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Hemostasis and Surgical Bleeding

Discuss the essentials of hemostasis and surgical bleeding

Explain the processes involved in hemostasis Discuss the evaluation of surgical patient as a hemostatic risk Describe the more common congenital / acquired hemostatic problems Discuss types of local hemostasis Discuss proper use of blood products in transfusion therapy

Dakila P. De los Angeles, M.D., FPCS, FPSGS Department of Surgery UST Faculty of Medicine & Surgery

Hemostatic System In Vivo

Primary hemostasis Fibrin formation Removal of fibrin

Hemostatic System In Vivo

Primary hemostasis
von Willebrand factor Sufficient hematocrit

http://www.mhhe.com/biosci/esp/2002_general/Esp/folder_structure/tr/m1/s7/trm1s7_3.htm

Vasoconstriction

Platelet Adhesion

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Hemostatic System In Vivo

Primary hemostasis
Platelet activation
Arachidonic acid converted to thromboxane A2
vasoconstriction

Release of serotonin, ADP, and thromboxane A2

Release of proteins from platelet storage granules

Platelet agonist: ADP, serotonin Coagulation factors: vWF, coagulation factor V Heparin-binding proteins: platelet factor 4, thromboglobulin Chemokine: PDGF, PTGF- EGF

Platelet plug

Components of blood coagulation reactions

Component/ Plasma Factors I. Fibrinogen II. Prothrombin Precursor of fibrin Precursor of thrombin; converts fibrinogen to fibrin; activates factors V, VII, and XIII; if bound to thrombomodulin activates protein C; vitamin K dependent When activated to factor Va, serves as cofactor for factor Xa Binds to TF and is then activated to form the enzymatic component of a factor VIIa/TF complex that activates factors IX and X; vitamin K dependent As factor VIIIa, serves as cofactor for the enzyme factor IXa in a factor IXa/VIIIa/phospholipid complex that activates factor X; bound to von Willebrand factor As factor Ixa, functions as the enzyme of a factor IXa/VIIIa/phospholipid complex that activates factor X; vitamin K dependent As factor Xa, functions as the enzyme of a factor Xa/Va/phospholipid complex that activates prothrombin; vitamin K dependent As factor XIa, activate factor IX with calcium as cofactor Purpose

V. Proaccelerin VII. Proconvertin

VIII. Antihemophilic globulin

IX. Christmas factor

X. Stuart-Prower XI. Plasma thromboplastin antecedent

Component/ Plasma Factors XII. Hageman factor XIII. Fibrin stabilizing factor

Purpose As factor XIIa activates prekallikrein and factor XI When activated by thrombin, catalyzes formation of peptide bonds between fibrin molecules helping stabilize the clot Inhibits by proteolysis the cofactor activity of factors VIIIa and Va,requires protein S and phospholipid as cofactors; vitamin K dependent Cofactor for activated protein C; vitamin K dependent Binds to lipoproteins and the endothelium; binds to factor Xa thereby inactivating it

Hemostatic System In Vivo

Blood coagulation
Extrinsic & intrinsic pathway Tissue factor-factor VII pathway

Protein C

Protein S Tissue factor pathway inhibitor (TFPI) Cell surface factors Tissue factor, tissue thromboplastin

Bound by factor VII, which is a key reaction initiating blood coagulation in hemostasis; a lipoprotein present on membranes of certain tissue cells Functions as a component of the factor IXa/VIIIa/phospholipid activator of factor X and of the factor Xa/Va/phospholipid activator of prothrombin; functions as the lipid moiety of tissue factor Is an endothelial cell surface binding site for thrombin

Procoagulant phospholipid

Thrombomodulin

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Hemostatic System In Vivo Cell-based model of coagulation

Initiation P P

Hemostatic System In Vivo Cell-based model of coagulation

Initiation P P

Hemostatic System In Vivo Cell-based model of coagulation

Initiation P P

Hemostatic System In Vivo

Blood coagulation
Thrombin
key enzyme in activation of coagulation Activator of platelet aggregation

Cross-linked fibrin: ultimate step in the coagulation cascade Synthesis of coagulation factors in the liver
(factors II, VII, IX & X)

Coagulation

Activation of factor X

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Activation of prothrombin

Creation of fibrin

Formation of blood clot Hemostatic System In Vivo

Natural anticoagulant mechanisms

Tissue factor pathway inhibitor (TFPI) Protein C, Protein S Antithrombin III

Hemostatic System In Vivo

Mechanism-based Fitzgerald Hypothesis
Platelet Cox-1 Arachidonic Acid Endothelial Cox-2

Fibrinolysis
Fibrinolytic system
Conversion of plasminogen to plasmin
Plasminogen activators tPA, uPA Present in endothelial cells Released by hypoxia and acidosis

Thromboxane TxA2 Prothrombotic state

Prostacyclin PGI2 Antithrombotic state

Inhibition of fibrinolytic system

PAI-1, 2-antiplasmin

Fitzgerald GA. N Eng J Med 2004, 351; 1709-1711

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Anticoagulant Agents
Antiplatelet agents
Aspirin
blocks formation of thromboxane A2 thru inhibition of cyclooxygenase

Anticoagulant Agents
Vitamin K antagonists Coumarin derivatives
Warfarin, Acenocoumarol, phenprocoumon Block carboxylation of factors II, VII, IX & X Prothrombin time (PT) International Normalized Ratio (INR)
Increasing INR - increasing intensity of anticoagulation

Dipyridamole
Antiplatelet effect thru inhibition of phosphodiesterase resulting in increased cAMP

ADP-inhibitors
Clopidogral

Glycoprotein receptor IIb/IIIa inhibitor

Potent inhibitors of platelet function Ticlopidine, Tirofiban, Abciximax

Side-effect: bleeding

Anticoagulant Agents
Heparin
Glycosaminoglycans, 4-20 kDa Binds to antithrombin III Immediate effect after IV administration aPTT for monitoring

Prohemostatic Agents
Platelets Transfusion guidelines for platelet concentrates
Platelet count <10 x 109/l Platelet count <50 x 109/l with demonstrated bleeding or a planned surgical/ invasive procedure Documented platelet dysfunction eg. Prolonged BT Bleeding patients or patients undergoing a surgical procedure who require >10 units of packed red cells

Low Molecular Weight Heparin

4-6 kDa More favorable antithrombotic effect, less bleeding complications No need for frequent monitoring and dose adjustments

Side-effect: bleeding, heparin-induced thrombocytopenia (HIT)

Prohemostatic Agents
Plasma Fresh or frozen plasma contains all coagulation factors Transfusion guidelines
Correction of multiple or specific coagulation factor deficiencies in bleeding patients or if surgical/invasive procedure is planned Volume replacement in case of severe bleeding to avoid massive transfusion of gelatin or crystalloid solutions Thrombocytopenic thrombotic purpura

Prohemostatic Agents
Prothrombin complex concentrates (PCC)
Contain vitamin K-dependent coagulation factors For immediate reversal of coumarin therapy If global replenishment of coagulation factors is necessary and large volumes of plasma are not tolerated

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Prohemostatic Agents
Cryoprecipitate Contains mainly vWF, factor VIII, and fibrinogen High likelihood of transmission of infectious agents

Prohemostatic Agents
Desmopressin, DDAVP Deamino-D-arginine vasopressin
Vasopressin analogue Induces release of vWF Potentiates primary hemostasis Treatment of bleeding in patients with von Willebrand disease or mild hemophilia A
Impaired primary hemostasis
Uremia, liver cirrhosis, aspirin-associated bleeding

Prohemostatic Agents
Antifibrinolytic agents
Aprotinin - inhibits activity of various serine proteases (plasmin, coagulation factors or inhibitors, and constituents of the kallikrein-kinin system)
Contraindicated in DIC, patients with renal failure

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Congenital coagulation abnormalities
von Willebrand Disease
Most frequent primary hemostatic defect 1:25,000 for severe 1 to 5:1,000 for mild vWF - carrier and stabilizing factor of plasma factor VIII Lifelong bleeding tendency Treatment: desmopressin, vWF concentrate

Lysine analogues
-aminocaproic acid, tranexamic acid Competitive binding to the lysine-binding site of a fibrin clot - prevents plasminogen binding Contraindicated in DIC

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Congenital coagulation abnormalities
Thrombocytopathies
Glycoprotein Ib deficiency Glycoprotein IIb/IIIa deficiency Syndrome of Bernard Soulier Glanzman thrombasthenia

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Congenital coagulation abnormalities
Thrombocytopathies
Hemophila A & B (factor VIII & IX) Best known congenital defects Severe type - spontaneous bleeding tendency Moderate type - bleeding after trauma Major surgical intervention - administer coagulation factor concentrate for 7 to 10 days

Incidence hard to estimate Increased bleeding time Desmopressin, platelet transfusion

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Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Liver Failure Low levels of coagulation factors
Vitamin K deficiency
Biliary tract obstruction

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Renal failure
Impaired platelet adhesion, aggregation and release Low hematocrit - impaired primary hemostasis Desmopressin +/- platelet concentrate Correction of anemia, hemodialysis

If associated with portal hypertension and splenomegaly - serious thrombocytopenia In cirrhosis - impaired platelet function Increased risk of perioperative bleeding
Assess platelet count, BT, aPTT, PT Tx: Vitamin K, plasma, PCC

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Vitamin K deficiency
Cofactor for factors II, VII, IX, & X
Inadequate dietary intake Insufficient adsorption Loss of storage sites

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Immune thrombocytopenia, ITP
Autoantibodies against glycoproteins Increased platelet destruction/removal results in splenomegaly
Human immunoglobulin - rapid but short-lived Platelet transfusion

Prolongs global coagulation times particularly prothrombin time

Vitamin K intravenously PCC for immediate correction

Low incidence of major bleeding complications after appropriate preoperative preparation

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

acquired hemophilia
Development of autoantibodies to a coagulation factor in patients being treated for congenital coagulation factor deficiency after transfusion of coagulation factor concentrates
Rare but serious disorder High morbidity and mortality from bleeding

Conditions Associated with an Enhanced Risk of Perioperative Bleeding

Myeloproliferative disorders Lymphoproliferative disorders Malignancies

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Identification of Patients at Risk for Bleeding

Medical history Physical examination Routine coagulation test NOT necessary Preop screening strategy
Platelet count, PT, aPTT BT, vWF assay Factor XIII, 2-antiplasmin

Finding
Thrombocytopenia

Potential Cause
ITP Impaired platelet production DIC HIT vonWillebrand dse, thrombocytopathy Uremia, liver failure, myeloproliferative disorder, etc Coagulation factor deficiency (VIII, IX, XI, XII) Use of heparin Coagulation factor deficiency (VII) Vitamin K deficiency Mild hepatic insufficiency

Further test
Antiplatelet antibodies, thrombopoietin CBC, bone marrow analysis aPTT, PT, fibrin degradation products HIT test Plalelet aggregation test, vWF _ Measure coagulation factor _ Measure coagulation factor Measure F VII & F V or administer vitamin K and repeat after 1-2 days _ Measure coagulation factor _ Measure coagulation factor Platelets, fibrin degradation products _

Prolonged BT

aPTT up, PT ok

PT up, aPTT ok

Both PT/ aPTT up

Coagulation factor deficiency (X, V, II, or fibrinogen) Use of oral anticoagulants Severe hepatic insufficiency DIC Loss/dilution caused by excessive bleeding/massive transfusion

Management of Postoperative Bleeding Know if bleeding is a result of systemic hemostatic defect or a local problem in surgical hemostasis Global coagulation screening
Platelet count, PT, aPTT If tests are abnormal, replace factors REOPERATE!

Clinical Indications and Use of Blood Components

Whole blood
Very few indications

Red blood cells

Mainly oxygen carrying components Consider shelf life
Platelets Factors

Leucocyte-reduced RBC Transfusion guidelines

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Clinical Indications and Use of Blood Components

Platelets
Thrombocytopenia and/or platelet dysfunction Transfusion guidelines for platelets

Risks of Blood Transfusion

Transfusion reactions Transmission of infection Bacterial contamination

Leucocyte concentrate
Profound granulocytopenia with evidence of infection unresponsive to antimicrobials

Fresh frozen plasma

Replace labile factors in patients with coagulopathy and documented factor deficiency Transfusion guidelines for FFP

Cryoprecipitate
Hemophilia A, von Willebrands disease, Hypofibrogenemia

Blood Substitutes and Alternatives to Transfusion

Massive Transfusion
Acid-base changes Changes in 2,3-DPG Changes in potassium Changes in calcium Hemostasis

Technique Autologous blood

Product

Disadvantages/ Status Requires donation in advance of surgery/ Potential for clerical error/ Cost No role in acute hemorrhage/ Increased logistic requirements

Acute normovolemic hemodilution Autologous cell salvage Iron supplementation Cell saver/ Chest tube/ Drains Ferrous gluconate or sulfate

Potential for contamination/ Cost Constipation or diarrhea/ False + fecal occult blood test/ Requires weeks for effect Hypertension, seizures, thrombotic events/ Cost FDA pending OK in S. Africa Phase III trials, FDA pending Phase III in cardiac surgery All phase II trials terminated

Recombinant human erythropoietin Perflourocarbon Hemoglobin-based substitutes (bovine) Hemoglobin-based substitutes (human) Hemoglobin-based substitutes (recombinant)

Epoeitin alfa or beta Oxygent HT Hemopure PolyHeme Hemolink Optro

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RCTs on the Efficacy and Safety of LMWH in the Prevention of Postoperative Venous Thromboembolism in Patients Undergoing General Surgery, Ortho Surgery and Trauma Surgery (Level 1 evidence)
Type of Surgery # of Trials # of Patients Incidence of venous thromboemb olism (95% CI) RRR of postop venous thromboemb olism Increase in bleeding complication s (95% CI) Increase in major bleeding complication s (95% CI)

General Surgery Ortho Surgery Trauma Surgery

12 30 5

4386 4712 437

5% 21% 28%

80% 71% 44%

16% 7% 11%

3% -1% 0%

10