hemostasis_surgury 1
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    hemostasis_surgury 1 hemostasis_surgury 1 Presentation Transcript

      Department of Surgery
      balance of the physiological processes
      prevent excessive bleeding after vessel injury
      maintain a viable circulation by keeping the blood in an uncoagulated state
      “Self-sealing” system to prevent excessive bleeding and potentially life threatening states
    • Four components
      Vessel function constriction of injured vessels
      Platelet function formation of platelet plugs
      Coagulation formation of fibrin plugs
      Fibrinolysis dissolution of blood clots
    • Normal Hemostasis
      Means stopping of blood – prevents blood loss
      Imbalance in one direction may lead to excessive bleeding, imbalance in the other may lead to thrombus formation
    • Overview of blood coagulation
    • Hemostasis
      Primary Hemostasis
      Formation of platelet plug
      Secondary Hemostasis
      Formation of blood clot
      response is dependent on overlapping and interdependent responses
    • Vascular Endothelium
      Blood vessel wall integrity is essential for prevention of blood loss – provides potent anticoagulation surface.
    • Vascular Endothelium
      ECs form monolayer resting on continuous basement membrane; constitutes first barrier of defense from hemostasis and thrombosis
    • EC Products Secreted into the Subendothelium
      EC surface products secreted into the blood stream
    • ECs provides numerous proteins to subendothelium essential for cell–to-cell interactions and formation of diffusion barrier to prevent blood loss.
      Vascular Endothelium
    • EC Products Secreted into the Subendothelium
      ● basement membrane ● elastin ●fibronectin
      ● collagen III and IV ● lamilin ● mucopolysaccharides
      ● microfibrils ● vibronectin ● vWf
      ● protease inhibitors
      These proteins essential for cell–to-cell interactions and formation of diffusion barrier to prevent blood loss into extravascular spaces.
    • Vascular Endothelium
      ECs also secrete numerous substances into the vascular lumen to prevent clotting (e.g. heparin)
      which promote fluidity of the blood
    • Procoagulants
      ● PGI2 ●glycosaminoglycans ● tissue factor
      ● EDRF ● ATIII/heparin sulfate ● vWf
      ● t-PA ● protein kinase/thrombomodulin ● Factor V
      ● urokinase ● plasminogen activators ● inhibitors (PAI-1, PAI-2
      ● nitric oxide ATIII)
      ● IL1, TNFα
      ● endothelin-1
      ● PAF
      EC surface products secreted into the blood stream
      These substances promote fluidity of the blood.
    • Vascular Endothelium
      Normal endothelium acts as a potent anti-coagulation surface, upon stimulation or injury, endothelium transforms into a potent pro-coagulation surface as subendothelial collagen is exposed
    • Primary Hemostasis
    • Primary Hemostasis
      response to vascular injury that produces a platelet plug at the site of damage
      immediately limit bleeding through the formation of a loose platelet plug
    • Platelets
      Minute round or oval discs (1-4 mm diameter).
      Do not have a nucleus and can not divide.
      Formed from megakaryocytes in bone morrow
      Normally 150-450,000 per ml of blood
    • Platelets
      Adhering to the endothelial wall at the site of injury
      Releasing potent anticoagulant compounds
      Aggregating to form a plug
      Providing a phospholipid surface for activated coagulation enzyme complexes
    • Platelets
      Have many functional characteristics of whole cells
      Contains contractile proteins (actin, myosin and thrombosthenin)
      Residuals of ER and Golgi apparatus
      Mitochondria and enzymes to form ATP and ADP
      Can synthesis prostaglandins (thromboxane A2)
      Forms fibrin stabilizing factor
      Forms growth factors
    • Platelets
      Cell membrane contains glycoproteins that reduces adherence to normal endothelium
      yet promotes adherence to injured areas of vessel wall, especially injured ECs and collagen of subendothelium.
      Membrane also contains phospholipids that play activating role at multiple points in the clotting process.
      Platelets have a half life of 8-12 days
      Eliminated from the circulation mainly by tissue macrophages, especially in spleen.
    • Platelets
      Endothelial cell injury exposes subendothelial collagen which causes change in platelet shape and adherence.
      vWf- bridges platelet membrane glycoprotein to the exposed collagen at site of injury.
    • Vascular Injury
    • Vasoconstriction
      an immediate reflex
      Initial response to injury
      diminishing blood loss
      Local constriction of smooth muscle
    • Vasoconstriction
      Transient, typically lasts minutes (severed limbs)
      Result of release of local humoral actors, neural reflexes (caused by pain), local myogenic spasm
      Small blood vessels, release of vasoconstrictor thromboxane A2 from platelets is primarily responsible
    • Platelet adhesion
      Exposed collagen from the damaged site will promote the platelets to adhere
      undergo degranulation and release cytoplasmic granules
      Occurs within 15 secs after injury
    • Platelet adhesion
      Injury to intima
      Subendothelial collagen
      (Glycoprotein receptor Ib)
      Platelet adhesion
    • Von Willebrand factor (vWF)
      • Multimeric plasma glycoprotein required for normal hemostatic platelet plug formation
      • Forms a bridge between platelet glycoprotein IB and exposed collagen in the subendothelium
      • It is the “glue” that binds platelets to collagen.
      • vWF is also responsible for the binding and transport of factor VIII (antihemophilic factor), a procoagulant protein in plasma.
    • Platelet adhesion
      cytoplasmic granules
      ADP and
      Thromboxane A2
    • Platelet adhesion
      serotonin, a vasoconstrictor
      ADP attracts more platelets to the area
      thromboxane A2 promotes platelet aggregation, degranulation, and vasoconstriction
    • EM of normal and activated platelets
      Aggregated Platelets
    • ADP and thromboxane A2 promote more platelet adhesion
      therefore more ADP and thromboxane
      “Second wave”
    • Platelet plug
      The positive feedback promotes the formation of a platelet plug
    • Primary platelet plug is only good for stopping bleeding in the first minute- it can not sustain hemostasis.
      Heparin does NOT interfere with this reaction
    • Arachidonic acid pathway
      ASPIRIN and other NSAID
    • Primary hemostasis
      Defects : associated with mucocutaneous bleeding, characterized by epistaxis, ecchymosis, genitourinary bleeding, or gingival bleeding
      “first wave” of aggregation
      “second wave” ( granule release )
    • Secondary Hemostasis
    • Secondary Hemostasis
      Cascade of enzymatic reactions that ultimately results in the conversion of fibrinogen to fibrin monomers
      cross-linked into insoluble strands that serve to stabilize the loose platelet clot formed in primary hemostasis
    • Secondary Hemostasis
      triggered by the release of tissue factor from epithelial cells
      Platelets, vascular wall and multiple circulating or membrane-bound coagulation factors
    • Formation of Prothrombin Activator
      Prothrombin activator formed in two ways:
      Extrinsic pathway
      Intrinsic pathway
      In both pathways, inactive forms of blood clotting factors are converted to active forms.
      Designated by Roman numerals, small “a” for active
    • The common pathway
      Vessel Injury
      Prothrombin Activator Complex (rate limiting step)
      Note that both the Extrinsic and Intrinsic Pathways converge on Factor X
    • Characteristics of clotting reactions in the cascade
      A proteolytic enzyme generates the next enzyme in the cascade by cleavage of a proenzyme
      The reactions occur on a phospolipid surface ( platelet membrane )
      Each reaction requires a helper protien to bring the enzyme and substrate together
    • Clotting Factors in the Blood
    • Extrinsic Pathway
      Process begins with trauma to vascular wall
      initiated by tissue factor release by damaged tissue
      initiated by contact with Factor VII and platelets with collagen in vessel wall
      Clotting begins within seconds
    • Extrinsic Pathway
      Release of Tissue Factor (thromboplastin).
      Functions as a proteolytic enzyme complex
      Activation of Factor X.
      Tissue Factor further complexes with Factor VII which in the presence of Ca++ activates Factor X to Xa.
      Formation of Prothrombin Activator
      Xa combines with phospholipids and Factor V to form prothrombin activator complex
      In the presence of Ca++, this splits prothrombin into thrombin in the Common Pathway
    • Extrinsic Pathway
      Release of Tissue Factor (thromboplastin).
      Functions as a proteolytic enzyme complex
    • Extrinsic Pathway
      Activation of Factor X.
      Tissue Factor further complexes with Factor VII which in the presence of Ca++ activates Factor X to Xa.
    • Extrinsic Pathway
      Formation of Prothrombin Activator
      Xa combines with phospholipids and Factor V to form prothrombin activator complex
    • Extrinsic and common pathways
      Tissue Trauma
      Tissue Factor
    • Intrinsic Pathway
      Initiated by trauma to blood or exposure of blood to vascular wall collagen
      Takes 1-6 minutes to cause clotting
      All components are “intrinsic to the circulating plasma” and NO surface is required to initiate clotting
    • Intrinsic Pathway
      Causes activation of Factor XII (to XIIa) and release of platelet phospholipids
      Activation of Factor XI by Factor XII. This reaction also requires High Molecular Weight (HMW) kininogen and is accelerated by prekallikrein.
    • Intrinsic and common pathways
      Prothrombin Activator
    • Factor X activation
      Extrinsic Xase
      TF- VIIa
      Intrinsic Xase
      50x more effective at catalyzing factor X activation
    • Functions of thrombin
      Conversion of fibrinogen to fibrin
      Activation of factors V, VIII, XI and XIII
    • Prothrombin
      unstable plasma protein that splits in half to form thrombin.
      Made by liver and requires vitamin K
    • Common Pathway
      In the presence of Ca++, this splits prothrombin into thrombin in the Common Pathway
    • Prothrombin Activator
      Thrombin Activation
      Phospholipid surface
    • Common Pathway
      large plasma protein formed in liver
      Acted on by thrombin (removes 4 peptides) to form fibrin which polymerizes into fibrin fibers
    • Common Pathway
      Fibrin-stabilizing factor from platelets trapped in clot is activated which causes formation of covalent bonds between fibrin monomer molecules
    • INTRINSIC PATHWAY (12-11-9-8-10)
      XII (Hageman Factor)
      XI XIa + Ca ++
      IXa + VIII + Ca++ + phospholipid, F3,Plt
      Prothrombin (Factor II)
      Fibrinogen Fibrin Clot XIII a
      Tissue thromboplastin + VII + Ca++
      • All coagulation factors synthesized in the liver except for thromboplastin, Ca++
      • Factors 2,7,9,10 – vitamin K dependent
    • The coagulation system
      Regulated system
      In addition to Clot formation :
      Balanced the propagation of clot
      Feedback inhibition of cascade
      Mechanism of fibrinolysis
    • Feedback inhibition of cascade
      Tissue factor pathway inhibitor (TFPI )
      Antithrombin III
      Protien C system
    • Tissue factor pathway inhibitor (TFPI )
      Tissue Factor