The THOR network best practices for females of childbearing potential with life‐threatening hemorrhage: Guidance for emergency medical services and hospitals

Hemorrhagic shock is a leading cause of early death from trauma and preventable mortality, including females of childbearing potential (FCP).1-3 A FCP is defined as a female child or adult who can become pregnant. Advances in resuscitation of patients with life-threatening hemorrhage have been associated with improved outcomes.1, 2 This has led to the concept of “damage control resuscitation,” which includes “hemostatic resuscitation”, a balanced blood-based resuscitation with either Low-Titer Group O+ Whole Blood LTOWB or blood components.4, 5 The use of LTOWB in the United States (US) has grown exponentially since the Trauma, Hemostasis, and Oxygenation Research (THOR) Network proposed a change to the Association for the Advancement of Blood however, the demand for these products far exceeds the supply of these scarce resources. Approximately 3%–4% of the US population can potentially donate Type O-negative products, based on Group O Rh-negative prevalence of approximately 7%–8%, and between 70% and 95% of donors meeting low titer criteria (Anti-A and B <256).17 Advances in maternal–fetal medicine have substantially reduced the morbidity and mortality associated with HDFN; however, monitoring and interventions remain highly specialized, requiring coordinated perinatal services outlined in the THOR Network and Allo Hope Foundation's recommendations on the optimal treatment of alloimmunized pregnant patients and the postnatal treatment of affected neonates.18 In emergencies involving life-threatening hemorrhage, immediate transfusion is critical for survival, and surveys suggest that many female respondents and caregivers would prioritize life-saving RhD-positive transfusion when RhD-negative products are unavailable, recognizing that the small subsequent risk of severe or fatal HDFN can be further significantly reduced with proactive guidance and optimal care.19-21 Recent evidence challenges the long-held assumptions regarding the risk of hemolytic disease of the fetus and newborn (HDFN) following RhD-positive transfusion. Traditionally, concerns about D-alloimmunization in FCP led to strict avoidance of RhD-positive products. However, contemporary data suggest this risk is much lower than previously thought: Several sequential events must occur to result in the development of severe (including fatal) hemolytic disease of the fetus and newborn (HDFN). Multiple models have examined the overall risk of HDFN in RhD-negative females of childbearing potential who are resuscitated with RhD-positive transfusion. One such model estimated one case of fetal death or permanent disability due to HDFN per 670 transfusions (~0.15%); another estimated a 0.04% chance of perinatal death due to HDFN and a 0.24% chance of death or other serious adverse event.8, 22 The data support a pragmatic and risk-based approach in emergency situations where the immediate need for transfusion outweighs the long-term alloimmune complications (Figure 1).13 The implementation of LTOWB has not been equitable between males and females with life-threatening hemorrhage. Upon adjusted analyses, FCP were 40% less likely to receive LTOWB than males.23 A growing body of evidence supports the prehospital use of group-O-positive blood products in life-threatening hemorrhage of any etiology for FCP when RhD-negative products are unavailable, provided that post-exposure antibody screening and appropriate education and counseling are ensured. Standardized informational documents for informing FCP regarding the risk of alloimmunization after exposure and guidance for what to do if alloimmunized are found in Appendices A and B. Recommendations from evidence-based guidelines organized by THOR Network and the Allo Hope Foundation, sponsored by the US Department of Defense state, “We recommend the use of RhD-positive blood products for the initial resuscitation of patients with life-threatening hemorrhage when RhD-negative blood products are not available, regardless of patient age or sex” and “We suggest the use of RhD-negative LTOWB for the initial resuscitation of ABO-type unknown female patients with life-threatening hemorrhage.24 If unavailable or impractical, we suggest the use of RhD-positive LTOWB”. Similar recommendations are further highlighted in the Prehospital Transfusion Coalition's Clinical Practice Guidelines for Civilian Emergency Medical Services.8 The rationale justifying the use of RhD-positive LTOWB or RBCs is that there is the potential for improved survival. Earlier use of LTOWB, plasma and RBCs for severe bleeding has been associated with improved survival and a decreased overall requirement for additional transfusions.25-27 However, delays in identifying and treating life-threatening hemorrhage continue to contribute to preventable deaths, which mostly occur in the prehospital phase of resuscitation.28 LTOWB offers a practical solution for prehospital care by combining red blood cells (RBCs), plasma, and platelets in a single unit.29-31 For both prehospital and hospital resuscitation of life-threatening hemorrhage, LTOWB is at least as effective, and logistically superior, compared to component therapy (CT), reducing donor exposures while enabling a more rapid and balanced resuscitation.30, 32-34 Based on data in a meta-analysis of close to 60,000 patients, LTOWB may improve outcomes compared to components when used for hospital-based resuscitation.30 This best-practices document aims to assist EMS systems and hospitals in establishing streamlined processes for managing the use of prehospital blood in cases of life-threatening hemorrhage involving FCPs. Establishing clear protocols for communication among EMS, hospital care providers, and blood banks is essential to ensure patient safety, promote system-wide performance improvement, minimize waste, and enhance clinical outcomes.8, 11, 14 Through these best practices, we aim to strengthen collaboration frameworks that align ethics, operations, and outcomes across the trauma continuum—ultimately improving patient care and system efficiency. This guidance includes early field recognition of hemorrhage and rapid initiation of balanced resuscitation, EMS-to-hospital handoffs, and post-exposure follow-up and education. Early recognition and treatment of hemorrhagic shock can improve patient survival. Physiologic indicators, such as hypotension and tachycardia, as well as additional metrics, including shock index, end-tidal capnography trends, point-of-care lactate (when available), and ultrasound, help identify hemorrhagic shock.1-3 Initiating blood products as soon as possible is associated with lower mortality as compared to crystalloid-based strategies, particularly when transport times are prolonged or hemorrhage control is difficult or delayed.1 As stated above, for FCP patients, RhD-negative LTOWB is ideal; however, scarcity necessitates a risk-stratified approach.10, 15, 23 The potential for sex-based inequity by withholding prehospital blood products or defaulting to scarce RhD-negative red cell-only transfusions for women, while men receive LTOWB, serves to intentionally widen survival gaps.10, 15, 23 Pediatric specific gender based inequity data have not been published as of this manuscript's writing. Fair access frameworks prioritize LTOWB for any patient in critical condition, while conserving scarce RhD-negative inventories through system stewardship and, when possible, appropriate switching to RhD-positive blood products within a given resuscitation timeline when blood type and screen have resulted.10, 34 Ethically, the risk–benefit calculations favor transfusing available (RhD-positive) blood prehospital in cases of exsanguination regardless of RhD status.10, 33, 34 In a life-threatening hemorrhage when RhD-negative blood is unavailable, RhD-positive LTOWB (or RBCs) are appropriate to preserve life.27 The EMS-to-hospital handoff of care is a critical juncture for ensuring patient safety following a transfusion event.35 See Figure 2 for an example of a form used by the Southwest Texas Regional Advisory Council (STRAC) that standardizes this process. It is essential that patient handoff from EMS to hospital-based teams provide detailed documentation and closed-loop communication with care team members of all care provided to specifically include the transfusion of any RhD-positive blood product to a FCP. Hospitals should establish procedures to accept and store prehospital unit segments for post-event testing, record all uncrossmatched transfusions administered in the field, and have immediate notification pathways for suspected reactions, even if the blood originated from an external blood bank.27 Policies and procedures should be developed jointly with the prehospital agency serving as the Transfusion Administration Service (TAS).30 Electronic medical records systems should allow prehospital transfusion data to be directly entered into the hospital transfusion service record.8 If direct entry isn't possible, paper records should be used and provided by the prehospital agency to ensure accurate documentation of transfusion data.36 Rh immunoglobulin (RhIg) is only recommended after small-volume (≤one unit) RhD-positive LTOWB or RBC transfusions in RhD-negative FCPs. When indicated, administration can occur up to 72 h post-exposure.31, 37 There is no role for RhIg for males or postmenopausal females.38, 39 Additional clinical considerations related to RhIg prophylaxis include the risk of severe hemolysis from rapid administration of large RhIg volumes (estimated 17–20 vials per RBC/LTOWB unit), as well as complexity in interpreting subsequent antibody screens (passive vs. allo-anti-D).37 Logistical considerations include prioritization strategies given supply chain and manufacturing limitations related to RhIg shortages.40 All RhD-negative FCPs exposed to RhD-positive LTOWB and RBCs should receive informational literature (1 and 2) and clear discharge documentation describing post-exposure implications and follow-up recommendations (Figure 3), including care coordination to facilitate scheduled antibody screening (e.g., 14 weeks to 6 months), as well as prior to, or early in, subsequent pregnancies, with results communicated to patients, outpatient clinicians, and maternal-fetal medicine specialists.8, 10, 12, 41 Post-exposure patient management of the RhD-negative FCP following transfusion or exposure to RhD-positive blood should follow standardized pathways (Figure 3).11, 12 EMS and hospital system best practices include the following (Table 1).1-4, 8, 19, 27-34 Implement life-threatening hemorrhage screening processes that trains clinicians to maintain a high index of suspicion based on mechanism of injury, systolic blood pressure, shock index, and point-of-care lactate. Establish prehospital blood (PHB) activation criteria and workflows so blood products can be initiated promptly when life-threatening hemorrhage is suspected. Ensure all relevant clinical personnel (including prehospital and in-hospital) receive education and competency validation on life-threatening hemorrhage recognition and intervention. Maintain reliable procedures for rapid vital sign assessment and assessment of shock. Initiate blood products as early as possible for life-threatening hemorrhage; avoid crystalloid-only resuscitation, as early blood product use is associated with lower mortality. Prioritize low-titer O whole blood (LTOWB) for initial resuscitation when available. If LTOWB is not available, transfuse liquid plasma and red blood cells (RBCs) together rather than either component alone. Define and follow criteria for transitioning from LTOWB to type-specific, crossmatched components once life-threatening hemorrhage has ceased and the patient's ABO type is known. When large-volume LTOWB resuscitation has occurred, transitioning to an ABO- compatible components is safe, and should be done so promptly when available. Administer Rh immunoglobulin (RhIg) to RhD-negative patients only after small-volume (≤1 unit) exposure to RhD-positive LTOWB or RBCs; do not routinely administer RhIg if more than 1 unit of RhD-positive LTOWB or RBCs was transfused during exsanguinating hemorrhage. In exsanguinating hemorrhage involving a FCP, do not delay transfusion when RhD-negative blood is unavailable; use RhD-positive LTOWB or RBCs to preserve life. Promote equitable access to PHB and LTOWB across all patient populations and care settings, with transparent policies that balance maternal-fetal considerations against immediate survival. Use closed-loop communication and document all blood products transfused to FCP across the care continuum (EMS through hospital discharge). Establish hospital procedures to accept and store prehospital unit segments for post-event testing, traceability, and documentation. Maintain real-time, bidirectional notification mechanisms between EMS, hospitals, and external blood suppliers for suspected transfusion reactions, including clear handoffs and escalation pathways. Provide standardized informational literature and counseling before discharge. Include exposure details and follow-up instructions in discharge documentation. Schedule antibody screening between 14 weeks and 6 months post-exposure. Ensure results are shared with the patient's outpatient clinicians (e.g., primary care, obstetrics/gynecology or maternal fetal medicine) and documented in the medical record for future pregnancies or transfusions. Registries should assess the cumulative burden of RhD alloimmunization, the percentage of individuals that develop high-titer antibodies, and related outcomes.12, 13, 34 Digital hemovigilance, which includes linking EMS records, hospital transfusion services, and regional blood banks, can enable real-time reaction detection, targeted recalls, and patient-specific counseling.8, 42 Over time, these networks can support pragmatic trials, equitable allocation models, and transparent public reporting. Multicenter trials (MATIC-2 NCT06070350, TROOP NCT05638581) are ongoing that will help to determine the impact of prehospital and in-hospital blood transfusion, specifically LTOWB, on mortality, transfusion efficiency, risk of alloimmunization in FCP who receive RhD-positive LTOWB and RBC, and adverse events in both pediatric and adult cohorts. Longitudinal tracking of alloimmunization and pregnancy outcomes after emergent RhD-positive exposure is a key research priority, as is the development of RBC antigen (RhD, K, E, etc.) agnostic future blood products.12, 13 The current development of RBCs produced from stem cells and artificial red cells is a promising product that could address this need.43 To improve survival in FCP suffering from life-threatening hemorrhage requires early recognition and immediate blood-based resuscitation. Because RhD-negative LTOWB or RBCs are not usually available, RhD-positive transfusion pathways after exposure begin with seamless EMS-to-hospital communication at the patient care transition, involving coordinated data sharing to enhance safety and accountability. By following standardized workflows, ensuring timely and safe transfusion practices, implementing transparent governance, and conducting structured follow-up and counseling, systems can optimize survival while ensuring long-term reproductive health. Through collaboration between EMS, specialized care, and transfusion medicine teams, a once-seemingly complex ethical dilemma has become a reproducible, evidence-based model for lifesaving best practices. Matthew J. Levy is a consultant with Stryker Medical Education and GMR. He is the chair of the Stop the Bleed Coalition. He is the EMS Medical Director of Continuing Education for the American Red Cross and is a member of the Scientific Advisory Council of the American Red Cross. John B. Holcomb is on the board of directors of QinFlow, Hemostatics, and Zibrio. He receives research grant support from the DoD and NIH, focused on hemorrhage control and resuscitation. He consults with WFIRM, Geneva Foundation, Aspen Medical, Infrascan, and is the coinventor of the Junctional Emergency Tourniquet Tool and thus receives royalties from UT Health. You received a blood transfusion with whole blood or red blood cells. This blood transfusion was provided emergently to help save your life. What is Rh(D)? Rh(D) is a protein found on the outside of red blood cells. If your blood has the protein, you are Rh(D) positive. If your blood does not have the protein, you are Rh(D) negative. The “+” or “-” you might see after your blood type shows if you are Rh positive or negative. You received a blood transfusion with a product called whole blood or RBCs. This blood transfusion was provided emergently to help save your life. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.