Initiation substances activate s by proteolysis a cascade of circulating precursor proteins which leads to the generation of thrombin which in turn converts soluble fibrinogen into fibrin.

Tests of Coagulation 1. Prothrombin Time (PT):  Tests the extrinsic & common pathways = Factors (VII) & (X, V, Prothrombin & fibrinogen). = Factors (VII) & (X, V, Prothrombin & fibrinogen).  Normal = 10 – 14 sec.  Test: Plasma + calcium + brain extract (thromboplastin)

Tests of Coagulation … (Cont … ) 2. Activated Partial Thromboplastin Time (APTT) or (PTT):  Tests intrinsic pathways (VIII, IX, XI, XII) & common pathway (X, V, prothrombin, fibrinogen).  Normal = 30 – 40 sec.  Test: Plasma + calcium + phospholipid + Kaolin (activates contact factors) 3. Thrombin Time:  Tests for fibrinogen  Normal = 10 – 12 sec.

Tests of Coagulation … (Cont … ) 4. Specific Factor Assay:  Functional Assay:  Based on PTT or PT  Tests principle:  Plasma deficient in suspected factor + patients plasma (A) patients plasma (A)  Plasma deficient in suspected factor + normal plasma (B). plasma (B).  The corrective effect of (A) is compared to (B) and the result is expressed as percentage of normal activity. 5. Immunological Assay Available for some coagulation factors

Hereditary Coagulation Disorders Hereditary deficiencies of coagulation factors are rare. However, the following disorders are more common:  Hemophilia A (Factor VIII deficiency)  Hemophilia B (Christma ’ s disease) (Factor IX deficiency)  Von Willebrand ’ s disease

Hemophilia A This is the most common hereditary disorder of blood coagulation.  Inheritance:  X-linked  Defect:  The absence or low level of factor VIII (clotting activity [VIII : C])

Correlation of Coagulation Factor Activity & Disease Severity in Hemophilia & Factor IX Deficiency Coagulation Factor Activity (% of normal) < Clinical Manifestation Clinical Manifestation  Severe disease. Frequent spontaneous bleeding episodes from early life. Joint bleeding episodes from early life. Joint deformity & crippling if not adequately treated. deformity & crippling if not adequately treated.  Moderate disease. Post-traumatic bleeding. Occasional spontaneous episodes. Occasional spontaneous episodes.  Mild disease. Post-traumatic bleeding.

Hemophilia A … (Cont.) Clinical Features: The clinical severity of the disease correlates well with the extent of factor deficiency. Severe (Factor level = <1% of normal):  Profuse post-circumcision bleeding.  Recurrent painful hemarthroses (I.e., bleeding into joints most commonly knees) with progressive joint deformity & crippling).  Muscle hematomas  Prolonged bleeding after dental extraction  Hematuria  Spontaneous intracerebral hemorrhage, uncommon.

Hemophilia A … (Cont.) Moderate: (Level of factor = 1-5% of normal):  Most post-traumatic bleeding  Occasional spontaneous bleeding Mild: (Level of factor = 5-20% of normal)  Post-traumatic bleeding  Spontaneous bleeding rare

Laboratory Features Abnormal  APTT  Factor VIII-C Normal  PT  Bleeding time : Prolonged :Decreased :Normal : l

Treatment Principles of Treatment:  For spontaneous bleeding: bleeding is controlled if the level of factor VIII is raised to above 20%.  For major surgery or serious post- traumatic bleeding: the level should be about 100%.

Complications of Treatment  Disease transmission:  HIV infection  Hepatitis  Development of antibodies (inhibitors to factor VIII):  Seen in 5-10% of patients  The antibodies make the patient resistant to treatment & make him require larger doses

Von Willebrand ’ s Disease Inheritance:Autosomal dominant Defect: 1. Reduced level of factor vWF (von Willebrand ’ s Factor). This results in rapid loss of factor VIII : C and abnormal coagulation. 2. Defective platelet-related activity of (Von Willebrand factor). This affect platelet ’ s adherence to subendothelial collagen & platelet aggregation induced by ristocetin. Thus vW disease has two manifestations:  Of low VIII C level  Of low vW Factor

Clinical Features of Von Willebrand ’ s Disease Operative & post-traumatic bleeding. Operative & post-traumatic bleeding. Mucous membrane bleeding e.g., epistaxes, menorrhagia. Mucous membrane bleeding e.g., epistaxes, menorrhagia. Hemarthroses & muscle hematomas are rare in contrast to hemophilia A. Hemarthroses & muscle hematomas are rare in contrast to hemophilia A.

Laboratory Features of VWD Abnormal: Bleeding time: prolonged Bleeding time: prolonged PTT: prolonged PTT: prolonged Factor Assay: Low levels: Factor Assay: Low levels: VWF VWF VIII C VIII C Platelet aggregation: defective with ristocetin.Normal with other reagents. Platelet aggregation: defective with ristocetin.Normal with other reagents.Normal: PT PT /

Treatment of VWD Cryoprecipitate Cryoprecipitate Factor VIII concentrate Factor VIII concentrate Desmopressin Desmopressin

Hemostasis Tests In Hereditary Coagulation Disorders Hemophilia A Normal Prolonged Normal Low Normal Hemophilia B Normal Prolonged Normal Low Von Willebrand ’ s Disease Prolonged Normal Prolonged Normal Low or normal Low Normal Bleeding Time Prothrombin Time Activated Partial Thromboplastin Time Thrombin Clotting Time Factor VIII vWF vWF : Ricof* Factor IX *Ristocetin cofactor activity

Disseminated Intravascular Coagulation (DIC) Widespread intravascular deposition of fibrin with consumption of coagulation factors and platelets. This occurs as a consequence of many disorders which release procoagulant material into the circulation or cause widespread endothelial damage or platelet aggregation. Forms of DIC: Fulmuninant hemorrhagic course Fulmuninant hemorrhagic course Chronic, less severe course Chronic, less severe course

Disseminated Intravascular Coagulation (DIC) (Cont … ) Pathology: Deposition of Fibrin in the microcirculation Deposition of Fibrin in the microcirculation Formation of large amounts of fibrin monomers Formation of large amounts of fibrin monomers Increased fibrinolysis with release of fibrin split products (FSPs) or fibrin degradation products (FDPs) Increased fibrinolysis with release of fibrin split products (FSPs) or fibrin degradation products (FDPs) These FDPs interfere with fibrin polymerization, thus causing coagulation defect. These FDPs interfere with fibrin polymerization, thus causing coagulation defect. Depletion of fibrinogen and other factors Depletion of fibrinogen and other factors Consumption of platelets Consumption of platelets

Disseminated Intravascular Coagulation (DIC) (Cont … ) Causes: Due to release of procoagulant material: e.g., in amniotic fluid embolism, premature separation of placenta, mucin secreting adenocarcinoma, M3 AML, falciparum malaria, hemolytic transfusion reaction, snake bites. Due to release of procoagulant material: e.g., in amniotic fluid embolism, premature separation of placenta, mucin secreting adenocarcinoma, M3 AML, falciparum malaria, hemolytic transfusion reaction, snake bites. Widespread endothelial damage: e.g., gram negative septicemia, meningococcal septicemia. Widespread endothelial damage: e.g., gram negative septicemia, meningococcal septicemia. Widespread intravascular platelet aggregation: e.g., some bacterial or viral infection. Widespread intravascular platelet aggregation: e.g., some bacterial or viral infection.

Disseminated Intravascular Coagulation (DIC) (Cont … ) Laboratory Features: Platelet count: Decreased Platelet count: Decreased Fibrinogen level: Decreased Fibrinogen level: Decreased FDPs: Prolonged FDPs: Prolonged PT: Prolonged PT: Prolonged PTT: Prolonged PTT: Prolonged (Thrombin Time) TT: Prolonged (Thrombin Time) TT: Prolonged Blood film: Features of microangiopathic hemolytic anemia: there is fragmentation of RBCs when they passed through fibrous strands in small vessels. Blood film: Features of microangiopathic hemolytic anemia: there is fragmentation of RBCs when they passed through fibrous strands in small vessels.

Factor IX Deficiency (Hemophilia B, Christman Dis.) The inheritance and clinical features are identical to hemophilia A. The inheritance and clinical features are identical to hemophilia A. The laboratory features are identical except in the factor assay, factor IX is deficient instead of VIII. The laboratory features are identical except in the factor assay, factor IX is deficient instead of VIII. Treatment with factor IX concentrate. Treatment with factor IX concentrate.

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