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Coagulation and Hemostasis

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Slide 1 :

Coagulation and Hemostasis Joy Loy, M.D. MetroHealth Medical Center December 2006

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Hemostatic process Coagulation cascade Fibrinolysis Laboratory studies Medications Coagulation disorders

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Hemostasis Purpose Ensure that coagulation mechanisms are activated when there is injury not unnecessarily activated Restore tissue blood flow after repair of injury (fibrinolysis)

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Hemostatic Process 3 main steps Primary hemostasis: local vasoconstriction & platelet plug formation Coagulation cascade Fibrinolysis

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Hemostatic ProcessPlatelet Plug Formation • vascular injury • release and binding of vWF to exposed blood vessel collagen • glycoprotein IB on platelet surface membrane binds to vWF • TxA2 ? vasoconstriction & platelet adhesion • platelet factor 3 (PF3) phospholipid layer (procoagulant)

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Platelet Activation & Aggregation exposed endothelial surface platelets exposed to collagen “activated” release contents of cytoplasmic granules adenosine diphosphate (ADP) thromboxane (Tx A2) accelerates platelet vasoconstriction aggregation/activation ? ADP release from platelets

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Hemostatic ProcessCoagulation Cascade to stabilize and reinforce the weak platelet plug fibrinogen ? fibrin 3 main steps: formation of prothrombin activator conversion of prothrombin into thrombin conversion of fibrinogen to fibrin

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Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Coagulation Mechanism activation of clotting factors requires a phospholipid surface tissue factor (TF) extrinsic to the blood activated platelet (platelet factor 3 phospholipid) intrinsic to blood vitamin-K dependent factors (II, VII, IX, X) formation of reaction complex labile factors : factors V and VIII

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Factor VIII extrahepatic origin 2 components (separate genetic control) VIII R : Ag VIII antigen + vWF VIII : C coagulant activity *absence ? hemophilia A von Willebrand factor (vWF) • mediates adhesion of platelets to surface collagen • carrier of VIII:C • vWD: appears to have defect in primary hemostasis & hemophilia A

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Factor VIII

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Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Newer Concepts of Coagulation Reactions 2 main functions of tissue factor (TF) 1) to activate factor X to Xa 2) to activate factor IX to IXa

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Control Mechanisms 1) TF pathway inhibitor 2) Protein C system 3) Antithrombin (e.g. AT III) 4) Glycoaminoglycans APC: activated protein C AT : antithrombin GAG: glycoaminoglycans T : thrombin PC : protein C S : protein S TF : tissue factor TM : thrombomodulin

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Antithrombin III (AT III) naturally-occuring anticoagulant binds to factors IXa, Xa, XIa, XIIa (slow) accelerated by heparin manyfold Implication: Heparin has almost NO anticoagulant action without AT III

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Coagulation Factors Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Fibrinolysis Plasminogen ? plasmin Release of tPA by the endothelium Lysis of clot? FDPs or FSPs Reopening of blood vessel

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Laboratory MonitoringProthrombin Time (PT) test of extrinsic pathway activity measures vitamin K - dependent factors activity (factors II, VII, IX, X) thromboplastin + Ca+2 to plasma = clotting time normal values: 12-14 seconds International Normalized Ratio (INR) ? standardizes PT reporting normal values: 0.8 -1.2 seconds

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Laboratory Monitoring Prothrombin Time (PT) monitors coumadin therapy most sensitive to alteration in F VII levels prolonged: 55 % ? of normal F VII activity antithrombotic activity: reduction of factor II and factor X activity (after several days)

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Laboratory Monitoring Activated Partial Prothrombin Time (aPTT) test for intrinsic and common pathways dependent on activity of all coagulation factors, except VII and XIII normal values: 25 -35 seconds monitors heparin tx & screen for hemophilia

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Laboratory Monitoring Activated Prothrombin Time (aPTT) prolonged: heparin, thrombin inhibitors, fibrin degradation products (FDP) citrated plasma + surface activators + phospholipid prolonged only if coagulation factors reduced to < 30 % of normal

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Laboratory Monitoring Activated Clotting Time (ACT) monitors heparin anticoagulation in the OR (cardiac and vascular surgeries) normal values: 90 - 120 seconds

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Laboratory MonitoringThrombin Clotting Time (TCT) reflects abnormalities in fibrinogen ? fibrin plasma + excessive amount of thrombin prolonged: heparin, thrombin inhibitors, low fibrinogen, dysfibrinogenemia monitors hirudin, bivalirudin, LMWH tx INR & PT may be normal or ? TCT prolonged with adequate therapeutic levels

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Laboratory Monitoring Thromboelastography (TEG) continuous profiles during all phases of clot formation provides more accurate picture of in vivo coagulation process to evaluate: • hypo / hypercoagulable state • hemophilia • dilutional coagulopathy • rare coagulation disorders anticoagulation tx • coagulation problems with liver transplantation

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Thromboelastogram (TEG)

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Bleeding time monitors platelet function not specific indicator of platelet function not very reliable very operator - dependent variable from each institution

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Bleeding time other factors: degree of venostasis, depth and direction of incision no evidence as • a predictor of risk of hemorrhage • useful indicator of efficacy of antiplatelet therapy insensitive to mild platelet defects

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Laboratory Monitoring Platelet Function Analyzer (PFA) - 100 relatively new global test of platelet adhesion and aggregation advantages noninvasive, simple, easy to perform very sensitive in detecting platelet defects associated with vWD sensitive to dx of acquired platelet defects (ASA, NSAID, dietary factors: excessive cocoa intake) monitors pro-hemostatic treatment DDAVP & platelet transfusions

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Laboratory Monitoring PFA-100 Limitations ¦ inflexibility ¦ results should be interpreted in the context of either a simultaneously or recently drawn full blood count ¦ platelet count < 80,000 or Hct < 30% will prolonged CT even if no platelet abnormal

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Implications for Therapy Congenital & acquired factor deficiencies history medications congenital factors: vWD, hemophilia, platelet disorders acquired disorders: multifactor-renal, hepatic, DIC Antiplatelet medications Anticoagulants

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Drugs affecting Coagulation

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Prostaglandin Synthesis arachidonic acid cyclooxygenase prostaglandin G2 peroxidase prostaglandin H2 prostacyclin thromboxane synthetase synthetase prostacyclin thromboxane A2 PG F1a thromboxane B2

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Mechanism of ActionASPIRIN arachidonic acid ASPIRIN cyclooxygenase prostaglandin G2 peroxidase prostaglandin H2 prostacyclin thromboxane synthetase synthetase prostacyclin thromboxane A2 PG F1a thromboxane B2

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Mechanism of ActionASPIRIN and NSAIDS arachidonic acid ASPIRIN cyclooxygenase prostaglandin G2 NSAIDS peroxidase prostaglandin H2 prostacyclin thromboxane synthetase synthetase prostacyclin thromboxane A2 PG F1a thromboxane B2

Slide 37 :

Antiplatelet Medications Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Non-steroidal Anti-inflammatory Medications Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Anticoagulants & Thrombolytics Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Other Anticoagulants Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

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Oral AnticoagulantsWarfarin inhibits synthesis of vitamin - k dependent factors II, VII, IX, X and protein C & S reversal: stopping medication and waiting for ~4 days for PT normalization vitamin K PO or IV (1-2mg) immediate: rFVIIa, FFP (1-2 units), prothrombin complex concentrate check PT prior to surgery

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Oral AnticoagulantsWarfarin biphasic effect on PT and INR initial ?: ? F VII (shortest t ½) to 55 % of normal subsequent ?: ? F II and X – therapeutic anticoagulant discontinuation return to normal: F VII followed by F II & X caution: INR =/< 1.4 no assurance of normal coagulation

Slide 43 :

Unfractionated Heparin negatively charged, water - soluble glycosaminoglycan extracted from porcine gut or bovine lung binds and ? anti - thrombin III (AT III) activity to 1,000 fold ?binds & inactivates factors IIa and factor Xa degree of inhibition: F Xa = IIa * LMWH inhibition of Xa > IIa lesser inhibition on F XIa, XIa and F XIIa

Slide 44 :

Unfractionated Heparin Low-dose or “minidose” 5,000 U SC q 12 hrs for thromboprophylaxis peak action: 40 - 50 minutes duration 4 - 6 hrs low risk for hemorrhage during anesthesia or surgery 4 reported cases of SEH with CNB

Slide 45 :

Unfractionated HeparinStandard Dose regular doses for therapeutic anticoagulation high risk of bleeding during & after surgery stop at least 6 hrs before surgery restarted ~ 12 hrs postop if needed with close monitoring immediate reversal: protamine

Slide 46 :

Low Molecular Weight Heparin (LMWH) 4,000-6,500 daltons (vs. standard heparin 3,000 -30,000 daltons retains anti-Xa activity less anti -IIa than standard heparin enhances AT-III interaction with F IIa & F Xa degree of inhibition: F Xa > IIa

Slide 47 :

LMWH in the U.S.

Slide 48 :

Standard Heparin vs. LMWH

Slide 49 :

Standard Heparin vs. LMWH

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Recombinant Factor VIIa(NovoSeven) FDA approved for use in hemophilia & patients with inhibitors enhances the TF pathway binds loosely to platelets and directly activates F X ? ? thrombin generation with F Va present never completely normalizes thrombin generation but enhances hemostasis dose: 90-120 mcg/kg q 2 hrs x 1st 24 hrs

Slide 51 :

Recombinant Factor VIIa variable individual thrombin- generating capacity megadoses: 150-300 mcg/kg “off label” use (non - FDA approved) liver disease liver transplant trauma ICH platelet disorders

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Recombinant Factor VIIa common denominator: defective thrombin generation thrombocytopenia ? hypothermia ? plasma coagulation proteins ? hyperfibrinolysis dilutional coagulopathy prophylactic use reported for retropubic prostatectomy, hepatectomy potential use: Jehovah’s witness

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Coagulation Disorders

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Disorders of Hemostatic Mechanism Classification: depends on involvement of platelets and/or clotting factors and/or presence of inhibitors (such as FDP) Treatment • transfusion of platelets and/or clotting factors • pharmacologic agents affecting Platelets fx (DDAVP, antiplatelet drugs) Clotting factors (vit. K, coumadin, heparin) Inhibitors (antifibrinolytics, protamine, fibrinolytics)

Slide 55 :

Hereditary Platelet Disordervon Willebrand Disease (vWD) most common congenital bleeding disorder quantitative or qualitative abn. of vWF Type 1: most common form partial quantitative deficiency of vWF autosomal dominant mucocutaneous bleeding hematology consult prior to surgery prolonged bleeding time, normal platelet

Slide 56 :

Hereditary Platelet Disordersvon Willebrand Disease (vWD) Type 2: qualitative alterations in the vWF structure & function Type 3: least common and most severe Complete absence of vWF in plasma or storage organelle Autosomal recessive acquired vWD Lymphoproliferative disease ? cardiac/valvular disease Tumors ? medications (valproic acid) Autoimmune disease ? hypothyroidism

Slide 57 :

Hereditary Platelet Disordersvon Willebrand Disease Treatment: Desmopressin (DDAVP) synthetic analog of vasopressin ? both F VIII and vWF 3 - 5x in 30 mins preop prophylactic dose: 0.3 mcg/kg IV in 50 -100 ml NS infused 30-60 mins q 12-24 hrs PRN duration 8-10 hrs intranasal dose: 300 mcg – for home treatment, not for preop prophylaxis

Slide 58 :

Hereditary Bleeding Disordersvon Willebrand Disease DDAVP vasomotor effect: flushing, ?HR, headache SE: hyponatremia, seizures not for children < 3 yrs old unresponsive to DDAVP (15%) cryoprecipitate FFP factor VIII / vWF concentrate

Slide 59 :

Acquired Platelet Disorders Thrombocytopenia : platelets <150,000/mm3 inadequate production by bone marrow splenic sequestration consumption coagulopathy dilutional thrombocytopenia immunogenic destruction Platelet dysfunction myeloproliferative and myelodysplastic syndromes renal failure, liver disease, DIC, CPB drugs: NSAIDS, ASA * DDAVP: tx platelet dysfunction due to uremia, liver disease, and patients on ASA for CABG

Slide 60 :

Hereditary Factor DeficienciesHemophilia x-linked recessive conditions (males only) type A : F VIII:C deficiency (Classical Hemophilia) B : F IX deficiency (Christmas disease) C : F XI deficiency unexplained bruising or bleeding in young males, usually ~ 1 yr of age joint & muscle bleeding ? arthropathy

Slide 61 :

Hereditary Factor DeficienciesHemophilia ¦ screening: prolonged PTT ¦ hemophilia A mild moderate severe : life-threatening (CNS bleed) treatment factor replacement rFVIIa

Slide 62 :

Factor VIII Concentrate Necessary for Hemostasis

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Acquired Factor Deficiencies Vitamin - K deficiency malabsorption syndromes pancreatic insufficiency biliary obstruction GI obstruction treatment: vitamin K

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Platelet Dysfunction, Factor Deficiencies & Presence of Inhibitors Liver disease • synthesis of coagulation factors (except VIII), anticoagulants, ATIII, protein C & S, plasminogen • clearance of activated clotting factors, tPA, FDPs DIC

Slide 65 :

Hypercoagulable StatesFactor V Leiden Mutation glutamine is substituted for arginine at position 506? resistant to inactivation by protein C dx: genetic screening ? risk for DVT in lower extremities & brain homozygous (20x) >heterozygous (7x) if asymptomatic: no anticoagulation

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Hypercoagulable StatesFactor V Leiden Mutation Treatment ? warfarin x 6 mos or until thrombosis free for 2 mos ? LMWH x 2 wks after warfarin then retested ? long term anticoagulation if persist or recurrent thrombotic event

Slide 67 :

Idiopathic Thrombocytopenic Purpura(ITP) more commonly found in children diagnosis of exclusion petechia <20,000x 109/l platelets bleeding <10,000x 109/l medical management

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Blood Component TherapyPlatelet Transfusion 1 unit ? platelets count 10,000 mm3 adult dose: 1 unit/10 kg BW within 24 hrs indications (NIH) ? thrombocytopenia with clinical coagulopathy 10, 000 in ITP 20, 000 in bone marrow suppression 40,000 during massive transfusion ? platelet dysfunction even with platelets>100,000 CPB drugs (ASA, etc) uremia thrombasthenia

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Blood Component TherapyTransfusion of FFP 1) replacement of isolated factor deficiency 2) reversal of coumadin 3) antitrombin III deficiency 4) treatment of immunodeficiencies 5) treatment of TTP 6) massive blood transfusion

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Blood Component TherapyCryoprecipitate contains significant levels of factor VIIIC, factor VIII: vwF, XIII, fibrinogen indications: 1) hemophilia 2) von Willebrand disease 3) fibrinogen deficiencies 4) uremic platelet dysfunction

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Slide 72 :

References Roberts HR, Monroe DM, Escobar MA. Current Concepts of Hemostasis. Anesthesiology 2004; 100:722-30. De Souza GJ. Anticoagulation and Central Neuraxial Anesthesia. Progress in Anesthesiology. 2000;vol XIV, Chap 9: 132-148. Petrovich, CT. An approach to the patient who may have a bleeding disorder. 2005 ASA nnual Meeting Refresher Course Lectures. Atlanta, GA. 2006;241:1-6. Kelly RE, Yao FF. Hemophilia and Coagulation Disorders. Yao & Artusio’s Problem Oriented Anesthesiology 4th Ed. Lippincott Williams & Wilkins. 1998. Chapter 40, pp 763-774. Fleisher LA. Evidence-based Practice of Anesthesiology. Saunders. 2004. Stoelting RK,Dierdorf, SF. Coagulation Disorders. Anesthesia and Co-existing diseases 3rd Ed. Churchill Livingston. 1993. Chapter 25, p 407-426.

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monitors heparin anticoagulation in the OR (cardiac and vascular surgeries); normal values: 90 .... more monitors heparin anticoagulation in the OR (cardiac and vascular surgeries); normal values: 90 .... subsequent ?: ? F II and X – therapeutic anticoagulant ... less

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