Inherited thrombocytopenias with reduced platelet size

Wiskott-Aldrich syndrome

• X-linked recessive disorder
• Associated with eczema and defects in cellular and humoral immunity
• Gene – WAS on chromosome Xp 11.1 which codes for protein WASp is affected (WASp is expressed only on hematopoietic cells)
• Death occurs at early age due to intracranial hemorrhage, infection or lymphoreticular malignancy.
• Treatment-
  • Supportive care- Antibiotics, IVIg replacement
  • Immunosuppression if autoimmune manifestations are seen
  • Splenectomy- To increase the platelet count
  • Hematopoietic stem cell transplantation

Inherited thrombocytopenias with normal platelet size

Congenital amegakaryocytic thrombocytopenia

• Autosomal recessive disorder
• Abnormalities in the expression of thrombopoietin receptor – C-mpl
• May be associated with skeletal abnormalities
• Bone marrow- Megakaryocytes are markedly decreased
• 50% develop aplastic anemia by 5 years of age
• Prognosis- Mortality is close to 100%
• Treatment
  • Stem cell transplantation
  • Transfusion support till HSCT is done.

Thrombocytopenia with absent radii syndrome (TAR)

• Autosomal recessive
• No mutation involving C-mpl
• Mutation in RBM8A gene on 1q21.1
• Lack of response to thrombopoietin in signal transduction pathway of thrombopoietin receptor (C-Mpl)
• Radial aplasia is not associated with aplasia of thumb
• Other associated anomalies
  • Absent ulnae, absent humerii, clinodactyly
  • Hip dislocation, coxavulga, femoral torsion, tibial torsion, abnormal tibiofubular joints
  • Capillary hemangiomas
  • Microcephaly, Hypertelorism, Strabismus
  • Heart defects- ASD, TOF, VSD
  • Genito-urinary anomalies
• Bleeding occurs in infancy and then improves after 1 year
• Cow’s milk allergy is common
• Investigations
  • Hemogram-
    • Thrombocytopenia- Usually <50,000/cmm
    • Leucocyte count is sometimes raised
  • BM- Megakaryocytes are absent. Rest is normal.
• Treatment:
  • Prophylactic use of platelets
  • HSCT if there life threatening bleeding

Inherited thrombocytopenia with increased platelet size (Megathrombocytopenia)

MYH-9 related thrombocytopenia syndromes

• Includes following disorders:
  • May Hegglin anomaly
  • Sebastian syndrome
  • Fechtner syndrome
  • Epstein syndrome
• Autosomal dominant disorder
• Mutation of MYH-9 gene which is located on chromosome 22q, which encodes non-muscle myosin heavy chain 2A which is expressed on platelets, kidney, leucocytes and cochlea.
• Manifestations of platelets and leucocytes are profound, as other organs have other isoforms of deficient protein.
• Abnormal NMMHC-IIA leads to abnormal organization of megakaryocyte cytoskeleton, which results in defective maturation of platelets from pro-platelets
• Features include
  • Giant platelets
  • Basophilic inclusions (Dohle’s bodies) within granulocytes
  • Sensorineural hearing loss
  • Cataract
  • Glomerulonephritis
• Diagnosis is done by DNA sequencing
• Treatment
  • Platelet transfusions during uncontrolled bleeding
  • Angiotensin inhibitors may be given to delay the onset of renal impairment.

Autosomal dominant thrombocytopenia with linkage to chromosome 10

• Defect is located on chromosome 10p11-12
• Mutation of gene FLJ 14813a which encodes a tyrosine kinase of unknown function
• There is incomplete differentiation of megakaryocytes
• Risk of bleeding is proportionate to thrombocytopenia

Grey platelet syndrome

• Autosomal dominant
• Large platelets with deficiency in the number and contain α- granules like fibrinogen, VWF, thrombospondin, β-thromboglobulin and PL factor 4.

Mediterranean macrothrombocytopenia

• Autosomal dominant
• Mutations within GpIb α or Ibβ genes

Jacobsen and Paris Trousseau syndrome

• Autosomal dominant
• Deletions in chromosome 11q 23.3 – 11q24.2 which includes FLI-1 gene. Product of this gene is involved in megakaryopoiesis.
• Clinical features:
  • Trigonocephaly
  • Facial dysmorphisms
  • Heart defects
  • Mental retardation
• Mild to moderate thrombocytopenia with platelet dysfunction
• Bone marrow shows 2 populations of megakaryocytes- Micromegakaryocytes and dysmorphic megakaryocytes
• Diagnosis is done by FISH test

Montreal platelet syndrome

• Associated with spontaneous in vitro PL aggregation

GATA 2 deficiency and related disorders

• GATA2 encodes zinc finger transcription factor that is required for hematopoiesis and lymphatic development
• Following diseases are associated with defect in GATA2 (Now they are considered as 1 disease entity with variable clinical presentation)
  • “MonoMAC” syndrome- Monocytopenia and mycobacterial infection
  • Dendritic cell, Monocyte, B and NK cell lymphoid deficiency
  • Emberger syndrome- Primary lymphedema with myelodysplasia, progressing to AML
  • Familial MDS
• Present with 
  • Recurrent infections
  • Cytopenia
  • Marrow hypocellularity with dysplastic megakaryocytes
• Flow- Decreased B cells and NK cells
• Cytogenetics- Monosomy 7 and trisomy 8 are common
• Other additional clinical findings include
  • Pulmonary alveolar proteinosis
  • Recurrent upper respiratory tract infections
  • Panniculitis
  • Lymphedema
  • Thrombosis
  • Hearing loss
• Treatment
  • HSCT- Familial donor must be screened for GATA2 mutation

Others

• Bernard Soulier syndrome- Refer “Qualitative platelet disorders” chapter
• Type II B VWD- Refer “Von Willebrand disease” chapter