A prehospital protocol for transfusion of low‐titer O‐positive whole blood in patients with hemorrhagic shock in Los Angeles County: Modeling the risk of hemolytic disease of the fetus and newborn

Abstract

Background

The Los Angeles Development and Rapid Operationalization of Prehospital Blood (LA‐DROP) pilot will protocolize prehospital administration of low titer O‐positive whole blood (LTO + WB) to patients with hemorrhagic shock in Los Angeles County (LAC). We sought to quantify the risk of death from hemolytic disease of the fetus and newborn (HDFN) associated with RhD‐negative alloimmunization in females of childbearing potential (FCPs) as a result of LA‐DROP.

Study Design and Methods

Retrospective data from LAC EMS databases were used in combination with estimates from published literature to assign probability distributions to each event in the sequence required for a transfusion of LTO + WB to result in a death from HDFN. Markov chain Monte Carlo simulation was used to derive risk estimates.

Results

We estimated that the proposed prehospital transfusion strategy would result on average in one death from HDFN for every 10,000 transfusions in the overall population (95% confidence interval [CI] 6000–25,000) and for every 1800 transfusions in FCPs (95% CI 1000–4300). Based on the projected annual volume of transfusions under LA‐DROP, this would result in one death due to HDFN approximately every 26 years (95% CI 15–64).

Discussion

The estimated per‐transfusion risk of HDFN is similar to previously published work from other populations. The estimated frequency of deaths from HDFN associated with LA‐DROP is lower than some previously published calculations, likely because of narrower eligibility criteria for transfusion.

1. INTRODUCTION

The concept of hemostatic resuscitation promotes the balanced approach to treating shock, endothelial dysfunction, and coagulopathy with either whole blood (WB) if available or a 1:1:1 unit ratio of plasma, platelets, and RBCs. Many retrospective and prospective observational studies, as well as a large meta‐analysis, have suggested a possible survival advantage with low titer group O whole blood (LTOWB) over individual blood components. ¹ , ² As the use of LTOWB increased in the US, with over 300 trauma centers incorporating it into their massive transfusion protocols, ³ the lack of production of RhD‐negative LTOWB by blood suppliers has led to the predominant use of RhD‐positive LTOWB, or LTO + WB, for patients with life‐threatening bleeding.

The transfusion of RhD‐positive red blood cell (RBC)‐containing products to RhD‐negative females of childbearing potential (FCPs) introduces the potential for D alloimmunization, which can lead to hemolytic disease of the fetus and newborn (HDFN) in future pregnancies. HDFN occurs when maternal anti‐D antibodies cross the placenta and destroy RhD‐positive fetal RBCs, which causes fetal anemia and, in rare cases, may cause fetal hydrops or fetal death. The risk of anti‐D alloimmunization and HDFN can be avoided by exclusively transfusing RhD‐negative products, but the limited availability of RhD‐negative pRBCs and low titer group O‐negative whole blood may necessitate the use of RhD‐positive blood products in resuscitation for hemorrhagic shock. Recent commentaries have assessed the bioethical implications of this practice and, based on the principle of double effect, the use of LTO + WB has been considered ethical. ⁴

Several simulation studies have quantified the risk of HDFN associated with an LTO + WB prehospital transfusion strategy to treat hemorrhage in various patient populations. ⁵ , ⁶ , ⁷ , ⁸ We aim to apply these methods to retrospective data from Los Angeles County's (LAC) large and diverse patient population in order to estimate the HDFN risk associated with the planned Los Angeles Rapid Operationalization of Prehospital Blood (LA‐DROP) pilot, which will protocolize the administration of LTO + WB in the prehospital setting to patients in hemorrhagic shock. This analysis leverages a combination of regionally specific, real‐world data and previously published literature to provide a region‐specific perspective, complementing prior studies in this area. ⁶

2. STUDY DESIGN AND METHODS

2.1. Population and setting

The system of regional trauma care in LAC has been described previously. ⁹ Briefly, LAC Emergency Medical Services (EMS) Agency oversees a regional trauma system consisting of 30 public provider EMS agencies, serving over 10 million people, which transports patients to 14 designated Trauma Centers (TCs) within the County's 4085 square miles. Criteria for patient transport to TCs have been previously published. ¹⁰ , ¹¹

2.2. LA‐DROP prehospital blood transfusion program

The Los Angeles Development and Rapid Operationalization of Prehospital Blood (LA‐DROP) program aims to provide prehospital transfusion to patients estimated to be aged ≥15 years suffering from severe bleeding, either due to trauma or postpartum hemorrhage. Patients are eligible to receive a prehospital blood transfusion if they have any of the following after initial attempts at hemorrhage control: a systolic blood pressure (SBP) < 70 mmHg, a simultaneous reading of SBP < 90 and heart rate (HR) ≥ 110, or cardiac arrest witnessed by paramedics. Patients who suffer cardiac arrest prior to paramedic arrival, who have isolated head injury, or whose only mechanism of traumatic injury is a ground‐level fall are not eligible. Patients who are able to provide verbal consent will be asked to do so and those who decline transfusion will not be transfused. Initially the program will be piloted in a subset of provider units at two EMS provider agencies; however, this analysis considers the effects of applying the protocol to LAC as a whole. LA‐DROP program's primary blood product transfusion strategy will be to transfuse low titer type O‐positive whole blood (LTO + WB) to eligible patients of any sex.

2.3. Data collection

LAC TCs submit data to the LAC EMS Agency regarding care for patients who have suffered trauma and meet criteria for transport to a TC. The data are maintained in LAC's Trauma and Emergency Medical Information System (TEMIS). Additionally, the LAC EMS agency maintains data regarding all EMS transports, including those for non‐trauma patients. This study was a retrospective analysis of deidentified patient data contained in LAC EMS databases between the dates of November 1st, 2021, and September 30th, 2023. In order to understand the number, demographic makeup, and hospital outcomes of patients who would receive prehospital blood transfusions in LAC under this program, we retrospectively applied the eligibility criteria for prehospital blood transfusion to this cohort. This study was determined to be exempt from IRB oversight by the Lundquist Institute IRB.

2.4. Statistics

• Model structure

We sought to emulate the analysis by Cardigan et al. for the patient population impacted by LA‐DROP, focusing only on the risk of HDFN (Cardigan et al. also considered the risk of immediate and future hemolytic transfusion reactions). ⁵ Specifically, we sought to estimate the risk of HDFN associated with the program and its effect on net life‐years (LY), taking into account LYs lost due to HDFN. While some observational studies have suggested survival benefits from LTOWB administration ranging from 10% to 50%, ¹² , ¹³ , ¹⁴ considering the uncertainty in these estimates, we conservatively assumed either a 0.5% or 1% mortality benefit. The sequence of events required to result in death from HDFN, which represents a chain of conditional probabilities, is shown in Figure 1.

• Model inputs

FIGURE 1.

Risk model. Events that must occur to result in death due to hemolytic disease of the fetus and newborn (HDFN) after the transfusion of Rh‐D‐positive blood products. Figure adapted from Yazer et al. ³⁷

The assumed probability distributions and their sources for each event in Figure 1 are described in the Supplementary Methods. Briefly, we used LAC data to estimate the expected annual number of prehospital transfusions under LA‐DROP, the annual number of transfusions to FCPs (which we defined as females of age < 50 years and ≥ 15 years, as the initial implementation of LA‐DROP will not include children <15), the probability of in‐hospital mortality, and the age distribution in patients eligible for transfusion. We used the US fertility rate by maternal age, as well as the ages of FCPs in the transfusion cohort, to estimate the expected total cumulative lifetime number of posttransfusion pregnancies in transfused patients in our dataset. We then divided by the size of the population (all patients or FCPs only) to obtain the mean number of expected posttransfusion pregnancies per patient. We performed 1000 iterations of a bootstrapping procedure to estimate the uncertainty around this mean (Supplementary Methods). For other model inputs, including assumptions regarding the rate of alloimmunization, we used probability distributions based on previously published estimates, relying on data specific to the US population where possible and favoring estimates from large multicenter studies (S1).

For the estimates of the utility of a prehospital LTO + WB transfusion strategy in terms of life‐years, we used the average age of patients eligible for transfusion in our cohort and assumed a surviving patient (or fetus/newborn) would live to the average U.S. life expectancy of 78 years.

• Estimation using Markov chain Monte Carlo (MCMC) simulation

TreeAge Pro™ software ¹⁵ was used to perform the Markov chain Monte Carlo (MCMC) simulation, with 100,000 simulations performed for each estimated quantity. We used R software for all other calculations. ¹⁶

3. RESULTS

Over the 23‐month period of data analyzed, 25,743 patients were transported to trauma centers in LAC. Retrospective application of prehospital blood transfusion criteria identified 743 patients who would have received prehospital LTO + WB transfusions for either severe traumatic injury (739) or postpartum hemorrhage (4), 131 of whom were FCPs. This equates to an average of 388 transfusions per year and 68 transfusions per year in FCPs. The median age of the population was 35 years (IQR 27–49 years) and 29 years for FCPs (IQR 24–36 years). The distribution of patient ages is shown in Figure 2. The average mortality rate during the initial hospitalization was 25% for the cohort as a whole (mortality data were not available for the four eligible patients with postpartum hemorrhage; thus, these patients were excluded from this calculation).

FIGURE 2.

Age distribution of patients. Age distribution of patients in LAC with severe hemorrhage and eligible for LA‐DROP.

The results of the MCMC simulation are shown in Table 1. The estimated average risk of death from HDFN was 1 per 10,000 transfusions when the population as a whole was considered and 1 per 1800 transfusions when FCPs were considered. Assuming annual rates of transfusion similar to those observed in our retrospective data, a death due to HDFN would be expected to occur on average approximately every 26 years during the time LA‐DROP is implemented.

TABLE 1.

Estimated risk of hemolytic disease of the fetus and newborn with the LA‐DROP prehospital transfusion strategy.

	One death due to HDFN every X transfusions (95% CI)	Estimated years to one death due to HDFN (95% CI)
All patients (Age ≥ 15)	1.0 × 104 (6.0 × 103–2.5 × 104)	26 (15–64)
Female of childbearing potential	1.8 × 103 (1.0 × 103–4.3 × 103)	26 (15–63)

A mortality benefit from a LTO + WB prehospital transfusion strategy as low as 0.5% would result in a net gain of life‐years: an average of 0.40 LY per transfusion when the population as a whole was considered and 0.37 LY when only FCPs were considered. The benefit would rise to 0.45 LY and 0.75 LY, respectively, if the program resulted in a 1% decrease in mortality.

4. DISCUSSION

Whole blood offers several benefits, including logistic simplicity, less infusion of additives and anticoagulants, decreased donor exposure compared to component therapy, ¹⁷ and potentially improved clinical outcomes in both traumatic and postpartum hemorrhage. ¹⁸ , ¹⁹ LTO + WB administered in emergent settings to individuals of unknown blood type poses risks compared to RhD‐negative cellular blood products, including hemolysis from transfusing the anti‐A/anti‐B containing group O plasma component to non‐group O individuals and RhD alloimmunization of RhD‐negative FCPs. However, the conventional practice of transfusing RhD‐negative cellular products to FCPs who are RhD‐negative or RhD‐unknown ²⁰ places a significant burden on a limited blood supply, in which only 10% of the donor pool is group O‐negative. ²¹ As the demand for whole blood increases, it will become increasingly difficult to maintain a sufficient inventory of RhD‐negative low titer whole blood.

Prehospital transfusion programs must weigh the risk of alloimmunization of FCPs with hemorrhagic shock against the risk of inadequate blood product supply, and there are currently no recommendations regarding the use of LTO + WB in FCPs in hemorrhagic shock. ²² Given these considerations, many prehospital transfusion programs, including our proposed LA‐DROP program, have chosen to administer LTO + WB, with only a minority (7%) incorporating RhD‐negative whole blood. ²³

The estimated per‐transfusion risk of HDFN for patients treated under the LA‐DROP protocol is similar to that calculated by Cardigan et al. ⁵ (1 in 2.9 × 10⁴, 95% confidence interval [CI] 1.2 × 10⁴–1.2 × 10⁵ for all transfusion recipients). The small difference in the point estimates is likely explained by the different distribution of age and gender in the LAC population eligible for transfusion and the fact that our assumptions about the risk of mortality from HDFN were drawn from a recently published international dataset. ²⁴ The estimated frequency of deaths due to HDFN under LA‐DROP is much lower than that estimated by Cardigan et al. (5.2 yr., 95% CI 2.2–21.6 years considering all transfusion recipients), because the projected annual number of transfusions in LAC is much smaller than Cardigan's estimate for England (388 vs. 5561), even after accounting for the difference in population size (LAC 10 million, ²⁵ England 57 million ²⁶ ). Cardigan estimated the annual number of prehospital transfusions in England from hospital‐based transfusion rates at 22 medical centers in the UK, whereas we derived our estimates from applying our protocol eligibility criteria (vital signs, age, mechanism) to prehospital data from the entirety of LAC. Additionally, the lower estimated annual transfusion rate for LA‐DROP reflects an effort to craft narrow eligibility criteria aimed at critically ill patients, who would most likely benefit from a prehospital rather than hospital‐based transfusion strategy.

Although we estimate the risk of death due to HDFN associated with LA‐DROP to be rare, delivering equitable care requires the development of systems to mitigate harm after possible alloimmunization from the transfusion of LTO + WB in a RhD‐negative FCP. Strategies such as scheduling follow‐up antibody screening after exposure and the provision of patient education materials will be incorporated into LA‐DROP and are a consideration for any similar program. These have the potential to reduce harm even after alloimmunization has occurred via the monitoring of affected pregnancies and the provision of treatments, such as intrauterine transfusion and/or other targeted therapies. ²⁷ , ²⁸ , ²⁹ , ³⁰ Importantly, our estimate of the risk of HDFN associated with LA‐DROP assumes early knowledge of alloimmunized status: the estimated risk of HDFN per alloimmunized pregnancy with an Rh‐positive fetus was derived from a cohort referred to specialty care centers at a median gestational age of 20 weeks and in whom the majority were referred for alloimmunized status without suspected fetal anemia. ²⁴ Thus, our estimate of risk associated with LA‐DROP assumes patient and physician awareness of alloimmunized status, as well as access to specialty follow‐up.

From the patient perspective, large surveys have been completed in women, parents of female children, and alloimmunized women regarding the acceptable risk/benefit trade‐off between the mortality benefit from transfusion and risks to potential future pregnancies. Each of these groups has reported that they are willing to accept the small risk of a future pregnancy complication in exchange for a possible small improvement in survival. ³¹ , ³²

5. LIMITATIONS

Our estimates were partly based on a retrospective dataset, in which documentation errors and/or missing data had the potential to influence results. The sources of the probability estimates for some of the events in Figure 1 had small sample sizes, producing wide confidence intervals for risk estimates. We made necessary but simplifying assumptions regarding the shapes of the distributions for the various probabilities of interest (Supplementary Methods). We did not incorporate uncertainty around the number of transfusions per year into our estimate of the variability of the frequency of death from HDFN.

In estimating the net LY change under various possible magnitudes of mortality benefit associated with LA‐DROP, we implicitly assumed that the value of LY from an unborn child is equivalent to that of adult LY; in the absence of an accepted convention regarding the relative utility weight of adult versus fetal outcomes, this is only one of several possible approaches. ³³ Further, we did not consider quality‐adjusted life‐years related to long‐term disability either due to the effects of traumatic hemorrhage or HDFN, because data on disability rates were not available in the datasets we used. We did not consider other risks associated with LTO + WB transfusion in RhD‐negative unknown patients (e.g. hemolytic transfusion reactions).

Lastly, because the initial implementation of the LA‐DROP program does not include pediatric patients aged <15 years, we did not consider them in our modeling. However, previously published work has shown higher rates of death in children in the context of severe hemorrhage, suggesting they stand to benefit even more than adults from an early, prehospital transfusion strategy. ³⁴ , ³⁵ , ³⁶ Future iterations of LA‐DROP are planned to include children aged <15 years; this will require local protocolization and training of a weight‐based prehospital transfusion volume for patients in that age group.

6. CONCLUSION

Our estimate of the per‐transfusion risk of HDFN associated with a proposed prehospital LTO + WB transfusion program for life‐threatening hemorrhage in LAC agrees with previously published work. Our estimate of the frequency of deaths from HDFN associated with LA‐DROP is much lower than estimates from other systems, likely because of narrower eligibility criteria for transfusion. Harm mitigation strategies, including education and follow‐up testing for RhD‐negative FCPs transfused with LTO + WB, should be incorporated into such programs and would further reduce risk.

CONFLICT OF INTEREST STATEMENT

The authors report there are no conflicts of interest to declare.

Supporting information

Data S1. Supporting Information.

Wilhelm K, Lauer C, Rangwala R, Zadeh T, Spinella PC, Tolles J. A prehospital protocol for transfusion of low‐titer O‐positive whole blood in patients with hemorrhagic shock in Los Angeles County: Modeling the risk of hemolytic disease of the fetus and newborn. Transfusion. 2025;65(Suppl. 1):S313–S319. 10.1111/trf.18184