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Pathology 430/826 Bleeding Diseases David Lillicrap.

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Presentation on theme: "Pathology 430/826 Bleeding Diseases David Lillicrap."— Presentation transcript:

1 Pathology 430/826 Bleeding Diseases David Lillicrap

2 Cardiovascular Disease 30% of all deaths in Canada 54% ischemic heart disease 20% stroke 23% heart attack

3 Venous Thromboembolism Incidence 5 cases per 100,000 person/year (<15 years old) 5 cases per 1,000 person/year (80 years old)

4 The hemophilias are less frequent than VWD, and have X-linked inheritance Deficient Coagulation Factor Incidence in General Population ChromosomeMode of Inheritance von Willebrand Factor 1:1000 or even more 12Autosomal dominant Factor VIII (Hemophilia A) 1:10 000XX-linked recessive Factor IX (Hemophilia B) 1:50 000XX-linked recessive

5 Hemophilia in Canada: 2015 Hemophilia A2,913 Severe28% Moderate10% Mild62% Hemophilia B691 Severe25% Moderate33% Mild42%

6 Coagulation System 1 3 2

7 Fibrin Insoluble end product Extrinsic pathway Thrombin FIIa

8 Coagulation System 1 3 2

9 Fibrin Insoluble end product Extrinsic pathwayIntrinsic pathway Amplification/Propagation Pathway Thrombin FIIa +ve feedback

10 Fibrin Insoluble end product Extrinsic pathwayIntrinsic pathway Amplification/Propagation Pathway Thrombin FIIa +ve feedback Tissue Factor Pathway Inhibitor

11 Fibrin Insoluble end product Common pathway Extrinsic pathwayIntrinsic pathway No FVIII or FIX Defective Hemostasis in Hemophilia Tissue Factor Pathway Inhibitor

12 cofactor Phospholipid surface Procoagulant Complex Formation substrate Enzyme Product (next enzyme) FIXa FVIIIa FX

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14 Untreated hemarthrosis of the knee in severe hemophilia

15 Clinical Complications of Hemophilia Critical bleeding events - rare central nervous system Severe Hemophilia 5/1,000/yr < 5 yrs 1-2%/yr >55 yrs

16 Tsar Nicholas II and Tsarina Alexandra Tsarevich Alexei, Grand Duchesses, Olga, Tatiana, Maria and Anastasia

17 2 August 1904 – 17 July 1918 Alexei Nikolaevich, Tsarevich of Russia

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19 The Royal Hemophilia Mutation Rogaev et al. Science October ’5’3’3’ CTCAAAG ATG G

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21 The circulating plasma level of FVIII or FIX is related to disease severity SeverityPlasma Coagulation Factor Level MILD hemophilia % MODERATE hemophilia 1 to 5% SEVERE hemophilia <1% NORMAL plasma range: 50 – 150%

22 ProteinPrevalence of Severe Factor Deficiency Size of Gene (kb) Number of Exons FVIII FIX FXI FVII FX FV Prothrombin 186 kb 23 kb 12 kb FGA 8kb FGB 8 kb FGG 9 kb 80 kb 20 kb Subunit A 160 kb Subunit B 28 kb 1 in 10,000 1 in 30,000 1 in 1,000,000 1 in 500,000 FXIII Fibrinogen 1 in 1,000,000 1 in 2,000,000 1 in 1,000, kb 22 kb 26 VWF 1 in 100, kb Subunit A 15 Subunit B 12 FGA 7 FGB 8 FGG 11

23 Fibrin Clot Formation

24 collagen Blood Flow collagen

25 Blood Flow collagen VWF

26 collagen Platelet adhesion GpIb/VWF Blood Flow

27 VWF collagen Platelet adhesion GpIb/VWF Blood Flow Platelet Rolling GpIb/VWF GpVI +  2  1/collagen

28 VWF collagen Platelet adhesion GpIb/VWF Blood Flow Platelet Rolling GpIb/VWF GpVI +  2  1/collagen Stable adhesion platelet activation aggregation GpIIb/IIIa – fibrinogen/VWF

29 Aland Islands from Space: 6,500 islands

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31 VWF Gene: Chromosome 12p 178 kbp

32 D’D3 A1A1 A1A1 C1 C2 C3 C4 A3A3 A3A3 A2A2 A2A2 D4 C5 C6 CKCK CKCK von Willebrand Factor Structure D2 D1 D Assembly Composition VWD-C8-TIL-E VWFpp 740 AA VWF mature subunit 2050 AA Y-F Zhou et al. Blood 2012

33 D’D3 A1A1 A1A1 C1 C2 C3 C4 A3A3 A3A3 A2A2 A2A2 D4 C5 C6 CKCK CKCK FVIII P-selectin VWFpp β2 integrins GPIbα Collagen VI OPG PSGL-1 β2GPI Ang2 ADAMTS13 Collagen I Collagen III TSP1 αIIbβ3 αvβ3 The Mature VWF Subunit with Associated Ligands

34 VWF Functions Atherothrombosis Venous thrombosis Inflammation Angiogenesis Platelet adhesion/aggregation Cell proliferation/ apoptosis Lenting et al. JTH 2012

35 Diagnosis of von Willebrand Disease 1. Personal history of excessive mucocutaneous bleeding. 2.Laboratory results consistent with deficiency of normally functional VWF or presence of a dysfunctional VWF protein. 3. Family history of von Willebrand disease.

36 The Diagnosis of von Willebrand Disease Standardized measurement of VWF:Ag VWF:RCo

37 Von Willebrand Disease Classification (ISTH 2006) Type 1Type 2Type3 Qualitative Variants Quantitative Variants 20% 80%1 per million

38 ISTH 2006 VWD Classification Type 2 - qualitative traits 2A 2B 2M 2N ~20%

39 Sites of Potential Pathogenic Changes Resulting in Quantitative VWF Traits Gene expression Constitutive secretion Storage and release from Weibel-Palade Bodies VWF clearance a) Differential glycan additions b) VWF misfolding Receptor-mediated clearance in liver & spleen a) Macrophages b) Sinusoidal endothelium VWF mRNA Processing Endoplasmic reticulum Dimer formation initial glycan additions Golgi Apparatus Multimer formation Propeptide cleavage Glycan modification Endothelial Cell


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