The Basics of Hemophilia

Hemostatic System Blood vessels Platelets Plasma coagulation system Proteolytic or Fibrinolytic system

How Bleeding Stops Vasoconstriction Platelet plug formation Clotting cascade activated to form fibrin clot

3. FACTOR DEFICIENCIES Disorders of coagulation I: Inherited Excessive bleeding may occur as a result of an inherited defect of one of the coagulation factors or other protein involved in coagulation.

Types of Bleeding Disorders Caused By Coagulation Factor Deficiencies Hemophilia A (factor VIII deficiency) Hemophilia B (factor IX deficiency) Hemophilia C (factor XI deficiency) von Willebrand Disease (vWD) Other

What is Hemophilia? Hemophilia is an inherited bleeding disorder in which there is a deficiency or lack of factor VIII (hemophilia A), factor IX (hemophilia B) or factor XI (hemophilia C)

Inheritance of Hemophilia Hemophilia A and B are X-linked recessive disorders Hemophilia is typically expressed in males and carried by females Severity level is consistent between family members ~30 % of cases of hemophilia are new mutations

Detection of Hemophilia Family history Symptoms –Bruising –Bleeding with circumcision –Muscle, joint, or soft tissue bleeding Hemostatic challenges –Surgery –Dental work –Trauma, accidents Laboratory testing

Degrees of Severity of Hemophilia Normal factor VIII or IX level = % Mild hemophilia –factor VIII or IX level = 6-50% Moderate hemophilia –factor VIII or IX level = 1-5% Severe hemophilia –factor VIII or IX level = <1%

Hemophilia A: 20.6 per 100,000 males –Severe: 50-60% Hemophilia B: 5.3 per 100,000 males –Severe: 44% U. S. Incidence of Hemophilia

Types of Bleeds Joint bleeding - hemarthrosis Muscle hemorrhage Soft tissue Life threatening-bleeding Other

Joint or Muscle Bleeding Symptoms –Tingling or bubbling sensation –Stiffness –Warmth –Pain –Unusual limb position

Life-Threatening Bleeding Head / Intracranial –Nausea, vomiting, headache, drowsiness, confusion, visual changes, loss of consciousness Neck and Throat Abdominal / GI

Other Bleeding Episodes Mouth bleeding Nose bleeding Scrapes and/or minor cuts Menorrhagia

Complications of Bleeding Flexion contractures Muscle atrophy Joint arthritis / arthropathy Chronic pain Neurologic impairment

Treatment of Hemophilia Replacement of missing clotting protein –On demand –Prophylaxis Antifibrinolytic Agents Others

Factor VIII Concentrate Intravenous infusion –IV push –Continuous infusion Dose varies depending on type of bleeding Half-life 8-12 hours Each unit infused raises serum factor VIII level by 2 %

Factor IX Concentrate Intravenous infusion –IV push –Continuous infusion Dose varies depending on type of bleeding Half-life hours Each unit infused raises serum factor IX level by 1%

History of Clotting Factor Concentrates Prior to 1950: whole blood 1952: Hemophilia A distinguished from B : FFP and Cryoprecipitate (IIIV, IIIX, I, VWF) Early 1970s: Commercial plasma-derived factor concentrates Mid-late 1970’s: Home infusion practices 1981: First AIDS death in the Hemophilia community

Complications of Treatment Inhibitors/Antibody development Hepatitis A Hepatitis B Hepatitis C HIV

Inhibitors Definition –IgG antibody to infused factor VIII or IX concentrates, which occurs after exposure to the extraneous VIII or IX protein. Prevalence –20-30% of patients with severe hemophilia A –1-4% of patients with severe hemophilia B

Hepatitis Hepatitis A - small risk of transmission –Vaccination recommended Hepatitis B - no transmissions since 1985 –Vaccination recommended Hepatitis C - no transmissions since 1990 –~90% of patients receiving factor concentrates prior to 1985 are HCV antibody positive

Human Immunodeficiency Virus No transmissions of HIV through factor concentrates since 1985 due to viral inactivation procedures

General points: Also known as Christmas disease. Females are almost exclusively asymptomatic carriers of the disorder, and may have inherited it from either their mother or father. When a blood vessel is injured, a temporary clot does form, but the missing coagulation factors prevent fibrin formation which is necessary to maintain the blood clot. Thus a haemophiliac does not bleed more intensely than a normal person, but for a much longer amount of time.

In severe haemophiliacs even a minor injury could result in blood loss lasting days, weeks, or not ever healing completely. The critical risk here is with normally small bleeds which due to missing factor VIII take long times to heal.

Laboratory features: Prolonged activated partial thromboplastin lime (APTT). Normal prothrombin time (PT). Normal bleeding time (BT). Plasma factor VIII or IX reduced Carriers have factor VIII or IX approximately 50% of normal. DNA analysis is helpful in carrier detection and counselling.

Von Willebrand factor level is normal. A family history is frequently present, although not essential.family history Recently, genetic testing has been made available to determine an individual's risk of attaining or passing on Haemophilia. A very small minority of patients have antibodies against factor VIII and XI that impair its functioning. Management of these patients is more complicated.antibodies

Haemophilia C Hemophaelia C was first discovered in a young Ashkenazic Jewish American in the 1950s. Haemophilia C is a mild form of haemophilia affecting both sexes.haemophilia However, it predominantly occurs in Jews of Ashkenazi descent.Ashkenazi It is the fourth most common coagulation disorder after von Willebrand's disease and haemophilia A and B.coagulation von Willebrand's diseasehaemophiliaAB

Von Willebrand disease Family of bleeding disorders Caused by a deficiency or an abnormality of von Willebrand Factor It arises from a qualitative or quantitative deficiency of von Willebrand factorvon Willebrand factor It is known to affect humans and dogs. There are four types of hereditary vWD.hereditary The disease is more frequent than haemophilia A. Males and females are affected equally.

vWF Production Vascular endothelial cells Megakaryocytes Most vWF is secreted Some vWF is stored –Endothelial cells –Alpha granules of platelets

Release stimuli (EC) –Thrombin –Histamine –Fibrin –C5b-9 (complement membrane attack complex) Release stimuli (platelets) –Thrombin –ADP –Collagen

vWF Function Adhesion –Mediates the adhesion of platelets to sites of vascular injury (subendothelium) –Mediates platelet to platelet interaction Binds GPIb and GPIIb-IIIa on activated platelets Stabilizes the hemostatic plug against shear forces vW Factor Functions in Hemostasis Carrier protein for Factor VIII (FVIII) –Protects FVIII from proteolytic degradation –Localizes FVIII to the site of vascular injury

vWD History 1931: Erik von Willebrand described novel bleeding disorder –Prolonged BT and normal platelet count –Mucosal bleeding –Both sexes affected 1950s: Prolonged BT associated with reduced FVIII 1970s: Discovery of vWF 1980s: vWF gene cloned

Most frequent inherited bleeding disorder Autosomal inheritance pattern –Males and females are affected equally

Clinical Manifestations Most with the disease have few or no symptoms For most with symptoms, it is a mild manageable bleeding disorder with clinically severe hemorrhage only with trauma or surgery The various types of vWD present with varying degrees of bleeding tendency (typically from mucous membranes (mouth. nose bleeds, bruising, menorrhagia which is heavy menstrual periods (in women) and blood loss during childbirth (rare) may occur).bleeding tendencybruising heavy menstrual periodschildbirth Excess blood loss following trauma or surgery. Death may occur.