Fresh Frozen Plasma Group Research Articles

Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage

BackgroundPatients with traumatic intracranial hemorrhage (TIH) anticoagulated with warfarin are at an increased risk of mortality. Fresh frozen plasma (FFP) and vitamin K have been the standard treatment for warfarin reversal; however, guidelines now recommend the use of prothrombin complex concentrate (PCC) for warfarin reversal in patients with life-threatening bleeding. Our protocol uses one vial (∼1000 units) of activated PCC (aPCC) for warfarin reversal, regardless of the weight or presenting international normalized ratio (INR). The purpose of this study was to determine the safety and efficacy of using fixed, low-dose aPCC for warfarin reversal in patients with TIH. MethodsThis was a retrospective chart review that included patients with an Abbreviated Injury Scale Head score of ≥3, TIH, and initial INR ≥ 1.5 on warfarin. Patients aged <18 years and those with no repeat INR were excluded. The primary outcome was to compare the percentage of patients with INR ≤ 1.4 after receiving aPCC versus FFP within 24 hours. ResultsEighty-nine patients were in the FFP group and 31 patients in the aPCC group. The INR was reversed more effectively in the aPCC group compared with the FFP group (90.3% versus 69.7%, P = 0.029). The median time (hours) to reversal was also significantly shorter in the aPCC group compared with the FFP group (3.75 versus 6.75, P = 0.003). However, there was no difference in mortality (35.5% aPCC versus 22.2% control, P = 0.162) or incidences of thrombosis. ConclusionFixed, low-dose aPCC is safe and more effective at reversing the effects of warfarin than FFP in patients with TIH.

Early or late fresh frozen plasma administration in newborns and small infants undergoing cardiac surgery: the APPEAR randomized trial

BackgroundIn newborns and small infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) and blood priming, it is unclear whether there is reduced blood loss if fresh frozen plasma (FFP) is added to the CPB priming volume. This single-centre, randomized trial tested the hypothesis that the administration of FFP after CPB (late FFP group) is superior to FFP priming (early FFP group) in terms of postoperative bleeding and overall red blood cell (RBC) transfusion. MethodsSeventy-three infants weighing <10 kg were randomly allocated to receive FFP to supplement RBCs in the CPB priming solution (n=36) or immediately after CPB (n=37). The primary endpoint was a difference in postoperative blood loss; secondary endpoints included the amount of RBCs and FFP transfused through the first 48 postoperative hours. ResultsAll patients were included in the analysis. Patients in the late FFP arm had greater postoperative mean blood loss than patients in the early FFP arm [33.1 (sd 20.6) vs 24.1 (12.9) ml kg−1; P=0.028], but no differences in transfusions were found. The subgroup of cyanotic heart disease patients had comparable results, but with greater use of RBCs in the late FFP group. ConclusionsIn infants undergoing cardiac surgery, FFP in the priming solution appears slightly superior to late administration in terms of postoperative bleeding. Clinical trial registration:www.ClinicalTrials.gov, NCT02738190.

Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial

Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure. This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18-80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635. Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25·34 [95% CI 5·47-240·03], p<0·0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3·04 [0·95-10·87], p=0·042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1·92 [95% CI 0·78-4·86], p=0·15). Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP. None.

The effect of the management with fresh frozen plasma on the outcome of patients with acute organophosphate poisoning

Background: Organophosphate (OP) poisoning is an important reason for hospitals and intensive care units admission in the developing countries. OP poisoning patients are classically treated with atropine and oximes, these methods are sometimes shown to be of limited benefit. Objective: Assessment of the effectiveness of the management with fresh frozen plasma (FFP) in improving the outcome of patients with acute OP poisoning. Patient and Methods: A randomized clinical trial study was conducted upon 70 acute OP poisoning patients that were referred to the Emergency Department, Suez Canal University Hospital, Ismailia, Egypt. These patients were randomly divided into two groups (35 each); Control group: Treated with the traditional management protocol of OP (atropine and oximes). FFP group: Treated with the traditional management protocol of OP plus FFP. Results: No significant difference was found in cholinesterase level on admission between both groups, Serum cholinesterase level in the FFP group significantly increased after an hour of FFP infusion (2.48 iu/ml vs. 10.36 iu/ml p

Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Vitamin K Antagonist Reversal in Acutely Bleeding Patients: A Retrospective Study

▪IntroductionVitamin K antagonist (VKA) drugs require immediate reversal in VKA-treated patients with major bleeding or requiring urgent surgery. 4-factor prothrombin complex concentrates (PCCs)are approved for urgent VKA reversalbecause they reverse the international normalized ratio (INR) more rapidly than fresh frozen plasma (FFP). Studies comparing the clinical benefits of PCC and FFP have focused on VKA reversal prior to urgent surgery. Few data comparing laboratory and clinical outcomes of patients receiving PCC or FFP for major hemorrhage have been published, and these pertain to intracranial hemorrhage (ICH) only. Given the complexity of performing randomized studies in this setting, observational studies are relevant to inform on this issue.AIMSTo compare the effects of PCC versus FFP on patient outcomes in VKA-associated major hemorrhage. The primary outcomes were the rate of INR reversal and blood product utilization. The secondary outcome was duration of intensive care and total hospital admission.MethodsWe performed a retrospective, single-center study of consecutive unselected patients receiving a 4-factor PCC for VKA reversal because of hemorrhage between January 2012 and April 2015 compared to consecutive unselected patients treated with FFP for the same indication from January 2010-December 2011, a period prior to introduction of PCC at the Meir Medical Center. Patients were identified by review of clinical and blood bank electronic medical records. We analyzed patient demographics, indication for VKA, underlying illnesses, aspirin use, site and severity of hemorrhage, INR pre- and post reversal, rate of INR reversal, transfusion requirements and duration of hospitalization, treatment.Results56 patients received PCC and were compared to 56 patients treated with FFP. In the PCC group 17 patients had ICH and 25 had gastrointestinal hemorrhage compared to 17 and 31 patients respectively in the FFP group. Patients were adjusted for age, sex, presence of renal failure, active cancer, aspirin use, site of hemorrhage, pre-treatment INR and hemoglobin concentration and hemorrhagic shock at presentation. Outcomes: Median time to INR of ≤1.3 was 0.5 (range 0.5-1.5) vs 15.5 (range 5-96) hours for PCC vs FFP respectively, P<0.001). Packed red cell transfusion did not differ between the groups: median =1(range 0-13) in the PCC group and median= 2(range=2-10) in the FFP group (P=0.3), but more FFP was transfused in the FFP vs PCC group median =0(range 0-8) in the PCC group and median= 4(range=2-8) in the FFP group (P<0.001). Duration of hospital admission was longer in the FFP (median=7 days, range 1-93) vs PCC patients (median =6 days, range=1-35) (P=0.04).ConclusionThis is the first observational study comparing PCC and FFP for VKA-related hemorrhage to our knowledge and the first study of PCC versus FFP for extracranial VKA-related hemorrhage. PCC was more effective than FFP in for reversal of the INR and was associated with less overall FFP use but not packed red cell transfusion. Similarly hospital admission duration was shorter among the PCC patients. Larger studies are required to determine whether PCC confers other clinical benefits over FFP for VKA reversal in acutely bleeding patients. DisclosuresEllis:Boehringer Ingelheim: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau.

Resuscitation with Pooled and Pathogen-Reduced Plasma Attenuates the Increase in Brain Water Content following Traumatic Brain Injury and Hemorrhagic Shock in Rats.

Traumatic brain injury and hemorrhagic shock is associated with blood-brain barrier (BBB) breakdown and edema formation. Recent animal studies have shown that fresh frozen plasma (FFP) resuscitation reduces brain swelling and improves endothelial function compared to isotonic NaCl (NS). The aim of this study was to investigate whether pooled and pathogen-reduced plasma (OctaplasLG® [OCTA]; Octapharma, Stockholm, Sweden) was comparable to FFP with regard to effects on brain water content, BBB permeability, and plasma biomarkers of endothelial glycocalyx shedding and cell damage. After fluid percussion brain injury, hemorrhage (20 mL/kg), and 90-min shock, 48 male Sprague-Dawley rats were randomized to resuscitation with OCTA, FFP, or NS (n = 16/group). Brain water content (wet/dry weight) and BBB permeability (transfer constant for 51Cr-EDTA) were measured at 24 h. Plasma osmolality, oncotic pressure, and biomarkers of systemic glycocalyx shedding (syndecan-1) and cell damage (histone-complexed DNA) were measured at 0 and 23 h. At 24 h, brain water content was 80.44 ± 0.39%, 80.82 ± 0.82%, and 81.15 ± 0.86% in the OCTA, FFP, and NS groups (lower in OCTA vs. NS; p = 0.026), with no difference in BBB permeability. Plasma osmolality and oncotic pressures were highest in FFP and OCTA resuscitated, and osmolality was further highest in OCTA versus FFP (p = 0.027). In addition, syndecan-1 was highest in FFP and OCTA resuscitated (p = 0.010). These results suggest that pooled solvent-detergent (SD)-treated plasma attenuates the post-traumatic increase in brain water content, and that this effect may, in part, be explained by a high crystalloid and colloid osmotic pressure in SD-treated plasma.

Comparative biochemical studies of fresh frozen plasma and pooled solvent/detergent-treated plasma (octaplasLG® ) with focus on protein S and its impact in different thrombin generation assay set-ups.

The solvent/detergent treatment enables effective and robust inactivation of all lipid-enveloped viruses, but also inactivates partly sensitive plasma proteins such as protein S. The aim of this study was to investigate the thrombin generation capacity of octaplasLG® , in particular focusing on the function of protein S in thrombin generation assay and the impact of assay settings. Sixteen octaplasLG® batches and 32 units of single donor fresh frozen plasma (FFP) were investigated. For protein S, both functional activity and free antigen levels were measured. Thrombin generation assay was performed using two fluorogenic tests with different triggers. Finally, rotational thromboelastometry was performed. Mean protein S levels were lower in octaplasLG® , but a wider range of values was found for FFP. Clotting parameters and thrombin generation capacities overlapped between the two plasma groups as demonstrated using both thrombin generation assays and different triggers. Spiking studies with protein S-depleted plasma, human purified protein S or antibodies against protein S confirmed a correlation between protein S and thrombin generation capacity under specific assay conditions, especially in an assay with low tissue factor concentration. Correlation between protein S and thrombin generation capacity was demonstrated in the TGA. Due to higher variability in protein S content in the FFP group, overlapping haemostatic potentials of the two plasma groups were found.

Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial

Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH. We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915. Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7-197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism). In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA. Octapharma.

Effects of fresh frozen plasma, Ringer’s acetate and albumin on plasma volume and on circulating glycocalyx components following haemorrhagic shock in rats

BackgroundEarly use of fresh frozen plasma (FFP) in haemorrhagic shock is associated with improved outcome. This effect may partly be due to protection of the endothelial glycocalyx and/or secondary to a superior efficacy of FFP as a plasma volume expander compared to crystalloids. The objective of the present study was to investigate if protection of the glycocalyx by FFP can be demonstrated when potential differences in plasma volume (PV) following resuscitation are accounted for.MethodsRats were subjected to a volume-controlled haemorrhage (30 ml/kg). At 2.5 h after haemorrhage, animals were randomized to resuscitation with FFP (37.5 ml/kg), albumin (30 ml/kg) or Ringer’s acetate (RA) (135 ml/kg, 4.5 times the bleed volume). PV was measured 2 h after completion of resuscitation using 125I-albumin and effects on endothelial glycocalyx were evaluated by measuring circulating heparan sulphate and syndecan-1. Hemodynamic effects of resuscitation were evaluated by measuring lactate and mean arterial pressure (MAP).ResultsResuscitation with FFP or albumin resulted in plasma volume expansion equalling the blood loss (to 55 ± 5 ml/kg and 54 ± 4 ml/kg (mean ± S.D.), respectively), whereas plasma volume expansion in RA group was lower (to 42 ± 7 ml/kg). Plasma concentration of heparan sulphate was lower in the FFP and albumin groups than in the RA group at 2 h after resuscitation. After correcting for differences in plasma volume, no significant difference in circulating amount of heparan sulphate was detected between the FFP and albumin groups (2879 ± 1075 μg/kg and 3318 ± 1814 μg/kg, respectively, P = 0.4) and the RA group (3731 ± 777 μg/kg). No differences between the groups in plasma concentration or amount of circulating syndecan-1 were detected after resuscitation. After resuscitation, MAP was higher in the FFP and albumin groups than in the RA group. Lactate did not differ between the FFP and RA groups after resuscitation.ConclusionsImproved outcome in trauma by FFP could in part be explained by better plasma volume expansion compared to crystalloids. The decrease in plasma concentration of markers of glycocalyx degradation after resuscitation with FFP are largely secondary to differences in plasma volume and may not accurately reflect effects of FFP on the glycocalyx.

Fresh frozen plasma for cardiovascular surgery.

Fresh frozen plasma (FFP) is a blood component containing procoagulant factors, which is sometimes used in cardiovascular surgery with the aim of reducing the risk of bleeding. The purpose of this review is to assess the risk of mortality for patients undergoing cardiovascular surgery who receive FFP. To evaluate the risk to benefit ratio of FFP transfusion in cardiovascular surgery for the treatment of bleeding patients or for prophylaxis against bleeding. We searched 11 bibliographic databases and four ongoing trials databases including the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2015), MEDLINE (OvidSP, 1946 to 21 April 2015), EMBASE (OvidSP, 1974 to 21 April 2015), PubMed (e-publications only: searched 21 April 2015), ClinicalTrials.gov, World Health Organization (WHO) ICTRP and the ISRCTN Register (searched 21 April 2015). We also searched the references of all identified trials and relevant review articles. We did not limit the searches by language or publication status. We included randomised controlled trials in patients undergoing major cardiac or vascular surgery who were allocated to a FFP group or a comparator (no plasma or an active comparator, either clinical plasma (any type) or a plasma-derived blood product). We included participants of any age (neonates, children and adults). We excluded studies of plasmapheresis and plasma exchange. Two authors screened all electronically derived citations and abstracts of papers identified by the review search strategy. Two authors assessed risk of bias in the included studies and extracted data independently. We took care to note whether FFP was used therapeutically or prophylactically within each trial. We included 15 trials, with a total of 755 participants for analysis in the review. Fourteen trials compared prophylactic use of FFP against no FFP. One study compared therapeutic use of two types of plasma. The timing of intervention varied, including FFP transfusion at the time of heparin neutralisation and stopping cardiopulmonary bypass (CPB) (seven trials), with CPB priming (four trials), after anaesthesia induction (one trial) and postoperatively (two trials). Twelve trials excluded patients having emergency surgery and nine excluded patients with coagulopathies.Overall the trials were small, with only four reporting an a priori sample size calculation. No trial was powered to determine changes in mortality as a primary outcome. There was either high risk of bias, or unclear risk, in the majority of trials included in this review.There was no difference in the number of deaths between the intervention arms in the six trials (with 287 patients) reporting mortality (very low quality evidence). There was also no difference in blood loss in the first 24 hours for neonatal/paediatric patients (four trials with 138 patients; low quality evidence): mean difference (MD) -1.46 ml/kg (95% confidence interval (CI) -4.7 to 1.78 ml/kg); or adult patients (one trial with 120 patients): MD -12.00 ml (95% CI -101.16 to 77.16 ml).Transfusion with FFP was inferior to control for preventing patients receiving any red cell transfusion: Peto odds ratio (OR) 2.57 (95% CI 1.30 to 5.08; moderate quality evidence). There was a difference in prothrombin time within two hours of FFP transfusion in eight trials (with 210 patients; moderate quality evidence) favouring the FFP arm: MD -0.71 seconds (95% CI -1.28 to -0.13 seconds). There was no difference in the risk of returning to theatre for reoperation (eight trials with 398 patients; moderate quality evidence): Peto OR 0.81 (95% CI 0.26 to 2.57). Only one included study reported adverse events as an outcome and reported no significant adverse events following FFP transfusion. This review has found no evidence to support the prophylactic administration of FFP to patients without coagulopathy undergoing elective cardiac surgery. There was insufficient evidence about treatment of patients with coagulopathies or those who are undergoing emergency surgery. There were no reported adverse events attributable to FFP transfusion, although there was a significant increase in the number of patients requiring red cell transfusion who were randomised to FFP. Variability in outcome reporting between trials precluded meta-analysis for many outcomes across all trials, and there was evidence of a high risk of bias in most of the studies. Further adequately powered studies of FFP, or comparable pro-haemostatic agents, are required to assess whether larger reductions in prothrombin time translate into clinical benefits. Overall the evidence from randomised controlled trials for the safety and efficacy of prophylactic transfusion of FFP for cardiac surgery is insufficient.

Comparison between Prothrombin Complex Concentrate (PCC) and Fresh Frozen Plasma (FFP) for the Urgent Reversal of Warfarin in Patients with Mechanical Heart Valves in a Tertiary Care Cardiac Center.

Fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC) reverse oral anticoagulants such as Warfarin. We compared the standard dosage of FFP and PCC in terms of efficacy and safety for patients with mechanical heart valves undergoing interventional procedures while receiving Warfarin. Fifty patients were randomized (25 for each group) with mechanical heart valves [international normalized ratio (INR) >2.5]. FFP dosage was administered based on body weight (10-15 mL/Kg), while PCC dosage was administered based on both body weight and target INR. INR measurements were obtained at different time after PCC and FFP infusion. The mean ± SD of INR pre treatment was not significantly different between the PCC and FFP groups. However, over a 48-hour period following the administration of PCC and FFP, 76% of the patients in the PCC group and only 20% of the patients in the FFP group reached the INR target. Five (20%) patients in the PCC group received an additional dose of PCC, whereas 17 (68%) patients in the FFP group received a further dose of FFP (P=0.001). There was no significant difference between the two groups in Hb and Hct before and during a 48-hour period after PCC and FFP infusion. As regards safety monitoring and adverse drug reaction screening in the FFP group, the INR was high (INR > 2.5) in 86% of the patients. There was no report of hemorrhage in both groups. PCC reverses anticoagulation both effectively and safely while having the advantage of obviating the need to extra doses.

The influence of cardiopulmonary bypass priming without FFP on postoperative coagulation and recovery in pediatric patients with cyanotic congenital heart disease.

Transfusion guidelines have been produced for the evidence-based use of fresh frozen plasma (FFP). However, the inappropriate use of FFP is still a worldwide problem, especially in the prophylactic settings. In the present study, 100 cyanotic pediatric patients (age 6months to 3years) undergoing cardiac surgery with cardiopulmonary bypass (CPB) were randomized to receive either 10-20ml/kg FFP (FFP group, n = 50) or 10-20ml/kg 4% succinylated gelatin (Gelofusine, GEL group, n = 50) in the priming solution. Rapid thromboelastography (r-TEG) was measured before skin incision and 15min after heparin neutralization. Postoperative renal and hepatic function, mediastinal chest tube drainage, transfusion requirements, and recovery time were observed. The relationships between hematologic and demographic data and postoperative bleeding volume were also analyzed. The results showed that there were significantly elevated levels of fibrinogen (r-TEG parameters: fibrinogen contribution to maximal amplitude (MAf) and fibrinogen level (FLEV)) in the FFP group compared to the GEL group. The postoperative blood loss, total transfusion requirements, and recovery time were not significantly different between the two groups, indicating that there were no obvious clinical benefits of using FFP in the priming. The maximal amplitude (MA) of r-TEG measured after heparin neutralization was correlated with the 6-h postoperative bleeding volume. In addition, preoperative fibrinogen level rather than FFP priming was an independent predictor of postoperative blood loss. Prophylactic use of FFP in the priming solution does not have obvious clinical benefits in cyanotic congenital heart disease (CCHD) patients. Gelofusine, an artificial colloid, is a safe and effective substitute of FFP in the priming solution. Furthermore, r-TEG can be used as a "real-time" assessment tool to evaluate postoperative bleeding and guide transfusion after cardiac surgery in pediatric patients.

Evidence-based use of FFP: the influence of a priming strategy without FFP during CPB on postoperative coagulation and recovery in pediatric patients.

Although fresh frozen plasma (FFP) is one of the most commonly used hemostatic agents in clinical specialties today, there is little evidence available supporting its administration. Our present study observed the effects of a priming strategy without FFP during cardiopulmonary bypass (CPB) on postoperative coagulation and clinical recovery in pediatric patients, aiming to supply new evidence for evidence-based use of FFP. Eighty pediatric patients with congenital heart disease undergoing cardiac surgery with CPB were randomized to receive either 10-20 ml/kg 4% succinylated gelatin (Gelofusine, GEL group, n = 40) or 1-2 units FFP (FFP group, n = 40) in the pump prime. Rapid-thromboelastography (r-TEG) and functional fibrinogen level were measured before skin incision and 15 minutes after heparin reversal. We recorded the volume of chest tube drainage, transfusion requirements and the dosage of pharmacological agents. The ventilation time, ICU length of stay and hospitalization time after surgery were also collected. After heparin neutralization, there were significantly elevated levels of fibrinogen in the FFP group, which were manifested by r-TEG parameters MAf and FLEV. No significant differences were observed between the two groups in postoperative bleeding, transfusion requirements and the usage of pharmacological agents. Recovery time was also comparable between the two groups. In conclusion, prophylactic use of FFP in the priming solution does not provide clinical benefits as presumed. Artificial colloids, such as Gelofusine, can be used safely and effectively as a substitute for FFP in the pump prime. TEG is an effective assessment tool to evaluate postoperative coagulation function in pediatric patients.

Fresh frozen plasma resuscitation attenuates platelet dysfunction compared with normal saline in a large animal model of multisystem trauma

Platelet dysfunction following trauma has been identified as an independent predictor of mortality. We hypothesized that fresh frozen plasma (FFP) resuscitation would attenuate platelet dysfunction compared with 0.9% normal saline (NS). Twelve swine were subjected to multisystem trauma (traumatic brain injury, liver injury, rib fracture, and soft tissue injury) with hemorrhagic shock (40% of estimated blood volume). Animals were left in shock (mean arterial pressure, 30-35 mm Hg) for 2 hours followed by resuscitation with three times shed volume NS (n = 6) or one times volume FFP (n = 6) and monitored for 6 hours. Platelet function was assessed by adenosine diphosphate (ADP)-induced platelet aggregation at baseline, after 2 hours of shock following resuscitation, and 6 hours after resuscitation. Fibrinogen levels and markers of platelet activation (transforming growth factor β [TGF-β], sP-Selectin, and CD40L) as well as endothelial injury (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]) were also assayed. Thromboelastography was used to measure clotting activity. ADP-induced platelet aggregation was significantly higher in the FFP group (46.3 U vs. 25.5 U, p < 0.01) following resuscitation. This was associated with higher fibrinogen levels (202 mg/dL vs. 80 mg/dL, p < 0.01) but lower endothelial activation (VCAM-1, 1.25 ng/mL vs. 3.87 ng/mL, p = 0.05). Other markers did not differ.After 6 hours of observation, ADP-induced platelet aggregation remained higher in the FFP group (53.8 U vs. 37.0 U, p = 0.03) as was fibrinogen levels (229 mg/dL vs. 153 mg/dL, p < 0.01). Endothelial activation was lower (ICAM-1, 21.0 ng/mL vs. 24.4 ng/mL, p = 0.05), whereas TGF-β levels were higher (2,138 pg/mL vs. 1,802 pg/mL, p = 0.03) in the FFP group. Other markers did not differ. Thromboelastography revealed increased clot strength in the FFP group at both postresuscitation time points. Resuscitation with FFP resulted in an immediate and sustained improvement in platelet function and clot strength compared with high-volume NS resuscitation. This was associated with an increase in fibrinogen levels and an attenuation of endothelial activation.

Treatment with a histone deacetylase inhibitor, valproic acid, is associated with increased platelet activation in a large animal model of traumatic brain injury and hemorrhagic shock

BackgroundWe have previously shown that resuscitation with fresh frozen plasma (FFP) in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS) decreases the size of the brain lesion, and that addition of a histone deacetylase inhibitor, valproic acid (VPA), provides synergistic benefits. In this study, we hypothesized that VPA administration would be associated with a conservation of platelet function as measured by increased platelet activation after resuscitation. Materials and methodsTen swine (42-50 kg) were subjected to TBI and HS (40% blood loss). Animals were left in shock for 2 h before resuscitation with either FFP or FFP + VPA (300 mg/kg). Serum levels of platelet activation markers transforming growth factor beta, CD40 L, P-selectin, and platelet endothelial cell adhesion molecule (PECAM) 1 were measured at baseline, postresuscitation, and after a 6-h observation period. Platelet activation markers were also measured in the brain whole cell lysates and immunohistochemistry. ResultsCirculating P-selectin levels were significantly higher in the FFP + VPA group compared with the FFP alone group (70.85 ± 4.70 versus 48.44 ± 7.28 ng/mL; P < 0.01). Likewise, immunohistochemistry data showed elevated P-selectin in the VPA treatment group (22.30 ± 10.39% versus 8.125 ± 3.94%, P < 0.01). Serum sCD40L levels were also higher in the FFP + VPA group (3.21 ± 0.124 versus 2.38 ± 0.124 ng/mL; P < 0.01), as was brain sCD40L levels (1.41 ± 0.15 versus 1.22 ± 0.12 ng/mL; P = 0.05). Circulating transforming growth factor beta levels were elevated in the FFP + VPA group, but this did not reach statistical significance (11.20 ± 1.46 versus 8.09 ± 1.41 ng/mL; P = 0.17). Brain platelet endothelial cell adhesion molecule 1 levels were significantly lower in the FFP + VPA group compared with the FFP group (5.22 ± 2.00 pg/mL versus 7.99 ± 1.13 pg/mL; P = 0.03). ConclusionsIn this clinically relevant large animal model of combined TBI + HS, the addition of VPA to FFP resuscitation results in an early upregulation of platelet activation in the circulation and the brain. The previously observed neuroprotective effects of VPA may be due to a conservation of platelet function as measured by a higher platelet activation response after resuscitation.

Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED

ObjectivesHigh International Normalized Ratio (INR) level resulting from warfarin use increases the risk of gastrointestinal hemorrhages. We aimed to compare the efficacy of prothrombin complex concentrates (PCC) and fresh frozen plasma (FFP) at lowering the INR level, decreasing active hemorrhages visible by endoscopy, and shortening the length of stay at the emergency department (ED). MethodThis study is a prospective cohort study of consecutive patents with gastrointestinal hemorrhages that received either PCC or FFP. With strict exclusion criteria, only patients over 18 years of age with a high INR level (>2.1) due to warfarin usage were included. ResultsA total of 40 patients (18 female) were included in the study, 20 each in the PCC and FFP groups. For the PCC group, the mean INR levels at the second and sixth hours were lower than those for the FFP group (second hour INR: 1.53 vs 4.50, P < .01, sixth hour INR: 1.52 vs 2.41, P < .01). Seven patients experienced active bleeding (Forrest 1) in the FFP group, whereas no patient experienced active bleeding in the PCC group based on the Forrest classification (35% vs 0%, P < .01), and only 3 patients in the FFP group underwent invasive/surgical treatment (15% vs 0%, P < .01). The ED length of stay was lower for the PCC group (1.62 days vs 3.46 days, P < .01). ConclusionFor patients experiencing a gastrointestinal hemorrhage, INR levels were reversed more quickly, there was less active bleeding on endoscopy, and the ED length of stay was lower in the PCC group than in the FFP group.

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Introduction: It is unclear if administering a 3-factor prothrombin complex concentrate (PCC) with or without fresh frozen plasma (FFP) reverses the international normalized ratio (INR) faster than FFP alone in patients with warfarin-associated intracranial hemorrhage (ICH). Methods: This was an IRB approved retrospective cohort study of adult patients with warfarin-associated ICH and an INR>1.5 who received Profilnine with or without FFP versus FFP alone. Results: Of the 68 patients who met criteria, 32 patients were included in the PCC group and 36 patients were included in the FFP only group. The time to reversal of the INR to ≤1.5 from admission to a hospital was 11.3 hours in the PCC group and 15.4 hours in the FFP group (p=0.023). The time to reversal from treatment administration was 4.2 hours in the PCC group and 9.1 hours in the FFP group (p=0.001). In patients with a pre-treatment INR<3, the mean PCC dose was 34 IU/kg and the time to reversal was 9.2 hours for the PCC group and 15.7 hours for the FFP group (p=0.001). In patients with a pre-treatment INR >3, the mean PCC dose was 34–41 IU/kg and there was no significant difference between groups in time to reversal of the INR. A greater percentage of patients in the PCC group than in the FFP group had an INR ≤1.3 at 24 hours (91% vs 58%, p=0.03). In-hospital mortality was 22% for the PCC group and 8% for the FFP only group (p=0.17). There were 9 patients with documented pulmonary edema after treatment in the FFP only group versus 4 patients in the PCC group (p=0.75). There were 3 thrombotic events documented after PCC treatment (9%). Conclusions: This study demonstrated that a 3-factor PCC administered with FFP corrected the INR faster than FFP alone in patients with warfarin-associated ICH. When stratified by pre-treatment INR, PCC reversed the INR faster for patients with an INR<3, but not for patients with an INR>3. This may be explained by the lower than recommended average PCC dose administered to patients with an INR>4. Significantly more patients in the PCC group had an INR ≤1.3 at 24 hours than in the FFP group.

Differential effects of fresh frozen plasma and normal saline on secondary brain damage in a large animal model of polytrauma, hemorrhage and traumatic brain injury

We have previously shown that the extent of traumatic brain injury (TBI) in large animal models can be reduced with early infusion of fresh frozen plasma (FFP), but the precise mechanisms remain unclear. In this study, we investigated whether resuscitation with FFP or normal saline differed in their effects on cerebral metabolism and excitotoxic secondary brain injury in a model of polytrauma, TBI, and hemorrhagic shock. Yorkshire swine (n = 10) underwent Grade III liver injury, rib fracture, standardized TBI, and volume-controlled hemorrhage, (40% ± 5%) and were randomly resuscitated with either FFP or normal saline. Hemodynamic parameters and brain oxygenation were continuously monitored, while microdialysis was used to measure the brain concentrations of pyruvate, lactate, glutamate, and glycerol at baseline; 1 hour and 2 hours after shock; immediate postresuscitation (PR); as well as 2, 4, and 6 hours PR. Cells from the injured hemisphere were separated into mitochondrial and cytosolic fractions and analyzed for activity of the pyruvate dehydrogenase complex (PDH). There were no baseline differences in cerebral perfusion pressure, brain oxygenation, as well as concentrations of pyruvate, lactate, glutamate, and glycerol between the groups. At 2 hours and 4 hours PR, the FFP group had significantly higher cerebral perfusion pressures (52 [5] mm Hg vs. 43 [2] mm Hg, p = 0.016; and 50 [7] mm Hg vs. 37 [1] mm Hg, p = 0.008, respectively). There was a sustained and significant (p < 0.05) drop in the glutamate and glycerol levels in the FFP group, implying a decrease in excitotoxicity and brain damage, respectively. Mitochondrial PDH activity was significantly higher (2,666.2 [638.2] adjusted volume INT × mm vs. 1,293.4 [88.8] adjusted volume INT × mm, p = 0.008), and cytosolic PDH activity was correspondingly lower (671.4 [209.2] adjusted volume INT × mm vs. 3070.7 [484.3] adjusted volume INT × mm, p < 0.001) in the FFP group, suggesting an attenuation of mitochondrial dysfunction and permeability. In this model of TBI, polytrauma, and hemorrhage, FFP resuscitation confers neuroprotection by improving cerebral perfusion, diminishing glutamate-mediated excitotoxic secondary brain injury and reducing mitochondrial dysfunction.

Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function after hemorrhagic shock in rats

Endothelial glycocalyx (EG) plays an essential role in endothelium integrity and may be compromised by hemorrhagic shock. The effects of currently available resuscitation fluids such as Hextend (HEX) or lactated Ringer's solution (LR) on vascular function and coagulation are not well understood. The aim of the present study was to compare the effects of fresh frozen plasma (FFP) with HEX or LR in their ability to repair EG structure, promote volume expansion, increase blood flow, and prevent coagulopathy. A total of 121 microvessels from cremaster muscle were studied in 32 anesthetized instrumented rats. After baseline systemic and microvascular measurements, 40% hemorrhage followed by resuscitation was performed, and measurements were repeated. Coagulation was evaluated using ROTEM to assay clot formation time, clotting time, firmness, strength, and lysis. Velocity and "platelet component" of strength were calculated. Fluorescein isothiocyanate or Texas Red bound to Dextrans was injected to estimate EG thickness in vivo. Respiratory rate, blood pH, base excess, and lactate returned to near-baseline levels in all treatments. Hemodilution caused by LR and HEX decreased firmness, prolonged clotting time, and lowered platelet counts. EG thickness in HEX- and LR-treated rats was 50% lower, and plasma syndecan 1 was 50% higher than sham and FFP groups. Blood flow and shear rate were restored in the HEX group. Resuscitation with FFP improved coagulation and blood flow. Our findings support the concept of cardiovascular and microvascular stabilization by infused FFP, in which the increase in microvascular perfusion associated with restored EG is essential for an optimal resuscitation strategy.

Fresh-frozen plasma resuscitation after traumatic brain injury and shock attenuates extracellular nucleosome levels and deoxyribonuclease 1 depletion

Traumatic brain injury and shock are among the leading causes of trauma-related mortality. We have previously shown that fresh-frozen plasma (FFP) resuscitation reduces the size of brain lesion and associated swelling compared with crystalloids. We hypothesized that this effect would be associated with an attenuation of circulating nucleosome levels, a biomarker of injury with cytotoxic potential, through reconstitution of circulating deoxyribonuclease-1 (DNAse1), an enzyme identified as critical in nucleosome clearance from the circulation. Twelve swine underwent a protocol of traumatic brain injury followed by 40% volume-controlled hemorrhage. Animals were left in shock (mean arterial pressure of 35 mmHg) for 2 hours before they were resuscitated with normal saline (NS) or FFP. Circulating levels of nucleosomes and DNAse1 were measured whereas extracellular nucleosomes were quantified on brain histology. Lesion size and brain swelling were also quantified. Nucleosome levels were significantly greater in the NS group 6 hours after resuscitation (0.32 mU vs 0.15 mU, P = .030) whereas DNAse1 levels were substantially greater in the FFP group (9.82 ng/mL vs 4.54 ng/mL, P = .010). Circulating nucleosomes levels correlated with lesion size (rho = 0.79, P = .002) as well as brain swelling (rho = 0.89, P < .001) whereas DNAse1 levels correlated with brain swelling (rho = -0.61, P = .036) but not lesion size (rho = -0.47, P = .124). Brain staining revealed nucleosome extracellularization in both groups, but this appeared more frequent in the NS-resuscitated animals. Our results show that resuscitation with FFP attenuates circulating nucleosome levels and prevents DNAse1 depletion. These factors may play a role in the neuroprotective effects observed during early resuscitation with FFP.