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  • 1. COAGULATION www.freelivedoctor.com
  • 2. HEMOSTASIS
    • The body’s intrinsic ability to slow down or stop hemorrhage
    • normal hemostasis involves a delicate balance between factors that promote blood coagulation and thrombus stabilization and factors that inhibit blood coagulation and promote thrombus dissolution
    clot RESOLUTION FORMATION www.freelivedoctor.com
  • 3. COAGULATION
    • vascular wall
    • coagulation factors
    • platelet
    www.freelivedoctor.com
  • 4. COAGULATION FIRST STEP
    • Smooth muscle
      • muscle constriction
        • luminal diameter reduction
        • retarding blood loss
        • enhancing platelet adherence
    • Endothelial cells
      • VIII-vWF synthesis
      • thromboplastin (III) release
      •  activation of ext pathway
      • activation of Factor IX & X
    • Subendothelium
      • collagen  platelet adherence, activation
    www.freelivedoctor.com
  • 5. PRIMARY HEMOSTASIS
    • Platelet
      • Adherence
      • Activation
      • Aggregation
      • (Contraction)
      • (Stabilization)
    www.freelivedoctor.com
  • 6. C O L L A G E N von Willebrand Factor fibrinogen endothelial cells Platelet Adhesion mediated by GP-Ib on platelet surface and vWF C O L L A G E N GP-Ib www.freelivedoctor.com
  • 7. von Willebrand Factor
    • Synthesized & stored in endothelial cells and megakaryocytes (also stored in platelets )
    • Forming bridge between subendothelial collagen and Plt
    • Carrier molecule for Factor VIII Coagulant Protein (vWF is also known as Factor VIII Related Antigen)
    • Circulates as series of multimers (in various sizes)
    • Large, high molecular weight multimers required for normal hemostasis
    www.freelivedoctor.com
  • 8.
    • Release of platelet’s cytoplasmic products
    • activation of platelet factor III (PF-3)
      • PF-3 serves as a binding site for cofactor V & VIII
    • production of thrombin
    C O L L A G E N Platelet Activation GP-IIb, IIIa release of  and electron dense granules www.freelivedoctor.com
  • 9.
    • formation of primary plug
    • activated platelets synthesize and secrete TXA 2
    • TXA 2 :
      • 1. promotes plt aggregation
      • 2. vasoconstriction
      • 3. release of plt factor (ADP)
    C O L L A G E N Platelet Aggregation GP IIb-IIIa - fibrinogen interaction Aspirin inhibits TXA 2 and ADP www.freelivedoctor.com
  • 10. www.freelivedoctor.com
  • 11. Coagulation Factors XII XI IX VIII VII X V I extrinsic pathway intrinsic pathway PT aPTT XIII Stable clot www.freelivedoctor.com II
  • 12. Coagulation Factors
    • Intrinsic Pathway
    • Extrinsic Pathway
    • Common Pathway
    • majorities are serine proteases
    • circulate as inactive forms (require activation to function)
    • majority produced in liver
    II XII XI IX VIII VII X V I extrinsic pathway intrinsic pathway PT aPTT XIII Stable clot negative charged surface tissue factor www.freelivedoctor.com
  • 13. Coagulation Factors
    • Intrinsic Pathway
    • Extrinsic Pathway
    • Common Pathway
    • majorities are serine proteases
    • circulate as inactive forms (require activation to function)
    • majority produced in liver
    • many require vit K for synthesis
      • II, VII, IX, X
      • protein C, S
    II XII XI IX VIII VII X V I extrinsic pathway intrinsic pathway PT aPTT XIII Stable clot negative charged surface tissue factor www.freelivedoctor.com
  • 14. Secondary Hemostasis
    • tissue factor
    • phospholipid complex
    • thrombin activation
    • fibrin polymerization
    • thrombin, ADP, TXA 2
    • Contraction
    • contraction of intraplatelet actomyosin
    • formation of secondary plug
    • uncover plt membrane receptors (GPIb, IIIa)
    • Stabilization
    • activation of XII thrombin
    • cross linking of fibrin monomers
    www.freelivedoctor.com
  • 15. A A B B fibrinopeptide A & B D domain E domain Spontaneous aggregation fibrinogen fibrin monomer soluble fibrin polymer www.freelivedoctor.com E D D E D D E D D E D D E D D E D D E D D E D D B A A B E D D E thrombin Factor XIIIa
  • 16. Stabilization of Fibrin Clot Thrombin Factor XII I Factor XIIIa soluble fibrin clot stabilized fibrin clot www.freelivedoctor.com E D D E D D E D D E D D E D D E D D E D E D E D D E D D E D D E D D E D D E D D E D E D
  • 17. Other Proteins in Blood Coagulation
    • Prekallikrein
    • activates XII and prekallikrein
    • High molecular wt. Kininogen (HMWK) (=binding protein)
    • supports reciprocal activation of XII, XI and prekallikrein
    www.freelivedoctor.com
  • 18. www.freelivedoctor.com
  • 19. ANTICOAGULATION & FIBRINOLYSIS
    • Vascular Wall
    • Anti-Coagulation Factors
    • Fibrinolytic Factors
    www.freelivedoctor.com
  • 20. ANTICOAGULATION & FIBRINOLYSIS Vascular Wall
    • Endothelial Cell
      • prostacyclin (PGl2)
      • heparan sulfate
      • thrombomodulin
      • tissue plasminogen activator (tPA)
    • Muscle
      • muscular dilation
    www.freelivedoctor.com
  • 21. ANTICOAGULATION & FIBRINOLYSIS Anti-Coagulation Factors
    • Antithrombin III (with thrombin & heparin)
      • negative feedback on thrombin
      • inactivates Xa (XIIa, XIa, IXa)
    • Prostacyclin (PGl2) from endothelial cells
      • vasodilation
      • conversion of ADP into products that inhibit plt aggregation
    • thrombin + endothelial cells
      • thrombomodulin binds & activates Protein C
      • inactivates Va & VIIIa
      • inhibits thrombin
    II XII XI IX VIII VII X V I XIII Stable clot www.freelivedoctor.com
  • 22.
    • Protein C
      • vit K dependent zymogen
      • produced in liver
      • inactivates Va and VIIIa
    • Protein S
      • vit K dependent binding protein
      • co-factor for protein C
      • binds C4b-binding protein
    II XII XI IX VIII VII X V I XIII Stable clot www.freelivedoctor.com
  • 23. Anticoagulation Heparin
    • Heparin activates Antithrombin III (AT III)
    • AT III inactivates Thrombin and Factor Xa
    • rapid onset of action
    • Laboratory monitoring:
      • aPTT : ~1.5X – 2.5X normal mean
      • heparin level :
        • 0.2 – 0.4 U/mL by protamine titration
        • 0.35 – 0.70 by Factor Xa inactivation assay
    II XII XI IX VIII VII X V I XIII Stable clot aPTT www.freelivedoctor.com
  • 24. Anticoagulation Heparin AT AT www.freelivedoctor.com
  • 25. II www.freelivedoctor.com
  • 26. II AT www.freelivedoctor.com
  • 27. II AT www.freelivedoctor.com
  • 28. II AT www.freelivedoctor.com
  • 29. II AT www.freelivedoctor.com
  • 30. II AT www.freelivedoctor.com
  • 31. Coumadin (Warfarin) Anticoagulants
    • inhibits hepatic synthesis of vit K-dependent clotting factors (II, VII, IX, X)
    • competitive inhibition of g-carboxylation
          • inactivate “acarboxy” forms synthesized
    • onset delayed 3 to 5 days
    • also inhibits synthesis of protein C & S
    II XII XI IX VIII VII X V I PT XIII Stable clot www.freelivedoctor.com
  • 32. Thrombolytic (Fibrinolytic) Factors
    • Urokinase : released from endothelial cells and monocytes
    • Tissue plasminogen activator (tPA)
    • conversion of plasminogen to plasmin
    • cleavage of fibrinogen & fibrin into fibrin split products
    • inhibit plt aggregation
    • thrombin activity
    • fibrin strands cross linking
    www.freelivedoctor.com
  • 33. www.freelivedoctor.com
  • 34. Plasmin Degradation of Fibrin Clot plasmin plasmin plasmin D-dimer E-fragment DED complex Fibrin Degradation Products www.freelivedoctor.com E D D E D D E D D E D D E D D E D D E D E D E D E D E D D D D E D D D D E
  • 35. Bleeding Disorders www.freelivedoctor.com
  • 36. Procoagulant Platelets Factors Fibrinogen von Willebrand Factor Anticoagulant Antithrombin III Protein C Protein S Profibrinolytic Plasminogen tPA Fibrin Fragment D-dimer Antifibrinolytic PAI-1 Alpha-2 Antiplasmin clot RESOLUTION FORMATION www.freelivedoctor.com
  • 37. Vessel Abnormalities increased vascular fragility
    • manifested by petechial hemorrhages of skin/mucous membranes
    • bleeding time, plt count, PT, aPTT --- normal
    • not life threatening bleeding
    • 1. congenital
    • a. Ehlers-Danlos syndrome (AD)
    • b. hereditary hemorrhagic telangiectasia (AD)
    • 2. acquired
    • a. hypersensitivity vasculitis
    • (1) drug reaction : immune complex deposit in vessel walls
    • (2) Henoch-Schonlein purpura
    • b. scurvy (vit C deficiency)
    www.freelivedoctor.com
  • 38. Henoch-Schonlein purpura
    • generalized hypersensitivity vasculitis
    • uncertain cause
    • clinical Sx:
      • purpura
      • colicky abdominal pain
      • polyarthralgia
      • acute glomerulonephritis
    www.freelivedoctor.com
  • 39. Coagulation Factor Abnormality
    • hematomas/ecchymoses after minor trauma
    • often severe bleeding
    • 1. congenital : usually single factor deficiency
    • a. sex-linked
    • (1) hemophilia A (Factor VIII def.)
    • (2) hemophilia B (Christmas disease, Factor IX def.)
    • b. autosomal dominant
    • (1) von Willebrand’s disease
    • c. autosomal recessive
    • 2. acquired : usually multi-factor deficiency and clotting abnormalities
    • a. vitamin K deficiency
    • b. severe liver disease
    www.freelivedoctor.com
  • 40. www.freelivedoctor.com
  • 41. Hemophilia A (Factor VIII deficiency)
    • bleeding into joints  crippling arthropathy
    • sex-linked inheritance
    • high rate of spontaneous mutation
      • 25% of pt’s do not have family history of hemophilia
    • decreased VIII-C, near normal VIII-vWF
    • >50% severe deficiency
    • increased aPTT
    • normal bleeding time, plt, PT
    II XII XI IX VIII VII X V I XIII Stable clot aPTT www.freelivedoctor.com
  • 42. hemophilia A www.freelivedoctor.com
  • 43. Hemophilia B (Christmas disease, Factor IX def.)
    • less common than hemophilia A
    • similar clinical Sx and inheritance pattern as hemophilia A (sex-linked)
    II XII XI IX VIII VII X V I XIII Stable clot www.freelivedoctor.com
  • 44. von Willebrand’s disease
    • easy bruisability (no bleeding into joints)
    • unable to release VIII-vWF
    • intact VIII-vWF synthesis
    • VIII-C level is also decreased (unknown reason)
    • autosomal dominant
      • 1 in 30,000 population
    • usually diagnosed in childhood or young adults
    • increased bleeding time
    • normal plt, PT
    • normal or increased aPTT
    www.freelivedoctor.com
  • 45. Vitamin K Deficiency vitamin K dependent factors : II, VII, IX, X
    • acquired disorder
      • may occur in malnutrition, malabsorption, biliary obstruction, drug
    • increased PT
    • normal bleeding time, plt
    • normal or increased aPTT
    II XII XI IX VIII VII X V I PT XIII Stable clot www.freelivedoctor.com
  • 46. Severe Liver Disease factors synthesized in liver : II, V, VII, IX, X, fibrinogen
    • increased PT, aPTT
    • normal bleeding time, plt
    II XII XI IX VIII VII X V I PT XIII Stable clot aPTT www.freelivedoctor.com
  • 47. PLATELET ABNORMALITIES
    • 1. Thrombocytopenia
    • a. decreased production
    • b. increased utilization
    • c. increased destruction
    • (1) isoimmune thrombocytopenia
    • (2) idiopathic thrombocytopenic purpura (ITP)
    • (3) thrombotic thrombocytopenic purpura (TTP)
    • (4) drug reaction
    • (5) mechanical destruction
    • (6) hypersplenism
    • 2. Functional abnormalities
    • a. congenital
    • (1) defective adhesion (Bernard-Soulier)
    • (2) defective aggregation (thrombasthenia)
    • b. acquired
    • (1) aspirin
    • (2) thrombocythemia
    www.freelivedoctor.com
  • 48. Thrombocytopenia
    • decreased in number of platelets
    • bleeding from small vessels (skin, GI, mucous membrane, GU, brain)
    • normal or increased bleeding time
    • decreased platelet
    • normal PT, aPTT
    www.freelivedoctor.com
  • 49. Thrombocytopenia
    • decreased production
    • diffuse bone marrow disease (aplastic anemia, tumor)
    • megakaryocyte disorder
    • increased utilization
    • DIC
    www.freelivedoctor.com
  • 50. Thrombocytopenia increased destruction
    • isoimmune thrombocytopenia
      • neonatal
      • [PLA 1 neg. mother] + [PLA 1 pos. baby]
      • production of anti-PLA 1 Ab (IgG)
      • post-transfusion
      • [PLA 1 neg. recipient] + [PLA 1 pos. platelet]
      • destruction of PLA 1 platelets and recipient's own platelets
    www.freelivedoctor.com
  • 51. Thrombocytopenia increased destruction
    • idiopathic thrombocytopenic purpura (ITP)
      • acute ITP
        • children following a viral infection
        • self-limiting disease
        • ? platelet as an “innocent bystander”
      • chronic ITP
        • adults (often premenopausal females)
        • may be associated with other “autoimmune diseases”
        • production of autoantibody against Pt’s own platelets
        • removal of opsonized platelets by reticuloendothelial system
        • decreased circulating platelet, but increased BM megakaryocytes
    www.freelivedoctor.com
  • 52.
    • idiopathic thrombocytopenic purpura (ITP)
      • clinical:
        • easy bruising and bleeding after minor trauma
      • treatment:
        • steroid
        • splenectomy
    www.freelivedoctor.com
  • 53. Thrombocytopenia increased destruction
    • thrombotic thrombocytopenic purpura (TTP)
      • abnormal platelet aggregation in microcirculation
      • microangiopathic hemolytic anemia
      • fever
      • transient neurologic deficits
      • renal failure
      • hemolytic uremic syndrome (HUS)
      • platelets start to aggregate in small vessels without particular reason
    www.freelivedoctor.com HUS
  • 54. Disseminated Intravascular Coagulation (DIC)
      • - an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases
      • - activation of clotting system resulting in wide spread formation of microthrombi throughout the microcirculation
      • - as a consequence, causing consumption of platelets, fibrin and coagulation factors, and activation of thrombolytic mechanism
      • Two major triggering mechanisms
      • 1. release of tissue factor or thromboplastic substance
      • 2. widespread endothelial injury
    www.freelivedoctor.com
  • 55. DIC
      • Triggering Mechanisms
      • 1. release of tissue factor or thromboplastic substance
      • - placental tissue
      • - granules from leukemic cells
      • - bacterial endotoxin
      • - mucus from adeno CA
      • 2. widespread endothelial injury
      • - Ag-Ab immune complex deposit
      • - extreme temperature
      • - microorganisms
    www.freelivedoctor.com
  • 56. DIC
      • Pathology: - wide spread thrombi
      • (brain, heart, lungs, kidneys, adrenals, spleen , liver)
      • - microinfarcts
      • Clinical: - ~50% associated with obstetric complications
      • - ~30% with carcinomatosis
      • - microangiopathic anemia
      • - dyspnea, cyanosis
      • - convulsions, coma
      • - oliguria, acute renal failure
      • - shock, circulatory failure
    www.freelivedoctor.com
  • 57. DIC
      • Clinical: acute DIC with a predominance of thrombin generation and consumption of coagulation factors
      • bleeding tendency
      • (oozing from venopuncutres or operating site)
      • subacute and chronic DIC
      • thrombotic tendency
    www.freelivedoctor.com
  • 58. DIC
      • Lab: - fibrinogen
      • - platelet
      • - PT
      • - aPTT
      • - fibrin degradation product
      • acute DIC: - prolongation of aPTT, PT and TT
      • - reduction of platelets, AT III and protein C
      • - decreased fibrinogen
      • - elevated fibrin degradation products
      • chronic DIC: - aPTT and PT may be within normal ranges
      • - slightly decreased platelets
      • - elevated fibrin degradation products and D-dimer
    www.freelivedoctor.com
  • 59. Platelet Functional Abnormalities congenital
    • Bernard-Soulier syndrome
      • defect in platelet adhesion
      • autosomal recessive
      • defect in platelet membrane glycoprotein (GP Ib)
    • thrombasthenia
      • defect in platelet aggregation
      • autosomal recessive
      • defect in platelet membrane glycoprotein (GP IIb & IIIa)
      • no fibrinogen linking of platelets
      • easy bleeding and no clot retraction
    1 2 www.freelivedoctor.com
  • 60. Platelet Functional Abnormalities acquired
    • aspirin
      • inhibits cyclooxygenase
          • suppression of TXA 2 synthesis
      • effect lasts for 72 hours
    • thrombocythemia
      • platelet : >3,000,000/ml
      • functionally abnormal platelets
      • occasionally seen in myeloproliferative disorders
    www.freelivedoctor.com
  • 61. Coagulation Tests
    • 1. Bleeding Time : in vivo test
    • measures adequacy of plt function
    • normal : <6 min.
    • 2. Platelet Count normal : >200,000/mL
    • 3. aPTT : intrinsic pathway (XII, XI, IX, VIII, X, V)
    • used to guide heparin therapy
    • 4. 50/50 mixing study
    • pt’s plasma + nl. plasma
    • if mixing correct aPTT = Pt is deficient in intrinsic factor(s)
    • no correction = circulating anticoagulants or inhibitors
    • 5. Prothrombin Time (PT) : extrinsic pathway (II, VII, V, X)
    • monitoring warfarin/coumadin effects
    www.freelivedoctor.com
  • 62. Coagulation Tests
    • 6. Fibrinogen Level normal : 200 – 500 mg/dL
    • 7. ADP platelet aggregation
    • 8. Ristocetin aggregation test
      • test for presence or activity of vWF
    • 9. Thrombin Time (TT) normal : 20 – 30 sec
      • measures 3 rd stage of coagulation
      • prolonged if
        • def or abnormality of fibrinogen
        • presence of fibrin split products
        • presence of heparin
    www.freelivedoctor.com
  • 63. History & Physical Exam are most important most sensitive most specific Tests of Hemostasis www.freelivedoctor.com
  • 64. www.freelivedoctor.com
  • 65. www.freelivedoctor.com
  • 66. www.freelivedoctor.com