Platelet to erythrocyte transfusion ratio and mortality in massively transfused trauma patients. A systematic review and meta-analysis.

BACKGROUND: Platelet transfusion during major hemorrhage is important and often embedded in massive transfusion protocols. However, the optimal ratio of platelets to erythrocytes (platelet-rich plasma [PLT]/red blood cell [RBC] ratio) remains unclear. We hypothesized that high PLT/RBC ratios, as compared with low PLT/RBC ratios, are associated with improved survival in patients requiring massive transfusion. METHODS: Four databases (Pubmed, CINAHL, EMBASE, and Cochrane) were systematically screened for literatures published until January 21, 2021, to determine the effect of PLT/RBC ratio on the primary outcome measure mortality at 1 hour to 6 hours and 24 hours and at 28 days to 30 days. Studies comparing various PLT/RBC ratios were included in the meta-analysis. Secondary outcomes included intensive care unit length of stay and in-hospital length of stay and total blood component use. The study protocol was registered in PROSPERO under number CRD42020165648. RESULTS: The search identified a total of 8903 records. After removing the duplicates and second screening of title, abstract, and full text, a total of 59 articles were included in the analysis. Of these articles, 12 were included in the meta-analysis. Mortality at 1 hour to 6 hours, 24 hours, and 28 days to 30 days was significantly lower for high PLT/RBC ratios as compared with low PLT/RBC ratios. CONCLUSION: Higher PLT/RBC ratios are associated with significantly lower 1-hour to 6-hour, 24-hour, 28-day to 30-day mortalities as compared with lower PLT/RBC ratios. The optimal PLT/RBC ratio for massive transfusion in trauma patients is approximately 1:1. LEVEL OF EVIDENCE: Systematic review and meta-analysis, therapeutic Level III.

Prolonged (post-thaw) shelf life of -80°C frozen AB apheresis plasma.

BACKGROUND: Early plasma transfusion is important in the treatment of patients with major hemorrhage. Prolonged shelf life of AB type frozen -80°C and cold-stored (4°C) deep frozen plasma (DFP) will improve strategic stock management, minimize need for resupply, and make pre-hospital implementation more feasible. METHODS AND MATERIALS: Plasma products type AB of different age and origin (-30°C Fresh Frozen [(FFP], -80°C DFP [short (±1 year) and long (±7 year)] stored) were thawed (Day 0), stored at 4°C, and sampled on Days 7 and 14. Additionally, samples of plasma containing blood products (Octaplas LG®, whole blood and platelets) were compared for coagulation factor activity, phospholipid clotting time (PPL), and kaolin TEG during 4°C or 22°C storage. RESULTS: Coagulation profiles of FFP, short- and long-stored -80°C DFP were not significantly different after thaw. Cold storage did not affect fibrinogen, Protein C, and Antithrombin III activities whereas factor V, VII, VIII, and Protein S decreased in all blood products. After 14 days DFP still meets the guidelines for clinical use, except for Protein S (0.4 IU/mL). With exception of Octaplas LG®, phospholipid activity and TEG coagulation were similar between plasma containing blood components during storage. CONCLUSION: AB DFP quality was unaffected by almost 7 years of frozen storage. Quality of thawed 14-day stored AB DFP met, with exception of Protein S, all minimal guidelines which implies that its quality is sufficient for use in the (pre)-hospital (military) environment for treatment of major hemorrhage.

The use of cryopreserved platelets in a trauma-induced hemorrhage model.

BACKGROUND: Cryopreserved platelet products can be stored for years and are mainly used in military settings. Following thawing, cryopreserved platelets are activated, resulting in faster clot formation but reduced aggregation in vitro, rendering their efficacy in bleeding unknown. Also, concerns remain on the safety of these products. The aim was to investigate the efficacy and safety of cryopreserved platelets in a rat model of traumatic hemorrhage. STUDY DESIGN AND METHODS: After 1 hour of shock, rats (n = 13/group) were randomized to receive a balanced transfusion pack (1:1:1 red blood cell:plasma:platelet) made from syngeneic rat blood, containing either liquid stored platelets or cryopreserved platelets. Primary outcome was the transfusion volume required to obtain a mean arterial pressure (MAP) of 60 mmHg. Secondary outcomes were coagulation as assessed by thromboelastometry (ROTEM®) and organ failure as assessed by biochemistry and histopathology. RESULTS: The transfusion volume to obtain a MAP of 60 mmHg was lower in animals receiving cryopreserved platelets (5.4 [4.1-7.1] mL/kg) compared to those receiving liquid stored platelets (7.5 [6.4-8.5] mL/kg, p < 0.05). ROTEM® clotting times were shorter (45 [41-48] vs. 49 [45-53]sec, p < 0.05), while maximum clot firmness was slightly lower (68 [67-68] vs. 69 [69-71]mm, p < 0.01). Organ failure was similar in both groups. CONCLUSIONS: Use of cryopreserved platelets required less transfusion volume to reach a targeted MAP compared to liquid stored platelets, while organ injury was similar. These results provide a rationale for clinical trials with cryopreserved platelets in (traumatic) bleeding.

-80 °C deep frozen erythrocytes during military operations. The Dutch frozen concept.

The Dutch military uses frozen blood products for the treatment of bleeding trauma patients during military deployments. With -80 °C frozen blood products it is possible to follow operational demand while reducing the number of resupply transports and loss of products due to expiration. In this paper lessons learned are described on efficient blood management with -80 °C deep-frozen erythrocytes (DEC).

Massive transfusion in The Netherlands.

OBJECTIVES: Massive transfusion protocols (MTPs) may improve survival in patients with uncontrolled haemorrhage. An MTP was introduced into the Dutch transfusion guidelines in 2011, the ninth edition of the advanced trauma life support course in 2012 and the third version of the European guideline in 2013. This is the first survey of MTPs in Dutch trauma centres. METHODS: The aim of the study was to compare MTP strategies in level 1 trauma centres in The Netherlands, and with (inter)national guidelines. A contact in each government assigned level 1 trauma centre in The Netherlands and the Dutch Ministry of Defence was approached to share their MTPs and elucidate their protocol in a survey and oral follow-up interview. RESULTS: All 11 level 1 trauma centres responded. The content of the packages and transfusion ratios (red blood cells/plasma/platelets) were 3:3:1, 5:5:1, 5:3:1, 2:3:1, 4:4:1, 5:2:1, 2:2:1 and 4:3:1. Tranexamic acid was used in all centres and an additional dose was administered in eight centres. Fibrinogen was given directly (n=4), with persistent bleeding (n=3), based on Clauss fibrinogen (n=3) or rotational thromboelastometry (n=1). All centres used additional medication in patients in the form of anticoagulants, but their use was ambiguous. CONCLUSION: MTPs differed between institutes and guidelines. The discrepancies in transfusion ratios can be explained by (inter)national differences in preparation and volume of blood components and/or interpretation of the '1:1:1' guideline. We recommend updating MTPs every year using the latest guidelines and evaluating the level of evidence for treatment during massive transfusion.

HLA genes and other candidate genes involved in susceptibility for (pre)neoplastic cervical disease.

This review focuses on common and genetic risk factors such as HLA and other genes that may be involved in susceptibility for (pre)neoplastic cervical disease. The goal of this review is the evaluation of polymorphisms that are either associated with cervical intraepithelial neoplasia (CIN) and/or cervical cancer. A pooled analysis was performed for DQA1, DQB1 and DRB1 alleles and 10 other genes that have been evaluated in more than one study. An association, either an increased or a decreased risk, with CIN and cervical cancer at a 5% significance level was found for 15 HLA II alleles. Four polymorphisms (Tp53, IL-10, CYP2D6 and the MTHFR) exhibited an increased CIN and cervical cancer risk. However, only the pooled analysis of the DQB1 alleles, the HLA-DR specificities and Tp53 genes had sufficiently large sample sizes to confirm or exclude the proposed association. Our data indicate that further analysis in larger sample sizes, especially for genes other than the HLA genes, is necessary to describe the exact relations between these genes and susceptibility for CIN and cervical cancer with an adequate power.

Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease.

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating the metabolism of folate and methionine. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair presents MTHFR as a candidate for being a cancer-predisposing gene. In the present study, we have examined a large study population to determine whether the C677T polymorphism at the MTHFR locus affects susceptibility for cervical cancer or its precursor, cervical intraepithelial neoplasia (CIN). In addition, we have investigated whether this polymorphism is causal, and not merely associated, by typing microsatellite markers in the region surrounding the MTHFR gene. A total of 311 CIN and 695 cervical cancer patients and 115 family-based and 586 unrelated controls was analysed. Association analysis showed a decreased cervical cancer risk for individuals heterozygous or homozygous for the T-allele, both for squamous cell carcinoma (heterozygous odds ration [OR] 0.66 [0.51-0.86]; homozygous OR 0.76 [0.49-1.16]) and adenocarcinoma (heterozygous OR 0.71 [0.49-1.03]; homozygous OR 0.34 [0.14-0.81]). No difference was found for high grade CIN (heterozygous OR 1.03 [0.76-1.40]; homozygous OR 0.91 [0.54-1.55]). A microsatellite haplotype containing the C allele was associated with an increased risk for cervical cancer and CIN (both among squamous cell carcinomas, adenocarcinomas and CIN II-III; OR = 2.61 [1.59-4.27]). Our study thus lends further support to the hypothesis that the MTHFR C677T polymorphism is involved in susceptibility cervical cancer but also illustrates that, despite the large sample size analysed, still larger studies are needed to establish fully the nature of this association.

Familial cervical cancer: case reports, review and clinical implications.

We report three Dutch families with familial clustering of (pre)neoplastic cervical disease, review the literature on familial risks of cervical intraepithelial neoplasia (CIN) and cervical cancer, and discuss possible practical guidelines for women with a family history of cervical cancer. Daughters and sisters of women with cervical cancer have been reported to have a relative risk of 1.5-2.3 to develop this type of cancer. From a practical clinical point of view, we suggest that as in women with an increased non-genetic risk to develop cervical cancer (e.g. because of immunosuppressive therapy) increased surveillance to detect this tumour should be considered in women with an increased risk based on family history. Cessation of smoking should be advised. As the use of condoms at least prevents HPV re-infection its use can be recommended as a way to lower the cervical cancer risk. Future studies to determine the genetic contribution to the development of cervical cancer should include the paternal family history of cancer and, because genetic predisposition might express itself as a higher risk to develop precursors of cervical cancer, carcinoma in situ and CIN grade II-III.