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Download PATH430-826-week03-BleedingDiseasesLecture2
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Pathology 430/826 Bleeding Diseases (2) David Lillicrap Inherited Factor VIII & IX Deficiencies Hemophilia A & B Platelet Plug Formation Blood Flow VWF collagen VWF collagen VWF collagen VWF Platelet Plug Formation Blood Flow RBC Rheological Effect "marginates" platelets VWF collagen VWF collagen VWF collagen VWF Platelet Plug Formation Anemia Effect (reduced red cell mass - hematocrit) Blood Flow reduced platelet margination VWF collagen VWF collagen VWF collagen VWF Platelet Plug Formation Platelet adhesion Blood Flow VWF collagen VWF-GpIb VWF collagen VWF collagen VWF Platelet Plug Formation Platelet Rolling VWF-GpIb Collagen-GpVI/α2β1 Platelet adhesion Blood Flow VWF collagen VWF-GpIb VWF collagen VWF collagen VWF Platelet Plug Formation Platelet Rolling VWF-GpIb Collagen-GpVI/α2β1 Platelet activation/aggregation Platelet adhesion Blood Flow VWF collagen Fibrinogen/VWF – VWF-GpIb VWF collagen Stable adhesion αIIbβ3 VWF collagen VWF Primary Hemostasis Platelet Participation in Hemostasis Platelet Aggregation Cross-linking of activated GPIIb-IIIa by fibrinogen or VWF Extracellular Matrix-Associated Bleeding Collagen defects - ~30% of total protein mass in mammals 28 different collagens Formation of triple helical structures Collagen Diseases Bone: Osteogenesis imperfecta Skin: Epidermolysis bullosa Bleeding: Ehlers-Danlos Syndrome - 10 types Clinical manifestations Skin and joint hypermobility and bleeding Skin and Joint Hypermobility in Ehlers-Danlos Syndrome Ehlers-Danlos Syndrome Diagnosis Prevalence - 1 in 5,000 • Skin capillary fragility • Evidence of skin/joint hypermobility • Skin biopsy – collagen synthesis analysis • Molecular genetic analysis > 6 different variant forms; > 11 different genes involved Platelet Plug Formation Platelet Rolling VWF-GpIb Collagen-GpVI/α2β1 Platelet activation/aggregation Platelet adhesion Blood Flow VWF collagen Fibrinogen/VWF – VWF-GpIb VWF collagen Stable adhesion αIIbβ3 VWF collagen VWF D1 D2 D’D3 A 1 A 2 A 3 D4 C1 C2 C3 VWFpp VWF mature subunit 740 AA 2050 AA Forms massive (>20 mDa) soluble polymeric strings C4 C5 C6 C K D Assembly Composition VWD-C8-TIL-E von Willebrand Factor Structure Y-F Zhou et al. Blood 2012 FVIII P-selectin VWFpp β2 integrins ADAMTS13 D’D3 A 1 A 2 A 3 αIIbβ3 αvβ3 D4 C1 C2 C3 C4 C5 C6 C K GPIbα Collagen I Collagen VI Collagen III OPG TSP1 PSGL-1 β2GPI Ang2 The Mature VWF Subunit with Associated Ligands Platelet Plug Formation Platelet Rolling VWF-GpIb Collagen-GpVI/α2β1 Platelet activation/aggregation Platelet adhesion Blood Flow VWF collagen Fibrinogen/VWF – VWF-GpIb VWF collagen Stable adhesion αIIbβ3 VWF collagen VWF Platelet Structure Resting Platelet George J. Lancet 2000; 355:1531-1539 Activated Platelet Platelet Pathologies 1. Reduction in Number - Thrombocytopenia • Reduced production • Accelerated clearance from the blood 2. Deficient/Defective Function • Surface membrane pathologies • Granule pathologies • Cytoskeletal pathologies Megakaryocyte Normal Blood Smear Pathological Blood Smear Laboratory Interpretation • Thrombocytopenia • Large platelets • Very poor binding to von Willebrand factor VWF VWF Glycoprotein Ib/V/IX Receptor Complex on Platelets (25,000 copies/platelet) Mutations of the GpIb/V/IX Complex Cause Bernard-Soulier Syndrome Mutations of the GpIb/V/IX Complex Cause Bernard-Soulier Syndrome GPIbα Autosomal recessive mutations of - GPIbβ GPIX Confirm with flow cytometry Alpha Granule Deficiency: Gray Platelet Syndrome Transmission Electron Microscopy of : a) normal platelet revealing alpha granules (arrowheads) and ; b) GPS with absent alpha granules
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