetic defects may exist in only the genes encoding GPIb or GPIX

Question 3

Glanzmann Thrombasthenia (GT) classification

Answer 3

• 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

Question 4

Six features contribute to the hemorrhagic diathesis in BS:

Answer 4

• 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.

Question 5

The most common symptom in BS

Answer 5

Epistaxis

Question 6

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

Answer 6

FERMT3-Related Functional Thrombasthenia

Question 7

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

Answer 7

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.)

Question 8

Caused by rare dominant gain-of-function variants in VWF has enhanced affinity for GPIbα

Answer 8

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

Question 9

Three mechanisms proposed to explain thrombocytopenia in PT-VWD

Answer 9

1. Ectopic platelet release in the marrow
2. Formation of larger but less (pro)platelets
3. Formation of GPIb-VWF positive platelets that are rapidly released from the circulation

Question 10

The most characteristic laboratory finding in PT-VWD

Answer 10

Enhanced platelet aggregation in response to low concentrations of ristocetin or botrocetin

Question 11

Possible mechanisms that could explain the thrombocytopenia in VWD2B

Answer 11

1. Electron microscopy showed their platelets are larger, with the presence of giant platelets and platelet agglutinates
2. 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
3. Platelets from VWD2B patients have a greater response at low ristocetin concentrations

Question 12

Examples of δ-Storage Pool Deficiency

Answer 12

• Hermansky-Pudlak syndrome
• Chédiak-Higashi syndrome
• Wiskott-Aldrich syndrome
• Others (less frequently)

Question 13

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

Answer 13

Hermansky-Pudlak syndrome (HPS)

Question 14

Essential criteria for diagnosis of HPS

Answer 14

• Tyrosinase-positive oculocutaneous albinism
• Delta-storage pool deficiency (δ-SPD) in platelets

Question 15

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

Answer 15

Chediak-Higashi syndrome

Question 16

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

Answer 16

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.

Question 17

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

Answer 17

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome

Question 18

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

Answer 18

Familial hemophagocytic lymphohistiocytosis (FHLH)

Question 19

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

Answer 19

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.

Question 20

An inherited disorder characterized at birth by severe thrombocytopenia with reduced megakaryocytes, which evolves into marrow aplasia during childhood

Answer 20

Congenital amegakaryocytic thrombocytopenia (CAMT)

Question 21

The most common cause of CAMT

Answer 21

Recessive variants in MPL, the gene encoding for the receptor of thrombopoietin (THPO)

Question 22

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

Answer 22

Thrombocytopenia absent radius (TAR) syndrome

Question 23

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

Answer 23

Paris-Trousseau (PT) syndrome

Question 24

Characterized by macrothrombocytopenia and Döhle-like leukocyte inclusions, and some patients also present with chronic kidney disease and nonsyndromic sensory-neural deafness

Answer 24

MYH9-related disorders

Question 25

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.

Answer 25

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.

Question 26

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).

Answer 26

Quebec Platelet Disorder (PLAU)

Question 27

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

Answer 27

ISTH-Bleeding Assessment Tool

Question 28

Dietary culprits that can affect platelet function

Answer 28

• Alcohol
• Caffeine
• Garlic
• Onion
• Ginger
• Herbal supplements