Download HEMOSTASIS

HEMOSTASIS
Damaged Blood Vessels.
On vessel injury
Vasoconstriction occurs as a neurogenic response. Injury
breaks the smooth endothelial lining, exposing Collagen
that promotes thrombus formation by causing the
adherence of platelets to the area of injury.
Collagen exposure also initiates the contact phase of
coagulation, which begins a series of biochemical
reactions known as the Intrinsic coagulation-pathway.
Tissue Thromboplastin is release from the injured vessel,
which-promotes coagulation through a different series of
reactions known as the Extrinsic pathway.
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Vessel wall, Blood flow & Coagulation Substances
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In Case if there is an Endothelial Injury
(Bleeding must be prevented at site of injury)
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Flow must be Maintained
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HEMOSTASIS
Primary Hemostasis
Is initiated by the exposure of platelets to the subendothelial connective tissue components of blood vessels
(collagen, microfilamients, basement membranes).
If acute injury occurs, the small vessels constrict, and
platelets immediately adhere to the exposed surfaces and
release ADP and ATP.
Thromboxane A also is released, which promotes further
Vasoconstriction.
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HEMOSTASIS
A reversible primary platelet aggregation takes place
during which platelets adhere to one another. Platelets
also change shape, and their organelles become
centralized. At this point, platelets may disaggregate in
the absence of further stimulation. However, with
continued stimulation, Secondary, irreversible, platelet
aggregation naturally occurs.
Important substances released during platelet
aggregation include ADP, ATP, and serotonin. The ADP
promotes secondary platelet aggregation and recruits
additional platelets to the site of injury. Serotonin
promotes further vasoconstriction.
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HEMOSTASIS
During aggregation, phospholipid (PL) becomes
available on the platelet membrane surface, providing a
site for fibrin formation and thrombo-genesis (the
formation of blood clots).
Secondary Hemostasis
The Intrinsic and Extrinsic Coagulation Pathways
The intrinsic system is activated in vivo by the contact of
certain coagulation proteins with subendothelial
connective tissue, which sets the secondary hemostatic
mechanism into motion.
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HEMOSTASIS
The extrinsic coagulation pathway, in contrast, is
initiated with the release of tissue factor from injured
vessel endothelial cells and sub-endothelium into the
vessel lumen.
Tissue factor, a high-molecular-weight lipoprotein, is
found in most organs, including the lungs, kidneys, liver,
brain, placenta, and spleen, as well as in large blood
vessels such as the vena cava and aorta.
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HEMOSTASIS
Both the intrinsic and the extrinsic coagulation pathways
lead to secondary hemostasis, namely, the formation of
the stable fibrin clot. The clot thus includes both fibrin
formed in secondary hemostasis and the platelet plug
formed in primary hemostasis.
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Hemostatic Plug Formation
PRIMARY
AGGREGATION
Platelet Aggregation
Clotting
Hemostatic
clot
Fibrin
SECONDARY
COAGULATION
Thrombin
0 min
5 min
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10 min
HEMOSTASIS
COAGULATION PROTEINS
The intrinsic and extrinsic coagulation pathways are a
series of reactions involve coagulation factors known as
1- enzyme precursors (zymogens)
2- non-enzymatic (cofactors)
3- calcium (Ca ++)
4- phospholipids (PL).
All coagulation factors normally are present in the
plasma, with PL being provided by platelets.
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HEMOSTASIS
The zymogens are factors II, VII, IX, X, XI, XII, and
prekallikrein
The cofactors are factors V, VIII, tissue factor, and highmolecular-weight kininogen (HMWK).
Zymogens are substrates that have NO biologic activity
until converted by enzymes to active enzymes called
serine proteases, which have exposed, serine-rich, active
enzyme sites.
Serine proteases selectively hydrolyzed arginine or
lysine-containing peptide bonds of other zymogens, thus
converting them to serine proteases.
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COAGGULATION FACTORS
Factor Nomenclature
The nomenclature of coagulation factors covers those
referred to by Roman numerals and the two factors in
the kinin system, prekallikrein and HMWK, which are
referred to by name only.
Each factor was assigned a Roman numeral by the
International Committee in Nomenclature of Blood
Coagulation Factors in the order of its discovery, not its
place in the reaction sequence.
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COAGGULATION FACTORS
An important aspect of coagulation factor nomenclature
is the “a” that sometimes accompanies a Roman numeral
(e.g., factor Xlla). It indicates the activated serine
protease form of that factor.
Tissue factor is sometimes referred to as factor III and
calcium ions, as factor IV. However, tissue and calcium
(Ca++) are the generally accepted terms today.
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COAGGULATION FACTORS
COAGULATION GROUPS
 The properties of the coagulation and kinin factors have
similarities that can divide these factors easily into three
groups:
1- Contact group;
2- Prothrombin or vitamin K-dependent group;
3- Fibrinogen group.
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COAGULATION GROUPS
 Contact Group
Prekallikrein and HMWK of the kinin group along with
factors XII and XI, make up the contact group.
The contact group is adsorbed by contact with a
negatively charged surface such as collagen or the
subendothelium in vivo.
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COAGULATION GROUPS
 This contact causes slow conversion of factor XII to XIIa,
which initiates both intrinsic system coagulation and
fibrinolysis.
 Factor XIIa, and HMWK together activate factor XI to
XIa, and convert prekallikrein to kallikrein. Kallikrein
and HMWK together play a role in intrinsic coagulation
activation, activation of fibrinolysis, kinin formation, and
activation of the complement system.
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COAGULATION GROUPS
Prothrombin (Vitamin K-Dependent) Group
Contains the vitamin K-dependent coagulation factors
II, VII, IX, and X.
These factors are synthesized in the liver in the presence
of vitamin K, which acts as a cofactor.
Vitamin K is fat soluble. It is normally ingested in the
diet and also is manufactured by the gut flora. There is
no substantial storage of vitamin K in the body.
Vitamin K is necessary to gamma-carboxylate the preformed enzyme precursors of factors (II, VII, IX, and X )
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COAGULATION GROUPS
Vitamin K-dependent gamma-carboxylation reactions
may be inhibited by several mechanisms:
(1) dietary vitamin K deficiency;
(2) administration of antibiotics that sterilize the
intestinal tract, where normal flora usually synthesize
vitamin K;
(3) oral anticoagulant therapy, such as with the coumarin
and warfarin drug, which interferes with gamma
carboxylation.
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COAGULATION GROUPS
Any of these mechanisms can cause the formation of
non-functional vitamin K-dependent coagulation factors.
When such factors are released to the circulation, they
cannot bind to the platelet PL surface and ultimately
prevent Prothrombin activation, causing a deficiency in
the coagulation pathway.
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COAGULATION GROUPS
Fibrinogen Group
The fibrinogen group includes fibrinogen (factor I) and
factor V, VIII, and XIII. These have the highest
molecular weights of all factors, are the most labile, are
consumed in coagulation, and are the only group that act
as substrates for the fibrinolytic enzyme plasmin.
Only the factors found in the fibrinogen group are found
in the platelets, specifically in the alpha granules with
two exceptions: (1) factor XIII is found in the general
platelet cytoplasm not in alpha granules, and (2) factor
VIII:C, the coagulant portion of factor VIII, is not found
in platelets.
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COAGULATION GROUPS
PHOSPHOLIPIDS CONTRIBUTING TO COAGULATION
 Tissue Factor
 The existence of a lipoprotein called Thromboplastin (a
complex of two parts, a PL and a protein).
 This substance initiates the extrinsic coagulation
pathway by binding its PL portion to factor VII,
converting factor VII to VIIa.
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PHOSPHOLIPIDS CONTRIBUTING TO COAGULATION
 The term extrinsic was applied to this pathway because
of the necessity of adding a tissue extract (PL) to plasma
samples in vitro to initiate and evaluate this coagulation
pathway in the laboratory.
 The Prothrombin Time (PT) test which evaluates the
extrinsic system, is performed using a reagent contained
(rabbit brain) or lung tissue Thromboplastin as well as
Ca++ to activate factor VII and initiate the extrinsic
pathway.
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COAGULATION CASCAED
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The KININ System
Kinins are peptides of low molecular weight composed of
a series of amino acids.
The kinin system contains factors that are activated by
the coagulation and fibrinolytic systems.
They mediate inflammatory responses, increase vascular
permeability, cause vasodilatation and hypotension.
Important in the contact activation phase of the intrinsic
coagulation pathway as in complement activation.
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KININ System
The kinin system factors do not have assigned Roman
numerals. They include:
1- prekallikrein
2- kallikrein
3- kininogen (low and high molecular weight)
Prekallikrein circulate in plasma as a complex with the
cofactor HMWK, and both also are a part of the contact
group.
Prekallikrein is converted to the serine protease
kallikrein in the presence of factor XIIa and HMWK.
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COAGGULATION & The KININ System
 Kallikrein accelerates factor XII activation
 Also involved in the fibrinolytic system.
 Kallikrein and activated XIIa form a complex known as
the plasminogen activator which converts plasminogen
to its active form, plasmin.
 Plasmin is necessary for the degradation of the fibrin clot
(fibrinolysis).
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