Pulmonary ConferenceAkshu Balwan

Case presentation 84/ F admitted with shortness of breathDiagnosed with CHF,AKI both of which were resolving Also found to have elevated right sided pressures. subsequent DVT positive in lower extremity Patient developed A fibb noted during the hospital stay MA was started on heparin on day 08/09 with normal PTT at baselinePTT 32 170 56 92Platelets 325278235Started on Coumadin 5mg on 08/10on 08/11 noted to develop mildly tender rash as shown , no significant change in platelet count since admission. Renal function were continuing to trend to baseline. Patient had overall improvement in her symptoms except the new rash.

Differential diagnosis Heparin induced bullous hemorrhagic dermatosisWarfarin induced skin necrosis (historically called Thrombophlebitis migrans disseminata )Necrotizing fascitis Calciphylaxis Leukocytoclastic vasculits Purpura fulminans (in children) Cholestrol microemboli (generally involve digits)

Pulmonary consult sought for co-managementRecommendation:1. Warfarin to be stopped2. Consider alternate form of anticoagulation, and if that is not possible IVC filter to be consideredhematology consulted bivalrudin was startedSkin biopsy done Patient discharged home on lovenox

Skin BiopsySent for expert consultation. Reported as non-inflammatory dermal hemorrhage and the presence of fibrin thrombi which is highly suggestive and consistent with early warfarin necrosis, especially in the appropriate clinical setting.Diffuse microthrombi withing subcutaneous vessels(cappilaries, venules and veins) and epithelial damage. Arterial involvement and perivascular inflammation is not common.

Warfarin Induced Skin Necrosis About 300 cases reported in literature First case 1916 by McLean J or 1943 by Flood etal Risk factors: low protein-C levels, protein-S deficiency, or Factor V leidenmutation, ATIII deficiency,mutation in the MTHFR gene and presence of anti-phospholipid antibody.Pathogenesis: Most widely accepted hypothesis is protein C deficiency, Half life of protein C is about 8 hours , Transient hypercoagulable stateClinical presentation - Propensity towards areas of skin with fat Acral involvement rareAcute onset(2-5 days) of paresthesia and edema followed by petechiae and ecchymosis progressing to hemorrhagic bullae. Literature is ripe with case reports of variable duration of warfarin therapy before presentationThis is followed by skin necrosis

TreatmentStop warfarinAdminister Vitamin K Consider protein C concentrate - no RCT to demonstrate effectivenessProstacyclin have been used for there vasodilator effect and inhibitor of platelet aggregation but there is no RCT (Norris PG. Clin Exp Dermatol 1987,104; 659-60)Attempts of warfarin re-initiation have mixed results. (Jillela AP. Reinstituting warfarin in patients who develop warfarin skin necrosis, Am J Hematol 1996;52; 117-19)Slow re-initiation can be considered with gradual up-titration over upto 10 days. (Samama M Successful progressive anti-coagulation in a sever protein C deficiency and previous skin necrosis at initiation of oral anti-coagulants Thromb Hemost 1984; 52: 132-5)

Coagulation

New- Coagulation cascade

Newer oral anticoagualants

WarfarinDabigatranRivaroxabanApixabanTargetVit K epoxide reductaseThrombinFactor XaFactor XaOral bioavailability99%6-7%60-80%80%Tmax72-96 h2 h2.5-4 h3 hHalf-life40 h14-17 h5-9 h9-13 h elderly8-15 hMetabolismCytochrome P45080% renal20% biliary66% renal33% biliary25% renal75% biliary

Dabigatran

Dose Stroke prevention in A fib: 110-150 mg bid110 mg dose not available in USFor patients with CrCl 15-30: 75 mg bidNot recommended for CrCl < 15 or dialysis dependentPrevention of recurrent VTE: 150 mg bidPostop VTE prophylaxis: 110-150 mg once dailyAffects PT/INR and PTT (but not useful for monitoring)Drug may degrade over time after exposure to air must be kept in original packaging

* Not FDA-approved indication

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial; J Thromb Haemost 2011; 9:2168 - basis for renal dose adjustment

Dabigatran trialsRE-LY trialFDA approved in 2010Newer study RELY-ABLE -During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death.(The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation. 2013 Jul 16;128(3):237-43)In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). (Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013 Feb 5;127(5):634-40)RE-COVER trial for DVT

RivaroxabanReducing stroke risk in nonvalvular atrial fibrillation (AF)Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. (There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.)Deep vein thrombosis (DVT) and pulmonary embolism (PE) treatment and reduction in the risk of recurrenceTreatment of DVT and PE ( EINSTEIN Study)Reduction in the risk of recurrence of DVT and of PE following initial 6 months treatment for DVT and/or PE.(EINSTEIN Extension study)DVT prophylaxis after knee or hip replacement surgeryProphylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Dosing15 mg twice daily with food for 3 weeks followed by 20 mg once daily with food(also long term). For AF 20 mg daily. Ppx dose is 10 mgUse with caution in moderate renal impairment (CrCL 30-49)Avoid use if CrCl < 30 (not dialyzable)Avoid use in severe liver diseaseNo dose adjustments needed for weightConversion from warfarin: Discontinue warfarin and initiate rivaroxaban as soon as INR falls to

TrialsROCKET-AFEINSTEIN- PEEINSTEIN- DVTEINSTEIN Extension

Searching for anti-doter-Antidote, PRT064445. (Lu G;A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa; Nat Med. 2013;19(4):446)Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.(Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9.)

ApixabanNon-valvular A fib Canadian labelling for post op VTE ppxPossibly for extended treatment for VTE and VTE itself as recent studies in NEJM indicate

DosingDose: Post op VTE prophylaxis: 2.5 mg twice dailyStroke prevention in Afib: 5 mg twice daily unless patient has any 2 of the following: Age 80 years, body weight 60 kg, or serum creatinine 1.5 mg/dL, then reduce dose to 2.5 mg twice dailyAvoid use in severe liver diseaseConversion from warfarin to apixaban: Discontinue warfarin and initiate apixaban when INR is

TrialsARISTOTLE- use for A fibbAPPRAISE use after ACSAgnelli G. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;Agnelli G. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21

The complex formed by tissue factor and factor VII participates in the activation of factor IX, indicating that the intrinsic and extrinsic coagulation pathways are linked almost from the beginning of the process.2.The complete process does not occur continuously but rather requires 3 consecutive phases: an initial phase, an amplification phase, and a propagation phase. Platelets and thrombin are actively involved in the last 2 phases