Download 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)
• Increase in identified number of people with
rare clotting factor deficiencies or platelet
function disorders (WFH)
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 membraneassociated 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
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
Syndromes associated with GPIb-IX-V
Bernard-Soulier syndrome:
– Autosomal recessive
– Macrothrombocytopenia
– Deficient aggregation with ristocetin
– Normal vWF multimeric pattern in plasma
– Loss-of-function mutations
Syndromes associated with GPIb-IX-V
Platelet- type vWD
– Autosomal dominant
– Thrombocytopenia
– Enhanced aggregation with ristocetin
– Loss of HMW vWF multimers from plasma
– Gain-of-function mutations
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
Hermansky – Pudlak syndrome
• Autosomal recessive
• Presentation:
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δ-granule deficiency
Oculocutaneous albinism
Pulmonary fibrosis
Granulomatous colitis
• Defects in three cytoplasmic organelles:
– Platelet dense granules
– Melanosomes
– lysosomes
MYH9-Related Disorders
• Autosomal dominant disorders of
macothrombocytopenia, platelet dysfunction,
and leuKocyte inclusions
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May-Hegglin Anomaly
Sebastian syndrome
Fechtner syndrome
Epstein syndrome
• Clinical aspects:
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Mild bleeding diathesis
Renal disease
Hearing loss
cataracts
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:
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–
–
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Epithelial cell organization
Cell-matrix adhesion
Cell migration and differentiation
Tissue morphogenesis
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
Glanzmann Thrombasthenia (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
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
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
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
Hematological Work Up
• CBC, Blood group, Ferritin, aPTT, PT, vWF Ag,
RiCof
• If abnormal : Specific Coagulation Assays
• If normal: suspect platelet dysfunction
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
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
• 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 alloimmunization and refractoriness develop