The contribution of religious objectors to transfusion in understanding the impact of anaemia and patient blood management—a narrative review

Introduction

There has been heterogeneity in transfusion practice since the development of modern blood banking. More recent randomised controlled trials have demonstrated that liberal transfusion practices common during the latter part of the twentieth century were often unnecessary, without a significant improvement in patient outcomes (1-3). These trials have led to a reappraisal of clinical practice and guidelines, with transfusion now considered at lower thresholds than previously (4).

A group of patients over this same period refused blood transfusion for religious reasons. Jehovah’s Witness hold a belief that blood transfusion is against God’s will and refuse transfusion alone. The group does not reject medical care and does not prohibit other interventions, but the transfusion of blood is forbidden, with many believers maintaining this stance to the point of death. Officially, Jehovah’s Witnesses do not accept whole blood (even autologous), cellular or plasma components, but allow fractionated products, such as albumin or immunoglobulin and even marrow transplantation as a matter of choice. However, the literature reports varying practices and individual patients must be involved in their decision making. In the literature, this does result in greater heterogeneity when looking at components other than whole blood and red cells.

Religious objection to transfusion challenges clinicians, particularly in an era where transfusion was considered both lifesaving and necessary. The medical literature has many reports of interventions in religious transfusion objectors. These highlight ways to overcome the perceived barriers and risks posed by the inability to transfuse blood, report on procedures successfully conducted in safety and in some cases on innovative techniques and therapies to manage anaemia.

The group also provides a unique opportunity to compare cohorts where the only differences in the medical care received arise from the choice not to receive blood. Selective refusal allows cohort studies comparing risks with and without transfusion which could not otherwise be done without major confounders. The willingness to continue therapy with the exception of blood transfusion highlights the potential value of blood transfusion and may give insight into the physiological implications of anaemia. This review aims to describe the contribution of religious objection to blood transfusion by Jehovah’s Witnesses advancing our understanding of the impact of anaemia, the role of transfusion and the development of patient blood management and alternatives to transfusion. I present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-24-20/rc).

Methods

A search was performed in the MEDLINE database, restricted to articles in English. The search terms “transfusion” and “Jehovah’s Witness” were used. The search was performed on 28 May 2017 and updated on 26 July 2020. Article titles and abstracts were examined to include papers reporting on medical outcomes in Jehovah’s Witnesses refusing blood transfusion. Case reports, case series, cohort studies and clinical trials, with or without comparator arms and systematic reviews, were acceptable. Papers focused only on religious, legal or ethical issues were excluded. Case reports not available within the authors library networks were not included. Additional papers were identified from references of included articles.

Articles were examined and key themes were extracted and collated. The reporting of novel interventions or approaches were extracted. Research comparing risks or interventions were also summarised. Meta-analysis or statistical analysis was not planned. As this research evaluated reported literature only, human research ethics committee review was not required. The search and selection strategy are shown in Table 1.

Key findings and interpretation

The search returned 700 articles published until July 2020. Of these 226 were excluded as they did not fulfill the inclusion criteria. One study was excluded as it had been retracted, while two papers were not found or indexed on the journal’s own repository. A further 52 case reports were not readily available in the author’s library networks and were excluded, leaving 419 papers to review from which key themes were identified. Most articles were case reports (n=331) or cohort studies (n=61), with case-control studies (n=15), trials (n=1) and reviews (n=11) making up the remainder of the reviewed papers.

Anaemia tolerance

There were numerous studies reporting on patients surviving despite very low haemoglobin concentrations. There were a number of reports of people surviving after refusing transfusion with haemoglobins as low as 14–18 g/L (5-8) in acute situations and as low as 13 g/L for seven days in a patient with longer term anaemia due to acute lymphoblastic leukaemia (9). With a haemoglobin of 18 g/L, Dicpinigaitis (6) observed that the calculated dissolved plasma oxygen at 100% inspired oxygen accounted for approximately one third of the blood oxygen delivered to the tissues. To support this, there have been individual reports of rapid improvement in function with hyperbaric oxygen, increasing dissolved oxygen when haemoglobin is likely to be already fully saturated (10). There are occasional reports of deaths due to anaemia also. Finfer and colleagues (7) reported on two patients, occupants in the same motor vehicle accident, both refusing bloods. The first survived with a haemoglobin of 16 g/L and other had a haemoglobin of 9 g/L at the time of death. Based on the severity of their injuries, a 99% survival was expected. Calculation of survival probabilities are based on patients receiving standard of care, including blood transfusion.

Despite the very low haemoglobin levels reported in survivors without transfusion, the lowest reported haemoglobins to the best of the author’s knowledge were significantly lower. A level of 4 g/L in a child with sickle cell disease and acute autoimmune haemolytic anaemia due to ceftriaxone resulted in recovery with severe neurological impairment (11). An adult with a haemoglobin of 6 g/L during liver transplant and a lack of available compatible blood resulted in full recovery despite cardiac ischaemia once blood was transfused (12). Another patient survived 10 hours intraoperatively for a severed artery with a haemoglobin less than 9 g/L and a nadir of 7 g/L due to a delay in blood product availability (13). There were no ischaemic changes on electrocardiogram and there was a full recovery with transfusion. Carson and colleagues showed that in surgical patients who refused transfusion post operative haemoglobin was a strong predictor of mortality with the relative risk of death increasing by 2.5 for each 10 g/L fall below 70 g/L (14). In severely anaemic patients, death is often delayed, with multiple complex causes including ongoing bleeding (38.5%), respiratory failure (36%), cardiac causes (31%) and renal failure (28%) predominating (15). Similar outcomes were confirmed in a retrospective study by Shander et al. (16).

In a review of previously published cases, Viele and Weiskopf found a high bleeding-attributed mortality rate when the haemoglobin fell below 50 g/L, whereas no deaths were reported due to anaemia above this threshold (17). Potential reasons for discrepancies in the level at which a low haemoglobin level is associated with increased mortality between this and the studies by Carson and Shander (14,16) could relate to study populations or the presence of comorbidities. Cardiovascular disease is known to be associated with a greater risk with anaemia, for example (18).

In a retrospective comparative study, Beliaev et al. found an approximately tenfold increased rate of death in anaemic Jehovah’s Witnesses who received erythropoiesis stimulating agents compared with controls who were receptive to transfusion as needed (19). Gastrointestinal bleeding, shock, cardiac ischaemia, cardiac arrhythmia, infective complications, acute renal deterioration, delirium, depression and syncope were all reduced in patients who could be transfused and the study found that red cell transfusion was cost saving. However, the two groups were incompletely matched, with an older age and increased comorbidities seen in those refusing transfusion.

Similar independent retrospective studies with propensity matching in general hospital and critical care patients with a haemoglobin less than 80 g/L found no increase in adverse outcomes in those refusing transfusion compared with controls (20,21). However in one of these studies, severe anaemia showed a trend to increasing mortality (20) and the other had patients with higher haemoglobin levels and may not have detected a difference due to this (21).

While severe anaemia has high mortality rates, for the majority of patients seeking medical intervention, a lack of transfusion did not adversely affect outcomes. In a review of published surgical studies, Kitchens found a death rate of only 1.4% in patients undergoing surgery, with cardiovascular surgery bearing the greatest risk (22). It is likely that with attention to optimising and preserving a patient own blood that most patients are able to be kept above haemoglobin thresholds where transfusion may be of benefit.

Pharmacological therapies for anaemia

Erythropoiesis stimulating agents have been used to treat anaemia in renal failure, myelodysplastic syndromes and during chemotherapy so it is unsurprising that they have been used to treat anaemia when red cells are refused. There are many case reports of erythropoietin use. Most are uncontrolled and it is therefore difficult to establish efficacy. In particular, in acute anaemia endogenous erythropoietin levels are increased so additional pharmacologic doses may not improve erythropoiesis. Comparative reports, based on matched cohorts (23) or comparisons derived from the medical literature (24), did not show a benefit from addition of erythropoietin in Jehovah’s Witnesses with anaemia. This contrasts with high quality metanalyses showing that these agents reduce the need for transfusion in the perioperative setting (25-28). The inconsistency likely arises as a result of different settings; erythropoietin seems effective in pre-operative optimisation of haemoglobin, but is likely adding little in the post-operative setting when erythropoietin levels are high in response to anaemia.

Erythropoietin has also been used in neonates (29-32) and paediatric (33-36) patients in families who refuse transfusion, despite the law in most circumstances allowing transfusion in minors if considered necessary. While erythropoietin is indicated for anaemia associated with chemotherapy, its use in haematological neoplasms with prolonged severe marrow suppression is not standard, although there are some reports of success, and being able to prevent red cell transfusion despite induction and consolidation chemotherapy (37).

Haemoglobin replacements

Artificial haemoglobin and red cell substitutes have been used in patients refusing transfusion. The potential for their use includes not only this cohort but also austere environments, retrieval and remote services and patients with cell antibodies precluding cross match. Perfluorochemical were initially targeted to patients who refused transfusion to expand volume while increasing oxygen delivery (38-40). Stabilised haemoglobin solutions, including polymerised or pegylated bovine haemoglobin and cross-linked human haemoglobin all have case reports suggesting efficacy (41-46). While some reports showed improvement in physiological parameters temporally associated with infusions, other patients were included in these reports who would now be considered around or above conventionally accepted transfusion triggers. Despite the enthusiasm from case reports, later trials showed increased vascular risks, including hypertension and myocardial infarction, likely due to the scavenging of free nitric oxide by haemoglobin in solution (47-49). While the recruitment of religious objectors to transfusion provided some impetus in this field, their refusal to accept blood transfusion means they would not participate in the pivotal clinical trials comparing haemoglobin-based oxygen carriers or alternatives to standard of care. Neither was transfusion refusal a key driver of the product development, with keen interest from manufacturers to use in place of transfusion and military interest for use in austere combat environments.

Coagulopathy

The literature on managing coagulopathy in Jehovah’s Witness is more complicated to interpret. There is heterogeneity in the interpretation of the Jehovah’s Witnesses’ cannon on transfusion, so that acceptance of plasma products is variable, with many accepting manufactured plasmas concentrates and some acellular plasma products (50,51). Refusal is not a binary comparison, creating variation in treatment modalities used. In systematic collections, some people will also accept red cell transfusions, even after initial refusal (52). which complicates comparisons since the timing of blood transfusion refusal and acceptance may also impact outcomes.

In the management of coagulopathy there are reports of thrombotic thrombocytopenic purpura being treated with steroids, vincristine, intravenous immunoglobulin and therapeutic plasma exchange with albumin or gelatine-based colloids (53-55). No claim is made that these approaches of benefit over plasma exchange and these reports are likely to be of value mostly in treating other patients refusing plasma.

Reports of recombinant factor VIIa in bleeding patients refusing blood are also common. The first of these was for intracranial haemorrhage in a patient with haemophilia A and high responding factor VIII inhibitors, and what is now an established indication (56). Additional reports in bleeding with cardiac surgery (57) and traumatic bleeding (58), liver transplantation (59) and immune thrombocytopenic purpura with coagulopathy (60) followed. A subsequent registry study of off-label use of recombinant factor VIIa showed that Jehovah’s Witnesses who received recombinant factor VIIa has less coagulopathy, higher pH and higher body temperature than those not identified as Jehovah’s Witnesses, indicating earlier use in critical bleeding. Outcomes were similar between the two groups (52).

Recombinant factor VIIa was reported in multiple cases of traumatic bleeding well before its use to manage transfusion refusal (61). Ultimately, the value of recombinant FVIIa remains unclear with trials and meta-analysis unable to demonstrate a significant benefit following its use in trauma (62,63). The data from patients refusing blood transfusion appear to mirror that from the bleeding literature more generally with the initial enthusiasm or recombinant factor VIIa overturned by a lack of improvement and potential for harm in subsequent systematic studies (63).

Intraoperative techniques

Both surgeons and anaesthetists have contributed to managing patients with the intent to reduce the need for blood. Standard techniques have included acute normovolaemic haemodilution (64), controlled hypotensive anaesthesia (65) and cell salvage (66). Neuromuscular blocks to reduce muscle oxygen consumption has been used. Surgical approaches to minimise blood loss, primarily revolve around meticulous technique, which may be the most important factor (67), although the need to minimise blood loss has often prompted surgeons to consider procedures that may have less blood loss (68-70).

Intensive chemotherapy and stem cell transplantation

Notwithstanding that stem cells are usually derived from blood, and that even marrow collections contain leukocytes, bloodless autologous and allogenic transplants have been reported (71). Erythropoietin and iron have been used pre-emptively to boost red cell numbers, as they have been pre-operatively (72). Lysine analogues have also been used (73), although subsequent studies have not confirmed a benefit of tranexamic acid for bleeding prevention in thrombocytopenia secondary to chemotherapy in haematological malignancies (74). While stem cell transplants may allow a little time for patients to have haemoglobin optimised prior to treatment, there are also reports of treating acute leukaemia, when there is no such opportunity prior to therapy initiation. These have generally involved lower-intensity chemotherapy, immunotherapy or hypomethylating agents to minimise myelotoxicity (37,75-77).

Patient blood management

Some institutions have developed specific programs to accommodate the needs of patients refusing transfusion. These generally aim to optimise pre-operative haemoglobin, reduced blood loss through techniques such as hypotensive anaesthesia, acute normovolaemic haemodilution, meticulous haemostasis, anti-fibrinolytics and anaemia tolerance. These approaches appear to be not only safe, but also reduced the risks, including myocardial infarction, re-operation for bleeding, intensive care and hospital length of stay, as well as overall survival (78). However, where pre-operative optimisation is not undertaken, lower initial haemoglobin levels combined with the inability to transfuse may lead to worse outcomes (79).

Patient blood management is now considered standard of care (80). The individual components of this care are not novel. It is encompassed by three pillars: optimising pre-operative haemoglobin, iron and haemostatic parameters; meticulous attention to surgical haemostasis and optimising intra-operative physiology to minimise blood; and considering tolerance of anaemia and asking whether patients truly benefit from transfusion rather than simply focusing on a number. Kitchens observed that after publishing outcomes on surgical patients refusing blood, a number of the original authors’ institutions adopted patient blood management strategies used in Jehovah’s Witnesses for the broader surgical population (22). Jehovah’s Witnesses became advocates in their own blood-free care. Institutions and clinicians responded variably but many developed “Jehovah’s Witnesses protocols” to minimise the need for blood (20,81-83). In doing so they put in place what should be regarded as best practice patient blood management and recognised its value for all patients.

Conclusions

Patients refusing blood transfusion have been described as a “natural experiment” (78). While a lack of blood for transfusion poses clinical dilemmas in many parts of the world where resources are constrained, it is not generally seen in advanced health care systems. By refusing only transfusion, religious objectors can therefore provide an insight into the potential benefit, or lack of benefit of blood transfusion in the modern advanced health care context where the principles of patient blood management are applied.

Historically, the development of many high-risk procedures has been underwritten by the availability of blood to transfuse. Cardiac bypass, liver transplantation and extracorporeal membrane oxygenation are some of the procedures associated with potential for large volume blood loss. Likewise, prolonged myelosuppression with chemotherapy and stem cell transplant have developed in an era with blood accessibility. Jehovah’s Witnesses have challenged clinicians to consider how such procedures can be offered while reducing the need for blood. Blood refusal can demonstrate the limits of anaemia tolerance and can be used to quantify the harm from anaemia. Finally, transfusion refusal encourages us to think about proactively managing the blood rather than relying on transfusion as a salvage therapy.

A traditional peri-operative transfusion trigger of 100 g/L has previously been reported and became the standard of care in many institutions (84). Widely attributed to an article from Adams and Lundy (85), the original authors presented no data to support this threshold, rather relying on experience to offer guidance. However, their comments related specifically to patients with impaired oxygenation, such as lung disease, and have been widely misconstrued to apply to all patients. Using current evidence-based guidelines, this threshold resulted in many patients receiving unnecessary transfusions, without benefit and potentially resulting in harm.

The numerous reports of patients refusing transfusion surviving with very low haemoglobin levels should not be interpreted as suggesting this is safe or ideal, although perhaps indicate that even with very severe anaemia, supportive care to minimise oxygen use, maximise oxygen delivery and prevent tissue hypoxia may not be futile. They do highlight the role of dissolved oxygen in the plasma in very severe anaemia (86). While there are some reports of deaths with very low haemoglobin levels in patients who refuse transfusion, these are very likely underreported, as evidenced by systematic reports showing high death rates at low haemoglobin levels. While survival following haemoglobin levels of under 20 g/L without transfusion are remarkable, the survival of patients with haemoglobin concentrations under 10 g/L is even more so and has been seen only when a blood transfusion as subsequently administered.

The most significant contribution to our understanding of anaemia tolerance comes from comparative studies between people who accept transfusion and those who do not. With a haemoglobin below 70 g/L mortality rates increase by 2–2.5 times for every 10 g/L fall in haemoglobin concentration (14,16). The risk may be low to modest, particularly in those without cardiovascular comorbidities, when the haemoglobin is above 50 g/L. The increased death due to anaemia would not be apparent without these studies as some of the causes of death, such as renal impairment or continued bleeding are not usually attributed to anaemia. There are however sound potential physiological mechanisms with poorer microvascular perfusion leading to renal impairment and rheological impacts of anaemia impairing haemostasis. By corollary, haemoglobin levels above 70 g/L are likely to be safe in most circumstances, a finding supported by clinical trials in various settings (1,2) and meta-analysis of case control studies comparing non-transfusable patients with those able to be transfused (87). Ongoing research into patients refusing transfusion and comparator studies will help further our understanding of the impact of anaemia and coagulopathy, particularly in more severe cases where randomised studies are considered unethical based on current knowledge.

While driven by a religious motive rather than scientific data, Jehovah’s Witnesses advocating for blood free care coincidentally were pushing the medical profession away from a harmful reliance on transfusion and towards patient blood management. This encouraged reconsideration of management so that a patient’s own blood is valued rather than seen as replaceable. To a point, this pushed centres to test and implement coordinated processes we now view as patient blood management standard of care. It was useful happenstance that the drive from religious conviction and not science pushed clinicians to see the value of these approaches. While it encouraged best practice to the point that transfusion is genuinely needed, there is likely a point beyond that where the objection to transfusion causes serious and quantifiable harm and further studies in this cohort will be helpful in defining appropriate limits in the setting of best-practice patient blood management.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-24-20/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-20/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-20/coif). P.C. serves as a board member of Australian and New Zealand Society of Blood Transfusion, and received speaker’s honorarium and travel to an educational event from Novo Nordisk and support for travel to an educational event from Janssen. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340:409-17. [Crossref] [PubMed]
2. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11-21. [Crossref] [PubMed]
3. Trentino KM, Farmer SL, Sanfilippo FM, et al. Systematic reviews and meta-analyses comparing mortality in restrictive and liberal haemoglobin thresholds for red cell transfusion: protocol for an overview of systematic reviews. BMJ Open 2019;9:e029828. [Crossref] [PubMed]
4. Carson JL, Guyatt G, Heddle NM, et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA 2016;316:2025-35. [Crossref] [PubMed]
5. de Araújo Azi LM, Lopes FM, Garcia LV. Postoperative management of severe acute anemia in a Jehovah’s Witness. Transfusion 2014;54:1153-7. [Crossref] [PubMed]
6. Dicpinigaitis PV. Optimization of tissue oxygenation in critically ill Jehovah’s Witness patients. Am J Med 2010;123:e17-author reply e19. [Crossref] [PubMed]
7. Finfer S, Howell S, Miller J, et al. Managing patients who refuse blood transfusions: an ethical dilemma. BMJ 1994;308:1423-6. [Crossref] [PubMed]
8. Howell PJ, Bamber PA. Severe acute anaemia in a Jehovah’s Witness. Survival without blood transfusion. Anaesthesia 1987;42:44-8. [Crossref] [PubMed]
9. Chojnowski K, Janus A, Bliźniewska K, et al. Long-lasting extreme anemia during the therapy of acute lymphoblastic leukemia in a Jehovah’s Witness patient. Transfusion 2016;56:2438-42. [Crossref] [PubMed]
10. Lorhan PH, Burch J. Anesthesia for a Jehovah’s Witness with a low hematocrit. Anesthesiology 1968;29:847-8. [Crossref] [PubMed]
11. Schuettpelz LG, Behrens D, Goldsmith MI, et al. Severe ceftriaxone-induced hemolysis complicated by diffuse cerebral ischemia in a child with sickle cell disease. J Pediatr Hematol Oncol 2009;31:870-2. [Crossref] [PubMed]
12. Kariya T, Ito N, Kitamura T, et al. Recovery from Extreme Hemodilution (Hemoglobin Level of 0.6 g/dL) in Cadaveric Liver Transplantation. A A Case Rep 2015;4:132-6. [Crossref] [PubMed]
13. Dai J, Tu W, Yang Z, et al. Case report: intraoperative management of extreme hemodilution in a patient with a severed axillary artery. Anesth Analg 2010;111:1204-6. [Crossref] [PubMed]
14. Carson JL, Noveck H, Berlin JA, et al. Mortality and morbidity in patients with very low postoperative Hb levels who decline blood transfusion. Transfusion 2002;42:812-8. [Crossref] [PubMed]
15. Tobian AA, Ness PM, Noveck H, et al. Time course and etiology of death in patients with severe anemia. Transfusion 2009;49:1395-9. [Crossref] [PubMed]
16. Shander A, Javidroozi M, Naqvi S, et al. An update on mortality and morbidity in patients with very low postoperative hemoglobin levels who decline blood transfusion (CME). Transfusion 2014;54:2688-95; quiz 2687. [Crossref] [PubMed]
17. Viele MK, Weiskopf RB. What can we learn about the need for transfusion from patients who refuse blood? The experience with Jehovah’s Witnesses. Transfusion 1994;34:396-401. [Crossref] [PubMed]
18. Carson JL, Duff A, Poses RM, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055-60. [Crossref] [PubMed]
19. Beliaev AM, Marshall RJ, Smith W, et al. Mortality risk stratification in severely anaemic Jehovah’s Witness patients. Intern Med J 2012;42:e1-3. [Crossref] [PubMed]
20. Shander A, Javidroozi M, Gianatiempo C, et al. Outcomes of Protocol-Driven Care of Critically Ill Severely Anemic Patients for Whom Blood Transfusion Is Not an Option. Crit Care Med 2016;44:1109-15. [Crossref] [PubMed]
21. Frank SM, Wick EC, Dezern AE, et al. Risk-adjusted clinical outcomes in patients enrolled in a bloodless program. Transfusion 2014;54:2668-77. [Crossref] [PubMed]
22. Kitchens CS. Are transfusions overrated? Surgical outcome of Jehovah’s Witnesses. Am J Med 1993;94:117-9. [Crossref] [PubMed]
23. Beliaev AM, Allen SJ, Milsom P, et al. Low-dose erythropoietin treatment is not associated with clinical benefits in severely anaemic Jehovah’s Witnesses: a plea for a change. Blood Transfus 2018;16:53-62. [PubMed]
24. Heh-Foster AM, Naber M, Pai MP, et al. Epoetin in the ‘untransfusable’ anaemic patient: a retrospective case series and systematic analysis of literature case reports. Transfus Med 2014;24:204-8. [Crossref] [PubMed]
25. Abram D, Tran MH. Effect of erythropoietin on perioperative blood transfusions in primary total hip arthroplasty: A systematic review. Transfus Apher Sci 2023;62:103718. [Crossref] [PubMed]
26. Hakim SM, Ahmad AHM, Amer AM. Effect of Preoperative Recombinant Human Erythropoietin on the Need for Blood Transfusion and Surgical Outcomes in Adult Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis with Trial Sequential Analysis. J Cardiothorac Vasc Anesth 2024;38:2402-11. [Crossref] [PubMed]
27. Kaur M, Khatri K, Kankaria A, et al. Efficacy and safety of combined administration of erythropoietin and iron in comparison to iron therapy alone in orthopaedic surgery: systematic review and metanalysis. Acta Ortop Mex 2021;35:547-56. [PubMed]
28. Shin HJ, Ko E, Jun I, et al. Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis. Medicine (Baltimore) 2022;101:e28920. [Crossref] [PubMed]
29. Lakatos L, Csáthy L, Nemes E. “Bloodless” treatment of a Jehovah’s Witness infant with ABO hemolytic disease. J Perinatol 1999;19:530-2. [Crossref] [PubMed]
30. Lee JM, Byon HJ, Kim JT, et al. Transfusion-free anesthetic management for open heart surgery in a neonate -A case report. Korean J Anesthesiol 2010;59:S141-5. [Crossref] [PubMed]
31. Pérez-Ferrer A, De Vicente J, Gredilla E, et al. Use of erythropoietin for bloodless surgery in a Jehovah’s witness infant. Paediatr Anaesth 2003;13:633-6. [Crossref] [PubMed]
32. Schweiger M, Dave H, Kelly J, et al. Strategic and operational aspects of a transfusion-free neonatal arterial switch operation. Interact Cardiovasc Thorac Surg 2013;16:890-1. [Crossref] [PubMed]
33. Miyaji K, Hannan RL, Ojito JW, et al. The Ross operation in a Jehovah’s Witness: a paradigm for heart surgery in children without transfusion. Ann Thorac Surg 2000;69:935-7. [Crossref] [PubMed]
34. Polley JW, Berkowitz RA, McDonald TB, et al. Craniomaxillofacial surgery in the Jehovah’s Witness patient. Plast Reconstr Surg 1994;93:1258-63. [Crossref] [PubMed]
35. Ratliff TM, Hodge AB, Preston TJ, et al. Bloodless pediatric cardiopulmonary bypass for a 3.2-kg patient whose parents are of Jehovah’s Witness faith. J Extra Corpor Technol 2014;46:173-6. [Crossref] [PubMed]
36. Woo da E. Recombinant Human Erythropoietin Therapy for a Jehovah’s Witness Child With Severe Anemia due to Hemolytic-Uremic Syndrome. Korean J Pediatr 2016;59:100-3. [Crossref] [PubMed]
37. Bareford D, Odeh B, Narayanan S, et al. Remission induction in a Jehovah’s witness patient with acute myeloid leukaemia using gemtuzumab ozogamicin. Transfus Med 2005;15:445-8. [Crossref] [PubMed]
38. Ohyanagi H, Nakaya S, Okumura S, et al. Surgical use of fluosol-DA in Jehovah’s Witness patients. Artif Organs 1984;8:10-8. [Crossref] [PubMed]
39. Tremper KK, Cullen BF U.S.. clinical studies of the treatment of anemia with fluosol-DA 20%. Artif Organs 1984;8:19-24. [Crossref] [PubMed]
40. Tremper KK, Friedman AE, Levine EM, et al. The preoperative treatment of severely anemic patients with a perfluorochemical oxygen-transport fluid, Fluosol-DA. N Engl J Med 1982;307:277-83. [Crossref] [PubMed]
41. Agrawal YP, Freedman M, Szczepiorkowski ZM. Long-term transfusion of polymerized bovine hemoglobin in a Jehovah’s Witness following chemotherapy for myeloid leukemia: a case report. Transfusion 2005;45:1735-8. [Crossref] [PubMed]
42. Sam C, Desai P, Laber D, et al. Pegylated bovine carboxyhaemoglobin utilisation in a thrombotic thrombocytopenic purpura patient. Transfus Med 2017;27:300-2. [Crossref] [PubMed]
43. Stefan DC, Uys R, Wessels G. Hemopure transfusion in a child with severe anemia. Pediatr Hematol Oncol 2007;24:269-73. [Crossref] [PubMed]
44. Thenuwara K, Thomas J, Ibsen M, et al. Use of hyperbaric oxygen therapy and PEGylated carboxyhemoglobin bovine in a Jehovah’s Witness with life-threatening anemia following postpartum hemorrhage. Int J Obstet Anesth 2017;29:73-80. [Crossref] [PubMed]
45. Anton N, Hitzler JK, Kavanagh BP. Treatment of life-threatening post-haemorrhagic anaemia with cell-free haemoglobin solution in an adolescent Jehovah’s Witness. Br J Haematol 2002;118:1183-6. [Crossref] [PubMed]
46. Lanzinger MJ, Niklason LE, Shannon M, et al. Use of hemoglobin raffimer for postoperative life-threatening anemia in a Jehovah’s Witness. Can J Anaesth 2005;52:369-73. [Crossref] [PubMed]
47. Samaja M, Malavalli A, Vandegriff KD. How Nitric Oxide Hindered the Search for Hemoglobin-Based Oxygen Carriers as Human Blood Substitutes. Int J Mol Sci 2023;24:14902. [Crossref] [PubMed]
48. Jahr JS, Mackenzie C, Pearce LB, et al. HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery. J Trauma 2008;64:1484-97. [Crossref] [PubMed]
49. Levy JH, Goodnough LT, Greilich PE, et al. Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: results of a randomized, double-blind trial. J Thorac Cardiovasc Surg 2002;124:35-42. [Crossref] [PubMed]
50. Silvetti S, Crivellari M, Castiglioni A, et al. CASE 12-2016 Ascending Aorta Dissection in a Jehovah’s Witness Patient on Warfarin. J Cardiothorac Vasc Anesth 2016;30:1709-15. [Crossref] [PubMed]
51. Alam A, Lin Y, Callum J. The variation of acceptable blood products and procedures amongst Jehovah’s Witness patients: analysis of a hospital pre-transfusion discussion tool. Can J Anaesth 2012;59:1148-9. [Crossref] [PubMed]
52. Kandane-Rathnayake RK, Isbister JP, Zatta AJ, et al. Use of recombinant activated factor VII in Jehovah’s Witness patients with critical bleeding. ANZ J Surg 2013;83:155-60. [Crossref] [PubMed]
53. Drummond MW, Green R, Callaghan T, et al. Management of a Jehovah’s witness with thrombotic thrombocytopaenic purpura/haemolytic uraemic syndrome. J Clin Apher 2000;15:266-7. [Crossref] [PubMed]
54. Martin MG, Whitlatch NL, Shah B, et al. Thrombotic thrombocytopenic purpura induced by trimethoprim-sulfamethoxazole in a Jehovah’s Witness. Am J Hematol 2007;82:679-81. [Crossref] [PubMed]
55. Walia SS, Walia MS, Walia HS. Thrombotic thrombocytopenic purpura treated with vincristine in a Jehovah’s witness. Asian J Transfus Sci 2011;5:180-1. [Crossref] [PubMed]
56. Majumdar G, Savidge GF. Recombinant factor VIIa for intracranial haemorrhage in a Jehovah’s Witness with severe haemophilia A and factor VIII inhibitors. Blood Coagul Fibrinolysis 1993;4:1031-3. [Crossref] [PubMed]
57. Tanaka KA, Waly AA, Cooper WA, et al. Treatment of excessive bleeding in Jehovah’s Witness patients after cardiac surgery with recombinant factor VIIa (NovoSeven). Anesthesiology 2003;98:1513-5. [Crossref] [PubMed]
58. Haan J, Scalea T. A Jehovah’s Witness with complex abdominal trauma and coagulopathy: use of factor VII and a review of the literature. Am Surg 2005;71:414-5. [Crossref] [PubMed]
59. Detry O, De Roover A, Kaba A, et al. Right lobe living-related liver transplantation in a Jehovah’s Witness. Transpl Int 2003;16:895-6. [Crossref] [PubMed]
60. Waddington DP, McAuley FT, Hanley JP, et al. The use of recombinant factor viia in a jehovah’s witness with auto-immune thrombocytopenia and post-splenectomy haemorrhage. Br J Haematol 2002;119:286-8. [Crossref] [PubMed]
61. Martinowitz U, Kenet G, Segal E, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma 2001;51:431-8; discussion 438-9. [Crossref] [PubMed]
62. McQuilten ZK, Crighton G, Engelbrecht S, et al. Transfusion interventions in critical bleeding requiring massive transfusion: a systematic review. Transfus Med Rev 2015;29:127-37. [Crossref] [PubMed]
63. Dutton RP, Parr M, Tortella BJ, et al. Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial. J Trauma 2011;71:12-9. [Crossref] [PubMed]
64. Estella NM, Berry DL, Baker BW, et al. Normovolemic hemodilution before cesarean hysterectomy for placenta percreta. Obstet Gynecol 1997;90:669-70. [Crossref] [PubMed]
65. Wong KC, Webster LR, Coleman SS, et al. Hemodilution and induced hypotension for insertion of a Harrington rod in a Jehovah’s Witness patient. Clin Orthop Relat Res 1980;237-40. [PubMed]
66. Nieder AM, Simon MA, Kim SS, et al. Intraoperative cell salvage during radical prostatectomy: a safe technique for Jehovah’s Witnesses. Int Braz J Urol 2004;30:377-9. [Crossref] [PubMed]
67. Brodsky JW, Dickson JH, Erwin WD, et al. Hypotensive anesthesia for scoliosis surgery in Jehovah’s Witnesses. Spine (Phila Pa 1976) 1991;16:304-6. [Crossref] [PubMed]
68. Couto WJ, Livesay JJ, Allam A. Off-pump repair of a giant pseudoaneurysm of a distal saphenous vein bypass graft. Ann Thorac Surg 2005;80:2376-8. [Crossref] [PubMed]
69. Frazier OH. Implantation of the Jarvik 2000 left ventricular assist device without the use of cardiopulmonary bypass. Ann Thorac Surg 2003;75:1028-30. [Crossref] [PubMed]
70. Kadohama T, Akasaka N, Sasajima T, et al. Staged repair for a chronic dissecting thoracic aortic aneurysm with no transfusion in a Jehovah’s Witness patient. Gen Thorac Cardiovasc Surg 2007;55:262-5. [Crossref] [PubMed]
71. Mazza P, Palazzo G, Minoia C, et al. Autologous and allogeneic stem cell transplant in Jehovah’s Witnesses: a single-center experience on 22 patients. Bone Marrow Transplant 2016;51:1002-3. [Crossref] [PubMed]
72. Estrin JT, Ford PA, Henry DH, et al. Erythropoietin permits high-dose chemotherapy with peripheral blood stem-cell transplant for a Jehovah’s Witness. Am J Hematol 1997;55:51-2. [Crossref] [PubMed]
73. Ballen KK, Ford PA, Waitkus H, et al. Successful autologous bone marrow transplant without the use of blood product support. Bone Marrow Transplant 2000;26:227-9. [Crossref] [PubMed]
74. Gernsheimer TB, Brown SP, Triulzi DJ, et al. Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial. Blood 2022;140:1254-62. [Crossref] [PubMed]
75. Garelius H, Grund S, Stockelberg D. Induction with azacytidine followed by allogeneic hematopoietic stem cell transplantation in a Jehovah’s Witness with acute monocytic leukemia. Clin Case Rep 2015;3:287-90. [Crossref] [PubMed]
76. Osby E, Liliemark E, Björkholm M, et al. Oral etoposide in patients with hematological malignancies: a clinical and pharmacokinetic study. Med Oncol 2001;18:269-75. [Crossref] [PubMed]
77. Yamamoto Y, Kawashima A, Kashiwagi E, et al. A Jehovah’s Witness with Acute Myeloid Leukemia Successfully Treated with an Epigenetic Drug, Azacitidine: A Clue for Development of Anti-AML Therapy Requiring Minimum Blood Transfusions. Case Rep Hematol 2014;2014:141260. [Crossref] [PubMed]
78. Pattakos G, Koch CG, Brizzio ME, et al. Outcome of patients who refuse transfusion after cardiac surgery: a natural experiment with severe blood conservation. Arch Intern Med 2012;172:1154-60. [Crossref] [PubMed]
79. Oladapo OT. Elective abdominal hysterectomy in Nigerian Jehovah’s Witnesses. J Obstet Gynaecol 2004;24:690-3. [Crossref] [PubMed]
80. WHO. The urgent need to implement patient blood management: policy brief. Geneva: World Health Organisation; 2021.
81. Gupta S, Onwude J, Stasi R, et al. Refusal of blood transfusion by Jehovah’s Witness women: a survey of current management in obstetric and gynaecological practice in the U.K. Blood Transfus 2012;10:462-70. [PubMed]
82. Suh YS, Nho JH, Choi HS, et al. A protocol avoiding allogeneic transfusion in joint arthroplasties. Arch Orthop Trauma Surg 2016;136:1213-26. [Crossref] [PubMed]
83. Tanaka A, Ota T, Uriel N, et al. Cardiovascular surgery in Jehovah’s Witness patients: The role of preoperative optimization. J Thorac Cardiovasc Surg 2015;150:976-83.e1-3.
84. Spence RK, Carson JA, Poses R, et al. Elective surgery without transfusion: influence of preoperative hemoglobin level and blood loss on mortality. Am J Surg 1990;159:320-4. [Crossref] [PubMed]
85. Adams RC, Lundy JS. Anesthesia in Cases of Poor Surgical Risk: Some Suggestions for Decreasing the Risk. Anesthesiology 1942;3:603-7. [Crossref]
86. Spiess B. Editorial Comment: Recovery from Extreme Hemodilution (Hemoglobin Level of 0.6 g/dL) in Cadaveric Liver Transplantation and Management of a Jehovah’s Witness Patient with Sepsis and Profuse Bleeding After Emergency Coronary Artery Bypass Graft Surgery: Rethinking the Critical Threshold of Oxygen Delivery. A A Case Rep 2015;4:137-9. [Crossref] [PubMed]
87. Seeber P, Döbel KU, Isbister JP, et al. Mortality and morbidity in non-transfusable and transfusable patients: A systematic review and meta-analysis. Transfusion 2022;62:685-97. [Crossref] [PubMed]