2. • Coagulation is the formation of a blood clot, and is essential
to haemostasis.
• Haemostasis is the body’s physiological response
to damaged blood vessels, to slow down, minimize and
eventually cease the bleeding.
• The coagulation process is characterized by a cascade of
events which lead to the formation of a blood clot. Proteins
called clotting factors initiate reactions which activate more
clotting factors
4. How bleeding is arrested?
•When blood vessels are injured mechanically,
chemically or physically, the first step is
vasoconstriction platelets will adhere to endothelial
cell membrane and forms the primary hemostatic plug
and stop blood leakage from injured site.
•Simultaneously activate the coagulation cascade (i.e
extrinsic, intrinsic and common pathway) and form the
fibrin mesh in clot which establish the plug and form
secondary haemostatic plug (which is stable and
irreversible) and arrest bleeding permanently.
5.
6. Extrinsic Pathway
• Agents extrinsic to blood and are widely distributed to all body tissues including
vascular endothelium.
• Damage to blood vessel + factor VII exits the circulation into surrounding tissues
• Tissue factor (factor III) is released by damaged cells outside the circulation
• Factor VII + factor III TF form TF-VIIa complex activates X into its active
form, Xa.
• Xa In conjunction with factor Va, this triggers the formation of thrombin.
• Note that the extrinsic pathway is believed to be responsible for the initial
generation of activated Factor X (Factor Xa), whereas the intrinsic pathway
amplifies its production
7. Intrinsic Pathway
•The intrinsic pathway is the longer and more intricate
pathway:
•Factor XII is activated once it comes into contact with
negatively charged collagen on the damaged endothelium
•e.g factors XIIa, XIa, Kallikrein
8.
9.
10.
11. Plasminogen
• Is a plasma glycoprotein i.e produced from liver
• Plasminogen gene is located on chromosome#6 and
having 19 exons
• Is activated by specific enzyme called plasminogen
activator
• It degrades the fibrin into FDPs and D-Dimers
• Lyse factor V and VIII
12. Mechanism of action of
Thrombolytics / Fibrinolytics
They all have common MOA By
stimulation of plasminogen activation
via converting Plasminogen (Pro-
Enzyme) to plasmin (Active
Enzyme) lysis of insoluble fibrin
clots into soluble derivatives.
13.
14.
15.
16. Extrinsic factors include
1.t-PA (tissue type plasminogen activator):
• is a protein (serine protease) found on endothelial cells, the cells that
line the blood vessels.
• produced using recombinant biotechnology techniques therefore
referred to as recombinant tissue plasminogen activator (rtPA).
• Include alteplase, reteplase, and tenecteplase.
• Has high affinity for fibrin
• Gene is located at chromosome#8 and consist of 14 Exons
• Physical exercise increases the t-PA
17. 2. u-PA (Urokinase plasminogen activator)
•is a serine protease present in humans and other animals, was
discovered in 1947.
•Urokinase was originally isolated from human urine, and it is
also present in the blood and in the extracellular matrix of many
tissues.
•3 types identified:
1. Single chain pro-urokinase
2. HMW urokinase
3. LMW urokinase
18. 3. Streptokinase
• was discovered in 1933. Derived from beta-hemolytic streptococci
• SK is non enzymatic polypeptide, which forms a stable 1:1 complex
with plasminogen
• Is a thrombolytic activating plasminogen by nonenzymatic mech.
• It is used to break down clots in cases of STE Myocardial
Infarction, pulmonary embolism, and arterial thromboembolism.
• It is given by injection in vein.
• Side effects include nausea, bleeding, low bp, and allergic reactions.
• A second use in a person's lifetime is not recommended. While no harm
has been found with use in pregnancy
• It is no longer commercially available in the United States
19. Regulation of Clotting
• To prevent excessive clotting and subsequent disease,mediators
including Protein C and Protein S provide -ve feedback on the
clotting cascade.
• Protein C is activated following contact by thrombomodulin,
which is itself activated by thrombin. Along with co-factors
including protein S, activated protein C degrades Va and
VIIIa, thus slowing the rate of clotting.
• Calcium++ ions play a role through their interaction with an
activation of several clotting factors. Low levels of calcium are
therefore inhibitory to the clotting cascade.
• Antithrombin is a protease inhibitor that degrades thrombin, IXa,
Xa, XIa and XIIa. It is constantly active, but can be activated
further by a group of common anticoagulants known
as heparins.
20. How the blood is kept in fluid state in circulation?
• Endothelial cell produces NO, PGI, ADPase act as anti-platelet agents.
• ADP produced by platelets favors binding to endothelial cells but ADPase
inactivates or digest ADP
• Healthy endothelium does not tolerate activated clotting factors.
• When anti-thrombin III binds with heparin sulfate. AT-III is activated and inhibit
thrombin molecule and activated clotting IXa, Xa.
• Normally thrombin helps in coagulation but when binds with thrombomodulin it
modulates the function of thrombin which activates protein-C
• Activated protein C digest Va and VIIIa
• Endothelial cells not only prevents platelet aggregation but also inhibit proteins
that involved in coagulation. They produce t-PA plasmin cleaves fibrin into
FDPs which are then removed by macrophages and eosinophils
• By this entire process the blood is kept in fluid state.
