Lecture 17 - Bleeding Due To Coagulation Defects

Coagulation course ( 5 lectures)

1: Haemostasis & role of platelets 2: Haemostasis, role of coagulation proteins 3: Bleeding disorders/ role of platelets & blood vessels 4: Bleeding disorders due to coagulation defects 5: Thrombophilia

Summary:

Bleeding Abnormalities in

Coag. proteins

Blood vessels

Platelets

inherited acquired Number

Function

Summary Inherited Coagulation Disorders Hemophilia A Hemophilia B VWD, FIX def,.. Acquired Coagulation Disorders Vit K def Liver dis, DIC, Massive transfusion

Hereditary Coagulation Disorders  Inherited

Diseases

Hemophilia A FVIII deficiency Hemophilia B FIX deficiency (Christmas disease) von Willebrand disease VWF deficiency FXIII def, FVII, …. rare

[inherited]

Hemophilia A Hemophilia

than B

A is 5 times more common

Prevalence:

1:10,000 (hemophilia B : 1:50,000)

Hemophilia A (deficiency of factor VIII)

An inherited disease

X- linked

affects males only (females are carriers)

Hemophilia A – mode of inheritance

Nicholas

Hemophilia A  FVIII

gene: Located on the long arm of X chromosome (a big gene = 26 exons)

The disease occurs due to deletion or mutation in the gene [in 33% of cases no family hx found (spontaneous mutation)]

Factor VIII in the Coagulation Cascade

Hemophilia – Clinical manifestations  Joint

& soft tissue bleeds  Excessive bruising  Bleeding following tooth extraction  Haemarthrosis ( bleeding into the joints)  Muscle hematomas

 If

poorly treated, progressive joint deformity  Social, psychological, economical problems

Hemophilia Intra-cerebral hemorrhage: * rare * major cause of death in hemophiliacs

- Hemophilia The clinical severity of the disease correlates with the extent of factor VIII deficiency (level of factor VIII)

Hemophilia-disease severity

< 1%

1-5%

5-20%

severe disease spontaneous bleeding episodes from early life joint deformity & crippling moderate disease post-traumatic bleeding occasional spontaneous episodes mild disease post- traumatic bleeding

Hemophilia Lab findings 1: prolonged APTT 2: normal PT & TT 3: normal bleeding time Hemophilia A Hemophilia B

decreased FVIII decreased FIX

Treatment of Hemophilia Ideally done in a specialized hemophilia center where collaboration between hematologists, dentists, orthopedicians and social workers

-Treatment of Hemophilia Treatment of bleeding episodes: Replacement therapy FVIII concentrate (or F IX in hemophilia B) For Rx of a joint or muscle bleed FVIII up to 20% For operative or post-operative bleed = = 100%

-Treatment of Hemophilia Concept of “ Home treatment” Prophylactic treatment Gene therapy

Complications of Hemophilia Treatment HIV Hepatitis Antibodies (inhibitors) to factor VIII

Hemophilia B Christmas disease (FIX def) Identical to hemophilia A Can only be distinguished by factor assay Rx

Replacement FIX concentrate

von Willebrand Disease von Willebrand Factor (VWF) • a large complex multimeric protein made up of several subunits • it is synthesized by endothelial cells and megakaryocytes • it is stored in “ Weibel-Palade” bodies in endothelial cells and in α granules in platelets

Role of von Willebrand Factor (VWF) • Involved in platelet adhesion to the vessel wall • involved in platelet aggregation • A carrier for Factor VIII c

von Willebrand disease Reduced level or abnormal function of VWF ? Most common inherited bleeding disorder Inherited as autosomal dominant

von Willebrand Disease  Lab

findings: prolonged bleeding time FVIII level is often low APTT may be prolonged Defective platelet aggregation with Ristocetin (in platelet function / aggregation testing)

Treatment of VWD Local

measures to stop bleeding DDAVP ( ADH analogue) Intermediate purity FVIII concentrate Cryoprecipitate

Factor XI deficiency: Autosomal recessive, Heterozygotes 8% in Ashkenazi Jews, variable bleeding tendency; but 1:100,000,000 in general population. Dx: prolonged PTT, normal PT Rx: fresh frozen plasma (FFP).

Contact Factors: XII –deficiency rare (patients do not bleed) paradoxical increased incidence of thrombosis; Prekallikrein and HMWK deficiencies – no bleeding; autosomal recessive. Prolonged APTT

Congenital Factors II, V, X and fibrinogen Deficiencies – prolonged PT and/ or APTT (common pathway) rare; autosomal recessive; bleeding tendency proportionate to severity of biochemical lesion. Rx: FFP and specific concentrates (e.g. for fibrinogen = cryoprecipitate).

Congenital Factor VII Deficiency – prolonged PT and normal PTT variable bleeding tendency incidence 1:500,000 autosomal recessive Rx: FFP and factor VII concentrate.

Factor XIII deficiency Factor XIII - fibrin stabilizing factor with abnormal urea solubility test. Not tested in usual screening tests. Severe cases have delayed bleeding and form keloid scars. Rare; autosomal recessive Rx: cryoprecipitate.

Vitamin K deficiency  Some

coagulation factors are vit K dependent (II, VII, IX, X, Pr C & S) Causes of vit K def: Neonatal/ fetal immaturity Dietary, drugs(warfarin / antibiotics) Hemorrhagic dis of newborn bleeding due to vit K def Diag: prolonged PT, APTT

Bleeding tendency due to Liver disease  With

severe liver disease:

Reduced synthesis of coag. Factors Reduced thrombopoietin production Chronic DIC

Massive Transfusion Syndrome  With

serious blood loss, loss of platelets & coag. Factors  Replaced stored blood lacks viable platelets and factors V &VIII Rx FFP + plts with massive blood transfusion

THE CLINICAL DISTINCTION BETWEEN DISORDERS OF PLATELETS AND DISORDERS OF BLOOD COAGULATION Disorders of Coagulation Disorders of Platelets Petechiae are Rare Deep Dissecting Hematomas are Characteristic •Superficial Ecchymoses are Common; usually Large and Solitary •Hemarthrosis is Common •Positive Family History is Common

Petechiae are Common Deep Dissecting Hematomas are Rare •Superficial Ecchymoses are Characteristic; usually Small and Multiple Hemarthrosis is Rare

•Positive Family History is Rare except for VWD

•80% to 90% of Inherited Forms are in Males

•Relatively more Common in Females