Anticlotting Mechanisms

Dr. REKHA
PROF & H.O.D
physiology Department
• Anticlotting mechanisms include
• Intravascular anticoagulants,
• Thrombin removal from blood,
• Heparin and clot lysis.
• Common associated disorders
 DEFINITION
• Coagulation or clotting is defined as the process in
which blood loses its fluidity and becomes a jelly like
mass few minutes after it is shed out or collected in a
container.
• Coagulation of blood occurs through a series of
reactions due to activation of a group of substances .
• Substances are necessary for clotting are called
clotting factors.
 FACTORS INVOLVED IN BLOOD CLOTTING
Thirteen clotting factors are identified .
Factor I Fibrinogen
Factor VIII Antihemophilic factor
Factor II Prothrombin
Factor IX Christmas factor
Factor III Thromboplastin
Factor X Stuart prower factor
Factor IV Calcium
Factor XI Plasma thromboplastin
Factor V Labile factor
(proaccelerin) antecedent
Factor VI Presence has not been Factor XII Hageman factor
proved Factor XIII Fibrin stabilizing
Factor VII Stable factor factor
 SEQUENCE OF CLOTTING
MECHANISM
• In general, blood clotting occurs in 3 stages.
Formation of prothrombin activator
Conversion of prothrombin into thrombin
Conversion of fibrinogen into fibrin
 STAGE : I
FORMATION OF PROTHROMBIN ACTIVATOR
• Blood clotting commences with the formation of a substances called
prothrombin activator , which converts prothrombin into thrombin .
• Its formation is initiated by substances produced either with in the
blood or outsider the blood .
• Thus, formation of prothrombin activator occurs through two
pathways.
1. Intrinsic pathway
2. Extrinsic pathway
 INTRINSIC PATHWAY

• In this pathway, the formation of prothrombin

activator is initiated by platelets, which are within
the blood itself.
 EXTRINSIC PATHWAY

• In this pathway, the formation of prothrombin

activator is initiated by the tissue thromboplastin,
which is formed from the injured tissues.
 BLOOD CLOT
• Blood clot is defined as the mass of coagulated blood
which contains RBCs, WBCs and platelets entrapped
in fibrin meshwork.
• These cells are trapped in it along with platelets .
• The trapped RBCs are responsible for the red colour
of the clot .
• The external blood clot is also called scab.
• It adheres to the opening of damaged blood vessel
and prevents blood loss
 CLOT RETRACTION
• After the formation , the blood clot starts contracting
and after about 30 to 45 minutes, the straw coloured
serum oozes out of the clot .
• The process involving the contraction of blood clot
and oozing of serum is called clot retraction.
• Contractile proteins, namely actin, myosin and
thrombosthenin in the cytoplasm of platelets are
responsible for clot retraction.
 FIBRINOLYSIS
• Lysis of blood clot inside the blood vessel is
called fibrinolysis.
• It helps to remove the clot from lumen of the
blood vessel .
• This process requires a substance called plasmin
or fibrinolysin.
 FORMATION OF PLASMIN
• Plasmin is formed from inactivated glycoprotein
called plasminogen.
• Plasminogen is synthesized in liver and it is
incorporated with other proteins in the blood clot.
• Plasminogen is converted into plasmin by tissue
plasminogen activator (t-PA), lysosomal enzymes and
thrombin.
• The t-PA and lysosomal enzymes are released from
damaged tissues and damaged endothelium.
• Thrombin is derived from blood .
• The t-PA is always inhibited by a substances called
t-PA inhibitor.
• It is also inhibited by factors V and VIII.
• Besides, t-PA, there is another plasminogen activator
called urokinase plasminogen activator (u-PA).
• It is also derived from blood.
 ANTICLOTTING MECHANISM IN
THE BODY
• Under physiological conditions , intravascular does not
occur . It is because of the presence of some
physiochemical factors in the body.
PHYSICAL FACTORS :
• Continuous circulation of blood.
• Smooth endothelial lining of the blood vessels.
CHEMICAL FACTORS- NATURAL ANTICOAGULANTS:
Presence of natural anticoagulant called HEPARIN that is
produced by liver.
Production of thrombomodulin by endothelium of the
blood vessels (except in brain capillaries).
• Thrombomodulin is a thrombin –binding protein.
• It binds with thrombin and forms a thrombomodulin-
thrombin complex .
• This complex activates protein C along with its cofactor
protein S INACTIVATES FACTOR V and factor VII.
• Inactivation of these 2 clotting factors prevents clot
formation.
All clotting factors are in inactive state .
 Intravascular Anticoagulants
• There are three intravascular anticoagulant mechanisms:
1. Smooth endothelial cell surface
• Smooth endothelial cell surface prevents activation of intrinsic clotting
system
2. Glycocalyx layer on endothelium
• It repels clotting factors & platelets
3. Thrombomodulin
• Thrombomodulin is a protein bound with endothelial membrane. It
binds thrombin to prevent clot formation.
 Thrombin Removal from Blood

Thrombin removal from blood is mediated by:

1. Fibrin fibers
2. Antithrombin III ( Antithrombin-Heparin
cofactor)
• 85 –90% of thrombin is bound to fibrin, which
prevents spread of thrombin.
• Remaining amount is bound to antithrombin-III.
 HEPARIN
• Heparin is a powerful anticoagulant, present in low concentration in
blood.
• It is released by mast cells and basophils.
• It is a highly negatively charged conjugated polyssacharide.
• Heparin + Antithrombin III complex has 100 fold increase in
effectiveness.
• Removal of thrombin and activated factors XII, XI, X, IX take place.
 USES OF HEPARIN
• Heparin is used as an anticoagulant both in vivo and in vitro .
• Clinical use:
• I v injection of heparin (0.5 to 1 mg /kg body weight )
postpones clotting for 3 to 4 hours ( until it is destroyed by
the enzyme Heparinase).
• It is used for many purposes such as :
• To prevent intravascular blood clotting during surgery.
• During cardiac surgery, which involves heart lung machine.
• To preserve the blood before transfusion.
 USE IN LABORATORY
• Heparin is also used as anticoagulant in vitro.
• Heparin is the most expensive anticoagulant.
 Clot Lysis
• Clot lysis is mediated by:
1. Plasminogen (Profibrinolysin) –which is a euglobulin
2. Proteolytic enzyme –which resembles trypsin
• They digest:
• Fibrin fibers
• Fibrinogen
• Factor V
• Factor VIII
• Prothrombin
• Factor XII
 BLEEDING DISORDERS
• Bleeding disorders are the conditions characterized by
prolonged bleeding time or clotting time.
• Bleeding disorders are of 3 types :
• Haemophilia
• Purpura
• Von Willebrand disease
 Excessive Bleeding
• Excessive bleeding may occur in following disorders:
• Vitamin K deficiency
• Hemophilia
• Thrombocytopenia ( ↓Platelets)
• Liver Disease e.g. hepatitis and cirrhosis
 Vitamin K
• Vitamin K is involved in formation of 5 clotting factors:
1.Prothrombin
2.Factor VII
3.Factor IX
4.Factor X
5.Protein C
 HEMOPHILIA

• Hemophilia is X-linked recessive disorder.

• Hemophilia A (Classic Hemophilia) occurs in 85% of cases,
in which there is deficiency of factor VIII.
• Factor VIII has 2 components:
• 1. Large component which has molecular weight in millions,
and is involved in von Willebrand’s disease
• 2. Smaller component which is important in intrinsic
pathway
 PURPURA
• Purpura is a disorder characterized by prolonged
bleeding time.
• However, the clotting time is normal .
• Spontaneous bleeding under the skin from ruptured
capillaries.
• It causes small tiny haemmorhagic spots in many
areas of the body .
• The haemmorhagic spots under the skin are called
purpuric spots.
 Thrombocytopenia

• Thrombocytopenia is the low platelet count due to

which bleeding occurs from small venules and
capillaries. Punctate hemorrhages and purplish blotches
are seen.
• Bleeding occurs when platelet count decreases below
50,000/μl.
• Below 10,000/μl, it can be lethal.
 IDIOPATHIC
THROMBOCYTOPENIA

Antibodies against platelets are formed in

this disorder. Treatment involves fresh whole
blood transfusions and splenectomy.
 VON WILLEBRAND
DISEASE
It is a bleeding disorder characterized by excess
bleeding even with a mild injury.
It is due to the deficiency of VON WILLEBRAND
FACTOR.
Deficiency of VON WILLEBRAND factor suppresses
platelet adhesion.
It also causes deficiency of factor VIII.
This result in excess bleeding.
 Thrombi & Emboli
• Thrombus is an abnormal clot in blood vessel.
• Embolus is a freely floating clot.
• These are formed by roughened endothelial surface
of vessel and slow blood flow through vessels.
• Femoral vein thrombosis is most important, which
may lead to massive pulmonary embolism.
• Disseminated Intravascular Coagulation
• Large amounts of traumatized / dead tissue in body or widespread
septicemia by bacterial endotoxins, leads to release of large
amounts of tissue factor.
• Due to this, small vessels are plugged leading to oxygen
deprivation of tissues resulting in:
• Septicemic shock
• Spontaneous bleeding