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 CoagulationTests of Coagulation

1.1. Prothrombin Time (PT):Prothrombin Time (PT): Tests the extrinsic & common pathwaysTests the extrinsic & common pathways

= Factors (VII) & (X, V, Prothrombin & = Factors (VII) & (X, V, Prothrombin & fibrinogen).fibrinogen).

Normal = 10 – 14 sec.Normal = 10 – 14 sec. Test:Test:

Plasma + calcium + brain extract Plasma + calcium + brain extract (thromboplastin)(thromboplastin)

Tests of CoagulationTests of Coagulation…… (Cont…)(Cont…)

2.2. Activated Partial Thromboplastin Time Activated Partial Thromboplastin Time (APTT) or (PTT):(APTT) or (PTT):

Tests intrinsic pathways (VIII, IX, XI, XII) & Tests intrinsic pathways (VIII, IX, XI, XII) & common pathway (X, V, prothrombin, fibrinogen).common pathway (X, V, prothrombin, fibrinogen).

Normal = 30 – 40 sec.Normal = 30 – 40 sec. Test:Test:

Plasma + calcium + phospholipid + Kaolin (activates Plasma + calcium + phospholipid + Kaolin (activates contact factors)contact factors)

3.3. Thrombin Time:Thrombin Time: Tests for fibrinogenTests for fibrinogen Normal = 10 – 12 sec. Normal = 10 – 12 sec.

Tests of CoagulationTests of Coagulation…… (Cont…)(Cont…)

4.4. Specific Factor Assay:Specific Factor Assay: Functional Assay:Functional Assay:

Based on PTT or PTBased on PTT or PT Tests principle:Tests principle:

Plasma deficient in suspected factor + Plasma deficient in suspected factor + patients plasma (A)patients plasma (A) Plasma deficient in suspected factor + normal Plasma deficient in suspected factor + normal plasma (B).plasma (B). The corrective effect of (A) is compared to (B) and The corrective effect of (A) is compared to (B) and

the result is expressed as percentage of normal the result is expressed as percentage of normal activity. activity.

5.5. Immunological AssayImmunological AssayAvailable for some coagulation factorsAvailable for some coagulation factors

Hereditary Coagulation DisordersHereditary Coagulation Disorders

Hereditary deficiencies of coagulationHereditary deficiencies of coagulation

factors are rare. However, the followingfactors are rare. However, the following

disorders are more common:disorders are more common:

Hemophilia A (Factor VIII deficiency)Hemophilia A (Factor VIII deficiency) Hemophilia B (Christma’s disease)Hemophilia B (Christma’s disease)

(Factor IX deficiency)(Factor IX deficiency) Von Willebrand’s diseaseVon Willebrand’s disease

Hemophilia A Hemophilia A

This is the most common hereditaryThis is the most common hereditary

disorder of blood coagulation. disorder of blood coagulation. Inheritance:Inheritance:

X-linkedX-linked

Defect:Defect: The absence or low level of factor VIII The absence or low level of factor VIII

(clotting activity [VIII : C])(clotting activity [VIII : C])

Correlation of Coagulation Factor Activity & Disease Correlation of Coagulation Factor Activity & Disease Severity in Hemophilia & Factor IX DeficiencySeverity in Hemophilia & Factor IX Deficiency

Coagulation Coagulation Factor Activity Factor Activity (% of normal)(% of normal)

<1<1

1-51-5

5-205-20

Clinical ManifestationClinical Manifestation

Severe disease. Frequent spontaneous 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. Moderate disease. Post-traumatic bleeding. Occasional spontaneous episodes.Occasional spontaneous episodes. Mild disease. Post-traumatic bleeding. Mild disease. Post-traumatic bleeding.

Hemophilia A Hemophilia A … … (Cont.)(Cont.)

Clinical Features:Clinical Features:The clinical severity of the disease correlates wellThe clinical severity of the disease correlates wellwith the extent of factor deficiency.with the extent of factor deficiency.

Severe (Factor level = <1% of normal):Severe (Factor level = <1% of normal): Profuse post-circumcision bleeding.Profuse post-circumcision bleeding. Recurrent painful hemarthroses (I.e., bleeding into joints most Recurrent painful hemarthroses (I.e., bleeding into joints most

commonly knees) with progressive joint deformity & crippling).commonly knees) with progressive joint deformity & crippling). Muscle hematomasMuscle hematomas Prolonged bleeding after dental extractionProlonged bleeding after dental extraction HematuriaHematuria Spontaneous intracerebral hemorrhage, uncommon.Spontaneous intracerebral hemorrhage, uncommon.

Hemophilia A Hemophilia A … … (Cont.)(Cont.)

Moderate:Moderate:(Level of factor = 1-5% of normal): (Level of factor = 1-5% of normal): Most post-traumatic bleedingMost post-traumatic bleeding Occasional spontaneous bleedingOccasional spontaneous bleeding

Mild:Mild:(Level of factor = 5-20% of normal)(Level of factor = 5-20% of normal) Post-traumatic bleedingPost-traumatic bleeding Spontaneous bleeding rareSpontaneous bleeding rare

Laboratory FeaturesLaboratory Features

Abnormal APTT Factor VIII-C

Normal PT Bleeding time

: Prolonged: Decreased

: Normal: Normal:

l

TreatmentTreatment

Principles of Treatment:Principles of Treatment:

For spontaneous bleeding: bleeding is For spontaneous bleeding: bleeding is controlled if the level of factor VIII iscontrolled if the level of factor VIII israised to above 20%.raised to above 20%.

For major surgery or serious post-For major surgery or serious post-traumatic bleeding: the level should traumatic bleeding: the level should be about 100%. be about 100%.

Complications of TreatmentComplications of Treatment

Disease transmission:Disease transmission: HIV infectionHIV infection Hepatitis Hepatitis

Development of antibodies (inhibitors Development of antibodies (inhibitors

to factor VIII): to factor VIII): Seen in 5-10% of patientsSeen in 5-10% of patients The antibodies make the patient resistant to The antibodies make the patient resistant to

treatment & make him require larger dosestreatment & make him require larger doses

Von Willebrand’s DiseaseVon Willebrand’s Disease

Inheritance:Inheritance: Autosomal dominantAutosomal dominantDefect:Defect:1.1. Reduced level of factor vWF (von Willebrand’s Factor). Reduced level of factor vWF (von Willebrand’s Factor).

This results in rapid loss of factor VIII : C and This results in rapid loss of factor VIII : C and abnormal coagulation.abnormal coagulation.

2.2. Defective platelet-related activity of (Von Willebrand Defective platelet-related activity of (Von Willebrand factor). This affect platelet’s adherence to factor). This affect platelet’s adherence to subendothelial collagen & platelet aggregation induced subendothelial collagen & platelet aggregation induced by ristocetin.by ristocetin.Thus vW disease has two manifestations:Thus vW disease has two manifestations:

Of low VIII C levelOf low VIII C level Of low vW FactorOf low vW Factor

Clinical Features of Clinical Features of Von Willebrand’s DiseaseVon Willebrand’s Disease

• Operative & post-traumatic bleeding.Operative & post-traumatic bleeding.• Mucous membrane bleeding e.g., Mucous membrane bleeding e.g.,

epistaxes, menorrhagia.epistaxes, menorrhagia.• Hemarthroses & muscle hematomas Hemarthroses & muscle hematomas

are rare in contrast to hemophilia A. are rare in contrast to hemophilia A.

Laboratory Features of VWDLaboratory Features of VWDAbnormal:Abnormal:• Bleeding time: prolongedBleeding time: prolonged• PTT: prolongedPTT: prolonged• Factor Assay: Low levels:Factor Assay: Low levels:

• VWFVWF• VIII VIII CC

• Platelet aggregation: defective with ristocetin.Normal with other Platelet aggregation: defective with ristocetin.Normal with other reagents.reagents.

Normal:Normal:• PTPT

/

Treatment of VWDTreatment of VWD

• CryoprecipitateCryoprecipitate• Factor VIII concentrateFactor VIII concentrate• DesmopressinDesmopressin

Hemostasis Tests In Hereditary Coagulation Disorders

Hemophilia A

NormalNormal

ProlongedNormal

LowNormalNormalNormal

Hemophilia B

NormalNormal

ProlongedNormalNormalNormalNormal

Low

Von Willebrand’s Disease

ProlongedNormal

ProlongedNormal

Low or normalLowLow

Normal

• Bleeding Time• Prothrombin Time• Activated Partial Thromboplastin Time• Thrombin Clotting Time• Factor VIII• vWF• vWF : Ricof*• Factor IX

*Ristocetin cofactor activity

Disseminated Intravascular Disseminated Intravascular Coagulation Coagulation (DIC)(DIC)

Widespread intravascular deposition of fibrinWidespread intravascular deposition of fibrinwith consumption of coagulation factors andwith consumption of coagulation factors andplatelets. This occurs as a consequence ofplatelets. This occurs as a consequence ofmany disorders which release procoagulantmany disorders which release procoagulantmaterial into the circulation or cause widespreadmaterial into the circulation or cause widespreadendothelial damage or platelet aggregation.endothelial damage or platelet aggregation.

Forms of DIC:Forms of DIC:• Fulmuninant hemorrhagic courseFulmuninant hemorrhagic course• Chronic, less severe courseChronic, less severe course

Disseminated Intravascular Disseminated Intravascular Coagulation (DIC) Coagulation (DIC) (Cont…)(Cont…)

Pathology:Pathology:• Deposition of Fibrin in the microcirculationDeposition of Fibrin in the microcirculation• Formation of large amounts of fibrin monomersFormation of large amounts of fibrin monomers• Increased fibrinolysis with release of fibrin split products (FSPs) or Increased fibrinolysis with release of fibrin split products (FSPs) or

fibrin degradation products (FDPs)fibrin degradation products (FDPs)• These FDPs interfere with fibrin polymerization, thus causing These FDPs interfere with fibrin polymerization, thus causing

coagulation defect.coagulation defect.• Depletion of fibrinogen and other factorsDepletion of fibrinogen and other factors• Consumption of plateletsConsumption of platelets

Disseminated Intravascular Disseminated Intravascular Coagulation (DIC) Coagulation (DIC) (Cont…)(Cont…)

Causes:Causes:• Due to release of procoagulant material: e.g., in amniotic fluid Due to release of procoagulant material: e.g., in amniotic fluid

embolism, premature separation of placenta, mucin secreting embolism, premature separation of placenta, mucin secreting adenocarcinoma, M3 AML, falciparum malaria, hemolytic adenocarcinoma, M3 AML, falciparum malaria, hemolytic transfusion reaction, snake bites.transfusion reaction, snake bites.

• Widespread endothelial damage: e.g., gram negative Widespread endothelial damage: e.g., gram negative septicemia, meningococcal septicemia.septicemia, meningococcal septicemia.

• Widespread intravascular platelet aggregation: e.g., some Widespread intravascular platelet aggregation: e.g., some bacterial or viral infection. bacterial or viral infection.

Disseminated Intravascular Disseminated Intravascular Coagulation (DIC) Coagulation (DIC) (Cont…)(Cont…)

Laboratory Features:Laboratory Features:• Platelet count: DecreasedPlatelet count: Decreased• Fibrinogen level: DecreasedFibrinogen level: Decreased• FDPs: ProlongedFDPs: Prolonged• PT: ProlongedPT: Prolonged• PTT: ProlongedPTT: Prolonged• (Thrombin Time) TT: Prolonged(Thrombin Time) TT: Prolonged• Blood film: Features of microangiopathic hemolytic anemia: there is Blood film: Features of microangiopathic hemolytic anemia: there is

fragmentation of RBCs when they passed through fibrous strands in small fragmentation of RBCs when they passed through fibrous strands in small vessels. vessels.

Factor IX DeficiencyFactor IX Deficiency(Hemophilia B, Christman Dis.)(Hemophilia B, Christman Dis.)

• The inheritance and clinical features are identical to The inheritance and clinical features are identical to hemophilia A.hemophilia A.

• The laboratory features are identical except in the The laboratory features are identical except in the factor assay, factor IX is deficient instead of VIII.factor assay, factor IX is deficient instead of VIII.

• Treatment with factor IX concentrate. Treatment with factor IX concentrate.

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