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Rare Bleeding Disorders

Rare Bleeding Disorders. Dr Joseph MAKDESSI TYR 31-07-2010. Clotting factor deficiencies (I, II, V, combined V & VIII, VII, X, XI, XIII) Platelet function disorders (e.g. Glanzmann Thrombasthenia , Bernard- Soulier Syndrome)

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Rare Bleeding Disorders

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  1. Rare Bleeding Disorders Dr Joseph MAKDESSI TYR 31-07-2010

  2. Clotting factor deficiencies (I, II, V, combined V & VIII, VII, X, XI, XIII) • Platelet function disorders (e.g. GlanzmannThrombasthenia, Bernard-Soulier Syndrome) • Increase in identified number of people with rare clotting factor deficiencies or platelet function disorders (WFH)

  3. GPIb-IX-V Complex • In 1948 Bernard & Soulier described a young man with a severe bleeding disorder, prolonged BT, thrombocytopenia and large platelets • BSS platelets fail to aggregate with ristocetin or adhere to blood vessel subendothelium • BSS platelets fail to express major membrane-associated glycoproteins: GPIbα, GPIbβ, IX and V • GPIb-IX-V complex is the receptor for Von Willebrand factor plus other adhesive proteins , and receptors, and thrombin

  4. Why the clinical effect • Macrothrombocytopenia: Megakaryocyte defects in the formation of demarcation membranes and proplatelet formation • Clinical bleeding: failure of platelets to adhere to VWF ligands in damaged vessel wall subendothelium

  5. Syndromes associated with GPIb-IX-V Bernard-Soulier syndrome: • Autosomal recessive • Macrothrombocytopenia • Deficient aggregation with ristocetin • Normal vWFmultimeric pattern in plasma • Loss-of-function mutations

  6. Syndromes associated with GPIb-IX-V Platelet- type vWD • Autosomal dominant • Thrombocytopenia • Enhanced aggregation with ristocetin • Loss of HMW vWFmultimers from plasma • Gain-of-function mutations

  7. Dense Granule deficiency • Mild to moderate mucocutaneous bleeding • Non syndromic • Associated with pigment abnormalities: • Hermansky-Pudlak syndrome • Chediak-Higashi syndrome • Griscelli syndrome • Associated with other inherited disorder • familial myeloid leukemia • Combined α,δ-granule deficiency • Acquired deficiencies

  8. Hermansky – Pudlak syndrome • Autosomal recessive • Presentation: • δ-granule deficiency • Oculocutaneous albinism • Pulmonary fibrosis • Granulomatous colitis • Defects in three cytoplasmic organelles: • Platelet dense granules • Melanosomes • lysosomes

  9. MYH9-Related Disorders • Autosomal dominant disorders of macothrombocytopenia, platelet dysfunction, and leuKocyte inclusions • May-Hegglin Anomaly • Sebastian syndrome • Fechtner syndrome • Epstein syndrome • Clinical aspects: • Mild bleeding diathesis • Renal disease • Hearing loss • cataracts

  10. Why The Clinical Effects • Macrothrombocytopenia: disordered cytoskeleton affecting proplatelet formation • Platelet dysfunction: abnormal cytoskeletal reorganization and shape change • Other organ dysfunction may be related to defects in: • Epithelial cell organization • Cell-matrix adhesion • Cell migration and differentiation • Tissue morphogenesis

  11. Inherited Platelet Disorders • Study of these rare platelet disorders: • Has identified specific molecular defects • Reveals the physiology of the normal • Understanding the basic mechanisms: • May explain unusual syndromic associations • Improves our understanding of more common diseases • May help to identify new therapeutic targets

  12. GlanzmannThrombasthenia (GT) • It was first described by Glanzmann in 1918 as hereditary hemorrhagic thrombasthenia • It is an autosomal, recessive, bleeding syndrome affecting megakaryocyte lineage • It is characterized by lack of platelet aggregation • It is moderate to severe disorder with mainly mucocutaneous bleeding

  13. Cell Biology • In GT, platelets fail to aggregate in response to all natural agonists,although they undergo normal shape change • Thrombasthenic platelets can also adhere to exposed subendothelial matrix and undergo exocytosis of storage granules • The inability of the platelets to bind these adhesive proteins explains the platelet phenotype in GT

  14. Epidemiology • GT is a rare disease with an estimated prevalence of 1/million • The disease is known to have a higher prevalence in communities where consanguinity is common • Examples of these communities include: Indians, Iranians, Iraki Jews, Palestinian and Jordanian Arabs, French gypsies • GT related bleeding is more common in females, probably due to menorrhagia

  15. Inheritance • GT is an autosomal recessive bleeding disorder • Heterozygote individuals are usually asymptomatic carriers • Heterozygote couples may have a homozygote offspring who will have moderate to severe disease

  16. Hematological Work Up • CBC, Blood group, Ferritin, aPTT, PT, vWF Ag, RiCof • If abnormal : Specific Coagulation Assays • If normal: suspect platelet dysfunction

  17. Platelet Function Tests • Prolonged BT or abnormal PFA 100 closure time • Defective aggregation with ADP, thrombin, epinephrin or collagen alone or in combination • Defective clot retraction test • Deficiency of αIIbβ3 in new patients should always be demonstrated by specific monoclonal antibodies using flow cytometry

  18. Transfusion in GT • Patients with GT may have frequent transfusions throughout their lives • They may be more exposed to transfusion complications mainly: transmission of viral diseases and Bacteria. • Immunological complications: • Allergy and anaphylaxis • Platelet isoantibody formation and refractoriness

  19. To avoid these complications the following requirements should be considered whenever possible: • Pathogen inactivated platelets • Leucoreduced cellular blood components • Reduction of plasma volume in RBCs and Platelets concentrates by the use of additive solutions • Use of HLA, HPA matched platelets, or cross matched platelets whenever platelet allo-immunization and refractoriness develop

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