ALBERT

Description: Introduction: rFVIIa has been touted as a pancoagulant to reverse untoward hemorrhage in various clinical situations. We describe 3 hypercoagulable patients with enox-induced bleeding treated successfully and safely with rFVIIa. Case Summaries: Patient 1, a 58 year old female, received enox 60mg SQ q12 h for a left femoral DVT. On day 2, a bleeding right femoral pseudoaneurysm was detected. On day 3, the patient’s hematocrit fell from 37.5% to 22%, as swelling and pain ensued in the right thigh 4h after receiving her AM dose of enox. The concurrent PT, INR and aPTT were 18.1, 1.72 and 34.2 sec respectively. rFVIIa (20μg/kg) was administered intravenously with rapid cessation of bleeding. Patient 2, a 42 year old male, with a history of SLE, antiphospholipid antibody syndrome, and a distant history of a distal DVT was admitted for acute renal failure (creatinine of 4.2) secondary to lupus nephritis. One day after a kidney biopsy, the patient was placed on coumadin 5mg and continuous infusion of unfractionated heparin which was then changed to enox 70 mg SQ q 12. Both coumadin and enox were held after 4 d, once his PT, INR and aPTT reached 30, 3.97 and 56.2 sec respectively. The next day, a CT scan to evaluate a new abdominal pain revealed a large bleed at the kidney biopsy site. Despite transfusions of 6 bags of red blood cells, 4 bags of fresh frozen plasma, and 10mg of SQ vitamin K1, his hematocrit dropped to 19% and his PT, INR, and aPTT remained elevated at 28, 3.49, and 60.8 sec respectively. Thromboembolization was achieved to terminate bleeding from 2 of his 3 renal biopsy sites, the last of which was technically inaccessible. rFVIIa (30μg/kg) was administered as an intravenous bolus with immediate cessation of active bleeding. The next day, the antifactor Xa level was 0.12 anti-Xa U/ml and the PT, INR, and aPTT were 13.7, 1.09 and 45.1 sec, respectively and remained at these levels for the next 4 days. Patient 3, a 56 year old female with a prior history of multiple PEs and proximal DVTs due to protein S deficiency, was admitted for total knee arthroplasty. Admission labs were all within normal limits. Enox 80mg sq was initiated 24 h post-operatively for DVT prophylaxis. Four h later, brisk bleeding developed acutely from the surgical site. The simultaneous antifactor Xa level was 0.49 anti-Xa U/ml. rFVIIa (20μg/kg) was administered as an intravenous bolus and bleeding from the JP drain ceased instantly. All 3 patients stabilized within hours following administration of rFVIIa for their acute bleeding events; all required multiple transfusions of FFP and packed RBCs before rFVIIa; and all resumed anticoagulation without further bleeding. Discussion: Many clinicians fear that the rare untoward hemorrhage associated with any low molecular weight heparin (LMWH) preparation cannot be efficiently or rapidly reversed as there is no specific or reliable antidote. rFVIIa concentrate has reversed the anti-Xa properties of LMWH in ex vivo plasma-spiking experimental models but experience with use of rFVIIa to reverse LMWH-induced bleeding in vivo is lacking. Conclusion: This report suggests that rFVIIa administered in low doses (20–30μg/kg) reverses clinically significant LMWH-induced bleeding complications effectively, rapidly, and safely and should be considered as an adjunct in the treatment of LMWH-induced bleeding in patients with either hypercoagulable conditions or acute VTE. Clinical trials are needed to confirm the effectiveness of rFVIIa in this clinical scenario.

Description: Data have been collected from 47 centers in Europe and North America on the treatment with porcine factor VIII concentrate of 74 acute bleeding episodes in 65 patients with acquired hemophilia. The median initial anti-human factor VIII auto-antibody inhibitor level was 38 Bethesda unit (BU)/mL (range 1.2 to 1,024) whereas that against porcine was 1 BU/mL (range 0 to 15). The mean initial dose of porcine factor VIII infused was 84 IU/kg, which increased the plasma factor VIII:C activity by 0.85 IU/mL. Therapy was continued for a mean of 8.5 days during which time the average number of infusions was 11. Objective clinical responses were rated as good or excellent in 78% of recipients. Side effects were uncommon; only one patient experienced a severe anaphylactic reaction necessitating the discontinuation of porcine FVIII therapy. After therapy, no increase in the median level of anti- human FVIII or anti-porcine antibody was noted in the group as a whole, although 13 patients showed individual increases in either anti-human or anti-porcine antibody levels or both of more than 10 BU/mL. Of the 7 patients who subsequently rebled, 5 were successfully re-treated and 2 did not respond to further porcine factor VIII treatment. Porcine factor VIII is safe and clinically effective treatment for bleeding episodes associated with acquired hemophilia and should be considered as first-line therapy for patients whose acquired anti-factor VIII:C antibody cross-reacts with porcine factor VIII:C at low levels.

Description: INTERCEPT Plasma (I-FFP) uses amotosalen (S-59, 150μM ) and UVA light (3 J/cm2 to inactivate pathogens in single plasma units. TPE is the mainstay therapy for TTP. Efficacy and safety of I-FFP for TPE of TTP were evaluated in a double-blinded, randomized, controlled trial. Eligible patients (pts) with TTP unrelated to cancer, cancer therapy, transplantation, AIDS, HUS, or SLE received daily TPE (1.0 to 1.5 blood volumes) with either I-FFP or conventional plasma (C-FFP) for up to 2 TPE cycles, each with a maximum of 35 days (d) of TPE. Treated pts were followed for 7 d after the last TPE to detect overall adverse events (AE) and for 60 d after achieving remission to detect relapse and serious adverse events (SAE). The primary endpoint was the proportion of pts in remission (platelet count ≥ 150,000/μL for 2 consecutive d without neurologic progression) within 30 d after the 1st TPE. Secondary endpoints were: time to 1st remission, volume of plasma used, number of TPEs, relapse rates after remission, vWF cleaving protease (vWF-CP) activity and inhibitor levels, antibodies to potential S-59 neoantigens, and safety. 35 pts (17 I-FFP, 18 C-FFP), mean age of 40 yr, 80% female were treated. TPE with I-FFP was comparable to C-FFP in remission rates (82% I-FFP, 89% C-FFP:p=0.66), median time to remission (6 d I-FFP, 6 d C-FFP:p=0.58), mean total volume of plasma exchanged (40.6 L I-FFP, 41.3 L C-FFP:p=0.86), mean number TPEs (11.3 I-FFP, 10.3 C-FFP:p=0.68), and relapse rates (36% I-FFP, 38% C-FFP:p=1.00). Baseline and post TPE vWF-CP activity and inhibitor levels were similar between groups. Overall AEs, serious AEs, deaths (1 I-FFP and 1 C-FFP: neither attributed to TPE), rates of discontinuation from study, laboratory abnormalities, and vital signs (VS) during TPE were comparable between groups. 1 C-FFP pt had TRALI. Five I-FFP pts had AEs coded to the cardiac system organ class compared to no C-FFP pts (p=0.02). In 4 of the I-FFP pts, these AEs were non-serious and did not interrupt TPE. One I-FFP pt with relapsing TTP had a serious AE after 12d of TPE, recovered without sequelae, was withdrawn from study, and continued on non-study FFP TPE with recurrent relapse. No antibodies to potential S-59 neoantigens were detected in any pts. In this trial, efficacy endpoints and safety profiles of TTP pts treated with I-FFP TPE were similar to those for TTP pts treated with C-FFP TPE.

Description: Data have been collected from 47 centers in Europe and North America on the treatment with porcine factor VIII concentrate of 74 acute bleeding episodes in 65 patients with acquired hemophilia. The median initial anti-human factor VIII auto-antibody inhibitor level was 38 Bethesda unit (BU)/mL (range 1.2 to 1,024) whereas that against porcine was 1 BU/mL (range 0 to 15). The mean initial dose of porcine factor VIII infused was 84 IU/kg, which increased the plasma factor VIII:C activity by 0.85 IU/mL. Therapy was continued for a mean of 8.5 days during which time the average number of infusions was 11. Objective clinical responses were rated as good or excellent in 78% of recipients. Side effects were uncommon; only one patient experienced a severe anaphylactic reaction necessitating the discontinuation of porcine FVIII therapy. After therapy, no increase in the median level of anti- human FVIII or anti-porcine antibody was noted in the group as a whole, although 13 patients showed individual increases in either anti-human or anti-porcine antibody levels or both of more than 10 BU/mL. Of the 7 patients who subsequently rebled, 5 were successfully re-treated and 2 did not respond to further porcine factor VIII treatment. Porcine factor VIII is safe and clinically effective treatment for bleeding episodes associated with acquired hemophilia and should be considered as first-line therapy for patients whose acquired anti-factor VIII:C antibody cross-reacts with porcine factor VIII:C at low levels.