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Pathology 430/826 Bleeding Diseases David Lillicrap
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Cardiovascular Disease
30% of all deaths in Canada 54% ischemic heart disease 20% stroke 23% heart attack
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Venous Thromboembolism
Incidence 5 cases per 100,000 person/year (<15 years old) 5 cases per 1,000 person/year (80 years old)
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Incidence in General Population
The hemophilias are less frequent than VWD, and have X-linked inheritance Deficient Coagulation Factor Incidence in General Population Chromosome Mode of Inheritance von Willebrand Factor 1:1000 or even more 12 Autosomal dominant Factor VIII (Hemophilia A) 1:10 000 X X-linked recessive Factor IX (Hemophilia B) 1:50 000 The hemophilias are less frequent than VWD where VWD occurs ~1 in 1000 live births or even more frequently than this. In comparision, FVIII deficiency (which causes HA) occurs approximately 1 in live births, or 1 in 5000 male births. FIX deficiency (which causes HB) is more rare than FVIII deficiency, and occurs about 1 in births, or 1 in males. HA and HB are also inherited differently than VWD. VWD is autosomal dominant inheritance, whereas the hemophilias follow sex-linked inheritance, since the FVIII and FIX genes are encoded by the X chromosome.
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Hemophilia in Canada: 2015 Hemophilia A 2,913 Hemophilia B 691
Severe 28% Moderate 10% Mild 62% Hemophilia B 691 Severe 25% Moderate 33% Mild 42%
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1 2 3 Coagulation System
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Extrinsic pathway Thrombin FIIa Fibrin Insoluble end product
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1 2 3 Coagulation System
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Amplification/Propagation
Extrinsic pathway Intrinsic pathway Amplification/Propagation Pathway +ve feedback Thrombin FIIa Fibrin Insoluble end product
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Amplification/Propagation
Extrinsic pathway Intrinsic pathway Amplification/Propagation Pathway Tissue Factor Pathway Inhibitor +ve feedback Thrombin FIIa Fibrin Insoluble end product
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Defective Hemostasis in Hemophilia
Extrinsic pathway Intrinsic pathway No FVIII or FIX Tissue Factor Pathway Inhibitor Common pathway Fibrin Insoluble end product Defective Hemostasis in Hemophilia
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Procoagulant Complex Formation
FIXa FX FVIIIa cofactor Product (next enzyme) Enzyme substrate Phospholipid surface Procoagulant Complex Formation
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Untreated hemarthrosis of the knee in severe hemophilia
This is an example of the type of bleeding that you can see , so here we have an untreated bleed into the knee of a patient with severe hemophilia.
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Critical bleeding events - rare
Clinical Complications of Hemophilia Critical bleeding events - rare central nervous system Severe Hemophilia 5/1,000/yr < 5 yrs 1-2%/yr >55 yrs
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Tsar Nicholas II and Tsarina Alexandra
Tsarevich Alexei, Grand Duchesses, Olga, Tatiana, Maria and Anastasia
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Alexei Nikolaevich, Tsarevich of Russia
2 August 1904 – 17 July 1918
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The Royal Hemophilia Mutation
Rogaev et al. Science October 2009 5’ 3’ 1 2 3 4 5 6 7 8 CTCAAAG ATG G
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Plasma Coagulation Factor Level
The circulating plasma level of FVIII or FIX is related to disease severity NORMAL plasma range: 50 – 150% Severity Plasma Coagulation Factor Level MILD hemophilia 5 - 40% MODERATE hemophilia 1 to 5% SEVERE hemophilia <1% The circulating plasma level of FVIII or FIX is releated to the severity of the disease. So the normal range for FVIII and FIX levels in between %. Once we`re under 50%, there becomes a risk for bleeding. So patients with MILD hemophilia have plasma factor levels between 6 to 40% of normal. MODERATE hemophila between 2 to 5% factor levels. SEVERE hemophilia 1% or less. And these levels will vary slightly depending on the reference youre looking at.
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Protein Prevalence of Severe Factor Deficiency Size of Gene (kb)
Number of Exons FVIII 1 in 10,000 186 kb 26 FIX 1 in 30,000 33 kb 8 VWF 1 in 100,000 175 kb 52 FXI 1 in 1,000,000 23 kb 15 FVII 1 in 1,000,000 12 kb 9 FX 1 in 500,000 22 kb 8 FGA 8kb FGB 8 kb FGG 9 kb FGA 7 FGB 8 FGG 11 Fibrinogen 1 in 1,000,000 FV 1 in 1,000,000 80 kb 25 Subunit A 160 kb Subunit B kb Subunit A Subunit B 12 FXIII 1 in 2,000,000 Prothrombin 1 in 1,000,000 20 kb 14
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Fibrin Clot Formation
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Blood Flow collagen collagen collagen collagen collagen collagen
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Blood Flow VWF VWF VWF VWF VWF collagen collagen collagen collagen
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VWF VWF VWF VWF VWF VWF Blood Flow Platelet adhesion GpIb/VWF collagen
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VWF VWF VWF VWF VWF VWF Blood Flow Platelet Rolling GpIb/VWF
GpVI +21/collagen Blood Flow Platelet adhesion GpIb/VWF VWF VWF VWF VWF collagen collagen VWF collagen collagen VWF
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VWF VWF VWF VWF VWF VWF Blood Flow Stable adhesion
platelet activation aggregation GpIIb/IIIa – fibrinogen/VWF Platelet Rolling GpIb/VWF GpVI +21/collagen Blood Flow Platelet adhesion GpIb/VWF VWF VWF VWF VWF collagen collagen VWF collagen collagen VWF
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Aland Islands from Space: 6,500 islands
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5 10 28 45 52 VWF Gene: Chromosome 12p 178 kbp
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von Willebrand Factor Structure
CK D1 D2 D’D3 D4 C1 C2 C3 C4 C5 C6 VWFpp 740 AA VWF mature subunit 2050 AA D Assembly Composition VWD-C8-TIL-E von Willebrand Factor Structure Y-F Zhou et al. Blood 2012
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The Mature VWF Subunit with Associated Ligands
FVIII P-selectin VWFpp β2 integrins αIIbβ3 αvβ3 ADAMTS13 A1 A2 A3 CK D’D3 D4 C1 C2 C3 C4 C5 C6 GPIbα Collagen VI OPG PSGL-1 β2GPI Ang2 Collagen I Collagen III TSP1 The Mature VWF Subunit with Associated Ligands
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adhesion/aggregation
Atherothrombosis Platelet adhesion/aggregation Venous thrombosis VWF Functions Inflammation Cell proliferation/ apoptosis Angiogenesis Lenting et al. JTH 2012
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Diagnosis of von Willebrand Disease
1. Personal history of excessive mucocutaneous bleeding. Laboratory results consistent with deficiency of normally functional VWF or presence of a dysfunctional VWF protein. 3. Family history of von Willebrand disease.
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Standardized measurement of VWF:Ag VWF:RCo
The Diagnosis of von Willebrand Disease Standardized measurement of VWF:Ag VWF:RCo
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Von Willebrand Disease Classification
(ISTH 2006) Qualitative Variants 20% Type 1 Type 2 Type3 80% 1 per million Quantitative Variants
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ISTH 2006 VWD Classification
Type qualitative traits 2A 2B 2M 2N ~20%
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Endothelial Cell Storage and release from Weibel-Palade Bodies
VWF clearance a) Differential glycan additions b) VWF misfolding Golgi Apparatus Multimer formation Propeptide cleavage Glycan modification Constitutive secretion Endoplasmic reticulum Dimer formation initial glycan additions Receptor-mediated clearance in liver & spleen a) Macrophages b) Sinusoidal endothelium VWF mRNA Processing Gene expression Endothelial Cell Sites of Potential Pathogenic Changes Resulting in Quantitative VWF Traits
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