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DR NILESH KATE
MBBS,MD ASSOCIATE PROF
DEPT. OF PHYSIOLOGY
HAEMOSTASIS IIANTIHAEMOSTATIC
MECHANISMS
OBJECTIVES. Anti-haemostatic
mechanism.
Bleeding disorders.
Laboratory tests
Monday, May 1, 2023
ANTIHAEMOSTATIC MECHANISM
The factors which balance the tendency of blood to
clot in VIVO forms Anti-Haemostatic Factors.
Factors preventing platelet aggregation
Factors preventing coagulation
Factors causing fibrinolysis.
Monday, May 1, 2023
FACTORS PREVENTING PLATELET AGGREGATION
PROSTACYCLIN – Endogenous factor inhibit Thromboxane A2( Promote Platelet Aggregation).
Normally balance between
Prostacyclin
Thromboxane A2 Prevents Intravascular spread of
plug.
Monday, May 1, 2023
FACTORS PREVENTING COAGULATION
Circulating Anticoagulant Heparin Anti-thrombin III or heparin Co-factor II Protein C.
Monday, May 1, 2023
HEPARIN Powerful Natural Anti-
coagulant. First isolated from Liver. Its Polysaccharides
containing sulphate groups Mol wt – 15000-18000
dalton. Secreted by Basophils &
mast cells. Destroyed by Heparinase.
Monday, May 1, 2023
HEPARIN MECHANISM OF ACTION
Prevents activation of Prothrombin to Thrombin.
Inhibits action of thrombin on fibrinogen.
Facilitate action of Antithrombin –III & inhibits factor IX,X,XII & XII
Monday, May 1, 2023
ANTI-THROMBIN III OR HEPARIN CO-FACTOR II
Present in plasma & vascular endothelium.
Inactivates Coagulation factors including thrombin.
Monday, May 1, 2023
PROTEIN C. Plasma protein from
liver. Along with
Thrombomodulin & protein S forms Negative feedback for Coagulatory process under control.
Monday, May 1, 2023
PROTEIN C PATHWAY INHIBITING COAGULATION & PROMOTING
FIBRINOLYSIN.
Monday, May 1, 2023
THROMBOMODULIN Thrombin binding
protein produced by endothelial cells except cerebral microcirculation.
Converts thrombin into protein C activator.
Monday, May 1, 2023
FIBRINOLYTIC MECHANISM FIBRINOLYSIS –
dissolution of Fibrin. Important component
is Plasmin or fibrinolysin present in inactive form called plasminogen or Profibrinolysin.
Monday, May 1, 2023
FACTORS CAUSING FIBRINOLYSIS Plasminogen plasmin. Extrinsic plasminogen
activator system Intrinsic plasminogen
activator system
Monday, May 1, 2023
PLASMINOGEN Beta globulin produced
by liver. It is associated with
fibrinogen molecule. Plasminogen is
activated by plasminogen activator system to produce PLASMIN.
Monday, May 1, 2023
PLASMIN. Powerful protease formed
from plasminogen. Lysis fibrin & fibrinogen into
fragments known as fibrin degradation products that inhibit thrombin.
2 plasminogen activator system. Extrinsic Intrinsic
Monday, May 1, 2023
EXTRINSIC PLASMINOGEN ACTIVATOR SYSTEM
Predominant mechanism
In its absence extensive fibrin deposition occurs.
Its absence causes delayed wound healing Defect in growth &
fertility.
Monday, May 1, 2023
FIBRINOLYTIC MECHANISM OPERATING THROUGH EXTRINSIC PLASMINOGEN
ACTIVATOR SYSTEM.
PLASMINOGEN
TPA
THROMBIN
UPA
PLASMIN
Fibrin Fibrin degradation product (FDP)
Monday, May 1, 2023
TISSUE PLASMINOGEN ACTIVATOR
Also called Vascular Plasminogen Activator released from vascular endothelium.
Its release depend upon release of Serotonin from platelets & release of adrenaline.
E.g – In soldier in battlefield there is massive fibrinolysis due to release of adrenaline.
TPA is now produced by Recombinant DNA technology & used clinically.
Monday, May 1, 2023
UROKINASE TYPE PLASMINOGEN ACTIVATOR
Found in endothelial cells, renal cells & Tumor cells.
E.g. – STREPTOKINASE & STAPHYLOKINASE are bacterial enzymes causes activation of Plasmin like TPA & UPA.
Monday, May 1, 2023
INTRINSIC PLASMINOGEN ACTIVATOR SYSTEM
Contact factor XIIa & Kallikrein intiate
clotting mechanism also stimulate
dissolution of clot by activating plasminogen
& form intrinsic plasminogen activator
system.
Monday, May 1, 2023
FIBRINOLYTIC MECHANISM OPERATING THROUGH INTRINSIC PLASMINOGEN
ACTIVATOR SYSTEM.
Prekallikrein XII XIIa
Kallikrein
Thrombin
Plasminogen Plasmin
Fibrin Fibrin Degradation Product (FDP)
Monday, May 1, 2023
FIBRINOLYSIS INHIBITORS Rate of fibrinolysis is influenced by
promoters & inhibitors. Various INHIBITOR s are
ANTIPLASMIN – alpha2 antiplasmin Drugs – aprotinin & Epsilon amino caproic acid
(EACA) Inhibitors are present in plasma, blood cells,
tissues & extracellular matrix.
Monday, May 1, 2023
PHYSIOLOGICAL ROLE OF FIBRINOLYSIS SYSTEM
Cleaning the minute clots of tiny vessels Promote normal healing process. Liquefaction of menstural clot. Liquefaction of sperms in the epididymis. Role in inflammatory response
Monday, May 1, 2023
ANTICOAGULANTS Substances which delay or prevent process of
coagulation of blood. In vitro – done by substances which sequester
calcium – sodium citrate or oxalate, sodium edetate(EDTA)
In vivo –done by Antagonizing clotting factors – heparin Destruction of fibrinogen By inhibiting synthesis of factors – II,VII,IX & X
Monday, May 1, 2023
ANTICOAGULANTS Endogenous Anticoagulants – inside body
naturally – Heparin, antithrombin III & protein C
Exogenous anticoagulants or decalcifying agents. Heparin Calcium sequesters Vitamin K antagonists Defibrination substances.
Monday, May 1, 2023
CALCIUM SEQUESTERS By removing Ca from the blood.
Two types of agent
One which form insoluble salts with Ca – Na citrate
& Na oxalate
Calcium Chelators – which binds with Ca – EDTA.
Monday, May 1, 2023
VITAMIN K ANTAGONISTS Used orally. MOA – occupy Vit K active site & prevent Vit K to
function – inhibit synthesis of Vit K dependent factors as VII,IX & X Eg- Coumarin derivatives Warfarin Phenindione Nicoumalone
Monday, May 1, 2023
DEFIBRINATION SUBSTANCES. Which causes destruction of fibrinogen. Malaysian pit viper venom Arvin or ancord – preparation of snake
venom.
Monday, May 1, 2023
BLEEDING DISORDERS Spontaneous escape of blood from blood
vessels or Persistent or excessive bleeding following
minor injuries like tooth extraction etc.
Monday, May 1, 2023
BLEEDING DISORDERS Classification of bleeding disorders.
Platelet disorders Deficiency of platelets Functional disorders of platelets
Coagulation disorders or defective coagulation mechanisms
Deficiency of clotting factors Vit K deficiency. Anticoagulant overdose. DIC
Monday, May 1, 2023
BLEEDING DISORDERS Classification of bleeding disorders.
Vascular disorders. Damage of capillary endothelium(Non-thrombocytopenic Purpura)
Infection by bacteria & toxins,Toxic effects of drugs & chemicals
Avitaminosis , alergic purpura, connective tissue diseases.
Monday, May 1, 2023
PURPURA Group of bleeding
disorders due to various causes.
PURPURA – purple coloured petechial hemorrhages & bruises in the skin.
Monday, May 1, 2023
CAUSES AND TYPES OF PURPURA
Platelet disorders. Deficiency of platelets. (thrombocytopenic Purpura) Normal count – 1.5 l- 4 lac/mm3
Below 1.5lac – thrombocytopenia Causes –
Primary – cause not known Secondary –
Bone marrow depression. Leukemia. Acute septicemia, toxemia & uremia Hypersplenism.
Monday, May 1, 2023
CAUSES AND TYPES OF PURPURA
Functional disorders of platelets.(Thrombosthenic purpura) Drug induced defects –aspirin Von-willebrand’s disease. Vascular disorders (Non-
thrombocytopenic Purpura)
Monday, May 1, 2023
CAUSES OF NON-THROMBOCYTOPENIC PURPURA.
Drug induced damage to capillary wall. Deficiency of vitamin-C Allergic purpura. Infections Senile purpura Connective tissue diseases.
Monday, May 1, 2023
HAEMOPHILIA Group of disorders
due to hereditary deficiency of coagulation.
Characterized by Bleeding tendencies with Increased clotting time.
Monday, May 1, 2023
HAEMOPHILIA Haemophilia-A Haemophilia-B Haemophilia-C
Monday, May 1, 2023
HAEMOPHILIA-A Classical haemophilia
due to Deficiency of factor VIII.
Sex linked recessive disease affects males and females carrier.
Clinical features not apparent since birth but start early in life.
Monday, May 1, 2023
HAEMOPHILIA-A c/f – tendency to bleed into soft tissues, muscle, joints , GI
tracts, urinary tracts & from nose
Severely damaged joints.
Hemorrhage into soft tissue of mouth cause respiratory
obstruction & death by suffocation.
Normal bleeding time, platelet count & PT but prolonged CT &
PTT.
T/t – repeated small fresh blood, fresh plasma, factor VIII
conc.
Monday, May 1, 2023
HAEMOPHILIA-B Known as Christmas
Disease due to Deficiency of factor IX.
Reccessive X-Linked disease occurs in males, transmitted by females.
T/t – Fresh blood transfusion.
Monday, May 1, 2023
HAEMOPHILIA-C Deficiency of
PTA(Factor X) Inherited as Mendelian
dominant affects both males & females.
Without bleeding tendencies.
CT may be prolonged or normal.
Monday, May 1, 2023
DISSEMINATED INTRAVASCULAR COAGULATION.
Condition when clotting mechanism is activated in widespread circulation.
Due to wide spread coagulation plugging of small vessels leads to decreased O2 & nutrient supply- organ damage.
Monday, May 1, 2023
DISSEMINATED INTRAVASCULAR COAGULATION.
Most of the coagulation factors & platelets used up leads to its deficiency causing bleeding tendencies. So called consumption coagulopathy.
Fibrin degradation product formed due to fibrinolysis of clot have anti-haemostatic effect further aggravate bleeding tendency.
Monday, May 1, 2023
LABORATORY TESTS IN BLEEDING DISORDERS
Bleeding time(BT) Definition – time interval between
skin prick and the arrest of bleeding. Procedure.
Duke’s method – take a prick at finger skin , blood is wiped at 15 sec interval till it stops
Normal time :- 1-6 min. Ivy’s method – apply 40 mm Hg at upper
arm with BP cuff & take deep prick on ant surface of skin of forearm
Normal time – 3-6min.
Monday, May 1, 2023
LABORATORY TESTS IN BLEEDING DISORDERS
Prolonged BT – occurs in purpura & normal in Haemophilia.
Capillary fragility tests of Hess or Tourniquet test – To assess
the mechanical fragility of capillary by raising pressure.
Procedure – A circle of 1 inch diameter is marked on forearm &
pressure midway between systolic & diastolic is applied on upper
arm for 15min using cuff. any purple spot is marked with blue ink.
Monday, May 1, 2023
PLATELET COUNT Normal Platelet Count – 1.5 – 4 lac/mm3 Procedure
Direct method – using Reese-E-Kar fluid counted in Haemocytometer.
Indirect method – from RBC count & RBC:platelet ratio. 1platelet :16-18 RBC.
Monday, May 1, 2023
COAGULATION TIME. Def – Time taken by the fresh
blood to get coagulated by formation of fibrin threads.
Procedure. Capillary tube method – 3-6 min Modified Lee & white test tube
method (whole blood coagulation time) – blood is collected by venepuncture & kept in a test tube & time is noted to form a clot.
Normal time – 8-12 min.
Monday, May 1, 2023
IMPORTANCE OF CLOTTING TIME
Physiologically – CT prolonged during mensturation & before & during Parturition.
Pathologically – Prolonged in Haemophilia, liver diseases, Afibrinogenemia, Christmas disease, vit K deficiency DIC
Monday, May 1, 2023
PROTHROMBIN TIME Procedure – Quick’s one stage
method Oxalated or citrated plasma of
patient are added to tissue thromboplastin & Ca chloride solution & mixture incubated at 37oc – result is conversion of fluid plasma to gel.
NT – 11-16 sec Importance – used to monitor pt
receiving anticoagulant therapy.
Increase in Pts on oral
anticoagulants, liver failure, vit K deficiency, deficiency of factor II,V,VII,X
Normal in Haemophilia &
Christmas disease
Monday, May 1, 2023
PARTIAL THROMBOPLASTIN TIME
Procedure – To oxalated & citrated plasma of patients kaolin & ca chloride are added & mixture is incubated at 370 C, Result is formation of plasma gel
Importance – used to monitor Heparin therapy Prolonged in – haemophilia, Von-willebrand disease,
liver failure, deficiency of XII, anticoagulant therapy & intravascular clotting.
Monday, May 1, 2023
THROMBOPLASTIN GENERATION TESTS.
Normal value – 12 sec or less Prolonged Value Indicates – Deficiency of
factors needed to form prothrombin activator by intrinsic mechanism i.e factor V, VIII,IX & X
In Haemophilia – PT is normal but TGT prolonged.
Monday, May 1, 2023
THROMBIN TIME Measures final step in coagulation i.e functional
fibrinogen available. Thrombin is added to plasma which covert
fibrinogen to fibrin End Point – Formation of clot NT – 10 sec Prolonged in Hyperfibrinogenemia,
dysfibrinogenemia, DIC & heparin treatment.
Monday, May 1, 2023
CLOT RETRACTION TEST. It measures time needed for contraction of
clot. Indicate function & number of platelets NT – 2-24 hrs. Increased in – thrombocytopenia. Clot is soft & small in – Thrombosthenia
( Functional disorder of platelet)
Monday, May 1, 2023
Thank You