Challenges in Coagulation

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2 Challenges in Coagulation Michael H. Rosove, MD Clinical Professor of Medicine UCLA Division of Hematology-Oncology April 30, 2016 Vitamin K Deficiency Vitamin K1 source from diet Vitamin K2 source from gut flora Vitamin K absorption requires bile salts, intact GI tract Vitamin K stores may last less than 1 week PT more sensitive than PTT TT, fibrinogen normal Bleeding risk correlates to PT/PTT Vitamin K (PO or IV), FFP, PCC Vitamin K antagonists (VKAs) warfarin, others available in other countries, rodenticides Matters affecting vitamin K availability Changes in drugs Changes in diet PT more sensitive than PTT TT, fibrinogen normal Bleeding risk correlates to PT/PTT Vitamin K (PO or IV), FFP, PCC Disseminated intravascular coagulation (DIC) Shock (all kinds), sepsis, obstetric emergencies, disseminated malignancy (especially adenocarcinomas), aortic dissection, IABP, extracorporeal circulations, peritoneal-venous shunts, massive tissue/tumor necrosis PT and PTT about equally sensitive, D-dimer high, possibly low fibrinogen, thrombocytopenia, RBC fragments Bleeding and/or thrombosis Treat the cause; FFP, cryoprecipitate, platelets, RBCs; UFH or LMWH for thrombosis Dilutional coagulopathy Exsanguination without adequate FFP/platelet support PT and PTT about equally sensitive fibrinogen low, D-dimer normal (unless DIC also present), thrombocytopenia, anemia Bleeding risk correlates to PT/PTT/fibrinogen abnormality Control the bleeding; FFP, cryoprecipitate, platelets, RBCs Liver failure By the time coagulopathy is present, liver dysfunction is clinically obvious PT and PTT about equally sensitive, fibrinogen low, D- dimer may be high, thrombocytopenia (portal hypertension) Bleeding; thrombosis (uncommon) Assure vitamin K repletion; FFP, cryoprecipitate, platelets, RBCs

3 Lupus anticoagulant Not a bleeding disorder; thrombosis the main concern (antiphospholipid syndrome) Background autoimmune disorder, false positive STS PTT much more sensitive than PT, PTT inhibitor present, fibrinogen normal, modest thrombocytopenia not unusual (autoimmune) Lupus anticoagulant assay (e.g., drvvt) positive, cardiolipin and/or beta2-glycoprotein I antibodies, and hypoprothrombinemia (if PT ) may coexist Factor VIII inhibitor Elderly patients, background autoimmune disorder, recent pregnancy Patients virtually always present as a serious recent bleeding tendency; diagnosis / management urgent PTT prolonged (inhibitor on 2 hr incubated testing); factor VIII very low; PT, TT, fibrinogen, platelets normal Corticosteroids, rituximab, other immunosuppressants FEIBA (activated PCC), recombinant factor VIIa, recombinant porcine factor VIII, human factor VIII Rare acquired coagulation disorders Factor X deficiency AL amyloid may absorb, PT and PTT equally sensitive, mixing studies correct Factor V inhibitor after topical bovine thrombin exposure, PT and PTT equally sensitive Case #1 An 82 y/o man with hypertension and coronary disease last night had a ripping sensation in chest and back, then felt better, went to sleep, then woke up this morning with gum and nose bleeding so went to the ER. Pulses asymmetrical. CBC normal, PT INR >10, PTT 85, fibrinogen <30, D-dimer >10,000. Acquired von Willebrand factor deficiency hypothyroidism; inhibitor (monoclonal gammopathy, Waldenstrom macroglobulinemia) Other acquired factor inhibitors exceedingly rare Case #2 Your 55 y/o male patient presents at 10pm with acute appendicitis, is stable and about to go to the OR. CBC normal, PT INR 1.1, PTT 45 (normal 23-32). No personal or family history of bleeding. His PTT was 24 before ankle fracture surgery 3 yr ago. Case #3 A 78 y/o woman with rheumatoid arthritis has had 1 week worsening bruising, RLQ pain, no nausea. Afebrile, multiple ecchymoses on extremities and trunk. WBC 5,600, Hgb 9.6 (new), platelets 285,000, INR 1.0, PTT 52 (normal 23-32).

4 The NOACs Dabigatran Pradaxa Rivaroxaban Xarelto Apixaban Eliquis Edoxaban Savaysa Comparison of the NOACs Dabigatran Rivaroxaban Apixaban Edoxaban Target IIa (thrombin) Xa Xa Xa Mol. Wt Oral? Yes Yes Yes Yes Prodrug? Yes* No No No Bioavailability 6.5%** 80% 50% 62% Time to peak (hr) Half-life (hr) Renal excretion 80% 65% 25% 50% * dabigatran etexilate ** increases by 75% if capsule shell is broken, opened, or chewed Comparison of the NOACs Dabigatran Rivaroxaban Apixaban Edoxaban Dosing Fixed Fixed Fixed Fixed Metabolism p-gp p-gp,3a4 p-gp,3a4 p-gp Effect of food? No No No No Affects clotting times? Yes Yes Yes Yes Monitoring No No No No Antidote? Yes Not yet Not yet Not yet Plasma protein binding 35% 92-95% 87% 55% Dialyzable? 62% at 2hr No No 7% Side effects GI (2%) NOACs FDA-Approved Indications Dabigatran Rivaroxaban Apixaban Edoxaban Non-valvular AFib X X X X* Acute VTE X X X X Long-term prophylaxis after acute VTE X X X THR VTE prophylaxis X X X TKR VTE prophylaxis X X *Inferior to warfarin with GFR >95 ml/min. Note: No FDA-approved VTE prophylaxis indications in non-orthopedic surgery or acutely ill medical patients. Dabigatran vs. Warfarin Aortic and/or Mitral Valve Replacement 12-week study aortic (68%), mitral (28%), both (4%) Group A: Post-op (79%); Group B >3 mos post-op (21%) 2:1 randomization (dabigatran:warfarin) Warfarin INR 2-3 (29%) or (71%) depending on risk Dabigatran 150, 220, or 300 mg BID depending on GFR, drug troughs Study terminated after 252 patients enrolled Stroke/ischemic events 9/168 (5.4%, all Group A) vs. 0/84 (0%) Major bleeding (all pericardial, Group A) 7/133 (4.2%) vs. 2/66 (2.4%) All bleeding Group A: 35/133 (26%) vs. 8/66 (12%) Group B: 10/35 (29%) vs. 2/18 (11%) Eikelboom JW, et al. RE-ALIGN Investigators. N Engl J Med Settings in which NOAC efficacy and/or safety not established Prosthetic heart valves Valvular atrial fibrillation stroke prophylaxis Advanced arteriosclerotic vascular disease Vascular surgery Vascular stents Splanchnic venous thrombosis Malignancy-induced thrombophilia (Trousseau syndrome) Heparin-induced thrombocytopenia Antiphospholipid syndrome Advanced hepatic and/or renal failure Pregnancy

5 NOACs Problems and Disadvantages NOACs Reversal of Anticoagulation Short half-lives makes patient compliance in taking medication especially important. Short half-lives mean less anticoagulant effect in the troughs. Lack of precise lab correlates makes it hard to differentiate treatment failure from compliance failure. Renal hyperfunction may result in over-rapid clearance of (especially) dabigatran, rivaroxaban, and edoxaban. Fixed dosing and lack of lab correlates denies practitioners the option to select on a rational basis an anticoagulant intensity. Non-specific interventions Drug discontinuation Supportive measures, e.g., RBC transfusion Bypass procoagulant materials Prothrombin complex concentrate (PCC) * Activated PCC (also known as FEIBA) * Recombinant factor VIIa (NovoSeven ) * Specific interventions Idarucizumab (Praxbind ) FDA approved Andexanet alfa ongoing clinical research * Off label Reversal of Dabigatran Idarucizumab (Praxbind ) Emergency reversal of dabigatran (only) Humanized monoclonal antibody, 5 mg IV once Healthy volunteers (n=14), dabigatran 220 mg BID x 3d PTT , ECT , TT , ACT Patients with serious bleeding (n=51), urgent procedures (n=39) 88%-98% elimination of detectable drug, normalization of TT and ECT within minutes Median time to complete hemostasis in bleeding patients 11.4 hr 33/36 evaluable procedure patients had normal hemostasis, 3 had mild to moderate bleeding 1 thrombotic event in a patient not restarted on dabigatran Reversal of the Xa inhibitors Andexanet alfa Drug half-life 1 hr 145 healthy volunteers, age Rivaroxaban subjects: 20 mg QD x few days, then andexanet 800 mg IV bolus (30 mg/min) mg IV over 2 hr Apixaban subjects: 5 mg BID x few days, then andexanet 400 mg IV bolus (30 mg/min) mg IV over 2 hr Primary efficacy endpoint: reduction in anti-xa activity (Clinical outcomes: no bleeding or thrombosis, 1 episode of urticaria, no neutralizing antibodies, 17% occurrence of transient non-neutralizing antibodies) Siegal DM, N Engl J Med 2015 Boehringer Ingelheim per FDA; Pollack CV, N Engl J Med 2015