HEMOSTASIS
Platelets & Blood clotting
Platelets (Thrombocytes)
• Involved in hemostasis
• Less than half the size of RBC
• Numerous (250,000-400,000 per mm3)
• Actually cell fragments rather than true
cells
• Life span is about 5-9 days
Platelets (Thrombocytes)
* Cell fragments bound to megakaryocytes
* “Bud Off” and are released into the blood
Hemostasis
• To stop bleeding from a damaged vessel
in order to maintain a constant blood
volume
• Three Steps involved in Hemostasis
1. Vascular Spasm
2. Formation of a platelet plug
3. Blood coagulation (clotting)
Blood Status Before Injury
• In the blood there are both pro-coagulants
and anticoagulants.
• The pro-coagulants are chemicals that are
in favor of blood clotting
• Whereas, anticoagulants prevent blood
clotting
• These chemicals are activated or
deactivated according to body needs
Blood Status Before Injury
• The pro-coagulants are mostly activated in
case of injury
• Whereas, anticoagulants are mostly active
in case there is no injury and to stop
clotting factors once the injury is dealt with
Blood Status Before Injury
• Blood normally remains in its liquid state
while it is within the blood vessels but when
it leaves them the blood may thicken and
form a gel (coagulation).
Blood Status Before Injury
• The endothelium normally promotes blood
fluidity, unless there is an injury.
• With damage, the normal response is to
promote coagulation at the wound site
while containing the coagulation response
and not allowing it to propagate beyond this
site.
Blood Status Before Injury
• The endothelium and ultimately the entire
vessel are normally geared to maintain
blood fluidity in the absence of injury.
• To that end, the endothelium possesses a
variety of functions whose ultimate goal is
to promote blood fluidity.
• The anticoagulant functions of the
endothelium inhibit all aspects of the
coagulation pathways
Blood Status Before Injury
• Prostacyclin (PGI2), a prostaglandin
produced by the endothelial-specific
cyclooxygenase enzyme system, is a
potent inhibitor of platelet aggregation.
Blood Status Upon injury
• Prostacyclin (PGI2), secretion at site of
injury stops
• Platelets, only at site of injury, become
activated and start to secret several
chemicals.
Blood Status Upon injury
▪Once activated, Platelets start to
secret:
▪Serotonin
▪ADP & Thromboxane A2
Stages of Hemostasis
• Step 1: Vascular spasms
▪ Mainly Serotonin
• Step 2: Formation of a platelet
plug
▪ ADP
▪ Thromboxane A2
Stages of Hemostasis
STEP 3:
COAGULATION
• Phase 1: Formation of
prothrombin activator
• Phase 2: Conversion
of prothrombin to
thrombin
• Phase 3: Conversion
of soluble fibrinogen
into insoluble fibrin
Steps in Hemostasis
DAMAGE TO BLOOD VESSEL LEADS TO:
1. Vascular Spasm:
• Caused mainly by:
• Serotonin
• Local reflexes
• Leading to:
• Immediate constriction of blood vessel
• Minimize blood loss
Steps in Hemostasis
2. Platelet Plug formation:
• Platelets adhere to exposed collagen from injured
vessel surfaces
b. Aggregation of platelets causes release of
chemical mediators (ADP, Thromboxane A2)
c. ADP attracts more platelets and make them
sticky
d. Thromboxane A2 promotes aggregation and
activation of more Platelets
Hence formation of platelet plug !
(+) Feedback promotes formation of platelet Plug !
Final Step in Hemostasis
3. Blood Coagulation (clot formation):
“Clotting Cascade”
-Transformation of blood from liquid to solid
-Clot reinforces the plug
-Multiple cascade steps in clot formation
Final Step in Hemostasis
The three stages involved in blood
coagulation are:
1- Formation of a complex of activated
substances collectively called Prothrombin
Activator
2- Conversion of Prothrombin to Thrombin
3- Conversion of Fibrinogen (soluble) to Fibrin
(insoluble)
Fibrinogen (plasma protein) Thrombin Fibrin
Clotting Cascade
Clotting Cascade
• Participation of 12 different clotting
factors (plasma glycoproteins)
• Factors are designated by a roman
numeral
• Cascade of proteolytic reactions
• Intrinsic pathway / Extrinsic pathway
Fibrinogen (Factor I) Adhesive protein that forms the fibrin clot
Prothrombin (Factor II) Activated form is main enzyme of coagulation
Tissue factor (Factor III) Lipoprotein initiator of extrinsic pathway
Calcium ions (Factor IV) Metal cation necessary for coagulation Reactions
Factor V (Labile factor) Cofactor for activation of prothrombin to thrombin
Factor VII (Proconvertin) With tissue factor, initiates extrinsic Pathway
Factor VIII (Antihemophilic factor) Cofactor for intrinsic activation of factor X
Factor IX (Christmas factor) Activated form for intrinsic activation of factor X
Factor X (Stuart-Prower factor) Activated form is enzyme for final common
pathway activation of prothrombin
Factor XI (Plasma thromboplastin Activated form is intrinsic activator of factor IX
Antecedent
Factor XII (Hageman factor) Factor that nominally starts aPTT-based
intrinsic pathway
Factor XIII (Fibrin stabilizing Transamidase that cross-links fibrin clot
factor)
High-molecular-weight William Cofactor
factor)
Prekallikrein (Fletcher factor) Activated form that participates in intrinsic pathway
Keep in Mind
▪Homeostasis and bood clotting are
localized at site of injury.
▪That is if all is fine with the blood
vessels and blood
Clotting Cascade
Prothrombin activator can be formed in two ways,
depending on which of two "systems" or "pathways"
apply.
• Extrinsic Pathway: This is initiated by liquid blood
making contact with damaged tissue.
• Intrinsic Pathway: This is initiated by liquid blood
making contact with a foreign surface
Both the intrinsic and the extrinsic systems involve
interactions between coagulation factors.
Intrinsic and Extrinsic Pathways
• The intrinsic pathway has low significance under
normal physiological conditions.
• Most significant clinically is the activation of the
intrinsic pathway by contact of the vessel wall with
lipoprotein particles, VLDLs and chylomicrons.
• This process clearly demonstrates the role of
hyperlipidemia in the generation of atherosclerosis.
• The intrinsic pathway can also be activated by
vessel wall contact with bacteria.
Hageman factor (XII)
X
inactive
active
CLOT !
Clotting Cascade
• Intrinsic Pathway:
• Stops bleeding from within the blood
• Contact with foreign Substances (test tube)
• Extrinsic pathway:
• Clots blood that has escaped into tissues
• Requires tissue factors external to blood
Clot dissolution
• Clot is slowly dissolved by the “fibrin splitting”
enzyme called Plasmin
• Plasminogen is the inactive pre-cursor that is
activated by Factor XII
• Plasmin gets trapped in clot and slowly dissolves it
by breaking down the fibrin meshwork
Fibrinolysis
• Fibrinolysis:
• Process of liquefaction of fibrin
Activator
plasminogen plasmin
fibrin fibrin degradation products
Activator: Tissue plasminogen activator (tPA), urokinase.
Plasmin, a serine protease, is inhibited by 2-antiplasma.
Factors Effecting Clot Formation
Normal coagulation:
-Adequate number of
platelets
-Availability of all clotting
factors, Vitamin K,
Calcium ions and TF
Anticoagulants
• Anticoagulants can be used in vivo and in vitro:
• Heparin (used both in vivo and in vitro):
• A polysaccharide produced in basophilic mast cells
• Abundant in lung, heart, liver, muscle tissues.
• Inhibit thrombin conversion.
• Promote antithrombin III activity.
• Dicumarol is a coumarin anticoagulant (used in vivo):
• Acts by inhibiting the hepatic synthesis of vitamin K–
dependent coagulation factors.
• Calcium ions precipitants (used in vitro) :
• Sodium citrate
Coagulation disorders
• Hemophilia A:
• Deficiency of FVIII. The disease severity usually
parallels the factor VIII levels.
• Therapy: administration of FVIII.
• Hemophilia B (Christmas Disease):
• FIX deficiency.
• Therapy: administration of FIX
Coagulation disorders
• Deficiency of Vitamin K leads to a decrease in the
production of coagulation factors:
• Liver disease, vitamin K malabsorption, dietary
deficiency of vitamin K.
• Thrombocytopenia purpura;
• Severe decrease in number of platelets
• Autoimmune disease
• Blue purple blotches all over the body
