Haemostasis ii

DR NILESH KATE
MBBS,MD
ASSOCIATE PROF
DEPT. OF PHYSIOLOGY
HAEMOSTASIS II
ANTIHAEMOSTATIC
MECHANISMS

OBJECTIVES.
 Anti-haemostatic
mechanism.
 Bleeding disorders.
 Laboratory tests
Monday, June 20, 2016

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.

FACTORS PREVENTING
PLATELET AGGREGATION
 PROSTACYCLIN – Endogenous
factor inhibit Thromboxane
A2( Promote Platelet
Aggregation).
 Normally balance between
Prostacyclin
Thromboxane A2
Prevents Intravascular spread of
plug.

FACTORS PREVENTING
COAGULATION
 Circulating Anticoagulant
 Heparin
 Anti-thrombin III or heparin Co-factor II
 Protein C.

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.

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

ANTI-THROMBIN III OR
HEPARIN CO-FACTOR II
 Present in plasma &
vascular endothelium.
 Inactivates
Coagulation factors
including thrombin.

PROTEIN C.
 Plasma protein from
liver.
 Along with
Thrombomodulin &
protein S forms
Negative feedback for
Coagulatory process
under control.

PROTEIN C PATHWAY INHIBITING
COAGULATION & PROMOTING
FIBRINOLYSIN.

THROMBOMODULIN
 Thrombin binding
protein produced by
endothelial cells
except cerebral
microcirculation.
 Converts thrombin
into protein C
activator.

FIBRINOLYTIC MECHANISM
 FIBRINOLYSIS –
dissolution of Fibrin.
 Important component
is Plasmin or
fibrinolysin present in
inactive form called
plasminogen or
Profibrinolysin.

FACTORS CAUSING FIBRINOLYSIS
 Plasminogen
 plasmin.
 Extrinsic plasminogen
activator system
 Intrinsic plasminogen
activator system

PLASMINOGEN
 Beta globulin
produced by liver.
 It is associated with
fibrinogen molecule.
 Plasminogen is
activated by
plasminogen activator
system to produce
PLASMIN.

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

EXTRINSIC PLASMINOGEN
ACTIVATOR SYSTEM
 Predominant
mechanism
 In its absence
extensive fibrin
deposition occurs.
 Its absence causes
 delayed wound healing
 Defect in growth &
fertility.

FIBRINOLYTIC MECHANISM OPERATING
THROUGH EXTRINSIC PLASMINOGEN
ACTIVATOR SYSTEM.
PLASMINOGEN
TPA
THROMBIN
UPA
PLASMIN
Fibrin Fibrin degradation
product (FDP)

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.

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.

INTRINSIC PLASMINOGEN
ACTIVATOR SYSTEM
 Contact factor XIIa & Kallikrein intiate
clotting mechanism also stimulate
dissolution of clot by activating plasminogen
& form intrinsic plasminogen activator
system.

FIBRINOLYTIC MECHANISM OPERATING
THROUGH INTRINSIC PLASMINOGEN
ACTIVATOR SYSTEM.
Prekallikrein
 XII XIIa
Kallikrein
Thrombin
Plasminogen Plasmin
Fibrin Fibrin Degradation
Product (FDP)

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.

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

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

ANTICOAGULANTS
 Endogenous Anticoagulants – inside body
naturally – Heparin, antithrombin III & protein
C
 Exogenous anticoagulants or decalcifying
agents.
 Heparin
 Calcium sequesters
 Vitamin K antagonists
 Defibrination substances.

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.

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

DEFIBRINATION SUBSTANCES.
 Which causes destruction of fibrinogen.
 Malaysian pit viper venom
 Arvin or ancord – preparation of snake
venom.

BLEEDING DISORDERS
 Spontaneous escape of blood from blood
vessels or
 Persistent or excessive bleeding following
minor injuries like tooth extraction etc.

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

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.

PURPURA
 Group of bleeding
disorders due to
various causes.
 PURPURA – purple
coloured petechial
hemorrhages &
bruises in the skin.

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.

CAUSES AND TYPES OF
PURPURA
 Functional disorders of platelets.
(Thrombosthenic purpura)
 Drug induced defects –aspirin
 Von-willebrand’s disease.
 Vascular disorders (Non-
thrombocytopenic Purpura)

CAUSES OF NON-
THROMBOCYTOPENIC PURPURA.
 Drug induced damage to capillary wall.
 Deficiency of vitamin-C
 Allergic purpura.
 Infections
 Senile purpura
 Connective tissue diseases.

HAEMOPHILIA
 Group of disorders
due to hereditary
deficiency of
coagulation.
 Characterized by
Bleeding tendencies
with Increased
clotting time.

HAEMOPHILIA
 Haemophilia-A
 Haemophilia-B
 Haemophilia-C

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.

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.

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.

HAEMOPHILIA-C
 Deficiency of
PTA(Factor X)
 Inherited as Mendelian
dominant affects both
males & females.
 Without bleeding
tendencies.
 CT may be prolonged or
normal.

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.

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.

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.

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.

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.

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.

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

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
37o
c – 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

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.

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.

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.

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)

Haemostasis ii

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