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Michael Laposata, M.D., Ph.D. Director of Clinical Laboratories Massachusetts General Hospital Clot Formation Vessel Wall Injury Vessel Wall Contraction --- -- --- Platelet Adhesion Fibrin Formation Platelet Aggregation The Appropriate Level of Hemostasis Bleeding Thrombosis Balance Too Much Anticoagulation in a Thrombotic Patient 1 2 Bleeding Balance Thrombosis The Acquired Risk Factors •Surgery / Trauma •Immobilization •Malignancy •Pregnancy •Oral Contraceptives •Estrogen Replacement Therapy •Lupus Anticoagulant •Anticardiolipin Antibody •Obesity •Nephrotic Syndrome •Polycythemia Vera •Smoking The Hereditary Risk Factors Activated protein C resistance Nearly always the factor V Leiden mutation May be heterozygous or homozygous Prothrombin G20210A mutation May be heterozygous or homozygous Hyperhomocysteinemia Acquired Form: From decreased intake of folate, vitamin B6 and/or vitamin B12 Congenital Form: From enzyme deficiencies in homocysteine degradative pathways The Hereditary Risk Factors •Protein C deficiency Essentially always heterozygous •Protein S deficiency Essentially always heterozygous •Antithrombin deficiency Esssentially always heterozygous •Rare: Plasminogen deficiency Dysfibrinogenemia The “Second HIT” Theory for Initiation of Thrombosis The presence of more than one risk factor is needed to manifest thrombosis in most patients EXAMPLE: 1 Congenital 1 Acquired + = Thrombosis Risk Factor Risk Factor First Point in Diffential Diagnosis: Coagulation Factors vs. Platelets Primary Prophylaxis Preventing the first thrombotic event Primary Prophylaxis Indications Post Surgery Trauma Medical Patients Multiple genetic +/- acquired Risk factors Secondary Prophylaxis Preventing a recurrence of a thrombotic event Secondary Prophylaxis Indications A first thrombotic event – may be lifelong therapy Treatment of an Existing Thrombosis Treatment of an Existing Thrombosis • Venous Thrombosis – Deep Vein Thrombosis and Pulmonary Embolism • Acute Coronary Syndrome • Arterial Thrombosis Anticoagulants in Use or Nearly Available Prophylaxis Treatment Oral/IV/SQ Coumadin X X Oral Unfractionated heparin X X IV/SQ LMW heparin (Lovenox, Fragmin, Innohep) X X SQ/IV Fondaparinux (Arixtra) X X SQ Hirudin – related compounds (Lepirudin, Refludan) X IV Argatroban (Novostan) X IV X Oral Ximelagatran (not yet FDA approved) X For Each Anticoagulant •Drug Action •Use in Prophylaxis •Use in Treatment Coumadin: Drug Action ACTION OF VITAMIN K CH2 Vitamin K Factor as unmodified CH 2 protein COOH Factor with CH2 gamma carboxyHC - COOH Vitamin K glutamic Epoxide acids COOH Coumadin Vitamin K epoxide reductase activity Anticoagulants Inhibit the Coagulation Cascade XII XIIa XI Warfarin (Coumadin) XIa IX IXa Warfarin (Coumadin) X VIIa III VII Xa II Fibrinogen IIa (Thrombin) Fibrin Clot ALGORITHM FOR WARFARIN USE Maintain As Necessary No Maintain INR at 2.0 - 3.5 Overdose? Yes Significant bleeding? Discontinue Yes warfarin - give plasma to stop bleeding Yes No Discontinue Desire to regain the warfarin & anticoagulated state Yes allow as soon as possible? PT to decline No Stop warfarin Decrease dose & administer from before vitamin K Coumadin: Use in Prophylaxis Recommended Intensity of Oral Anticoagulation for Common Indications Indication DVT / PE MI Cardiogenic Embolus Tissue Heart Valve Valvular Heart Disease Atrial Fibrillation Mechanical Heart Valve INR 2.0 - 3.0 2.0 - 3.0 2.5 - 3.5 2.0 - 3.0 2.0 - 3.0 2.0 - 3.0 2.5 - 3.5 Monitoring of Anticoagulants Used for Prophylaxis Against Venous Thrombosis Coumadin to INR 2.0 – 3.0 Monitoring with INR no less than once/month after stabilization of INR Coumadin to INR 1.5 - 2.0 Monitoring with INR once every other month Coumadin: Use in Treatment How Long Until Warfarin Affected Factors Decrease? VII Approximate Half Life 4 - 7 hours IX 12 - 24 hours X 40 - 45 hours II 60 – 70 hours Factor Differences Between Rabbit Brain/lung Thromboplastins in the U.S. 1 Plasma Sample Split into 3 for PT Determinations in 3 Different Laboratories Hospital A Hospital B Hospital C 13 Seconds 15 Seconds 17 Seconds 1 Sample Tested Using 3 Different Lots of Same Thromboplastin Reagent from Same Manufacturer 14 Seconds 15 Seconds 16 Seconds The International Normalized Ratio - INR Patient PT INR = Mean of Normal PT Range ISI ISI: International Sensitivity Index for Thromboplastin Used for PT Determination Low ISI = High Sensitivity High ISI = Low Sensitivity to Factor Deficiencies to Factor Deficiencies Example: ISI = 2 17.3 3.0 = 10 INR = 3.0 2 PT = 17.3 Seconds ISI = 3 14.4 3.0 = 10 3 PT = 14.4 Seconds Consequences of an INR Miscalculation INR Goal = 3.0 and PT = 20 sec Actual ISI = 2.0 and Mistaken ISI = 1 2 20 = 4 10 (Actual) 1 20 = 2 10 (Mistaken) For INR = 4, withhold dose For INR = 2, increase dose Unfractionated Heparin: Drug Action The Antithrombin Pathway + + AT + + Heparin + + AT Xa AT Antithrombin Conformational Change Heparin Inhibition of Xa Heparin AT: Antithrombin + + AT Thrombin (IIa) Inhibition of Thrombin + Heparin Anticoagulants Inhibit the Coagulation Cascade XII XIIa XI Unfractionated Heparin XIa III IX IXa VIIa X Xa II Fibrinogen VII Unfractionated Heparin IIa (Thrombin) Fibrin Clot Unfractionated Heparin: Use in Prophylaxis This has essentially no meritpossible exceptions include patients with renal failure and those anticipating epidurals Unfractionated Heparin: Use in Treatment Heparin to Coumadin Heparin Clot Warfarin Algorithm for Heparin Use Prophylaxis Yes No Monitoring No Low molecular weight heparin prophylaxis or therapy in non-obese adults with normal renal function? Yes Maintain as Necessary No Full-dose unfractionated heparin PTT to > 1.5 X mean of normal range Significant Overdose? Yes bleeding? Yes No Discontinue heparin - & watch carefully for at least 2 hours Stop heparinNeutralize with protamine sulfate Persistent bleeding? Yes Decrease heparin dose No Yes Bleeding? No More protamine sulfate Heparin response curves of different lot numbers of Ortho Activated Thromboplastin over the years. Each year represents a different lot number. Heparin Concentration (u/mL) Low Molecular Weight Heparin: Drug Action FDA Approved Low Molecular Weight Heparin Preparations • Enoxaparin (Lovenox) • Dalteparin (Fragmin) • Ardeparin (Normiflo) • Tinzaparin (Innohep) Pharmacology • When injected subcutaneously, the bioavailability of unfractionated heparin ranges from 10 to 90%, depending on the dose given • In contrast, the bioavailability of LMW heparin is greater than 90% and is independent of dose Anticoagulants Inhibit the Coagulation Cascade XII XIIa XI XIa III IX IXa VIIa X Xa II Fibrinogen VII Low Molecular Weight Heparin Fondaparinux IIa (Thrombin) Fibrin Clot Low Molecular Weight Heparin: Use in Prophylaxis Comparison: Unfractionated (UF) Heparin vs. Low Molecular (LMW) Heparin • Efficacy approximately the same with a trend to better efficacy for LMW heparin • Much lower incidence of heparin-induced thrombocytopenia (HIT) with LMW heparin • Essentially no bleeding risk with prophylactic doses of either anticoagulant spinal puncture is a noteworthy exception Dosage Options & Conversions Approximate Equivalence: Between LMW heparins 2500 U Fragmin QD 40 mg Lovenox QD 5000 U Fragmin QD 30 mg Lovenox BID Low Molecular Weight Heparin: Use in Treatment Which Heparin or LMW Heparin can be used for Treatment of an Existing Venous Thrombosis? UFH or LMWH Warfarin Unfractionated (UF) Heparin vs. Low Molecular Weight (LMW) Heparin • Shorter half life for unfractionated heparin (1-2 hr) than LMW heparin (3-5 hrs), so preference is for UFH for briefly interrupted anticoagulation Monitoring of Anticoagulants used as Treatment for Existing Venous Thrombosis None, unless serum creatinine > 2.0, obesity (BMI >30), very low BMI, pregnancy, child esp LMW neonate, long term treatment Heparin if monitoring is needed, use anti-factor Xa assay with target range 0.5 - 1.0 U/mL Dosage Options & Conversions Approximate Anticoagulant Equivalence: Between LMW heparins 100 U Fragmin/kg BID 1 mg Lovenox/kg BID 200 U Fragmin/kg QD 1.5 mg Lovenox/kg QD Reversal of LMW Heparin • Protamine sulfate (1% solution) cannot reverse all of the anti-Xa activity, but it is recommended when emergent reversal of anticoagulation is required • The protamine dose is 1 mg per mg enoxaparin, 1 mg per 100 units ardeparin, or 1 mg per 100 units dalteparin by slow intravenous injection Adverse Effects • Heparins have three major adverse effects: bleeding, heparin-induced thrombocytopenia (HIT), and osteoporosis • Most of the clinical trials have reported similar or decreased bleeding with LMW heparin as compared to unfractionated heparin Adverse Effects Less bone resporption by LMW heparins may account for the decreased frequency of osteoporosis relative to unfractionated heparin Adverse Effects • Although the incidence of HIT is lower with LMW heparin than unfractionated heparin, it is advisable to also follow the platelet count in patients receiving LMW heparin • It is not currently known how often the platelet count should be determined in such patients Proposed mechanism for the pathogenesis of heparin-induced thrombocytopenia Adverse Effects • In patients who develop HIT from unfractionated heparin, the HIT antibody frequently cross-reacts with LMW heparin • Therefore, LMW heparin should not be used in patients with HIT Cost • A dose of LMW heparin in the USA is significantly more expensive than a dose of unfractionated heparin • Despite the higher cost per dose, LMW heparin may actually be most cost-effective than unfractionated heparin Fondaparinux: Drug Action FONDAPARINUX ACTION Fondaparinux • Does not increase PT or PTT • Cleared renally and contraindicated in patients with a CrCl < 30 • Reversal using Factor VIIa and possibly FFP Fondaparinux: Pharmacokinetic Profile in Healthy Young Volunteers • Tmax=1 to 3 hours following SC injection • t1/2=17 to 21 hours – Once-daily dosing • Predominantly eliminated unchanged in the urine Fondaparinux: Use in Prophylaxis Fondaparinux: Overall Efficacy and Odds Reduction in DVT/PE Prophylaxis Fondaparinux better Study Hip fracture1 THR2 Enoxaparin better –62% –58% THR3 –28% Major knee surgery4 –63% All studies P=10-17 –55% –80 –60 –40 –20 0 20 40 (%) Overall odds reduction for proximal DVT=57.4 %[CI 72.3-35.6]; P=10-6 1 Eriksson BI, et al. N Engl J Med. 2001;345:1298-1304. 2 Lassen MR, et al. Lancet. 2002. In press. 3 Turpie, AGG, et al. Lancet. 2002. In press. 4 Bauer KA, et al. N Engl J Med. 2001;345:1305-1310. 60 80 Effect on Bleeding of Timing of Fondaparinux Injection After Closure P=0.028 3.0 1.8 Fondaparinux started <6 h after closure n=1337 Fondaparinux started >6 h after closure n=2229 Turpie AGG, et al. Blood. 2001;98(11):266A. Data on file, Organon Sanofi~Synthélabo LLC. No Effect of Timing on Overall Venous Thromboembolism Rate P=0.33 7.1 7- Overall VTE rate (%) 6.3 65- Risk reduction >50% over enoxaparin in both subgroups 43210Fondaparinux started <6 h after surgical closure n=993 Fondaparinux started >6 h after surgical closure n=1680 Turpie AGG, et al. Blood. 2001;98(11):266A. Fondaparinux: Use in Treatment Fondaparinux Treatment Dose • 5 mg SQ QD – Small size person • 7.5 mg SQ QD – Average size person • 10.0 mg SQ QD – Large size person Hirudin – Related Compounds: Drug Action Anticoagulants Inhibit the Coagulation Cascade XII XIIa XI XIa III IX IXa VIIa X VII Xa II Fibrinogen IIa (Thrombin) Hirudin Fibrin Clot Argatroban Lepirudin •Lepirudin (Refludan) is a biotechnologically manufactured desulfatohirudin from S.cerevisiae •Lepirudin has been proven as a safe and effective thrombin inhibitor in patients with HIT Hirudin – Related Compounds: Use in Prophylaxis Desirudin Desirudin, which differs from lepirudin only in the first two N-terminal amino acids (ValVal), has a licensed indication for the prevention of deep vein thrombosis (DVT) Hirudin – Related Compounds: Use in Treatment Lepiruden & Refludan Description: Recombinant Protein Action: Direct Thrombin Inhibitor Monitoring: PTT to 1.5 - 2.5 x Mean of normal range Administration: Intravenous - Bolus with Continuous Infusion Lepiruden & Refludan Primary Use: Patients with heparinInduced thrombocytopenia and adequate renal function Half-Life: 1 hour if normal renal function and 52 hours (avg) in end stage renal disease Elimination: Mostly renal Reversal: None Lepirudin • Approximately 40% of patients receiving lepirudin develop antibodies, and the antibodies increase activity • Dose adjustment is necessary in renal failure patients Lepirudin Dosing • 0.4 mg/kg bolus up to 110 kg • Maintenance: 0.15 mg/kg continuous IV infusion • Do not use bolus in patients with a PTT greater than 2.5 baseline – some suggest no bolus at all Lepirudin Dose Adjustments – Based Upon Results of PTT • Goal: PTT 1.5 to 2.5 baseline • Measure first PTT 4 hours after initiation If PTT >2.5 baseline, stop infusion for 2 hours then restart at 50% original infusion rate If PTT less than 1.5 baseline increase infusion rate by 20% Argatroban: Drug Action Argatroban • Argatroban is a synthetic direct thrombin inhibitor derived from arginine • Anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT) Argatroban Description: Synthetic chemical compound Action: Direct thrombin Inhibitor Monitoring: PTT to 1.5 - 2.5 x mean of normal range Administration: Intravenous Argatroban Primary Use: Patients with heparin induced thrombocytopenia, especially those with impaired renal function Half-Life: 20 minutes Elumination: Mostly hepatic Reversal: None Argatroban: Use in Prophylaxis None Argatroban: Use in Treatment Argatroban • Anticoagulant effects are produced immediately upon infusion but steady state levels are reached within 1 – 3 hours • Upon discontinuation of therapy, anticoagulant parameters return to baseline within 2 – 4 hours Argatroban • Hepatic impairment decreases argatroban clearance • The dosage must be reduced for patients with liver dysfunction Guidelines for Conversion to Oral Anticoagulant Therapy • All direct thrombin inhibitors, especially argatroban, increase the prothrombin time (PT) • Therefore, argatroban interferes with the International Normalized Ratio (INR) How to Monitor Warfarin Effect When Argatroban and Warfarin Are Co-adminstered • Use Chromogenic Factor X instead of INR • INR 3 hours after discontinuation of argatroban • Use of manufacturer nomogram to extrapolate to INR without argatroban MGH A NTICOAGULATION & E PIDURAL A NESTHESIA /A NALGESIA G UIDELINES MONITORING C ATHETER P LACEMENT AFTER L AST D OSE C ATHETER R EMOVAL AFTER P OST -O P D OSE R ESTART M ED AFTER C ATHETER R EMOVAL None 48 Hours 48 Hours 12 Hours CLOPIDOGREL* (PLAVIX) None 7 Days EPTIFIBATIDE (INTEGRILIN) None 8 Hours 8 Hours 4 Hours FONDAPARINUX ** (ARIXTRA) None > 24 Hours > 24 Hours 2 Hours HEPARIN SC None HEPARIN IV PTT 2 -4 Hours 2 -4 Hours 1 Hour LMW HEPARIN *** LOW DOSE DALTEPARIN (FRAGMIN) < 5000 U QD ENOXAPARIN (LOVENOX)< 60 mg QD TINZAPARIN (INNOHEP) None 12 Hours 12 Hours 2 Hours None > 24 Hours DRUG (GENERIC) COMMON TRADE NAMES ABCIXIMAB (REOPRO) LMW HEPARIN *** HIGH DOSE BID DOSING = HIGH DOSE DALTEPAR IN (FRAGMIN) (see below ***) ENOXAPARIN (LOVENOX) (see below ***) TINZAPARIN (INNOHEP) NSAID, ASA CELEBREX; MOTRIN; NAPROSYN; VIOXX; ETC. Critical Time Intervals WITHIN 24 Hours* No Significant R None 24 Hours isk Catheter SHOULD be removed prior to first dose. IF NOT: wait > 24 Hours. 2 Hours No Sign ificant Risk THROMBOLYTICS: STREPTOKINASE (STREPTASE) ALTEPLASE (TPA) (ACTIVASE) None 10 Days 10 Days 10 Days TICLOPIDINE (TICLID) None 14 Days 14 Days 24 Hours TIROFIBAN (AGGRASTAT) None 8 Hours 8 Hours 4 Hours Check INR if treatment > 24 Same Day Hours * NOTE: Clopidogrel (Plavix) has a 24 -48 hour window to remove an epidural catheter once the medication is given. If it has been more than 48 hours since dosing of Clopidogrel (Plavix), you MUST wa it 7 days. **NOTE: Fondaparinux should NOT be given if regional anesthesia is anticipated or has been used. If, however, fondaparinux is given, we suggest the above guidelines. WARFARIN (COUMADIN) INR (<1.5) 3 -5 day s, check INR *** NOTE: SINGLE DAILY LMWH DOSING may be started 6 - 8 hours postoperati vely. TWICE DAILY LMWH DOSING should be started AT LEAST 24 hours postoperatively. Postoperative BID dosing is considered "HIGH DOSE LMWH". Epidural catheters should be removed prior to the initiation of BID dosing. Please refer to the ASRA Guidelines at www.ASRA.com . Summary Drug Action & Use in Prophylaxis and Treatment for: • • • • • • Coumadin Unfractionated Heparin Low Molecular Weight Heparin Fondaparinux Hirudin Related Compounds Argatroban MGH A NTICOAGULATION & E PIDURAL A NESTHESIA /A NALGESIA G UIDELINES MONITORING C ATHETER P LACEMENT AFTER L AST D OSE C ATHETER R EMOVAL AFTER P OST -O P D OSE R ESTART M ED AFTER C ATHETER R EMOVAL None 48 Hours 48 Hours 12 Hours CLOPIDOGREL* (PLAVIX) None 7 Days EPTIFIBATIDE (INTEGRILIN) None 8 Hours 8 Hours 4 Hours FONDAPARINUX ** (ARIXTRA) None > 24 Hours > 24 Hours 2 Hours HEPARIN SC None HEPARIN IV PTT 2 -4 Hours 2 -4 Hours 1 Hour LMW HEPARIN *** LOW DOSE DALTEPARIN (FRAGMIN) < 5000 U QD ENOXAPARIN (LOVENOX)< 60 mg QD TINZAPARIN (INNOHEP) None 12 Hours 12 Hours 2 Hours None > 24 Hours DRUG (GENERIC) COMMON TRADE NAMES ABCIXIMAB (REOPRO) LMW HEPARIN *** HIGH DOSE BID DOSING = HIGH DOSE DALTEPAR IN (FRAGMIN) (see below ***) ENOXAPARIN (LOVENOX) (see below ***) TINZAPARIN (INNOHEP) NSAID, ASA CELEBREX; MOTRIN; NAPROSYN; VIOXX; ETC. Critical Time Intervals WITHIN 24 Hours* No Significant R None 24 Hours isk Catheter SHOULD be removed prior to first dose. IF NOT: wait > 24 Hours. 2 Hours No Sign ificant Risk THROMBOLYTICS: STREPTOKINASE (STREPTASE) ALTEPLASE (TPA) (ACTIVASE) None 10 Days 10 Days 10 Days TICLOPIDINE (TICLID) None 14 Days 14 Days 24 Hours TIROFIBAN (AGGRASTAT) None 8 Hours 8 Hours 4 Hours Check INR if treatment > 24 Same Day Hours * NOTE: Clopidogrel (Plavix) has a 24 -48 hour window to remove an epidural catheter once the medication is given. If it has been more than 48 hours since dosing of Clopidogrel (Plavix), you MUST wa it 7 days. **NOTE: Fondaparinux should NOT be given if regional anesthesia is anticipated or has been used. If, however, fondaparinux is given, we suggest the above guidelines. WARFARIN (COUMADIN) INR (<1.5) 3 -5 day s, check INR *** NOTE: SINGLE DAILY LMWH DOSING may be started 6 - 8 hours postoperati vely. TWICE DAILY LMWH DOSING should be started AT LEAST 24 hours postoperatively. Postoperative BID dosing is considered "HIGH DOSE LMWH". Epidural catheters should be removed prior to the initiation of BID dosing. Please refer to the ASRA Guidelines at www.ASRA.com .