Hemostasis and Coagulation Disorders Quiz

Coagulation Disorders

• Coagulation disorders are conditions affecting blood clotting.

Inherited Coagulation Disorders: Overview

• Hemophilia:
  • Hemophilia A – Factor VIII deficiency
  • Hemophilia B – Factor IX deficiency
• von Willebrand's Disease (vWD):
  • Types 1-3
  • Characterized by lack or insufficient production of von Willebrand factor (vWF)

Hemophilia

• Also known as "love of bleeding"
• Bleeding manifestations of both Hemophilia A & B are identical
• Some infants are asymptomatic until experiencing minor trauma, resulting in bruising and spontaneous bleeding, particularly into deep tissues (joints, muscles, soft tissues).
• Bleeding after trauma or surgery can be life-threatening.
• Causes lifelong bleeding problems.

Hemophilia A

• Bleeding due to deficiency of Factor VIII coagulant activity.
• Severity related to Factor VIII level in the blood.
• Low levels (<1 iu/dL) result in frequent spontaneous bleeding into joints or muscles.
• Inherited as recessive X-linked.
• Males are affected, females are carriers.
• Defect is an absence/low level of plasma Factor VIII.

X-linked recessive inheritance

• Diagram showing inheritance pattern of X-linked recessive disorders (Males affected, females carriers).

Clinical Features of Hemophilia A

• Infants may experience joint and soft tissue bleeds and excessive bruising when becoming active.
• Dental extraction can lead to prolonged bleeding.
• Hemarthrosis (recurrent joint bleeding) leads to joint deformity and disability (if poorly treated).
• Hemophilic pseudotumor is a rare complication of hemophilia involving progressive cystic swelling in muscles/bones caused by repeated bleeding.
• Hematuria (blood in urine) is possible.
• Gastrointestinal bleeding is a possible symptom.

Severity of Hemophilia A

• Severity related to Factor VIII level (iu/dL)
  • Severe: Factor level 0-1
  • Moderate: Factor level 2-5
  • Mild: Factor level 5-30

Coagulation Pathway

• Diagram illustrating intrinsic and extrinsic pathways.
• Key factors: Factor XII, XI, IX, VIII, X, VII, V, prothrombin, thrombin, fibrinogen, fibrin.
• Key times: aPTT, PT, TT.

Laboratory Investigations (Hemostasis Tests) for HA

• Initial work includes complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), and bleeding time (BT).
• In HA & HB, PTT prolonged, whilst PT & BT are normal.
• Mixing study is followed after prolonged PTT is detected.
• If factor deficiency suspected, PTT should normalize in mixing study.
• Hemophilia is usually diagnosed if factor activity is less than 40% of normal factor activity.
• Molecular genotyping confirms diagnosis and predicts severity.

Other Laboratory Investigation for Carrier Detection and Antenatal Diagnosis

• Measure plasma levels of Factor VIII.
• DNA probes detect mutations in carriers.
• Fetal DNA analysis through 8-10 weeks gestation biopsies.
• Antenatal diagnosis via UV- ultrasound guided needle aspiration in 16-20 weeks gestation.

Treatments

• Factor VIII replacement therapy (recombinant factor or frozen plasma concentrate).
• Desmopressin (synthetic vasopressin analog): stimulates release of FVIII and vWF from endothelial cells, boosting plasma levels.
• Prophylactic treatments: stored FVIII at home to reduce cerebral and muscle bleeds, reducing hospitalizations, and improving quality of life.

Non-Genetic Form of Hemophilia A

• Caused by autoantibodies against Factor VIII (acquired hemophilia A).
• Associated with certain cancers, autoimmune diseases/response to treatment, or occurring after childbirth.

Hemophilia B

• Also known as Christmas disease; Factor IX deficiency.
• Similar inheritance and clinical features to Hemophilia A.
• Distinguished from Hemophilia A by specific coagulation assays.
• Incidence approximately 1/5 that of Hemophilia A.
• Factor IX levels are initially low at birth, but reach normal levels around six months.
• Umbilical cord blood samples are more accurate for finding Factor VIII deficiencies (lower than Factor IX at birth).

Hemophilia B: Treatments and Findings

• Treatment: FIX infusions (longer half-life than FVIII).
• Abnormal Findings:
  • Prolonged aPTT
  • Reduced FIX clotting assay
  • Normal bleeding time
  • Normal PT

Additional Info: Hemophilia

• Hemophilia can occur even without a family history; it can arise due to spontaneous mutations affecting the F8 or F9 gene (affecting clotting factors).
• The vast majority of Hemophilia cases are due to gene defects.
• Over 1000 mutations in factor VIII and IX genes identified, approximately 30% resulting from spontaneous mutations.

von Willebrand's Disease (vWD)

• Abnormalities in vWF levels (reduced levels or abnormal function) result from point mutations / major deletions.
• vWF is a large protein (300 kDa) forming multimers.
• Inherited as autosomal dominant.
• Characterized by mucosal bleeding (nosebleeds, gum bleeding).
• Bleeding can occur after dental extraction and following trauma.

vWF – Multi-functional Proteins

• vWF promotes platelet adhesion & aggregation to damaged endothelium.
• vWF acts as a carrier molecule for FVIII, protecting it from premature destruction.

vWD - 3 Types

• Type 1: Reduced vWF (mild).
• Type 2: Abnormal vWF.
  • 2A: Loss of high molecular weight multimers (HMWM).
  • 2B: Increased affinity of vWF for platelets (abnormal vWF attachment when no injury to platelets, causing thrombocytopenia and reduced vWF production when clotting is required)
  • 2M: Defective binding site on GPIb preventing vWF from attaching to platelets and causing poor platelet aggregation.
  • 2N: Reduced affinity for FVIII.
• Type 3: Very low or lacking vWF (severe).

vWD – Lab Findings

• Prolonged bleeding time
• Low FVIII
• Prolonged aPTT
• Low vWF
• Defective platelet aggregation
• Normal platelet count (except low in type 2B)

Specialized Lab Investigations for vWD

• VWF:Ag (immunoassay): measures vWF protein concentration in plasma.
• vWF:RCo (functional assay): measures ability of vWF to interact with normal platelets (ristocetin-induced platelet agglutination).

vWD Treatments

• Antifibrinolytic agents (type 2B)
• Desmopressin (type 1 vWD)
• FVIII and vWF infusions for patients with very low vWF levels.

Hemophilia A vs. vWD: Differences

• Gender: Hemophilia A mainly affects males, whereas vWD affects both genders equally.
• Bleeding symptoms: Hemophilia A typically involves deep tissue bleeding (joints, internal organs), while vWD often presents with mucosal bleeding (in tissues and cavities exposed to the environment).

Acquired Coagulation

• More common than inherited disorders.
• Involves deficiencies in multiple clotting factors.

Vitamin K Deficiency

• Causes:
  • Inadequate diet
  • Malabsorption
  • Inhibition by drugs (e.g., warfarin).
• Results in deficiencies of factors II, VII, IX, X, protein C, and protein S.
• Hemorrhagic disease of the newborn may be a consequence.
• Associated with obstructive jaundice, or pancreatic problems.

Hemorrhagic Disease of the Newborn

• Vitamin K deficiency due to immature liver cells, lack of gut bacteria, low vitamin K levels in breast milk.

Liver Disease and Hemostasis

• Liver disease can affect hemostasis in several ways, including:
• Impaired vitamin K absorption.
• Reduced synthesis of coagulation factors (II, VII, IX, X).
• Synthesis of coagulation inhibitors and promoting DIC(disseminated intravascular coagulation).
• Thrombocytopenia
• Dysfibrinogenaemia.

Disseminated Intravascular Coagulation (DIC)

• Widespread fibrin deposition and consumption of coagulation factors & platelets.
• Triggered by many factors releasing procoagulants and causing endothelial damage/activation of haemostasis.
• Pathogenesis: entry of procoagulants into circulation (amniotic fluid embolism, liver disease, placental separation, cancer, snake venom, endothelial damage, infections/immune response/vasculitis; severe burns).
• Lab findings: low platelet counts, prolonged PT, PTT, increased D-dimers, and fibrin degradation products.

DIC Treatments

• Fresh frozen plasma or plasma concentrate
• RBC transfusion
• Antithrombin and protein C to inhibit further DIC.

Coagulation Deficiency Caused by Antibodies

• Alloantibodies to Factor VIII in some hemophilia cases cause bleeding.
• SLE ( Systemic Lupus Erythematosus) and other autoimmune disorders can cause lupus anticoagulant which interferes with coagulation.
• Treatment: immunosuppression or factor replacement.

Massive Transfusion Syndrome

• Characterized by dilution effects on platelets, coagulation factors, and inhibitors.
• Platelet counts and coagulation function are often reduced after prolonged 24hr blood storage at 4°C.
• Preexisting bleeding disorders can increase these problems.