Hemophilia A Quiz

Coagulation Disorders

• Coagulation disorders are conditions affecting the blood's ability to clot properly.

Inherited Coagulation Disorders: Overview

• Hemophilia:
  • Hemophilia A – deficient factor VIII.
  • Hemophilia B – deficient factor IX.
• von Willebrand's Disease:
  • Types 1-3 – lack/inadequate production of von Willebrand factor (vWF).

Hemophilia

• Also known as "love of bleeding".
• Bleeding manifestations of both Hemophilia A and B are indistinguishable clinically.
• Some infants are asymptomatic until experiencing trauma.
• Bruising can occur easily in early childhood.
• Spontaneous bleeding commonly affects deep tissues (joints, muscles, soft tissues).
• Life-threatening bleeding can result from trauma or surgery.
• Long-term bleeding problems can be a consequence.

Hemophilia A

• Bleeding due to a deficiency in factor VIII coagulant activity.
• Bleeding severity is related to factor VIII blood levels
• Low levels of factor VIII (less than 1 iu/dL)
• Common bleeding complications include frequent joint or muscle bleeding.
• X-linked recessive Inheritance. Males are affected, females are carriers.
• Mutation/absence of factor VIII gene.

Hemophilia B

• Inheritance and clinical features are similar to Hemophilia A.
• Factor IX deficiency.
• Distinguishable from Hemophilia A specifically by coagulation assays.
  • Incidence - 1/5 of Hemophilia A.
  • Carriers and prenatal diagnosis are similar to Hemophilia A.
  • Factor IX levels can be low at birth, taking approximately six months to reach normal levels, thereby impacting umbilical cord blood sampling.

Clinical Features of Hemophilia A

• Infants may develop excess joint and soft tissue bleeds when becoming more active.
• Prolonged bleeding can occur after dental extractions.
• Recurrent and painful joint bleeds.
• Poorly treated hematomas can lead to joint deformity and disablement during activities like walking.
• Hemophilic pseudo-tumors are rare but significant complications, characterized by progressive cystic swelling in muscles or bones due to repeated bleeding.
• Hematuria.
• Gastrointestinal bleeding.

Recurrent Hemarthrosis

• Can cause joint deformity and disability.

Severity of Hemophilia A

• This relates to factor VIII levels in the blood.
  • Severe – Factor VIII level 0-1 iu/dL: spontaneous bleeding, severe bleeding.
  • Moderate – Factor VIII level 2-5 iu/dL: few bleeds, hemarthroses, mainly traumatic.
  • Mild – Factor VIII level 5-30 iu/dL: post-traumatic, post-surgical, post-dental extraction bleeds; few occurrences.

Coagulation Pathway

• Intrinsic pathway (aPTT).
• Extrinsic pathway (PT).
• Common pathway.

Laboratory Investigations (Hemostasis Tests) for HA

• Includes:
  • Complete blood count (CBC).
  • Prothrombin time (PT).
  • Partial thromboplastin time (PTT).
  • Bleeding time (BT).
• In Hemophilia A and B:
  • PTT is prolonged, while PT and BT are normal.
• Mixing studies are essential if PTT is prolonged to detect factor deficiencies.
• Factor VIII activity levels below 40% of normal.
• Molecular genotyping confirms diagnosis.

Other Laboratory Investigation: Carrier Detection and Antenatal Diagnosis

• Measuring plasma factor VIII levels.
• DNA probes to detect mutations in carriers.
• Fetal DNA analysis using 8-10 weeks gestation biopsies.
• Antenatal diagnosis using fetal blood samples at 16-20 weeks gestation through ultrasound-guided needle aspiration.

Treatments

• Factor VIII replacement therapy using recombinant factor or frozen plasma concentrate.
• Desmopressin – a synthetic vasopressin analogue that stimulates FVIII and vWF release from endothelial cells.
• Prophylactic treatments with stored factor VIII at home can help reduce cerebral and muscle bleeds, hospitalizations, and improve patients' quality of life.
• Social and physiological care.

Non-Genetic Form of Hemophilia A

• Acquired by autoantibodies against factor VIII.
• Associated with cancers, autoimmune disorders, or pregnancy.

von Willebrand's Disease

• Abnormalities due to either reduced levels or abnormal vWF function via point mutations or major deletions.
• vWF is a large protein (300 kDa) forming multimers.
• Autosomal dominant inheritance
• Typically involves mucous membrane bleeding (nose, gum bleeding), bleeding after dental extractions, and post-traumatic hemorrhage.
• Variable severity depending on the type of vWD.
• vWF promotes platelet adhesion to damaged endothelium and subsequent aggregation.
• Acts as a carrier for factor VIII, preventing premature destruction of factor VIII, thus reducing factor VIII in vWD disease.
• Three main types:
  • Type 1 – Reduced vWF levels.
  • Type 2 – Abnormal vWF protein function.
  • Type 3 – Very low or no vWF levels, most severe.
  • Type 2 sub-types (2A, 2B,2M, 2N) with specific malfunctions and consequences.
• Laboratory findings include prolonged bleeding time, low factor VIII, and prolonged aPTT. Low vWF, defective platelet aggregation.

Laboratory Findings in Hemostatic Tests for vWD

- Prolonged bleeding time
- Low factor VIII
- Prolonged aPTT
- Low vWF
- Defective platelet aggregation
- Normal platelet count (mostly, except in type 2B)

Specialized Laboratory Investigations for vWF

• vWF:Ag (immunoassay) – Measures the concentration of vWF protein in plasma.
• vWF:RCo (functional assay) – Measures vWF interaction with normal platelets.

Treatments for vWD

• Antifibrinolytic agents (type 2B).
• Desmopressin (Type 1 vWD).
• Factor VIII and vWF infusions (very low vWF levels).

Hemophilia A vs. vWD Differences

• Gender: Hemophilia A mostly affects males, while vWD affects both genders equally.
• Bleeding symptoms: Hemophilia A commonly causes deep tissue bleeding (joints, internal organs), whereas vWD predominantly causes mucosal bleeding (nose, mouth, gums), and less often deep tissue bleeding.

Acquired Coagulation

• More common than inherited disorders.
• Involves multiple coagulation factor deficiencies.

Vitamin K Deficiency

• Causes: Inadequate diet, malabsorption, and inhibition by drugs (e.g., warfarin).
• Effects: Decreased functional activity of factors II, VII, IX, and X and proteins C and S, possibly leading to hemorrhagic disease of the newborn.

Hemorrhagic Disease of the Newborn

• Vitamin K deficiency due to:
  • Immature liver (incomplete absorption).
  • Lack of gut bacteria (synthesis impairment).
  • Low breast milk content Vitamin K
  • Leads to Hemorrhage.
• Laboratory findings:
  • Prolonged PT and aPTT.
  • Normal platelet count and fibrinogen.
  • Deficient vitamin K-dependent clotting factors (II, VII, IX, X).
• Treatments:
  • Vitamin K supplementation.

Vitamin K Deficiency in Liver Disease

• Due to obstructive jaundice, pancreatic, or small bowel disease.
• Prolonged PT and aPTT.
• Normal platelet count and fibrinogen.
• Deficient vitamin K-dependent clotting factors (II, VII, IX, X).
• Treatment: Oral Vitamin K.

Hemostasis Disorders in Liver Disease

• Impaired vitamin K absorption.
• Reduced synthesis of coagulation factors.
• Fibrinogen synthesis abnormalities (dysfibrinogenaemia).
• Thrombocytopenia (reduced thrombopoietin).
• Increased coagulation inhibitors.
• Disseminated intravascular coagulation (DIC)

Liver Disease (Causes)

• Biliary obstruction – Impaired vitamin K absorption and reduced coagulation factor synthesis.
• Severe hepatocellular disease – Abnormalities in fibrinogen synthesis (dysfibrinogenaemia), reduced thrombopoietin production leading to thrombocytopenia, and DIC.

Disseminated Intravascular Coagulation (DIC)

• Widespread fibrin deposition within blood vessels, excessive consumption of coagulation factors, and platelets.
• Result of various disorders releasing procoagulants, injuring endothelium, and initiating coagulation pathways.
• Various causes of procoagulants release can include:
  • Amniotic fluid embolism
  • Liver disease
  • Placental separation
  • Cancer cells
  • Snake bites
  • Endothelial injuries
  • Infections (immune responses/vasculitis)
  • Severe burns
• Laboratory findings include:
  • Low platelet counts
  • Prolonged PT, aPTT, and TT
  • Elevated D-dimer or fibrin degradation products (FDPs).
  • Hemolytic anemia and red blood cell (RBC) fragmentation.
• Treatments include:
  • Fresh frozen plasma or plasma concentrates.
  • Red blood cell (RBC) transfusions.
  • Antithrombin and protein C supplementation.

Coagulation Deficiency Caused by Antibodies

• Alloantibodies to factor VIII (5-10% hemophilia cases).
• Autoimmune diseases like SLE (Lupus anticoagulant).
• Treatment options:
  • Immunosuppression
  • Factor replacement.

Massive Transfusion Syndrome

• Reduced platelets and coagulation factors due to dilution.
• 24-hour blood storage at 4°C can impair platelet function and counts.
• Some patients have pre-existing bleeding disorders.