Haemostasis

By several mechanisms

- Vascular spasm
o Nervous reflexes
o Local myogenic spasm (main)
o Local humoral factors
o Blood platelets
- Forming platelet plug
o Contact with damaged vascular surface
o Begin to swell, assume irregular forms with numerous irradiating pseudopods protruding from their
surfaces
o Contractile proteins contract forcefully and cause release of granules that contain multiple active
factors
o Become sticky so they adhere to collagen in the tissue and to von Willebrand’s factor
o Secrete large quantities of ADP, their enzymes form thromboxane A2.
o ADP and thromboxane act on nearby platelets to activate them as well
o Stickiness of additional platelets causes them to adhere to the originally activated platelets
o Damaged vascular wall elicit activation of successively increasing numbers of platelets  attract
more platelets  platelet plug
o Fibrin threads form, attach to platelets, constructing unyielding plug
- Formation of blood clot
o Initiation of coagulation: formation of prothrombin activator
 Extrinsic pathway for initiation clotting


 Release of tissue factor (tissue thromboplastin)
o From traumatised tissues
o Complex of several factors
o Composed of phospholipids from membranes of tissues + lipoprotein
complex that functions as proteolytic enzyme
  Activation of Factor X
o Lipoprotein complex above complexes with blood coagulation Factor VII
o In presence of Ca2+, activates Factor X
 Effect of activated factor X (Xa) to form prothrombin activator – role of factor V
o Xa combines with tissue phospholipids (part of tissue factor or with
additional phospholipids)
o And factor V to form prothrombin activator
o In presence of Ca2+, prothrombin  thrombin
o Proteolytic action of thrombin activates factor V
 Strong accelerator of prothrombin activation
o Factor X is the actual protease which causes prothrombin  thrombin
 Intrinsic pathway for initiation clotting


 Blood trauma causes
o Activation of Factor XII
 In coming into contact with collagen
 Takes in a new molecular configuration  XIIa
o Release of platelet phospholipids
 Trauma damages platelets
 Adherence to collagen  releases platelet phospholipids
 Contain platelet factor 3
o Plays a role in subsequent clotting reactions
 Activation of Factor XI
o Factor XII activates XI Xia
 o Requires HMW (high molecular weight) kiniogen
o Accelerated by prekallikrein
 Activation of Factor IX
o By activated XI
 Activation of Factor X – role of Factor VII
o Activated IX with VIIIa and platelet phospholipids and factor 3 from
traumatized platelets  Xa
o Factor VIII missing  classic haemophilia
 VIII – antihaemophilic factor
 Platelets lacking – thrombocytopenia
 Action of activated Factor X to form prothrombin activator – role of factor V
o Same as extrinsic pathway
o Factor X + Factor V and platelet or tissue phospholipids  prothrombin
activator
o Then prothrombin to thrombin
 Role of calcium ions in intrinsic and extrinsic pathways
 Promoting / accelerating all blood-clotting reactions except first 2 steps in intrinsic
pathway
 Interactions between extrinsic and intrinsic pathways (Summary)

Intrinsic Pathway Extrinsic Pathway

Happens Simultaneous
Triggered by Contact of Factor XII and platelets with collagen Tissue factor (TF)
in vascular wall
Speed Slower, 1-6 minutes Explosive speed, limited by TF, X, VII, V
Measured PTT (partial thromboplastin time) PT (prothrombin time)
by
Slowed test Deficiencies in VIII, IX, XI, XII, von Willebrand’s II (thrombin), V, VII, X, fibrinogen
(rare)

o Conversion of prothrombin (produced by liver, with Vit K) to thrombin


 After prothrombin activator formed by rupture of blood vessel
 Causes conversion of prothrombin to thrombin in presence of Ca 2+
 Thrombin  polymerisation of fibrinogen molecules into fibrin fibres
 Platelets have prothrombin receptors, attract prothrombin, accelerates formation of
thrombin
o Conversion of fibrinogen (formed in liver) to fibrin – formation of the clot
  Action of thrombin on fibrinogen to form fibrin
 Acts on fibrinogen  removes peptides  fibrin monomer  fibrin polymer
 Fibrin stabilising factor cause covalent bonds between fibrin monomers and cross
linkages between adjacent fibrin fibres  3D strength of fibrin meshwork
o Thrombin activates fibrin stabilising factor
o Released from platelets trapped in clot
o Present in small amounts in plasma globulins
 The blood clot
 Composed of
o Meshwork of fibrin fibres running in all directions
 Adhering to damaged surfaces of blood vessels
o Entrapping blood cells, platelets, plasma
 Clot retraction – serum
 Clot contracts
 Expresses most of fluid in clot (serum)
o Fibrinogen and most of clotting factors have been removed
 Platelets are essential
o Still continue to release procoagulant substances
 E.g. Fibrin stabilising factor  more cross linking bonds
o Activate platelet thrombosthenin, actin, myosin
 Cause contraction of platelet spicules attached to fibrin
 Compress fibrin meshwork into smaller mass
 Accelerated by thrombin and Ca2+
 Edges of blood vessel pulled together
o Vicious cycle of clot formation
 Thrombin acts on many other clotting factors in addition to fibrinogen
 Direct proteolytic effect on prothrombin  thrombin
 Acceleration of Factors VIII, IX, X, XI and XII, aggregation of platelets

Prevention of Blood Clotting in Normal Vascular System – Intravascular Anticoagulants

- Endothelial
surface
factors
(prevent
clotting)
 o Smoothness of the endothelial surface
 Prevents contact activation of the intrinsic clotting system
o Layer of glycocalyx on endothelium
 Repels clotting factors and platelets
o Thrombomodulin (bound with endothelial membrane)
 Binds thrombin
 Thrombomodulin-thrombin complex activates protein C
 Inactivates Va and VIIIa
- Antithrombin action of fibrin and antithrombin III
o Thrombin adsorbed to fibrin fibres
o Prevent spread of thrombin into remaining blood, prevents excessive spread of clot
o Thrombin which does not adsorb combines with antithrombin III  blocks effect of thrombin on
fibrinogen, inactivates thrombin
- Heparin
o Combines with antithrombin III, effectiveness of antithrombin III increases hundred fold
o Removes XIIa, XIa, IXa, X

Lysis of Blood Clots – Plasmin

- Activation of Plasminogen to Form Plasmin: Then Lysis of Clots

o Plasmin digests fibrin fibres, fibrinogen, V, VII, XII, prothrombin
 Causes lysis of clot
o Clot formed
 Large amount of plasminogen trapped
 Injured tissues and vascular endothelium slowly release tissue plasminogen activator (t-PA)
 A day or so later, plasminogen  plasmin  removes blood clot