Bleeding Disorders JANUARY 19, 2012 Erin M. Kwolek

3 important questions… Is the bleeding significant? Is the bleeding likely related to an underlying health problem or to medication/chemical ingestion? Is there a family history of a bleeding disorder?

Important historical information The nature of bruising Site of bleeding Bleeding with trauma Duration of bleeding tendency General health Drug and chemical ingestion Family history of bleeding

Bleeding/Bruising Platelets Vascular System Coagulation Proteins

Bleeding/Bruising Platelets Vascular System Coagulation Proteins Congenital Acquired

hemophilia 1.Hemophilia 2.Porphyria 3.HIV/AIDS 4.Smallpox 5.Plague 6.Cholera 7.Tuberculosis 8.Syphillis 9.Influenza 10.Malaria 11.Yellow Fever 12.Irish Potato Blight

Hemophilia A history Talmud – babies did not have to be circumcised if two brothers had died from the procedure 1803 – “hemorrhagic disposition existing in certain families” hemophilia

Hemophilia severity Factor VII or IX levelSeverityType of bleeding <0.01 IU/mLSevereSpontaneous, minimal trauma, young age 0.01 – 0.05 IU/mL (1-5%) ModerateWith trauma or surgery, can be spontaneous 0.06 – 0.40 IU/mL (6-40%) MildOnly with trauma or surgery, can present in adulthood

Hemophilia A Factor VIII 1:10,000 Classic hemophilia, Royal disease

Hemophilia B Factor iX 1:60,000 Christmas disease

Hemophilia treatment Replace missing clotting factors Education and lifestyle On demand vs. Prophylactic

Clotting factors in canada ProductIntroduction in Canada Fresh whole blood1947 Cryoprecipitate (Factor VIII)1965 Factor VIII (lyophilized, unheated)1968 Factor VIII (lyophilized, dry heat-treated) Factor IX (lyophilized, dry heat-treated) 1985 Factor VIII (viral inactivation: vapour heat, solvent detergent) 1987 High purity factor VIII (monoclonal antibody purified) Purity factor IX GE recombinant factor VIII concentrate GE recombinant factor IX concentrate

Von willebrand Von Willebrand factor is made and stored in endothelial cells Anchors platelets to subendothelium Factor is made up of protein multimers – the more repeating units the “stickier” (more effective) the factor is Stabilizes factor VIII in plasma

VW Dx severity TYPE 1 – partial quantitative deficiency 80% of people with VW Dx have type 180% of people with VW Dx have type 1 TYPE 2 – qualitative defect TYPE 3 – virtually complete quantitative deficiency Very rareVery rare First type describedFirst type described Variable expressivity and incomplete penetrance

Von willebrand treatment Exogenous - Desmopressin ~3x increase in plasma VWF and factor VIII~3x increase in plasma VWF and factor VIII Not useful if qualitative abnormality (type 2)Not useful if qualitative abnormality (type 2) Not useful if complete deficiency (type 3)Not useful if complete deficiency (type 3) Endogenous – factors Plasma derived VWF concentrate – contains VWF and factor VIIIPlasma derived VWF concentrate – contains VWF and factor VIII

Hemophilia AHemophilia BVon Willebrand Inheritance X-linked autosomal dominant Deficiency Factor VIIIFactor IVVW factor, VIIIC Bleeding sites muscle, joint mucous membranes, skin, menstrual PT normal PTT prolonged prolonged or normal Bleeding time normal prolonged or normal Factor VIII activity lownormallow or normal VW factor antigen normal low VW factor activity normal low Factor IX normallownormal Platelet aggregation normal

Hemophilia AHemophilia BVon Willebrand Inheritance X-linked autosomal dominant Deficiency Factor VIIIFactor IVVW factor, VIIIC Bleeding sites muscle, joint mucous membranes, skin, menstrual PT normal PTT prolonged prolonged or normal Bleeding time normal prolonged or normal Factor VIII activity lownormallow or normal VW factor antigen normal low VW factor activity normal low Factor IX normallownormal Platelet aggregation normal

Hemorrhagic disease of the newborn Normal PTT, prolonged PT VKDB – early, classic, late Prophylactic Vitamin K Intracranial VKDB Vitamin K Deficiency Child/AdultNewborn

Bleeding/Bruising Platelets Thrombocytopenia Quantitative Defect Disordered Function Qualitative Defect Congenital Acquired Vascular System Coagulation Proteins

< 10 severe mucosal/internal bleeding< 10 severe mucosal/internal bleeding petechiae, purpura, ecchymoses10-30 petechiae, purpura, ecchymoses easy bruising30-50 easy bruising > 50 asymptomatic> 50 asymptomatic

Thrombocytopenia Decreased production Increased destruction Abnormal sequestration Normal value – x 10 9 /L Lifespan 7-10d

Thrombocytopenia decreased production Toxins/drugs/alcohol Aplastic anemia Intrinsic bone marrow Displacement Nutritional deficiency Hereditary thrombocytopenias

Thrombocytopenia Increased destruction Auto Immune - ITP

Thrombocytopenia non-immune DICTTPVasculitisHELLP

DIC Activation of coagulation – failure of homeostasis with bleeding and/or thrombosis; consumption of clotting factors and platelets InfectionTrauma Abnormal endothelial surface Cancer Obstetrical complications

Thrombocytopenia Increased sequestration Splenomegaly

Platelet dysfunction Congenital causes are rare! Glanzmann thrombastheniaGlanzmann thrombasthenia Glycoprotein IIb/IIIaGlycoprotein IIb/IIIa Bernard-Soulier syndromeBernard-Soulier syndrome Glycoprotein Ib/IX/VGlycoprotein Ib/IX/VAcquired DrugsDrugs Renal diseaseRenal disease Bone marrow disordersBone marrow disorders

3 important questions… Is the bleeding significant? Is the bleeding likely related to an underlying health problem or to medication/chemical ingestion? Is there a family history of a bleeding disorder?