Hemostasis Shaina Eckhouse 10/12/2010

Objectives Biology of Hemostasis Congenital Hemostasis Defects Aquired Hemostasis Defects Hypercoagulable States Venous thromboembolism Transfusion Evaluation of the Surgical Patient at Hemostatic Risk

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Biology of Hemostasis Complex process that prevents or terminates blood loss from a disrupted intravascular space Major physiologic events Vascular constriction Platelet plug formation Fibrin formation fibrinolysis

Biology of Hemostasis Vascular Constriction Initial vascular response to injury Vasoconstriction linked to platelet plug formation TXA2 ET 5-HT Bradykinin & Fibrinopeptides TXA2—derived from the release of arachadonic acid from platelet membranes during aggregation, is a powerful VC ET (endothelin)—acts as a VC 5-HT (Serotonin)—released during platelet aggregation, is another VC Bradykinin, Fibrinopeptides are also capable of contracting vascular smooth muscle

Biology of Hemostasis Platelet Function 150-400K circulating platelets ~30% sequestered in the spleen Thrombopeptin, IL-1, IL-6 mediate platelet production

Biology of Hemostasis Platelets play an integral role in: Formation of a hemostatic plug Contributes to thrombin formation Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere to in ~15 seconds vWF is a protein within the subendothelium that binds to glyoprotein I, IX, and V on the platelet membrane Platelet adhesion also mediated by the intrxn between collagen in the subendothelium and GP IaIIa on the platelet surface. Following this, the platelets expand and develop pseudopodal processes and also initiate a release reaction that recruits other platelets from the process Second wave of platelet aggregation—release reaction of ADP, Ca++, 5-HT, TXA, and alpha-granule proteins are discharged. Fibrinogen is a required cofactor for this process, acting as a bridge for GP IIbIIIa receptor on the activated platelets during formation of a platelet plug Thrombospondin stabilizes fibrinogen binding to the activated platelet surface and strengthens the platelet-platelet interaction

Biology of Hemostasis VC + platelet plug formation = PRIMARY HEMOSTASIS Reversible Not associated with secretion Because it is not associated with secretion, heparinized patients can still form clots

Biology of Hemostasis

Biology of Hemostasis Intrinsic Pathway All the components leading to the fibrin clot formation are intrinsic to the circulating plasma Elevated PTT associated with an abnormality in the intrinsic clotting pathway Begins with Factor XII and through the cascade, activates factor XI, IX, and VII in sequence

Biology of Hemostasis Extrinsic Pathway Requires exposure of tissue factor on the surface of the injured vessel wall Starts with Factor VII Abnormality of the extrinsic pathway is associated with an elevated PT

Biology of Hemostasis Both arms of the coagulation cascade merge into a common pathway at factor 10 and activation proceeds in sequence of factor II (prothrombin) and factor I (fibrinogen) Clot formation occurs after proteolytic conversion of finbrinogen to fibrin

Biology of Hemostasis Fibrinolysis = lysis of the fibrin clot Plasminogen Plasmin degrades fibrin, Factor V and VIII Plasminogenplasmin by several activators—tPA, (kalikrein increases release of tPA), uPA, factor XII Plasminogen levels rise due to exercise, venous occlusion, and anoxia Breakdown of the clot permits restoration of blood flow and fibrin clot in vessel wall may be replaced with collagen Antithrombin III Binds and inhibits thrombin and factors IX, X, XI Protein C Vitamin K-dependent Degrades fibrinogen and factors V and VIII Protein S Protein C cofactor

Biology of Hemostasis How do SCDs work? The squeeze stimulates the release of tPA from the endothelial cells of vessels. Induction of fibrinolysis. (tPA is selective for fibrin-bound plasminogen and converts to plasmin; therefore, fibrinolysis occurs mostly at the site of clot formation.)

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Congenital Hemostatic Defects Coagulation Factor Deficiencies Hemophilia Factor VIII deficiency = Hemophilia A Sex-linked recessive Both prolonged aPTT and PT Need level to be 100% pre-op and 30% post-op Crosses placenta Hemophiliac Joint No aspiration; ice; ROM exercises, factor VIII concentrate or cryoprecipitate Factor IX deficiency = Hemophilia B/Christmas Disease Need level 50% pre-operatively Prolonged aPTT and normal PT Tx-factor IX concentrate or cryoprecipitate Severe hemophilia—spontaneous bleeds; crippling arthropathies; develop intramuscular hematomas; retroperitoneal bleeds; GI and GU bleeding Mild hemophilia-do not bleed spontaneously For more detailed replacement and how to replace-refer to table 3-3 and 3-4 in schwartz

Congenital Hemostatic Defects von Willibrand’s Disease MOST COMMON congenital bleeding disorder Low levels of vWFvariable decrease in Factor VIII due to loss of the carrier protein vWF is necessary for normal platelet aggregation; therefore deficiency presents in a similar fashion to platelet disorders Prolonged bleeding time, possible abnormal PTT, normal PT Types- I-partial quantitative deficiency (AD) II-qualitative defect (AD) III-total deficiency (AR) Tx—intermediate purity factor VIII or DDAVP (Type I or II only) vWF links Gp1b receptor on platelets to collagen Discrepancy between types and treatments between Schwartz and ABSITE review---go with Schwartz Sx=bruising and mucosal bleeding

Congenital Hemostatic Defects Platelet disorders Glanzmann’s thrombocytopenia—deficiency in GIIbIIIa receptor of platelets; therefore, platelets cannot bind to each other Tx-platelets Bernard Soulier—Gp1b receptor deficiency; therefore, platelets cannot bind collagen via vWF

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Acquired Hemostatic Defects Anticoagulation Heparin—potentiates ATIII action Reversed with administration of protamine (1mg protamine for every 100u heparin received) Follow aPTTwant 1.5-2.5x upper limit of nl (60-90) Does not cross placental barrier Lovenox—potentiates ATIII and inhibits both thrombin and Factor Xa “more reliable therapeutic anticoagulation can be achieved” Drug effect can be determined by anti-Xa assay No definitive reversal Warfarin (Coumadin) Inhibits Vitamin K synthesis Reversed by FFP or Vitamin K administration Follow INR/PT Inhibits Vitamin K synthesis by inhibiting cyclo-oxygenase or decarboxylation step

Acquired Hemostatic Defects Why do we bridge with heparin or Lovenox when initially starting Coumadin? Protein C and S are inhibited before factors II, VII, IX and X which makes the patient relatively hypercoaguable for 5-7 days

Acquired Hemostatic Defects Antiplatelet Medications Asprin—Platelet cyclooxygenase is irreversibly inhibited ; decreases TXA2 which promotes platelet aggregation Plavix (Clopidogrel)—ADP receptor antagonist Pentoxifylline—inhibits platelet aggregation and decreases viscosity of blood; used in treatment of peripheral arterial disease

Acquired Hemostatic Defects Heparin Induced Thrombocytopenia 2/2 antiplatelet Ab (IgG) that results in platelet destruction Platelet count falls to <100K or by <50% in 5-7 days if first exposure or in 1-2 days if re-exposure High incidence of platelet aggregation and thrombosis (white clot) If suspected— STOP heparin Start alternate anticoagulation (lepirudin or argatroban) Alternative anticoagulation is important to prevent thrombosis that is associated with HIT Lepirudin—direct thrombin inhibitor; made from leech spit; don’t use in the setting of renal failure Argatroban—direct thrombin inhibitor; metabolized by CYP450 system; don’t use in the setting of liver disease

Acquired Hemostatic Defects Disseminated Intravascular Coagulation Systemic process producing both thrombosis and hemorrhage Exposure of blood to procoagulants Formation of fibrin in the circulation Fibrinolysis Depletion of clotting factors end-organ damage Dx= decreased platelets, prolonged PT and aPTT, low fibrinogen, high fibrin split products, high D-dimer Treat the underlying disease (sepsis, trauma, burns, malignancy)

Acquired Hemostatic Defects Thrombocytopenia MOST COMMON abnormality of hemostasis Variety of etiologies (ITP, TTP, HUS, SLE, lymphoma, secondary hypersplenism, portal HTN, uremia…) In setting of massive transfusion—exchange of 1L of blood volume (~11units) decreases platelet count from 250K to 80K. Associated impaired ADP- stimulated aggregation if >10units of blood transfused.

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Hypercoagulable States Factor V Leiden Deficiency MOST COMMON congenital hypercoagulable disorder AD Leiden variant of Factor V cannot be inactivated by Protein C Increased risk for DVT, spontaneous abortion Tx = heparin or warfarin

Hypercoagulable States AT-III deficiency Spontaneous venous thrombosis Heparin does not work on these patients unless pretreated by FFP Tx: AT-III concentrated Antiphospholipid Antibody Syndrome Presence of lupus anticoagulant that bind to phospholipids and proteins on the cell membrane an interfere with clotting; HOWEVER, associated with thrombosis and habitual abortions (prolonged PTT in the face of a hypercoagulable state) Tx: Heparin, coumadin

Hypercoagulable States Amicar Aminocaproic acid Inhibits fibrinolysis by inhibiting plasmin Indications: DIC, persistent bleeding following CPB, thrombolytic overdose Aprotinin Inhibits fibrinolysis by inhibiting activation of plasminogen to plasmin

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Venous thromboembolism DVT and PE Virchow’s triad = stasis, endothelial injury, hypercoagulability Treatment for DVT 1st= warfarin x 6months 2nd= warfarin x 1year 3rd or significant PE = lifetime warfarin Greenfield filters For patients with contraindications to anticoagulation Documented PE while on anticoagulation Free-floating iliofemoral clot IVC or femoral DVT Patients who have undergone previous pulmonary embolectomy PE most commonly caused by DVT in iliofemoral region

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Transfusion PRBCs 1unit=~250mL Storage life ~35days 1unit increases Hgb by 1 and Hct by 3 Fever without hemolysis is the most common transfusion reaction (1 in 6,000) Usually recipient antibody reaction against WBCs in donor blood Acute Hemolytic reactions occur 1 in 35,000 Caused by ABO incompatibility or Ab mediated usually from human error (Ab in recipient binding to surface Ag on donor RBC) Sx=hypotension, fever, dyspnea, chest pain, low back pain Tx=fluids, diuretics, HCO3, histamine blockers, pressors Sx can develop with only 5mL of blood Indications for transfusion in STICU: improved oxygen delivery and volume expansion 7g/dL or less with symptoms 5g/dL or less

Transfusion Platelets 50-100 billion in 50mL plasma Can be stored for ~7 days (viability declines after 3 days) Each platelet concentration should raise circulating platelets by >5,000 (4-6 pack of platelets shound increase platelets by 20-30K) Febrile nonhemolytic reactions more common than with PRBCs (incidence is ~30%) Antiplatelet antibodies develop in 20% of patients after 10-20 transfusions Indictions in active bleeding: plt<50K or plt<100K in setting of ICH; trauma victims who have received multiple transfusion Contraindicated in HIT and TTP

Transfusion FFP ~250 mL collected from 1 unit whole blood by apheresis Stored between -18 and -30 degree C and is good for 1 year Dose is ~10-15mL/kg Contains all coagulation factors, protein C, protein S, and AT-III (only blood product with factor V) Indications-warfarin overdose, liver failure, dilutional coagulopathy associated with massive transfusion Highest risk of TRALI—important to distinguish from volume overload. Tx=supportive

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Evaluation of the Surgical Patient at Hemostatic Risk Preoperative Assessment History Bruises without apparent injury Prolonged bleeding after injury PMHx—liver disease, congenital or acquired bleeding disorders Medications Labs—CBC, Coagulation panel, T&S or T&C Intraoperative and Postoperative Ineffective local hemostasis Complications of blood transfusion Consumptive coagulopathy Fibrinolysis

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