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1.
Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial
Davenport, R., Curry, N., Fox, E. E., Thomas, H., Lucas, J., Evans, A., Shanmugaranjan, S., Sharma, R., Deary, A., Edwards, A., et al
Jama. 2023
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Editor's Choice
Abstract
IMPORTANCE Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage. OBJECTIVE To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol. DESIGN, SETTING, AND PARTICIPANTS CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion. INTERVENTION Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. RESULTS Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%). CONCLUSIONS AND RELEVANCE Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.
PICO Summary
Population
Bleeding patients with trauma enrolled in the CRYOSTAT-2 trial, at 26 UK and US major trauma centers (n= 1,604).
Intervention
Usual care plus 3 early pools of cryoprecipitate (n= 799).
Comparison
Standard care (n= 805).
Outcome
The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. Data from 1,531 (95%) patients were included in the primary analysis population. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs. 25.3% in the cryoprecipitate group (odds ratio, 0.96; 95% CI [0.75, 1.23]). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs. cryoprecipitate group (12.9% vs. 12.7%).
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2.
Empiric Cryoprecipitate Transfusion in Patients with Severe Hemorrhage: Results from The US Experience in the International Cryostat-2 Trial
Van Gent, J. M., Kaminski, C. W., Praestholm, C., Pivalizza, E. G., Clements, T. W., Kao, L. S., Stanworth, S., Brohi, K., Cotton, B. A.
Journal of the American College of Surgeons. 2023
Abstract
BACKGROUND Hypofibrinogenemia has been shown to predict massive transfusion and is associated with higher mortality in severely injured patients. However, the role of empiric fibrinogen replacement in bleeding trauma patients remains controversial. We sought to determine the effect of empiric cryoprecipitate as an adjunct to a balanced transfusion strategy (1:1:1). STUDY DESIGN Sub-analysis of the single US trauma center in a multi-center randomized controlled trial. Trauma patients (>15 years of age) were eligible if they had evidence of active hemorrhage requiring emergent surgery or interventional radiology, massive transfusion protocol (MTP) activation, and received at least one unit of blood. Transfer patients, those with injuries incompatible with life, or >3 hours from injury were excluded. Patients were randomized to standard MTP (STANDARD) or MTP plus 3 pools of cryoprecipitate (CRYO). Primary outcome: all-cause mortality at 28 days. Secondary outcomes: transfusion requirements, intra-operative and post-operative coagulation labs, and quality of life measures (Glasgow Outcome Score, GOS). RESULTS 49 patients were enrolled between 05/21-10/21 (CRYO-23 and STANDARD-26). Time to randomization was similar between groups (14 minutes vs 24 minutes); p=0.676. Median time to cryoprecipitate was 52 minutes [IQR, 47,60]. There were no differences in demographics, arrival physiology, laboratory values, or injury severity. Intra-operative and ICU TEG values, including functional fibrinogen, were similar between groups. There was no benefit to CRYO with respect to post-ED transfusions (intra-op and ICU through 24 hours), complications, GOS, or mortality. CONCLUSION In this study of severely injured, bleeding trauma patients, empiric cryoprecipitate did not improve survival or reduce transfusion requirements. Cryoprecipitate should continue as an "on demand" addition to a balanced transfusion strategy, guided by laboratory values and should not be given empirically.
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3.
Practice patterns of ABO-matching for cryoprecipitate and patient outcomes after ABO-compatible versus incompatible cryoprecipitate
Raycraft T, Bartoszko J, Karkouti K, Callum J, Lin Y
Vox sanguinis. 2022
Abstract
BACKGROUND AND OBJECTIVES This sub-study of the FIBRES trial sought to examine the patterns of ABO-compatible cryoprecipitate administration and to identify adverse consequences of ABO-incompatible cryoprecipitate. MATERIALS AND METHODS This was a post hoc analysis of data collected from the FIBRES randomized clinical trial comparing fibrinogen concentrate with cryoprecipitate in the treatment of bleeding related to hypofibrinogenemia after cardiac surgery. The primary outcome was the percentage of administered cryoprecipitate that was ABO-compatible. Secondary outcomes were adverse events at 28 days. A follow-up survey was distributed to the FIBRES participating sites to examine the rationale behind the identified cryoprecipitate ABO-matching practice patterns. RESULTS A total of 363 patients were included: 53 (15%) received ABO-incompatible cryoprecipitate and 310 (85%) received ABO-compatible cryoprecipitate. There was an increased incidence of post-operative anaemia in the ABO-incompatible group (15; 28.3%) in comparison to the ABO-compatible (44; 14.2%) group (p = 0.01) at 28 days, which was unrelated to haemolysis, without a significant difference in transfusion requirement. In the multivariable logistic regression models accounting for clustering by site, there was no observed statistically significant association between the administration of ABO-incompatible cryoprecipitate and any other adverse outcomes. Nine out of 11 sites did not have a policy requiring ABO-matched cryoprecipitate. CONCLUSION This sub-study demonstrated that most cryoprecipitate administered in practice is ABO-compatible, despite the absence of guidelines or blood bank policies to support this practice. A signal towards increased risk of post-operative anaemia may be explained by higher rates of urgent surgery (vs. elective) in the ABO-incompatible group. Future studies should prospectively examine the impact of ABO-compatible versus incompatible cryoprecipitate to conclusively establish if there is a meaningful clinical impact associated with the administration of ABO-incompatible cryoprecipitate.
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Early cryoprecipitate transfusion versus standard care in severe postpartum haemorrhage: a pilot cluster-randomised trial
Green, L., Daru, J., Gonzalez Carreras, F. J., Lanz, D., Pardo, M. C., Pérez, T., Philip, S., Tanqueray, T., Khan, K. S.
Anaesthesia. 2022;77(2):175-184
Abstract
There is a lack of evidence evaluating cryoprecipitate transfusion in severe postpartum haemorrhage. We performed a pilot cluster-randomised controlled trial to evaluate the feasibility of a trial on early cryoprecipitate delivery in severe postpartum haemorrhage. Pregnant women (>24 weeks gestation), actively bleeding within 24 h of delivery and who required at least one unit of red blood cells were eligible. Women declining transfusion in advance or with inherited clotting deficiencies were not eligible. Four UK hospitals were randomly allocated to deliver either the intervention (administration of two pools of cryoprecipitate within 90 min of first red blood cell unit requested plus standard care), or the control group treatment (standard care, where cryoprecipitate is administered later or not at all). The primary outcome was the proportion of women who received early cryoprecipitate (intervention) vs. standard care (control). Secondary outcomes included consent rates, acceptability of the intervention, safety outcomes and preliminary clinical outcome data to inform a definitive trial. Between March 2019 and January 2020, 199 participants were recruited; 19 refused consent, leaving 180 for analysis (110 in the intervention and 70 in the control group). Adherence to assigned treatment was 32% (95%CI 23-41%) in the intervention group vs. 81% (95%CI 70-90%) in the control group. The proportion of women receiving cryoprecipitate at any time-point was higher in the intervention (60%) vs. control (31%) groups; the former had fewer red blood cell transfusions at 24 h (mean difference -0.6 units, 95%CI -1.2 to 0); overall surgical procedures (odds ratio 0.6, 95%CI 0.3-1.1); and intensive care admissions (odds ratio 0.4, 95%CI 0.1-1.1). There was no increase in serious adverse or thrombotic events in the intervention group. Staff interviews showed that lack of awareness and uncertainty about study responsibilities contributed to lower adherence in the intervention group. We conclude that a full-scale trial may be feasible, provided that protocol revisions are put in place to establish clear lines of communication for ordering early cryoprecipitate in order to improve adherence. Preliminary clinical outcomes associated with cryoprecipitate administration are encouraging and merit further investigation.
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Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial
Curry N, Rourke C, Davenport R, Beer S, Pankhurst L, DearyA, Thomas H, Llewelyn C, Green L, Doughty H, et al
British Journal of Anaesthesia. 2015;115((1)):76-83.
Abstract
BACKGROUND Low fibrinogen (Fg) concentrations in trauma haemorrhage are associated with poorer outcomes. Cryoprecipitate is the standard source for Fg administration in the UK and USA and is often given in the later stages of transfusion therapy. It is not known whether early cryoprecipitate therapy improves clinical outcomes. The primary aim of this feasibility study was to determine whether it was possible to administer cryoprecipitate, within 90 min of admission to hospital. Secondary aims were to evaluate laboratory measures of Fg and clinical outcomes including thrombotic events, organ failure, length of hospital stay and mortality. METHODS This was an unblinded RCT, conducted at two civilian UK major trauma centres of adult trauma patients (age >16 yrs), with active bleeding and requiring activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy (STANDARD) (n=22), or to standard haemorrhage therapy plus two early pools of cryoprecipitate (CRYO) (n=21). RESULTS 85% (95% CI: 69-100%) CRYO participants received cryoprecipitate within 90 min, median time 60 min (IQR: 57-76) compared with 108 min (67-147), CRYO and STANDARD arms respectively (P=0.002). Fg concentrations were higher in the CRYO arm and were maintained above 1.8 g litre(-1) at all time-points during active haemorrhage. All-cause mortality at 28 days was not significantly different (P=0.14). CONCLUSIONS Early Fg supplementation using cryoprecipitate is feasible in trauma patients. This study supports the need for a definitive RCT to determine the effect of early Fg supplementation on mortality and other clinical outcomes. TRIAL REGISTRY NUMBER ISRCTN55509212.Copyright © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Cryoprecipitate for the correction of coagulopathy associated with liver disease
French CJ, Bellomo R, Angus P
Anaesthesia and Intensive Care. 2003;31((4):):357-61.
Abstract
In patients with liver disease at risk of pulmonary oedema, cryoprecipitate (small volume) might be a viable alternative to fresh frozen plasma (FFP, large volume) in the correction of coagulopathy. However, the efficacy of cryoprecipitate in these patients has not been tested. We evaluated the role of cryoprecipitate in the correction of the coagulopathy of liver disease. To establish initial evidence of efficacy, six consecutive patients with hepatic failure and coagulopathy received five units of cryoprecipitate. Then, using a crossover design, 11 consecutive patients were randomized to receive either four units of FFP or five units of cryoprecipitate. Pre and post infusion International Normalized Ratio (INR), activated Partial Thromboplastin Time (aPTT), fibrinogen D-dimers, Factors V and IX, and reptilase time were measured. In the first six patients, cryoprecipitate improved the INR, aPTT and fibrinogen concentration (P = 0. 03). In the crossover study, FFP administration produced a greater improvement in INR (P = 0. 007) and aPTT (P = 0. 005) than cryoprecipitate. However, there were no differences in any of the other measured variables. One patient developed acute pulmonary oedema while receiving FFP. Cryoprecipitate improves the coagulopathy of liver disease. Four units of FFP are more efficacious than five units of cryoprecipitate. Cryoprecipitate may have a role in correction of the coagulopathy associated with liver disease where concerns about pulmonary oedema exist.
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7.
Application of cryoprecipitate as a hematostatic glue
Shiono N, Koyama N, Watanabe Y, Tokuhiro K, Suzuki N, Fujii T, Ozawa T, Sakuragawa H, Ohsawa H, Iwashita Y, et al
Journal of Cardiovascular Surgery. 1998;39((5):):609-12.
Abstract
BACKGROUND The effectiveness of cryoprecipitate, harvested from a patient's own fresh frozen plasma, for use in cardiac surgery as a hematostatic glue was studied in 32 randomized elective adult cardiac surgery patients from January 1993 to July 1994. MATERIALS AND METHODS Patients from the Toho Sakura Hospital were randomly allocated to two groups: Group 1 (n=11) received conventional fibrin glue presently available in our institution; while Group 2 (n=21) received autologous cryoprecipitate as a hematostatic glue. Surgical procedures broken down by group were as follows: Group 1: 4 CABG, 5 valvular surgeries and 2 other. Group 2: 11 CABG, 6 valvular surgery, 4 other. We preserved the patient's own blood and stored pure red cell and fresh frozen plasma (FFP). Cryoprecipitate was prepared from the FFP and preserved until required. RESULTS Cryoprecipitate had a 5-fold increase in fibrinogen activity (1190+/-311 mg/dl vs 238+/-34 mg/dl p<0.001), a 10-fold increase in factor VIII activity (362+/-219% vs 34+/-11%, p=0.001), and 4.5-fold increase in factor XIII activity (538+/-213% vs 119+/-50%, p<0.001), compared to serum. The amount of bleeding postoperatively was slightly lower in the cryoprecipitate glue group compared to the conventional glue group, but this was not significantly different. CONCLUSIONS We conclude that autologous samples of human cryoprecipitate prepared from a patient's own FFP had a strong hematostatic effect compared to conventional fibrin glue and was a very valuable hematostatic agent during cardiac surgery.
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8.
Fibronectin in severe sepsis
Stevens LE, Clemmer TP, Laub RM, Miya F, Robbins L
Surgery, Gynecology & Obstetrics. 1986;162((3):):222-8.
Abstract
Fibronectin was given in the form of cryoprecipitate of human plasma to patients with severe surgical sepsis in a double blind, prospective and randomized clinical study. Of the 19 patients assigned to the control group receiving no fibronectin, only eight (42 per cent) survived. Of the 12 patients given the cryoprecipitate, nine survived (75 per cent) (p less than 0.05). In the control group, initial serum fibronectin levels were depressed to 121 micrograms per milliliter (normal = 313). The mean values in the blank plasma controls did not increase after 24 hours, with a mean of 122. In contrast, the group treated with cryoprecipitate increased serum fibronectin values after 24 hours to 216 micrograms per milliliter, up from initial values of 161 micrograms per milliliters. Improvements in pulmonary function, serum bilirubin and serum creatinine values were also noted, but the changes fell short of statistical significance. Fibronectin appears to benefit patients in severe surgical sepsis in this study of a relatively small number of patients.
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9.
Fibronectin and other DIC-related variables in patients with moderately severe infections receiving cryoprecipitate
Brodin B, Hesselvik F, Blomback M, Cedergren B, Lieden G, Maller R, Strindberg J
Scandinavian Journal of Clinical and Laboratory Investigation Supplement. 1985;178:57-65.
Abstract
Plasma fibronectin (Fn), a glucoprotein of suggested importance in host defence during infections also seems to be involved in blood coagulation and to be consumed during clot formation. Low Fn concentrations have been found in patients with DIC, but also in patients with infections without signs of overt DIC. In a randomized trial of Fn supplementation 28 patients with moderately severe infections, hospitalized in the Department for Infectious Diseases, were scheduled to receive either cryoprecipitate from 30 donors (n = 14) or 250-300 ml of stored plasma (n = 14). To elucidate the relationship between Fn plasma levels, Fn-rich cryoprecipitate infusion, and possible low-grade DIC in these patients, we measured platelet count, prothrombin complex (NT), fibrinogen, F V, F VIIIRAg, F VIIIC, F XII, plasminogen (Plg), antiplasmin (AP), antithrombin III (AT), kallikrein-inhibiting activity (KI) and spontaneous proteolytic activity (SPA). Compared to healthy controls, high initial values (p less than .001) were found for fibrinogen, F VIIIRAg, F VIIIC and SPA. Most values for platelets, F V, Plg, AP and KI were within the reference range. Low levels (p less than .001) were found for Fn, NT, F XII, AT and for the ratio F VIIIC/F CIIIRAg. A significant correlation was found between F XII, Plg and AT. Fn correlated poorly to the other variables. Cryoprecipitate infusion normalized the Fn concentration, but had no influence on other measured variables. Thus, although no patient had clinically overt DIC, and all survived, we observed a distinct pattern indicating activation of the coagulation system. Fn levels were low, but were not specifically related to this activation.