Table 6. Continued from page 4. References Continued from page 5. Primary 7. Kearon C. Hirsh J. Management of anticoagulation before and after elective surgery. New England Journal of Medicine. 336(21):1506-11, 1997. Anticoagulation Reversal Anticoagulant Half-Life Excretion Therapeutic Anticoagulation Dose 8. Hanley JP. Warfarin reversal. Journal of Clinical Pathology. 57(11):1132-9, 2004 Nov. Action Monitoring Agents Mode 9. Holland L. Warkentin TE. Refaai M. Crowther MA. Johnston MA. Sarode R. Suboptimal effect of a three-factor prothrombin complex concen- trate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 49(6):1171-7, 2009 Pediatrics Adults 10. Bauer KA. New . Hematology Am Soc Hematol Educ Program. 2006:450-6. Xa-Inhibitors 11. O'Connell NM. Perry DJ. Hodgson AJ. O'Shaughnessy DF. Laffan MA. Smith OP. Recombinant FVIIa in the management of uncontrolled hemorrhage. Transfusion. 43(12):1711-6,2003. Winter 2011 Fondaparinux: 17-21 Renal Anti- 0.15 mg/kg, daily, SC <50 kg: 5 mg, SC, Typically no rFVIIa 12. O'Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human factor (Arixtra) hours mediated inhibi- daily monitoring (NovoSeven) VIIa. JAMA. 2006 Jan 18;295(3):293-8. tion of factor Xa 50-100 kg: 7.5 mg, required SC, daily Anti-factor Xa 13. Riess HB. Meier-Hellmann A. Motsch J. Elias M. Kursten FW. Dempfle CE. Prothrombin complex concentrate (Octaplex) in patients requiring >100 kg: 10 mg daily (Calibrated with immediate reversal of oral anticoagulation. [Clinical Trial. Journal Article. Multicenter Study. Research Support, Non-U.S. Gov't] Thrombosis Arixtra curve) Research. 121(1):9-16, 2007. Reversal of Anticoagulation 14. van Ryn J. Stangier J. haertter S. Liesenfeld KH. Feuring M. Clemens A. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: Rivaroxaban: 5.7 to 9 Renal Direct Xa Not available 10 mg (prophylaxis No monitoring rFVIIa (Novo interpretation of coagulation assays and reversal of anticoagulant activity. Thrombosis and Haemostasis. 2010 Jun; 103(6):1116-27. Anne Greist, MD (Xarelto) hours inhibition only), PO, daily required Seven), aPCC Direct March is Hemophilia Awareness Month Patients who receive anticoagulation may require reversal  appreciating the risk of acute thrombosis if anti- Bivalirudin: 25 Enzymatic Direct inhibition Loading dose: PCI APTT, TCT, ACT Desmopressin of their treatment. This typically occurs for two main coagulation is reversed. (Angiomax) minutes cleavage of thrombin 0.25 mg/kg, IV Loading dose: Acetate; see how the IHTC is helping patients reasons: there is a complication or the patient 0.75 mg/kg, IV Cryoprecipitate; It is important to note the time the last dose of the anti- Maintenance, CI: Maintenance, CI: : needs to undergo surgery or other invasive procedure. The IHTC has created the "Thrive" website, www.seehowithrive.org, and it features 0.07±0.16 1.75 mg/kg/hr, IV Amicar (EACA); The approach to reversal of anticoagulation depends upon coagulant was given to appropriately select the reversal mg/kg/hour hemophilia facts and a series of videos highlighting the stories of people in Indiana who the circumstances that require cessation of treatment, and agent for the situation. Consultation with a hematologist Unstable angina live with hemophilia. The videos and website were created to emphasize that with care Load: 0.1 mg/kg whether the situation is emergent or elective. may be necessary for dosing and follow-up recommenda- Maintenance: and treatment, those affected with hemophilia are living productive, normal lives. tions. Agents utilized for the reversal of anticoagulation 0.25 mg/kg/hr Hemophilia is one of the most expensive chronic medical conditions largely due to the General Considerations: have the potential to precipitate a thrombosis; for example, Argatroban 40-50 Biliary, Liver Direct inhibition Loading dose: Loading dose: None APTT Desmopressin cost of required therapy to treat or prevent bleeding episodes. People with bleeding disorders require expert medical Bleeding complications that arise while on anticoagulation , used to reverse heparin, has an anticoagu- minutes of thrombin 65-250 mg/kg, IV Acetate; are classified as either major or minor. Major bleeding is Maintenance, CI: care from dedicated experts who have extensive experience and a wide range of available services to address the many lant property if an excessive dose is administered. Newer Cryoprecipitate; bleeding that carries a risk of death or long-term morbidity, anticoagulants may not have a specific antidote. CI:0.5- 0.5-2.0 mg/kg/hr, Antifibrinolytics: aspects of life that are impacted by hemophilia; these include individually tailored medical needs, physical and social Amicar (EACA); functioning, and the impact on their family, work, and school. such as intracranial or intraocular bleeding; need for transfu- Tranexamic acid sion; or bleeding from a non-compressible vessel. Bleeding Warfarin: As Indiana’s only federally recognized hemophilia treatment center, the IHTC offers lifelong, comprehensive, patient- that has the potential to result in loss of life, organ, limb Lepirudin 80 Renal Direct inhibition Loading dose: Loading dose: APTT, Desmopressin Warfarin is the most common anticoagulant in use and acts (Recombinant minutes of thrombin Not recommended 0.4 mg/kg Ecarin clotting Acetate; centered, multidisciplinary healthcare that goes beyond what we often consider as event or disease based interventions. or digits, should be considered an emergency that requires by inhibiting the terminal gamma carboxylation step in the Hirudin, time, Cryoprecipitate; The IHTC’s multidisciplinary team includes hematologists, nurses, physical therapists, social workers, dental hygienists, reversal of anticoagulation. All other bleeding events are production of coagulation factors II, VII, IX and X. Patients Refludan) Maintenance, CI: Maintenance, CI: Chromogenic Antifibrinolytics: dietician, career counselor, and an integrated onsite pharmacy – all of these are focused on serving the patient, and 0.1 mg/kg/hr 0.15 mg/kg/hr, IV classified as minor and include bruising, oozing from are anticoagulated to a target INR of 2.0-3.0, although the Lepirudin assay Amicar (EACA); supporting and educating the patient’s family. The IHTC also provides medical education to assist care providers in caring injection sites, injuries, surgical sites, gingival bleeding, target is higher (2.5-3.5) for patients with mechanical heart Tranexamic acid for the bleeding disorder community throughout the state. Educational efforts include on-line learning modules through epistaxis that is easily controlled with local measures, and valves. For ophthalmic surgery, other than cataracts, and Dabigatran 12-17 hrs Biliary, renal Direct inhibition Not available 150 mg, PO, BID APTT, rFVIIa our PartnersPRN.org website, local grand rounds and medical in-services as requested, and distribution of IHTC developed menorrhagia not requiring transfusion. It is often possible procedures such as lumbar puncture or endoscopy, warfarin of thrombin Ecarin clotting (NovoSeven), educational materials. The IHTC is Indiana’s center of excellence for bleeding disorders. time, aPCC to manage minor bleeding by holding one or two doses of should be held for three days preoperatively. Otherwise, the TCT anticoagulant therapy with provision of supportive care. To learn more about Hemophilia Awareness Month and how the IHTC helps our patients thrive, visit Continued on page 2 Xa-Inhibitors http://www.seehowithrive.org. For more information about the IHTC, visit www.ihtc.org. For patients who are in need of emergency surgery, the Idraparinux 5-6 days Renal Anti-thrombin Not available 2.5 mg/week, SC No monitoring Avidin (NOT risk of bleeding due to the use of anticoagulants must be March is Hemophilia Awareness Month (Pending FDA mediated required available in US)*; weighed against the risk of immediate thrombosis if reversal March is designated approval) inhibition of rFVIIa is performed. There are some procedures that may be per- factor Xa (NovoSeven) Hemophilia Awareness formed without reversal of anticoagulation. These include Month, dedicated to Apixaban 12 Biliary, Renal Direct Xa Not available 5-10 mg, PO, BID No monitoring rFVIIa placement of peripherally inserted central catheter (PIC) increasing awareness (Pending FDA inhibition required (NovoSeven) lines, or tympanostomy tubes, removal of chest tubes, and approval) about bleeding disorders, 8402 Harcourt Road, Suite 500 cardiac catheterization. Minor dental procedures, minor Indianapolis, IN 46260 inspiring advancements in References Continued on back page. dermatological procedures, cataract surgery, and endometrial diagnosis and treatment, ablation are also examples of procedures where reversal of 1. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). and dispelling common American College of Chest Physician. Chest. 2008 Jun; 133(6 Suppl):67S-968S. anticoagulation may not be necessary. misconceptions. To 2. Monagle P, Chan AKC, deVeber G, Massicotte P. Andrew’s Pediatric Thromboembolism and Stroke; Third edition advance these objectives in our state, the Indiana 3. Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus There are a number of important points to be considered for reversal of anticoagulation and fibrinolytic therapy. Hemophilia and Thrombosis Center (IHTC), has created a on new anticoagulant agents. Blood. 2008 May 15;111(10):4871 "Thrive," 4. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev. 2007 Jan;21(1):37-4 Knowledge of a variety of issues is required for appropriate Hemophilia Awareness Campaign, for which a 5. Baker RI. Coughlin PB. Gallus AS. Harper PL. Salem HH. Wood EM. Warfarin Reversal Consensus Group.Warfarin reversal: consensus guidelines, medical decision making and include: website, www.seehowithrive.org, is available. It features hemophilia facts and a series of videos highlighting the on behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia. 2004 Nov; 181(9):492-7.  6. Baglin TP, Keeling DM, Watson HG; British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third having a clear understanding of the underlying reason stories of people in Indiana living with hemophilia. edition--2005 update. Br J Haematol. 2006 Feb;132(3):277-85. for a patient’s anticoagulation; © Copyright Indiana Hemophilia & Read more about “Thrive” on the back page. 5 Thrombosis Center, Inc. 2012  understanding the need for reversal; and warfarin should be discontinued five days before surgery, and If immediate reversal of warfarin is needed, such as for be concurrently administered with either PCCs or rFVIIa Direct thrombin inhibitors include argatroban, the recombinant tPA products such as alteplase. Fibrinolytic drugs tion and thrombocytopenia, for which a platelet transfusion ideally the INR should be checked the day before the procedure intracranial bleeding, is inadequate. Infusion to normalize the INR once the effect of the clotting factor hirudins, and the recently available oral agent, dabigatran. have very short half-lives, ranging from 5-20 minutes, and may be necessary in addition to the measures described above. to assure that it is <1.5. Warfarin may be resumed 24 hours of fresh frozen plasma (FFP) may be utilized; however, an concentrate attenuates. The parenteral drugs have short half-lives; therefore discon- are usually administered through a continuous infusion. If In cases of life-threatening intracranial or intracavitary bleed- postoperatively. infusion of 15-20 ml/kg may require 4-6 units in a 70 kg tinuation, monitoring of the patient, and transfusion support major bleeding occurs, continuous infusion should be stopped ing, rFVIIa has been used (90 microgram/kg every 2-4 hours); adult. Consequently, this reversal mechanism is time Table 3. Dosing of NovoSeven® (rFVIIa) may be sufficient in the event of bleeding or need for rever- immediately. The most serious adverse effect of thrombolytic however its use should be restricted to this scenario with the Patients considered high risk for thromboembolism if their antico- consuming, carries with it a risk of transfusion reaction, Dose of rFVIIa in sal. It is preferable to avoid use of rFVIIa as these agents are therapy is intracranial bleeding; however, soft tissue hemor- underlying clinical thromboembolic condition requiring fibri- agulation is interrupted include those with antiphospholipid INR Before Reversal Micrograms/kg syndrome, recurrent venous thromboembolism (VTE), mechanical and may result in fluid overload. Most importantly, FFP in commonly utilized to treat patients with heparin-induced rhage, and retroperitoneal and gastrointestinal bleeding are nolytic therapy seriously considered. A CBC and coagulation heart valves, and atrial fibrillation. Bridging with unfractionated a dose of 15-20 ml/kg will only raise the level of the clotting 3.0 10 thrombocytopenia, a highly prothrombotic condition and also examples of major hemorrhage. studies should be repeated every few hours to assess response factors by 15-20% which may be insufficient to correct the one in which the patient may have already experienced a to replacement therapy until these have stabilized at a clinically heparin (UFH), or low molecular weight heparin (LMWH) should To assess the situation rapidly and be prepared for potentially . Therefore, the treatment of choice for rapid 5.0 20 thromboembolic complication. Dabigatran is indicated for acceptable level and the bleeding has been controlled. be implemented in these groups and in situations where reversal required therapy, a stat CBC, platelet count, , type warfarin reversal is a prothrombin complex concentrate patients with atrial fibrillation. Reversal is somewhat more is required. Preoperatively, a therapeutic dose of LMWH is initiat- 8.0 30 and cross match, and comprehensive metabolic panel are A vast number of patients in all fields of medicine are treated (PCC), such as Bebulin® or Profilnine®. These products are problematic as the half-life is longer: 11 hours in young ed once the INR has become subtherapeutic. The last dose of required. The primary reversal agents utilized include cryopre- with anticoagulant drugs. With the advent of many new agents, labeled based on their factor IX content and the the dose 10.0-15.0 40-50 healthy subjects and 14-17 hours in the elderly. Use of aPCCs LMWH is given at 50% of the therapeutic dose 24 hours before cipitate and an agent. Cryoprecipitate is the anticoagulation arena has become increasingly complex. administered ranges between 25-50 international units/kg. >20 50-90 or rFVIIa has been considered, and the drug can be dialyzed surgery. Resumption of LMWH commonly occurs 24-48 hours infused to achieve a target fibrinogen level of S80 mg/dL; in Understanding procedures for reversal of these agents is essen- postoperatively; dosing, whether prophylactic or therapeutic, is It may be advisable to administer these products in incre- in a patient with renal insufficiency and life-threatening an adult this may require 10 units of cryoprecipitate. An anti- tial in order to minimize the risk of treatment-related bleeding, dependent on the risk of bleeding which is weighed against the ments, particularly in patients at high risk for thrombosis. bleeding. Rivaroxaban, an oral factor Xa inhibitor is also fibrinolytic medication is also administered if the patient is or thrombosis. Scientific publications and reviews that address risk of early thrombosis. If UFH is used, it should be held for four PCCs contain low concentrations of factor VII; therefore, Heparins: commercially available, and is approved for prophylaxis experiencing a life-, organ- or limb-threatening bleed. Either practical aspects of anticoagulation reversal such as specific hours prior to surgery, and the aPTT checked one hour preopera- additional FFP may be required, depending on the specific If a patient on LMWH or UFH experiences bleeding which following joint replacement surgery. If emergent reversal aminocaproic or tranexamic acid may be utilized. Both drugs reversal agents and dosing are essential for primary providers, tively. Transition to warfarin may be initiated 24 hours after the product utilized and the individual’s response. A stat PT/INR requires immediate reversal, protamine sulfate may be is required, rVIIa or aPCCs may be utilized. may be administered intravenously: tranexamic acid dosing is medical, and surgical subspecialists. With this in mind, the surgery or on a subsequent postoperative day depending on the should be sent out approximately 15 minutes after adminis- administered. Protamine sulfate should be infused at a rate Reversal of anticoagulation may be further complicated if 10 mg/kg IV every 3-4 hours, and is dosed Indiana Hemophilia and Thrombosis Center developed a pock- perceived bleeding risk and feasibility of oral intake. At the time tration of the PCC to evaluate the response [Table 2]. of 5 mg/minute, with 50 mg as the maximum single dose. the patient is also taking an antiplatelet therapy due to heart with an initial bolus of 50-100 mg/kg (maximum 5 g) followed et-sized handbook entitled Reversal of Anticoagulant Therapy. of initiation, the regular maintenance dose is administered, and Protamine sulfate may exert an anticoagulant effect if an disease. Antiplatelet agents are divided into categories based by 30 mg/kg/hour (maximum 1.25 g/hour) IV until bleeding To request a copy, please contact the IHTC at 317-871-0011. the LMWH or UFH is continued until two consecutive INRs are Table 2. PCC dosing for warfarin reversal excessive dose is administered. LMWHs are not fully reversed upon their mechanism of action. Cox-2 inhibitors include has ceased or a maximum dose of 18 grams is reached. in the target range. by protamine sulfate, which only neutralizes approximately ~ IU/dL activity PCC dose, aspirin and non-steroidal anti-inflammatory medications. For a summarized list of commonly used anticoagulants Hemostatic 60% of the anticoagulant activity; nonetheless, protamine Fibrinolytic therapy may be associated with platelet dysfunc- along with their reversal agents, refer to Table 6. If warfarin reversal is emergently required, the medication is INR of factors based on FIX U/kg, Persantine is a phosphodiesterase inhibitor that is most Condition sulfate may be sufficient to control or slow bleeding in an held and vitamin K is administered, either intravenously or orally. based on INR target 50 U/dL commonly prescribed for secondary stroke prevention in a Subcutaneous and intramuscular vitamin K injections are not emergency situation [Tables 4 & 5]. Excessive >5.0 5% 45-50 IU/kg long acting form combined with aspirin. The thienopyridines Table 6. Continued on page 5. recommended because of unpredictable absorption and the risk include ticlopidine, clopidogrel and prasugrel. Finally, the Table 4. Unfractionated Heparin Primary of intramuscular bleeding. Intravenous administration produces anticoagulation 4.0-4.9 10% 40 IU/kg Anticoagulant Anticoagulation Reversal glycoprotein IIb-IIIa receptor antagonists, eptifibatide and Anticoagulant Half-Life Excretion Therapeutic Anticoagulation Dose a more rapid response compared to oral, with a significant partial mg Protamine Sulfate Action Monitoring Agents Therapeutic 2.6-3.2 15% 35 IU/kg Time since last heparin dose abciximab, are most commonly utilized on a short-term basis Mode effect observed in 4-6 hours, and the full effect in 12-24 hours. If Per 100 Units Heparin anticoagulation during coronary intervention procedures. These agents affect the patient has liver dysfunction, vitamin K may not be effective Pediatrics Adults 0-30 minutes 1.0 platelet function, but occasionally may also be associated due to decreased synthetic capacity and resultant abnormal pro- 2.2-2.5 20% 30 IU/kg with acute thrombocytopenia. The action of these agents Vitamin K duction of factors II, VII, IX and X. Intravenous administration of 30-60 minutes 0.5-0.75 1.9-2.1 25% 25 IU/kg may be counteracted with platelet transfusion. Desmopressin Coumadin: 42 hours Liver Inhibits Vitamin Loading dose: Loading dose: INR Vitamin K1 vitamin K has a small risk of if infused too rapidly, 60-120 minutes 0.375-0.5 Subtherapeutic 1.7-1.8 30% 20 IU/kg (DDAVP) may also be used, with the exception of eptifibatide, Warfarin K mediated 0.2 mg/kg, PO 5-10 mg PO (Antidote); largely due to the presence of the preservative benzyl alcohol. gamma- (NOT necessary) PCC; 6-8 hours 0.25-0.375 and use of an antifibrinolytic agent such as aminocaproic or Maintenance dose: Consequently, physicians may be reluctant to administer vitamin carboxylation rFVIIa anticoagulation 1.4-1.6 40% 10 IU/kg 0.1 mg/kg Maintenance dose: K intravenously; the risk is minimized through a slow infusion tranexamic acid may be considered when appropriate. of Factor II, (NovoSeven); >8 hours No protamine sulfate required (max dose: 5 mg), 5-10 mg daily, PO rate, with administration over at least 15-30 minutes [Table 1]. Normal 1.0-1.3 100% 0 IU/kg Eptifibatide has a short duration of action, 2-6 hours; there- VII, IX, X FFP fore rapid discontinuation of treatment is important in the PO Table 1. Recommended adult dosing of vitamin K as an Table 5. Low molecular weight heparin management of bleeding. The dose of intravenous DDAVP INR reversal with recombinant factor VIIa (rFVIIa) is partial, Heparin antidote for warfarin mg Protamine/ is 10 micrograms/meter2 intravenously or subcutaneously. Time since last dose UFH 90 Majority Anti-thrombin Loading dose: Loading dose: APTT Protamine as the product only contains factor VIIa and does not replace (mg or 100 Units LMWH) Clinical Alone or with Administration of DDAVP should be undertaken with caution minutes reticuloen- mediated 50-75 U/kg, IV 50-75 IU/kg, IV sulfate INR Dose the other vitamin K-dependent clotting factors also affected May also use: Condition adjunctive treatment as patients on these antiplatelet agents likely have vascular (range: dothelial inhibition of (Antidote), by warfarin. Although, rFVIIa may correct the prolonged INR, <4 hours 1 mg per mg Maintenance, CI: Maintenance, CI: ACT Anti 1-2 system (faster thrombin rFVIIa >1.3 Life-threaten- 10 mg IV PCC, rFVIIa, FFP; repeat disease. DDAVP should not be given to anyone with an acute < 1 year: 12-18 IU/kg/hr, IV factor-Xa as the test is sensitive to factor VII activity, interpreting the >4 hours 0.5 mg per mg hours) clearance); & factor Xa (NovoSeven) coronary syndrome or other significant coronary history, 28 IU/kg/hr (Heparin level) ing bleeding Vit K based on INR degree of anticoagulant reversal may be overestimated and Liver and is often not tolerated well by patients greater than 65 >1 year: must be correlated with clinical bleeding response. The half- >1.3 Serious 10 mg IV PCC, rFVIIa, FFP; repeat years of age. 20 IU/kg/hr bleeding Vit K Q 12 hrs life of rFVIIa is short, approximately 2 1/2-4 hours, and there- Other Anticoagulants: LMWH: Single Renal Anti-thrombin < 2 months: 1 mg/kg/dose, SC, Typically no Protamine S fore repeat dosing may be required [Table 3]. rFVIIa’s mecha- The reversal of newer antithrombotic drugs may be problem- The last group of patients to be considered, for whom acute 9.0 No significant 2.5-5.0 mg PO Alone dose: mediated 1.5-2 mg/kg/dose, q12 hr; monitoring sulfate nism of action in this setting is likely not the same as that atic. These agents include fondaparinux, an indirect factor Xa Enoxaparin bleeding reversal of antithrombotic treatment may be required include (Lovenox) 4.5 hours inhibition of SC BID 1.5 mg/kg daily, SC required (Partial in hemophilic individuals with inhibitors, i.e. generation of a inhibitor, and direct thrombin inhibitors. rFVIIa in a dose of those undergoing thrombolytic therapy. Reversal in this Other agents: factor Xa >2 months-12 yrs: antidote), S5.0 - <9.0 No significant 1.25-2.5 mg PO Alone or hold warfarin Anti-factor Xa thrombin burst via the tissue factor pathway or independent 90 ug/kg has been used to counteract the anticoagulant effect group is almost always emergent and is due to untoward Dalteparin Repeat 1.5 mg/kg/dose rFVIIa (Heparin level) bleeding based on clinical setting (Fragmin) dosing: SC BID (NovoSeven) of tissue factor in association with phospholipid on the cell of fondaparinux; reversal is typically rapid, although repeat bleeding. Commonly used fibrinolytic agents in the past have using drug Tinzaparin 7 hours <5.0 No significant None Hold warfarin, based on membrane. Reversal of anticoagulation using rFVIIa carries dosing may be required in 4-6 hours. Use of this agent for included and . These have largely specific curve (Innohep) bleeding clinical setting the risk of thromboembolism development. Vitamin K should reversal may carry a risk of thromboembolic complications. been supplanted by tissue plasminogen activator (tPA), and 2 3 4