HEMOSTASIS

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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
  sub-endothelial 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
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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 high-molecular-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
  pre-formed 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 VIIIC, 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).