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1.  Safety of a Four‐factor Prothrombin Complex Concentrate Versus Plasma for Vitamin K Antagonist Reversal: An Integrated Analysis of Two Phase IIIb Clinical Trials 
Academic Emergency Medicine  2016;23(4):466-475.
Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four‐factor prothrombin complex concentrate (4F‐PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F‐PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure.
This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F‐PCC, n = 191; plasma, n = 197) aged ≥ 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F‐PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively.
The proportion of patients with AEs (4F‐PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F‐PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F‐PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F‐PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F–PCC group (25 [12.7%] and 9 [4.7%], respectively).
These safety data represent the largest controlled assessment of a 4F‐PCC to date. For patients requiring urgent VKA reversal, 4F‐PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.
PMCID: PMC5071715  PMID: 26822172
2.  Increased risk of volume overload with plasma compared with four‐factor prothrombin complex concentrate for urgent vitamin K antagonist reversal 
Transfusion  2015;55(11):2722-2729.
Plasma is commonly used for vitamin K antagonist (VKA) reversal, but observational studies suggest that it is associated with transfusion‐related adverse reactions (e.g., volume overload). However, this issue has not previously been addressed in a randomized controlled trial (RCT).
Factors associated with volume overload were examined using data from two Phase IIIb RCTs comparing plasma with four‐factor prothrombin complex concentrate (4F‐PCC, Beriplex/Kcentra, CSL Behring) for urgent VKA reversal. VKA‐treated patients with major bleeding (NCT00708435) or requiring an urgent surgical or invasive procedure (NCT00803101) were randomly assigned (1:1) to receive either plasma or 4F‐PCC, concomitant with vitamin K. Adverse events (AEs) and serious AEs were prospectively captured up to Day 10 and 45, respectively. Volume overload predictors were evaluated on a univariate and multivariate basis.
A total of 388 patients (4F‐PCC, n = 191; plasma, n = 197) were enrolled. Volume overload occurred in 34 (9%) patients (4F‐PCC, n = 9; plasma, n = 25). In univariate analyses, use of plasma (vs. 4F‐PCC), use of nonstudy plasma and/or platelets, race, history of congestive heart failure (CHF), and history of renal disease were associated with volume overload. In multivariate analyses, use of plasma (vs. 4F‐PCC), history of CHF, and history of renal disease were independent volume overload predictors. In an additional analysis restricted to volume overload events recorded up to Day 7, only use of plasma (vs. 4F‐PCC) was an independent volume overload predictor.
After adjusting for other potential risk factors, plasma use was independently associated with a greater risk of volume overload than 4F‐PCC in patients requiring urgent VKA reversal.
PMCID: PMC4755192  PMID: 26135740
3.  Heparin-Induced Thrombocytopenia Associated with Massive Intracardiac Thrombosis: A Case Report 
Case Reports in Hematology  2012;2012:257023.
A 60-years old patient was admitted to a community hospital with septic arthritis. He was treated with antibiotics and subcutaneous unfractionated heparin (UH) was used for venous thromboprophylaxis. After three days, he developed leg deep venous thrombosis and was treated with IV heparin. One day later, the patient developed pulmonary emboli, which was found using ventilation/perfusion scan. He was transferred to the University Hospital for further management. Upon arrival, antibiotic and intravenous UH were continued. Trans-Esophageal Echocardiogram showed a thrombus in the right atrium, a small portion of which extended to the left atrium through a patent foramen ovale. Another large thrombus was noted in the right ventricle, which extended to the pulmonary artery. Review of the patient's medical records revealed a halving of his platelet count three days following the heparin administration. Therefore, HIT seemed very likely. Intravenous UH was stopped and an emergency thrombectomy was performed. ELISA testing of HIT antibodies came negative. This made HIT diagnosis unlikely and the patient received dalteparin. A week later, as the platelet count declined again, HIT antibodies' testing using ELISA and C-14 serotonin release was repeated, and both assays were positive. Argatroban was restarted and the platelet count normalized.
PMCID: PMC3420555  PMID: 22937322

Results 1-3 (3)