Prophylactic plasma transfusion for patients without inherited bleeding disorders or anticoagulant use undergoing non-cardiac surgery or invasive procedures
The Cochrane database of systematic reviews. 2019;11:Cd012745
BACKGROUND In the absence of bleeding, plasma is commonly transfused to people prophylactically to prevent bleeding. In this context, it is transfused before operative or invasive procedures (such as liver biopsy or chest drainage tube insertion) in those considered at increased risk of bleeding, typically defined by abnormalities of laboratory tests of coagulation. As plasma contains procoagulant factors, plasma transfusion may reduce perioperative bleeding risk. This outcome has clinical importance given that perioperative bleeding and blood transfusion have been associated with increased morbidity and mortality. Plasma is expensive, and some countries have experienced issues with blood product shortages, donor pool reliability, and incomplete screening for transmissible infections. Thus, although the benefit of prophylactic plasma transfusion has not been well established, plasma transfusion does carry potentially life-threatening risks. OBJECTIVES To determine the clinical effectiveness and safety of prophylactic plasma transfusion for people with coagulation test abnormalities (in the absence of inherited bleeding disorders or use of anticoagulant medication) requiring non-cardiac surgery or invasive procedures. SEARCH METHODS We searched for randomised controlled trials (RCTs), without language or publication status restrictions in: Cochrane Central Register of Controlled Trials (CENTRAL; 2017 Issue 7); Ovid MEDLINE (from 1946); Ovid Embase (from 1974); Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCOHost) (from 1937); PubMed (e-publications and in-process citations ahead of print only); Transfusion Evidence Library (from 1950); Latin American Caribbean Health Sciences Literature (LILACS) (from 1982); Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (Thomson Reuters, from 1990); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Search Platform (ICTRP) to 28 January 2019. SELECTION CRITERIA We included RCTs comparing: prophylactic plasma transfusion to placebo, intravenous fluid, or no intervention; prophylactic plasma transfusion to alternative pro-haemostatic agents; or different haemostatic thresholds for prophylactic plasma transfusion. We included participants of any age, and we excluded trials incorporating individuals with previous active bleeding, with inherited bleeding disorders, or taking anticoagulant medication before enrolment. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included five trials in this review, all were conducted in high-income countries. Three additional trials are ongoing. One trial compared fresh frozen plasma (FFP) transfusion with no transfusion given. One trial compared FFP or platelet transfusion or both with neither FFP nor platelet transfusion given. One trial compared FFP transfusion with administration of alternative pro-haemostatic agents (factors II, IX, and X followed by VII). One trial compared the use of different transfusion triggers using the international normalised ratio measurement. One trial compared the use of a thromboelastographic-guided transfusion trigger using standard laboratory measurements of coagulation. Four trials enrolled only adults, whereas the fifth trial did not specify participant age. Four trials included only minor procedures that could be performed by the bedside. Only one trial included some participants undergoing major surgical operations. Two trials included only participants in intensive care. Two trials included only participants with liver disease. Three trials did not recruit sufficient participants to meet their pre-calculated sample size. Overall, the quality of evidence was low to very low across different outcomes according to GRADE methodology, due to risk of bias, indirectness, and imprecision. One trial was stopped after recruiting two participants, therefore this review's findings are based on the remaining four trials (234 participants). When plasma transfusion was compared with no transfusion given, we are very uncertain whether there was a difference in 30-day mortality (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; risk ratio (RR) 0.38, 95% confidence interval (CI) 0.13 to 1.10; very low-quality evidence). We are very uncertain whether there was a difference in major bleeding within 24 hours (1 trial comparing FFP transfusion vs no transfusion, 76 participants; RR 0.33, 95% CI 0.01 to 7.93; very low-quality evidence; 1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; RR 1.59, 95% CI 0.28 to 8.93; very low-quality evidence). We are very uncertain whether there was a difference in the number of blood product transfusions per person (1 trial, 76 participants; study authors reported no difference; very low-quality evidence) or in the number of people requiring transfusion (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; study authors reported no blood transfusion given; very low-quality evidence) or in the risk of transfusion-related adverse events (acute lung injury) (1 trial, 76 participants; study authors reported no difference; very low-quality evidence). When plasma transfusion was compared with other pro-haemostatic agents, we are very uncertain whether there was a difference in major bleeding (1 trial; 21 participants; no events; very low-quality evidence) or in transfusion-related adverse events (febrile or allergic reactions) (1 trial, 21 participants; RR 9.82, 95% CI 0.59 to 162.24; very low-quality evidence). When different triggers for FFP transfusion were compared, the number of people requiring transfusion may have been reduced (for overall blood products) when a thromboelastographic-guided transfusion trigger was compared with standard laboratory tests (1 trial, 60 participants; RR 0.18, 95% CI 0.08 to 0.39; low-quality evidence). We are very uncertain whether there was a difference in major bleeding (1 trial, 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence) or in transfusion-related adverse events (allergic reactions) (1 trial; 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence). Only one trial reported 30-day mortality. No trials reported procedure-related harmful events (excluding bleeding) or quality of life. AUTHORS' CONCLUSIONS Review findings show uncertainty for the utility and safety of prophylactic FFP use. This is due to predominantly very low-quality evidence that is available for its use over a range of clinically important outcomes, together with lack of confidence in the wider applicability of study findings, given the paucity or absence of study data in settings such as major body cavity surgery, extensive soft tissue surgery, orthopaedic surgery, or neurosurgery. Therefore, from the limited RCT evidence, we can neither support nor oppose the use of prophylactic FFP in clinical practice.
A randomized controlled trial of fresh frozen plasma for coagulopathy in Russell's viper (Daboia russelii) envenoming
Journal of Thrombosis and Haemostasis : Jth. 2017;15((4):):645-654
BACKGROUND Russell's viper (Daboia russelii) envenoming is a major health issue in South Asia and causes venom induced consumption coagulopathy (VICC). OBJECTIVES We investigated the effect of fresh frozen plasma (FFP) and two antivenom doses in correcting VICC. METHODS We undertook an open-label randomized controlled trial in patients with VICC at two Sri Lankan hospitals. Patients with suspected Russell's viper bites and coagulopathy were randomly allocated (1:1) high-dose antivenom (20 vials) or low-dose antivenom (10 vials) plus 4U FFP. The primary outcome was the proportion of patients with an international normalized ratio (INR)<2, 6h post-antivenom. Secondary outcomes included anaphylaxis, major haemorrhage, death and clotting factor recovery. RESULTS From 214 eligible patients, 141 were randomized; 71 to high-dose antivenom, 70 to low-dose antivenom/FFP; five had no post-antivenom bloods. The groups were similar except for a delay of 1h in antivenom administration for FFP patients. 6h post-antivenom 23/69 (33%) patients allocated high-dose antivenom had an INR<2 compared with 28/67 (42%) allocated low-dose antivenom/FFP [absolute difference 8%;95%Confidence Interval:-8% to 25%]. 15 patients allocated FFP did not receive it. Severe anaphylaxis occurred equally frequently in each group. One patient given FFP developed transfusion related acute lung injury. Three deaths occurred in low-dose/FFP patients including one intracranial haemorrhage. There was no difference in recovery rates of INR or fibrinogen, but more rapid initial recovery of factor V and X in FFP patients. CONCLUSION FFP post-antivenom in Russell's viper bites didn't hasten recovery of coagulopathy. Low-dose antivenom/FFP did not worsen VICC, suggesting low-dose antivenom is sufficient. This article is protected by copyright. All rights reserved.
Plasma transfusions prior to insertion of central lines for people with abnormal coagulation
The Cochrane Database of Systematic Reviews. 2016;((9)):CD011756.
BACKGROUND The insertion of central venous catheters (CVCs) may be associated with peri- and post-procedural bleeding. People who require a central line often have disorders of coagulation as a result of their underlying illness, co-morbidities or the effects of treatment. Clinical practice in some institutions is to mitigate the risk of bleeding in these patients by prophylactically transfusing fresh frozen plasma (FFP) in order to correct clotting factor deficiencies prior to central line insertion. However, FFP transfusion is not without risk, and it remains unclear whether this intervention is associated with reduced rates of bleeding or other clinically-meaningful outcomes. OBJECTIVES To assess the effect of different prophylactic plasma transfusion regimens prior to central line insertion in people with abnormal coagulation. SEARCH METHODS We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 3), PubMed (e-publications only), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 1 March 2016. SELECTION CRITERIA We included RCTs involving transfusions of plasma to prevent bleeding in people of any age with abnormal coagulation requiring insertion of a central venous catheter, published in English. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We identified four trials eligible for inclusion, of which three are ongoing. We did not exclude any studies because they were not published in English.The included study randomised 81 adults in intensive care whose INR (International Normalised Ratio) was greater than or equal to 1.5 to no FFP or to a single dose of 12 mL/kg FFP prior to undergoing central venous catheterisation (58 participants) or other invasive procedure (23 participants). It is the subgroup of 58 adults undergoing CVC insertion that were included in this review, the study authors provided unpublished data for this review's outcomes.The quality of the evidence was low or very low across different outcomes according to the GRADE methodology. The included study was at high risk of bias due to lack of blinding of participants and personnel and imbalance in the number of participants who had liver disease between study arms.There was insufficient evidence to determine a difference in major procedure-related bleeding within 24 hours (one RCT; 58 participants; no events in either study arm, very low-quality evidence). We are very uncertain whether FFP reduces minor procedure-related bleeding within 24 hours of the study (one RCT; 58 participants, RR 0.67, 95% CI 0.12 to 3.70, very low-quality evidence).No studies were found that looked at: all-cause mortality; the proportion of participants receiving plasma or red cell transfusions; serious adverse reactions (transfusion or line-related complications); number of days in hospital; change in INR; or quality of life.The three ongoing studies are still recruiting participants (expected recruitment: up to 355 participants in total). and are due to be completed by February 2018. AUTHORS' CONCLUSIONS There is only very limited evidence from one RCT to inform the decision whether or not to administer prophylactic plasma prior to central venous catheterisation for people with abnormal coagulation. It is not possible from the current RCT evidence to recommend whether or not prophylactic plasma transfusion is beneficial or harmful in this situation. The three ongoing RCTs will not be able to answer this review's questions, because they are small studies and do not address all of the comparisons included in this review (355 participants in total). To detect an increase in the proportion of participants who had major bleeding from 1 in 100 to 2 in 100 would require a study containing at least 4634 participants (80% power, 5% significance).
A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura
BACKGROUND Photochemical treatment of fresh-frozen plasma (FFP) with amotosalen and ultraviolet (UV) A light (PCT FFP) results in inactivation of a broad spectrum of pathogens while retaining coagulation factor activity, antithrombotic proteins, and von Willebrand factor-cleaving protease (VWF-CP) activity. STUDY DESIGN AND METHODS A randomized, controlled, double-blind Phase III trial was conducted with PCT FFP or control FFP for therapeutic plasma exchange (TPE) in patients with thrombotic thrombocytopenic purpura (TTP). Owing to the rarity of this diagnosis, the trial was not powered to demonstrate small differences between treatment groups. Patients were treated with study FFP for a maximum of 35 days until remission was achieved (for a maximum of 30 daily study TPEs with no remission) plus an additional 5 days after remission. RESULTS Among the 35 patients treated, the primary endpoint, remission within 30 days, was achieved by 14 of 17 (82%) PCT patients and 16 of 18 (89%) control patients (p = 0. 658) The 90 percent confidence interval for treatment difference in remission rate for test - control was (-0. 291 to 0. 163). Time to remission, relapse rates, time to relapse, total volume and number of FFP units exchanged, and number of study TPEs were not significantly different between groups. Improvement in VWF-CP and inhibitors was similar for both groups. The overall safety profile of PCT FFP was similar to control FFP. No antibodies to amotosalen neoantigens were detected. CONCLUSION The comparable results between treatment groups observed from this small trial suggest that TPE with PCT FFP was safe and effective for treatment of TTP.
Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet
British Journal of Haematology. 2005;129((1):):79-86.
A randomized prospective trial compared cryosupernatant plasma (CSP) to fresh frozen plasma (FFP) for treatment of thrombotic thrombocytopenic purpura (TTP). A total of 236 patients were required: 28 patients were treated with CSP and 24 with FFP within 30 months. There were no differences in survival at 1 month. By day 9, 17 of 26 patients with CSP and 18 of 24 with FFP had a platelet count >100 x 10(9)/l. At entry, von Willebrand factor (VWF) multimers were normal in all patients (range 1. 1-3. 95 IU/ml). ADAMTS-13 levels showed large variations ranging from 10% to 100% activity. At entry, no individual had <5% VWF cleaving protease. By day 9 (end of cycle), 89% (FFP) and 67% (CSP) had levels >50% of the controls. At 6 months some patients showed inhibitors to the enzyme in spite of adequate or normal platelet counts. The data from this study do not show an apparent advantage to the use of CSP in TTP. A large number of patients will be required to determine appropriate replacement therapy. We were not able to find a statistically significant relationship between the low level of protease activity at presentation of TTP and response.
Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura (TTP)
Journal of Clinical Apheresis. 2001;16((1):):19-22.
Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease that is treated with plasma exchange and typically with replacement with fresh frozen plasma (FFP). This approach results in an approximate 50% response rate following 1 week of therapy and 80% survival. Cryoprecipitate poor plasma (CPP) is plasma from which the cryoprecipitate fraction is removed. CPP has been reported to be successful as salvage therapy in refractory TTP and has been suggested to be superior to FFP in retrospective studies. The present report compares initial therapy of TTP with exchange using replacement with either FFP or CPP in a multi-institutional prospective randomized study performed by the North American TTP Group (NATG Group) from 1993 to 1995. Initial therapy also included corticosteroids. Antiplatelet drugs or vinca alkaloids were not employed. A severity score index, response score, and individual clinical parameters (platelet count, LDH x upper limit of normal, hemoglobin level, and creatinine) were compared at their nadir or peak values, baseline, and days +6 and +13 of therapy. Thirteen patients were randomized to FFP exchange and 14 to CPP exchange. Results were equivalent for all parameters. Survival was equal with three deaths in each group. These data indicate that the efficacy of FFP and CPP are the same in the initial treatment of TTP in adults.
Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group
Annals of Internal Medicine. 1995;122((8):):569-72.
OBJECTIVE To determine the incidence and timing of relapses in patients who have recovered from an acute episode of thrombotic thrombocytopenic purpura. DESIGN Clinical follow-up for 3 to 10 years. SETTING General community outpatient study; patients who had relapse were hospitalized. PARTICIPANTS 63 of 72 surviving patients who had participated in a randomized study that compared plasma exchange and plasma infusion as treatments for thrombotic thrombocytopenic purpura and for whom continued clinical follow-up was obtained. OUTCOME MEASURES Recurrence of thrombotic thrombocytopenic purpura as defined by a decrease in platelet count to less than 100 x 10(9)/L and by the onset of microangiopathic hemolytic anemia as identified by erythrocyte fragmentation in a peripheral blood film. RESULTS 37 of the 63 patients have not had recurrence of thrombotic thrombocytopenic purpura and have remained completely well; 6 patients have not had recurrence but have developed other medical problems; 3 patients have not had recurrence but have residual neurologic defects from the original episode; and 17 patients have had one or more recurrences, occurring 7 months to 8 years after the original episode. As determined by Kaplan-Meier analysis, the projected recurrence rate after 10 years in all surviving patients is 36% (95% CI, 23% to 59%). CONCLUSIONS More than one third of patients who survive an acute episode of thrombotic thrombocytopenic purpura will have at least one relapse during the following 10 years.
Thrombotic thrombocytopenic purpura: outcome in 24 patients with renal impairment treated with plasma exchange. Canadian Apheresis Study Group
The Canadian Apheresis Study Group recently completed a randomized clinical trial involving 102 patients with thrombotic thrombocytopenic purpura (TTP), in which treatment with plasma infusion and treatment with plasma exchange were compared. Thirty-three other patients were ineligible or refused to be randomly assigned in the trial. Of the 33 patients, 24 were assessed as ineligible because they would be unable to tolerate the fluid input that would occur if they were randomly assigned to receive plasma infusion. All 24 patients had oliguria and elevated creatinine and/or blood urea nitrogen level. These 24 patients were treated with acetylsalicyclic acid, dipyridamole, and plasma exchange according to the standardized protocol defined in the trial. Blood for tests of factors possibly involved in the pathogenesis of TTP was drawn before exchange and at intervals during and after exchange. The mean platelet count before exchange was 35.5 x 10(9) per L. In 12 of the 24 patients, the platelet count reached 150 x 10(9) per L or greater by 7 days after the initiation of plasma exchange. Three patients responded partially, in that their platelet count increased to at least twice that at presentation, but remained below 150 x 10(9) per L. One patient died during the first week. Of the eight other patients who experienced treatment failure at the 7-day assessment point, six subsequently responded, four while continuing to receive plasma exchange and two after plasma exchange had been discontinued. Of the 15 patients who either responded fully or responded partially by the end of the first cycle, all survived.(ABSTRACT TRUNCATED AT 250 WORDS)