COAGULATION DISORDERS

COAGULATION DISORDERSCoagulation CascadeXIIaIIaIntrinsic system (surface contact)XIIXIXIaTissue factorIXIXaVIIaVIIVIIIVIIIaExtrinsic system (tissue damage)XVVaIIFibrinogenFibrin(Thrombin)IIaVitamin K dependant factors

Xa2KEY POINT: The efficacy/safety ratio for currently available therapies is less than satisfactory due to their ill-defined, multitargeted activity. New antithrombotic strategies are needed that offer an improved efficacy/safety profile compared with existing antithrombotic agents.1,2

Currently available antithrombotic agents include the heparins (UFH and Enoxaparin), vitamin K antagonists (warfarin), and direct thrombin inhibitors (hirudins).36The most widely used agents, heparins and vitamin K antagonists, have a range of actions on various components of the coagulation cascade. This contributes to the unpredictable clinical responses associated with these agents.35Other limitations of currently available antithrombotics include37 High incidence of serious adverse effects, particularly bleeding complications Routine monitoring of coagulation markers may be needed and represents a substantial burden in terms of time and costs Narrow therapeutic margin Limited effectiveness in preventing VTEFactor Xa inhibitors are a novel class of antithrombotic agents designed to selectively target only 1 core step in the coagulation cascade, leading to potent and targeted effectiveness.8

For training purposes onlyNot for distributionProthrombin Time (PT) Extrinsic Pathway

Activated Partial Thromboplastin Time (aPTT) Intrinsic Pathway

Thrombin Time (TT) - Fibrinogen

D dimer Test Fibrin degradation ProductsScreening TestsIntrinsic Path (XII,XI,IX,VIII)Extrinsic Path(VII)Fibrinogen FibrinCommon Path (V,II)(PT)(aPTT)(TT)(Fibrin & FDP)(Factor X)(Thrombin)Screening Tests4EtiologyHereditaryHemophilia AHemophilia Bvon Willebrands Disease

AcquiredVitamin K DeficiencyDICCongenital deficiency -Factor VIII(A) or IX(B)Bleeding Haematoma, jointGene on X chromosome.(Carrier females, Males suffer)Prolonged PTT but normal PTFFP or Factor replacement Life longHemophilia

Inheritance

Reduction - amount or activity of factor VIII

X linked recessive disorder

Males suffer

Females carriers

Rare homozygous females

Hemophilia A2 componentsVIIIc Smaller Procoagulant fractionLiver

vWFLarger fractionCarries factor VIIIcEndothelial cells & megakaryocytes

Factor VIII

InheritanceDeficiency of FVIIIc

FVIIIc - gene on long arm of X

Deletion / point mutation

PathogenesisHemarthrosis 70-80% cases

Knee, elbow, ankle & wrist

A/w pain

Affected joint warm, tender, swollen

Repeated hage destruction & deformities of joints Clinical FeaturesSoft tissue hemorrhage hematoma

Prolonged bleeding out of proportion to injury

Intracranial hemorrhage in patients < 18yrsClinical Features

Clinical FeaturesJoint Bleeding

16Severity Based on amount of FVIII activityClinical FeaturesSeverityFVIII activityAgeClinical FeaturesJoint BleedsMild5-25%Adolescence & youngPost traumatic or surgery bleedingRareModerate1-5%1-5yrsBleeding episodes + on slight injurySomeSevere