Blood clotting

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  1. Hemostasis  =  a  process  that minimizes:
    1. hemorrhage  when  a  blood  vessel wall  is damaged  damaged


    2. formation  of  untimely  clots  (thrombi)  in undamaged  vessels
  2. Primary  Hemostasis
    Vasoconstriction  of  damaged  vessels

    Formation of  a  temporary seal  by platelets
  3. Secondary hemostasis
    formation  of  a blood lot is fibrin clot (coagulation)
  4. Platelet adherence to damaged vessel endothelium “activates”platelets by triggering
    Platelet shape change resulting in interaction with other platelets and adherence to vessel endothelium

    Platelet release of ADP and thromboxane A2, which bind to specific receptors on other platelets causing further platelet activatio
  5. how do platelet get activated? (initial and advance)
    by bind to vessel endothelium 

    by binding of ADP and throboxane A2
  6. Adherence to vessel endothelium occurs
    via ....
    interaction with collagen and other proteins, e.g., von Willebrand factor (vWf)
  7. PG2
    a specific prostacyclin released by endothelial cells inhibits platelet aggregation when the vessel wall is not damaged
  8. PG2 is pro-aggregation
  9. drug that blocks  binding of  ADP  to its  receptor on platelets
  10. drug inhibits  synthesis of  thromboxane  A2
  11. the plasma protein fibrinogen
    that acts as a cross bridge by binding to specific receptors on platelets for the interaction with other platelet
  12. fibrin clot is similar to a platelet clot

    one is secondary hemostatsis and the other is primary clot
  13. Secondary hemostasis - fibrin clot formation
    fibrin mononer --> soft clot --> hard clot (transamination rxn)
  14. how is fibrin exist in the blood and what is the implication?

    so that blood wont clot in undmg vessel
  15. Requirements of Blood Clotting
    A. Rapid and efficient

    B. No clotting under normal conditions

    C. Self-limiting.

    D. Removal of clots as healing occurs
  16. Fibrinogen rxn (fibrinogen --> fibrin)
    protease remove negative charge (A and B peptide) for the aggregation
  17. Factors involved in blood clotting are synthesize in...
  18. Clotting cascade - intrinsic pathway
    all factors are present in blood; it is activated in vitro by interaction of factor XII, kininogen and kallikrein with the damaged surface of container
  19. Deficiencies of factor XII, kininogen and kallikrein cause bleeding problem
  20. Clotting cascade - extrinsic pathway require
    requires TF, which is present in fibroblast membranes assuring that blood is exposed to TF at a damaged blood vessel site (trauma)
  21. Clotting cascade - extrinsic pathway's main role
    to initiate clotting, but this action is somewhat transient because certain inhibitors present in blood become active and inhibit factor VIIa
  22. There is no distinction bw intrinsic and extrinsic pathway in vivo but there is one in vitro. because...
    cross-talked in vitro but not in vivo
  23. Platelet is required for clotting in vitro
  24. what is used clinically to speed clotting?
    recombinant VIIa
  25. What activates intrinsic and extrinsic pathway?
    intrinsic: dmged surface (dmg endothelium)

    extrinsic: trauma or TF
  26. which one is faster, extrinsic and intrinsic?
    extrinsic (1 factor vs 3)
  27. why needs so many factor?
    for amplification of clotting cascade
  28. Roles  of  Thrombin
    1.Cleave  a thrombin  receptor  on platelets  to  activate Platelets.  This is a second pathway of platelet activation (which is initiated by tissue factor.)

    2.Cleave  V  and  VIII  to form active  Va  and VIIIa

    • 3.Limit  clot 
    • formation  by eventually  cleaving 
    • Va  and  VIIIa
  29. Role  of  Platelets
    Activated platelets also release certain growth factors that facilitate the healing of injured blood vessels.
  30. stop clot formation at sites of injury (2 way)
    Thrombin-thrombomodulin complex activate protein C which form hydrolysis product from Va and VIIIa via protein S

    Heparin present in the blood inactivate protease-antithrombin complex
  31. Role of Vitamin K in Clotting
    • 1.The following  coagulation  factors require  the  binding of calcium  to be  active:
    •    II, VII, IX, X and proteins C and S

    • 2. After  synthesis,  some glutamate  residues  of  these    factors  have  to 
    • be  modified  in order  to  bind calcium

    • 3.This modification  requires  vitamin 
    • K  (a  fat  soluble vitamin), which is a cofactor of the enzyme that catalyzes the modification reaction
  32. Vitamin k involve in what kind of tranformation
    Glu to gla transformation
  33. wafarin, coumadin, heparin's pharm usage
    prevent clotting or anticoagulant
  34. adding coumadin/warfarin to a blood test tube, would it clot? why?
    will clot because coumadin work in the liver to inactivate the factor
  35. adding heparin to blood testube, will it clot? why?
    it wont clot because of antithrombin
  36. pt overdose on anticoagulant. dont know whether it heparin or warfarin. how to differentiate?
    • mixing blood experiment 
    • clot --> warfarin
    • wont clot --> heparin
  37. Low  molecular  weight heparin (LMWH)  is  likely to  be  used more  frequently because...
    • 1) less  non-specific binding  to  plasma proteins  and    thus better control  of  true 
    • dosage,  and

    2)fewer  adverse side  effects, eg., inhibition  of  platelets, and

    • 3) *LMWH  can  be injected subcutaneously  and  thus    can be  administered  at 
    • home  by patient  or nurse.
  38. Dissolution of the clot
    tPA (from endothelium) activate plasminogen (into plasmin)

    Plasmin is protease for fibrin --> disease clot
  39. what are D-dimers?
    pairing of D-domain after clotting 

    lab finding: there has been finding and the clot broke down
  40. Plasma levels  of D-dimers  are increased  in:


  41. Clinical test - bleeding time
    measure primary hemostasis by nicking the pt and measure how long it take to clot  

    not useful very much now
  42. Prothrombin time
    clotting time in presence of added Tissue Factor

    • INR =  international  normalization 
    • ratio  is  used to  standardize results

    used to assess warfarin levels

    high INR --> excessive bleeding
  43. Activated  Partial  Thromboplastin  Time 
    Partial Thromboplastin  Time  (PTT) (clotting time in presence of added clay or kaolin, etc.)

    used to assess heparin levels
  44. pt with bleeding problem. PT is normal but prolonged APTT
    problem with intrinsic pthway (factor XII, XI, IX)
  45. pt with bleeding problem, APTT is normal and PT is abnormal
    problem with extrinsic pathway (factor VII)
  46. pt with bleeding problem, both APTT and PT are abnormal
    problem with final common pathway (factor X, prothrombin, fibrinogen)
  47. there is no crosstalk between intrinsic and extrinsic pathway of blood clotting
  48. for LMWH, need clotting test.
  49. what test is need to access LMWH?
    antiXa activity test
  50. Hemophilia A
    • 1. X-linked recessive deficiency of
    • factor VIII

    2. Incidence: 1/10,000

    3. Prevalent in European royal families

    4. Affected patients have <5% of normal factor VIII activity

    • 5. Symptoms include:
    •   ease of bruising 
    •   hemorrhage into joints
    •   prolonged bleeding
  51. Hemophilia B
    X-linked recessive deficiency of factor IX
  52. von Willibrand disease
    gum bleeding 

    Deficiency of von Willibrand factor
  53. Thrombophilia - definition
    • Untimely  intravascular clot  formation 
    • due  to  an imbalance between  the  anticoagulant  and  prothrombotic activities  of plasma.
  54. Hereditary throbophilia
    • 1. Factor  V  mutation  (“Factor  V 
    • Leiden”)
    •   a. Resistance  to  protein C
    •   b.  Most common  hereditary thrombophilia 

    • 2. “Prothrombin G20210A” mutation
    •   a. Overproduction  of  prothrombin

    • 3. Deficiency  in  the level  or  activity of:
    •   protein C
    •   protein S, or
    •   antithrombin,  

    4. Often  manifest  only when  other factors  occur, eg., drugs  (oral  contraceptives),  another 

      thrombophilia  mutation
  55. Acquired  thrombophilia - precipitating factors
    • a. Vascular infection or inflammation  
    • b. Severe trauma
    • c. Cancer
    • d. Obstetrical  disorders,  
    •   e.g.,  amniotic fluid  embolism 
    • e. Antiphospholipid  Syndrome
    •   Autoimmune  production of  anti-  phospholipid  antibodies  that  can cause:
    •   1) thrombosis in  vivo  by  an  unknown mechanism
    •   2) inhibition  of  coagulation vitro
    •   3) fetal  loss  or damage during  pregnancy
  56. Acquired  thrombophilia - possible cause
    • a. Inflammation or cancer-induced expression of tissue  factor
    •       1) Certain chemicals can induce tissue factor   expression by normal endothelial cells   and by normal monocytes

    •       2) Tissue factor exists in blood in an
    • inactive   state on particles derived from
    • dead WBC;   activation can occur by some
    • unknown   mechanism, e.g., lipid
    • reorganization
    • b. Reduced  levels of  antithrombin, protein 
    • C  and protein S  due  to ongoing coagulation  and inflammation.
  57. DIC
    intravascular deposition of fibrin  --> throbosis of small and midsize vessels and organ failure

    Depletion of platelet and coagulation factors --> bleed
  58. acquired throbophilia - tx
    anticoagulants, platelets, plasma

    control of  underlying   condition (eg., infection).
Card Set:
Blood clotting
2013-07-25 21:49:35

blood clotting
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