Approach to the patient who declines blood transfusion

INTRODUCTION — Disagreements between patients and clinicians can strain the clinician/patient relationship. Few disagreements have drawn as much attention in the medical, legal, and public spheres as refusal of blood transfusion.

This topic discusses alternatives to transfusion and strategies for treating bleeding in individuals who decline blood transfusion for any reason. Indications for transfusion and strategies to minimize transfusion in the operating room are discussed separately.

●Transfusion thresholds and indications:

•Red blood cells (RBCs) – (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for RBC transfusion in adults".)

•Platelets – (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion'.)

•Plasma – (See "Clinical use of plasma components", section on 'Indications'.)

•White blood cells (WBCs) – (See "Granulocyte transfusions", section on 'Indications and clinical efficacy'.)

●Mortality risk from severe anemia – (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Impact of anemia on morbidity and mortality'.)

●Minimizing need for transfusion during surgery – (See "Perioperative blood management: Strategies to minimize transfusions" and "Techniques to reduce blood loss during abdominal or laparoscopic myomectomy".)

COMPONENTS OF SHARED DECISION-MAKING

Understand patient beliefs and reasons for declining transfusion — Understanding the needs and perspectives of the individual who declines transfusion is essential to shared decision-making and to identifying acceptable alternatives [1,2].

Sometimes, the refusal of transfusion is based solely on the perceived risks of transfusion [3]. Other common reasons include cultural and/or religious beliefs. These vary widely from those who express a desire not to take in someone else's "life force" to those (such as certain Native Americans) who only accept blood from "spiritual relatives."

These views highlight two important principles [4,5]:

●The need for attention to the multiple symbolic associations of blood

●The importance of practicing "cultural humility" in applying culture-based training to specific patients

Understanding the wishes of each patient requires a broad approach, without preconceived notions of what is appropriate in a given population [6]. Culture-based training may not provide every answer; each patient must be approached with the understanding that the person's illness experience lies at a unique nexus of religious, political, historical, and cultural forces, all of which may bear on the patient's clinical care.

Since it is impossible to generalize, it is helpful to ask patients about specific beliefs when obtaining informed consent for blood components or derivatives. (See 'Be clear about the patient's wishes regarding consent' below.)

Jehovah's Witnesses — The most well-known reason for declining blood transfusion involves Christians known as Jehovah's Witnesses (JW; Witnesses). There are at least eight million active Witnesses worldwide and over one million in North America. Witnesses are generally pacifists and are not particularly litigious [7].

Witnesses are encouraged to purchase health insurance and avail themselves of modern medical care, except for certain forms of blood transfusion [7]. This aversion to transfusion stems from their interpretation of Biblical scripture (eg, Genesis 9:3,4; Leviticus 7:26,27; 1 Samuel 14:32,33; Acts 15:28,29) [8-10]. Witnesses believe that voluntarily accepting blood transfusion may affect their eternal salvation [11]. Further information about specific reasons that Witnesses do not accept blood transfusion is provided on their website [12].

For Witnesses, the differentiation between acceptable and unacceptable blood fractions may be complex, as outlined in the table (table 1). As a result, it is especially important to gain a clear understanding of the individual patient's wishes. (See 'Components of shared decision-making' above.)

General examples of "typical" JW beliefs include the following:

●Devout Witnesses generally will not accept transfusions of whole blood or any of the four major components (red blood cells [RBCs], platelets, plasma, and white blood cells) [7]. Most devout Witnesses are prepared to die rather than compromise this refusal.

●Devout Witnesses do not consider preoperative autologous blood donation to be an acceptable alternative, due to a belief that blood should not be taken out of the body and stored for any length of time (based on scriptures such as Deuteronomy 12:16). However, if the blood circulates back into the patient (eg, during cardiopulmonary bypass, therapeutic apheresis, or certain intraoperative and postoperative blood salvage systems), this may be acceptable to many Witnesses. (See 'Optimize preprocedure patient preparation' below and "Surgical blood conservation: Preoperative autologous blood donation".)

●Some patients who are "studying" with Witnesses will identify themselves as such, even though they have not been baptized. Some patients who are not Witnesses may initially refuse transfusion out of respect for a family member who is a Witness. Most of these individuals will accept blood in extremis. This reinforces the need for the clinician to have a frank discussion in private about the patient's religious commitment, treatment desires, and the possible outcome of those treatment choices [13]. It also is important at subsequent hospitalizations to ask whether these wishes have changed [14].

●There can be substantial variation among Witnesses regarding which blood products they will or will not accept. Many Witnesses will accept plasma derivatives (typically called "subfractions" by Witnesses). This includes immunoglobulins, albumin, coagulation factor concentrates, and recombinant coagulation factors. Albumin naturally crosses the placenta between mother and fetus and is often considered acceptable. The choice is left up to individual discretion and religious conscience; some will accept certain products while others will not (table 1) [7]. An informed discussion with patients may relieve their concern regarding certain plasma derivatives. A chart review of obstetric patients found that among 61 Witnesses who had filled out an advance health care directive, 24 (39 percent) would accept certain blood derivatives [15]. An additional 10 percent indicated they would accept donated RBCs, suggesting that not all who identify themselves as Witnesses would decline RBC transfusion.

In the past, the practice of "disfellowshipping" was applied to unrepentant Witnesses who accepted blood transfusion. However, this policy has become less stringent, since in the act of accepting transfusion itself, patients have already dissociated themselves spiritually from God.

Other reasons for declining transfusion — A different approach should be taken if patients refuse blood for reasons other than religious or cultural beliefs:

●Concern about safety of the blood supply – Understanding the patient's psychosocial history and carefully explaining the risks and benefits of transfusion particular to their situation may resolve the fear of disease. The safety of the blood supply is continuously improving, as summarized in the table (table 2) and discussed separately. (See "Blood donor screening: Medical history" and "Blood donor screening: Laboratory testing" and "Pathogen inactivation of blood products".)

●Previous transfusion reaction – Investigation of a previous transfusion reaction may allay patient fears and provide valuable clinical information. If the patient has had a prior anaphylactic transfusion reaction, prevention of future problems begins with establishing the diagnosis. (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions' and "Selective IgA deficiency: Management and prognosis".)

●Desire to avoid getting blood unless "absolutely necessary" – As patients become more empowered in determining their health care, some might specify that they are only willing to receive blood when at a certain degree of extremis. They might desire to let their hemoglobin level fall farther than the typical threshold suggested in institutional or published guidelines. In such cases, the patient is not necessarily refusing transfusion as much as desiring to negotiate regarding the transfusion trigger. These individuals should be encouraged to sign the consent for transfusion in case it becomes necessary; they can stipulate their additional restrictions on the consent form.

Be clear about the patient's wishes regarding consent — It is important to ask the individual about their beliefs and not to assume that all individuals identifying with a certain group (such as Jehovah's Witnesses) share the same beliefs or the same rationales for them. (See 'Understand patient beliefs and reasons for declining transfusion' above.)

It is important to clarify with the patient what they mean when they say that they "do not want blood," to find out which blood "fractions" they are (or are not) willing to accept, and under what circumstances they will or will not accept them. Witnesses also refer to these personal choices as a matter of their own personal conscience. A sample checklist for clinicians obtaining informed consent is provided in the table (table 3).

Having these discussions with patients and their relatives or caregivers who might be present takes additional time and energy. Nevertheless, clinicians are obliged to provide the best management possible, factoring in the time required to assess the specific preferences of patients and sometimes interacting with their relatives or caregivers. This time also includes educating the patient and family regarding the various options and the possible consequences of their decisions. A thorough understanding of these issues, combined with a precise determination of the patient's wishes, will enable a clinician to outline the most appropriate treatment plan or to refer the patient to a more appropriate colleague when clinically possible.

It has been suggested that members of ancillary services such as pharmacists and blood bank technologists should also be made aware of the patient's wishes [14,16]. However, just as a do not resuscitate (DNR) order can be rescinded by the patient at any time, a patient can change their mind about accepting blood products at any time. In a life-threatening situation, this information is best documented and acted on at the bedside by the clinical team rather than by other individuals; otherwise, there may be a delay in obtaining or administering a life-saving product. This analogy also explains why members of the pharmacy and blood bank generally should not act as product gatekeepers, although they may assist in the patient's care (eg, by drawing smaller blood volumes for laboratory testing or ensuring that hemostatic products are provided as rapidly as possible).

Discuss contingency plans for life-threatening situations — It is important to discuss contingency plans in advance, before the patient's hemoglobin declines to the point that thinking becomes clouded.

Many people hold beliefs about the refusal of blood transfusion that they value more than their own lives. Others may be willing to accept transfusion in extremis. Clinicians should direct patients to examine their preferences in light of possible adverse health consequences as well as the possible increased risk of death when they refuse transfusion [17-19]. It is important to ask the patient specifically if their wishes would change in the event that refusal of transfusion is expected to be fatal, as some individuals may allow certain interventions only in such an event.

●Most patients can survive critically low levels of hemoglobin (≤5 g/dL) [19,20]. However, there are no clear indicators the patient will die from anemia until it is too late [21]. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Impact of anemia on morbidity and mortality'.)

●A retrospective review covering 11 years of data from the Duke University Hospital Center for Blood Conservation calculated that in patients admitted with severe anemia (hemoglobin <8 g/dL) who declined transfusion, mortality increased by 55 percent for each 1 g/dL decrease in nadir hemoglobin (odds ratio [OR] 1.55) [22].

Having conversations in advance prevents the need for the clinician to "second guess" the patient's wishes. It also allows the patient to be explicit about their wishes to whomever may become their health care decision maker (proxy). Specific questions should be asked concerning what should occur under the worst-case scenario, namely, the potential for death or morbidity (stroke, myocardial infarction, kidney failure) resulting from severe anemia or hypovolemic shock. These advance care directives should be clearly documented and available to all clinicians involved in the patient's care. (See 'Document well, including advance directives' below.)

For emergency care, if there is any doubt in a clinician's mind concerning the wishes of a patient or what is legally appropriate, the prudent course would be to treat according to the accepted standard of care. Once the patient is stabilized, then there will be additional time to investigate more thoroughly.

Consent — During the consent process, the clinician must make it clear that the patient will die if bleeding cannot be stopped in a reasonable amount of time if transfusions are declined.

Eliminating the option of transfusion may also lead a clinician to proceed more rapidly towards a more aggressive intervention or it may lead the clinician to choose a suboptimal treatment or surgical approach. This may require discussing options that would not be the clinician's first choice if the patient were willing to accept blood products. As an example, a contingency plan may state that a hysterectomy or colectomy might be required, rather than let a patient bleed to death, if the surgeon cannot achieve sufficient hemostasis. A cesarean delivery and/or hysterectomy might be performed earlier during a difficult labor than it would be in an individual who is willing to accept transfusions [23]. In rheumatology or oncology, a second tier treatment might be pursued to avoid a myelosuppressive drug [24,25]. (See 'Reports of successful outcomes' below.)

Some patients may be willing to accept blood products when a licensed physician determines that death is likely without transfusion. In reluctant patients, it may sometimes be useful to suggest an arrangement where blood will not be given unless two independent physicians agree that death is likely without transfusion. In the operative setting, the surgeon and anesthesiologist can fulfill this requirement.

In cases where declining transfusion affects a major part of the patient's treatment plan, it is helpful to involve next of kin or other power of attorney to ensure that they understand the patient's wishes and desires. As patients experience severe anemia, they often lose the mental ability to actively make decisions for themselves. A clinician may avoid misunderstandings, resentment, and confusion if this possibility is discussed early in the treatment course with the individuals who may become decision makers in the future.

Maintain patient rapport — Respecting the wishes of competent, informed patients who refuse blood transfusion demands high standards of ethics and professionalism [7,26].

Provide advocacy — If at all possible, the clinician should confirm the treatment plan with the patient in private (possibly with another member of the health care team with whom the patient feels comfortable). In most cases, this initial discussion should occur in private, as friends or family members may influence the patient's decision [13]. However, this discussion should only be used to confirm the patient's wishes and not to pressure the patient to change their decision.

It may be tempting to engage a patient refusing blood in debate regarding the appropriateness of their decision; however, this casts the clinician into an adversarial role, making it easier for the patient to discount what the clinician is saying and refuse treatments that might otherwise have been acceptable [27]. The clinician should avoid delays in care or refusal of treatment based on a patient's rejection of blood products. This violates ethical, medical, and legal responsibilities to the patient.

An alternate approach involves serving as the patient's advocate, with the focus on finding the best possible therapy within the boundaries of the patient's religious beliefs, values, and preferences. Except in urgent circumstances, ample time should be set aside for the discussion of transfusion issues.

Whether a person accepts a product sometimes depends on how adequately the clinician can explain it in a straightforward and nonjudgmental way. If a patient senses a misleading or condescending discussion, they may choose to reject everything to "stay safe." In these situations involving Witnesses, the JW Hospital Liaison Committee may provide useful patient education and help to establish positive communication between the patient and medical team [23]. Other resources that may be helpful are listed below. (See 'Resources for clinicians' below.)

Minimize distress — Discussion aimed at convincing a Witness to violate personal religious beliefs may cause harm by pressuring the patient to compromise ethical values. A Witness or a family member of a Witness who unwillingly receives a transfusion may consider such transfusion a form of battery (as opposed to something affecting eternal salvation) and suffer the related emotional stress [28]. On the other hand, willing acceptance of a transfusion of blood products may result in the patient being cut off from a broad community of friends and family. In some cases, such rejection may influence the decision more than any personal belief regarding transfusion.

Preserve confidentiality — A Witness who receives a transfusion secretly (without the knowledge of family members, friends, or other members of the congregation) will not be investigated and is unlikely to be discovered unless they admit the fact [29]. These individuals may communicate a wish to receive transfusions privately. The clinician should take whatever steps are necessary to ensure complete confidentiality concerning this point, including actions to ensure privacy from family, friends, and even hospital personnel not directly caring for the patient.

An exception to strict privacy might be in the case where the patient refuses transfusion but the family desires it. In this case, the patient might be asked to share their convictions with family members to lessen the family pressure on the clinical team to transfuse against patient wishes [13]. Although this conversation may be initially stressful to the patient, it may reduce stress in the long run.

Document well, including advance directives — Documenting a patient's wishes concerning blood transfusion should have the same importance as a 'do not resuscitate' (DNR) order. Either one could mean the difference between life and death if any misunderstanding is involved.

Items the clinician may want to address with patients who are uncomfortable accepting blood transfusion are summarized in the checklist (table 3). The final agreement between patient and clinician may be complex and should be recorded clearly in the medical record, including any differences in plans for a potentially life-threatening event. (See 'Discuss contingency plans for life-threatening situations' above.)

It is best if wishes are documented in an advance care directive; Witnesses are encouraged to carry one on their person. If there is an advance health care directive in place, then this should be amended to reflect the final agreement. The clinician may choose to have the patient sign a copy of the clinical note outlining the final agreement.

Standard templates for advance directives may not have sufficient information to cover the acceptance or rejection of many blood product derivatives. The attending clinician(s) should review the written directive personally with the patient and make sure that a copy is placed in the medical record along with a clinical note summarizing patient desires and clarifying anything that may not be clear. (See "Advance care planning and advance directives".)

Some hospitals include this note in the section of the electronic medical record that contains "Urgent Clinical Documents" such as advance directives and code status (resuscitation orders). Inclusion in this section of the chart ensures that the entire health care team will see it, and it may prompt them to review and update it during subsequent hospitalizations.

In many cases, there will not be any written documentation from the patient, and the clinician must discuss the risks and benefits of each blood product, subfraction, or derivative and determine what the patient is comfortable receiving (table 3). (See 'Be clear about the patient's wishes regarding consent' above.)

In medical centers that are less familiar with patients who decline transfusions, it may be prudent to indicate prominently that the patient has chosen not to receive certain blood products. A brief statement such as "some blood products and related procedures not acceptable per patient preference" might be kept with the documentation of a patient's allergies. This would prompt caregivers to review the complete documentation that might be kept in the section of the medical record that contains "Urgent Clinical Documents" (or in a regular note).

Some medical centers find it helpful to flag the front of the patient's physical chart and the patient's identification wristband with "No Blood" in cases where no blood is desired. However, a sticker on the chart or an armband that states "No Blood" might erroneously be interpreted as a rejection of all blood products, derivatives, and associated procedures. Care should be taken so the team does not assume that "we can’t give anything" whenever that sticker is used.

A mechanism to remind phlebotomists to draw pediatric-size tubes is also important (see 'Reduce blood draws (phlebotomy)' below). In the absence of another mechanism, signs above the patient's bed and on the door may help.

The patient's entire clinical care team must be made aware of the patient's wishes. Nurses are sometimes left out of these discussions, and this may add to the potential stress from watching their patient die from severe anemia [30]. Nurses are also typically most current on the needs and desires of their patients.

THE ACTIVELY BLEEDING PATIENT

Aggressively treat bleeding — During surgery, delivery, or other procedure, meticulous technical attention should be paid to hemostasis and blood losses (use of hemostatic surgical devices, fibrin glue, and tissue adhesives; controlled hypotension; elevating the surgical field above the rest of the body, etc) [8,31-33]. The clinical team and patient must realize that, in a patient who refuses transfusion, if the bleeding cannot be stopped, the patient will die [7]. An approach to trauma patients is provided separately. (See "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Diagnosis' and "Ongoing assessment, monitoring, and resuscitation of the severely injured patient", section on 'Management' and "Etiology and diagnosis of coagulopathy in trauma patients".)

Anesthesiology considerations for reducing blood loss may include positioning, ventilation mode, local/regional anesthesia, deliberate hypotension, tourniquets as appropriate, and aggressive surgical hemostasis. Hypothermia can worsen hemostatic function and is generally not used to reduce blood loss.

Cell salvage and acute normovolemic hemodilution (ANH) may be appropriate in patients who qualify [31,34-37]. A continuous circuit may need to be maintained to make this acceptable to some Witnesses [34]. (See "Perioperative blood management: Strategies to minimize transfusions" and "Surgical blood conservation: Intraoperative blood salvage" and "Surgical blood conservation: Acute normovolemic hemodilution".)

Surgical and critical care resuscitation — If a competent, well-informed patient declines transfusion (based on documentation or a contemporaneous discussion) and there is significant, acute blood loss, the following may be considered to optimize outcomes [14].

●Maintain hemodynamic stability – Resuscitate as needed with intravenous fluids, pressors, and/or arterial tourniquets. Evaluate the possible use of blood conservation techniques such as intraoperative or postoperative cell salvage or acute normovolemic hemodilution; some of these blood conservation techniques are acceptable to some Witnesses, as discussed above. (See 'Jehovah's Witnesses' above and "Surgical blood conservation: Acute normovolemic hemodilution".)

●Reduce blood loss – Use of surgical, endoscopic, and radiologic interventions to identify and treat ongoing bleeding is essential. Minimize diagnostic phlebotomy (use pediatric collection tubes, avoid routine collection of multiple tubes, and avoid other unnecessary testing). (See 'Minimize blood loss' below and "Surgical blood conservation: Intraoperative blood salvage".)

●Assess hemostasis and correct coagulopathy – Maintain normothermia and stop medications that inhibit clotting. Obtain laboratory tests such as hemoglobin, coagulation studies such as the prothrombin time (PT), fibrinogen, and platelet count (and/or thromboelastography, if available) [38]. If laboratory testing reveals a coagulopathy, additional medications and clotting factor products may be needed. (See 'Medications and clotting factor products' below.)

These interventions are mostly based on clinical experience with patients in various settings and extrapolated to individuals who decline transfusions. Randomized controlled trials enrolling patients at risk of death from life-threatening anemia are extremely challenging to conduct, both technically and ethically. Therefore, clinicians must rely on information from related studies accompanied by recommendations from experts with experience in the field.

Medications and clotting factor products — In addition to localized treatments, the following medications and clotting factor products may be considered:

●Antifibrinolytic agents – Tranexamic acid (TXA) or epsilon-aminocaproic acid (EACA) are effective in reducing bleeding, especially in mucosal sites [39-42]. Randomized trials in trauma, hemorrhagic shock, and postpartum hemorrhage have shown significant efficacy and safety with early antifibrinolytic therapy [39,43,44]. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Antifibrinolytics and other pro-hemostatic therapies'.)

●Clotting factors – Coagulation factor concentrates or recombinant factor products may be used when specific coagulation factors are deficient. These may include one or more of the following products:

•PCCs – Prothrombin complex concentrates (PCCs, not activated) may be used if the levels of factor II, VII, IX, and/or X (2, 7, 9, and/or 10) are low, or if the patient is receiving an anticoagulant that interferes with these factors (eg, warfarin or a direct factor Xa inhibitor). PCCs are increasingly being used to treat major bleeding in patients who are not taking anticoagulants [45-48]. While there may be a theoretical risk of increased thrombosis, the benefit may outweigh the risk in individuals who decline transfusion. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'PCCs'.)

•Fibrinogen – Plasma-derived or recombinant fibrinogen may be used if the fibrinogen level is low. If these are not available, Cryoprecipitate may be used as a source of fibrinogen, if acceptable to the patient. Some clinicians believe that as long as the fibrinogen concentration is >100 mg/dL (1 g/L), everything is fine with their patient's hemostasis [49]. Randomized controlled trials have yet to fully assess the role of fibrinogen supplementation in critically bleeding patients; however, observational and cohort studies, a meta-analysis, and recommendations from the European Society of Anaesthesiology support our recommendation that a fibrinogen level of >200 mg/dL (2 g/L) may be a reasonable target in severely bleeding patients who cannot receive regular blood products [50-53]. (See "Disorders of fibrinogen", section on 'Fibrinogen concentrate: Dosing and monitoring' and "Disorders of fibrinogen", section on 'Cryoprecipitate and Fresh Frozen Plasma (FFP): Dosing and monitoring'.)

•Activated coagulation factors – Activated factors such as recombinant activated factor VII (rF7a) or activated PCC (factor eight inhibitor bypassing agent [FEIBA]) have been used to reduce hemorrhage in some individuals with bleeding who are unable to receive blood products. This use is considered off-label, and activated coagulation factor products carry a prothrombotic risk (including venous and arterial thrombosis) [54-56]. In one report of 27 consecutive liver transplants in Jehovah's Witnesses (JW; Witnesses), rF7a as a single-dose infusion at the beginning of the operation was used in 13 patients to augment coagulation [31]. However, meta-analyses have shown an apparent lack of effect regarding bleeding prophylaxis in hepatobiliary surgery using rF7a [57]; an analysis of many pharmacologic interventions suggests that adequate studies have not been done [58,59]. (See "Recombinant factor VIIa: Administration and adverse effects".)

For patients with uremic platelet dysfunction or those receiving anti-platelet drugs, desmopressin (DDAVP) may be considered. (See "Uremic platelet dysfunction", section on 'Treatment of bleeding'.)

The choice among these products is individualized according to the severity and site of bleeding, the presence of coagulation or platelet dysfunction, and the availability of the product. Early involvement of the consulting specialist (hematologist, intensivist, transfusion medicine specialist, hepatologist for individuals with severe liver dysfunction) is advised. (See "Hemostatic abnormalities in patients with liver disease", section on 'Bleeding'.)

Anticoagulant reversal — Anticoagulation increases the severity of bleeding, and a patient who is anticoagulated, hemorrhaging, and refusing blood products is in special peril.

Emergency reversal of anticoagulation (if present) is a top priority. This subject is summarized briefly below and discussed in more detail separately.

●Warfarin – Warfarin (and other vitamin K antagonists) can be rapidly reversed with a 4-factor prothrombin complex concentrate (PCC). (See "Management of warfarin-associated bleeding or supratherapeutic INR".)

●Direct oral anticoagulants (DOACs) – The DOACs have shorter half-lives than warfarin, and their anticoagulant effect will reverse more rapidly over time (although their half-lives may be prolonged in individuals with kidney or liver insufficiency). Reversal is discussed in detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants".)

●Heparins – Heparins have a relatively short half-life. Protamine sulfate can be used for reversal (most effective for unfractionated heparin). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.)

Antiplatelet medications — There is no direct reversal agent for antiplatelet medications. Some small studies have shown that there might be some clinical improvement of platelet function with the use of an antifibrinolytic medication such as tranexamic acid [60].

Maximize tolerance of anemia — The overall goal is to reduce oxygen demand and maximize oxygen delivery to reduce the chance of end organ hypoxia or dysoxia.

Strategies to improve red blood cell production can also be used, although they may take several days to be effective. (See 'Optimize red blood cell production' below and "Perioperative blood management: Strategies to minimize transfusions".)

Reduce oxygen demand — When a patient cannot oxygenate vital organs, it may be helpful to reduce the need for oxygen (O₂) using bedrest, sedation, and mechanical ventilation with pharmacologic paralysis. Case reports have described successful use of these procedures in Witnesses [7,61-63]. Meticulous control of fever is also critical to reduce oxygen demand.

Critical care physicians familiar with the detection, correction, and prevention of tissue hypoxia can help when making a treatment plan [64,65].

Improve oxygen delivery — Witnesses may accept a number of forms of oxygen adjuncts to improve their oxygen-carrying capacity (table 3).

Supplemental and hyperbaric oxygen — All severely anemic patients should receive supplemental oxygen titrated to respiratory demand.

Tissue oxygenation is mainly accomplished via oxygen delivery from red blood cells, with a minor contribution from oxygen dissolved directly in plasma. However, in patients with severe anemia, increasing plasma oxygen can produce a small yet significant increase in oxygen delivery.

The basis for this is explained by the formula for arterial oxygen content, designated CaO₂ (CaO₂ [mL O₂/dL] = [1.34 x hemoglobin concentration x SaO₂] + [0.0031 x PaO₂]). The PaO₂ is the arterial oxygen tension and the SaO₂ is the arterial oxyhemoglobin saturation. (See "Oxygen delivery and consumption", section on 'Oxygen content'.)

Based on this formula, in an individual with a hemoglobin concentration of 5 g/dL, raising the PaO₂ from 100 to 300 mmHg, CaO2 is increased by nearly 10 percent, from 7 to 7.7 mL O₂/dL (table 4).

Use of near infrared spectroscopy (NIRS) of skeletal muscle and cerebral tissue has been suggested as an option to monitor tissue oxygenation [66]. Several case reports have described using a hyperbaric chamber to provide hyperbaric oxygen [67-69]. If the patient is placed intermittently in a hyperbaric chamber, plasma itself may aid in carrying dissolved oxygen [70]. (See "Hyperbaric oxygen therapy".)

Extracorporeal membrane oxygenation (ECMO) has also been reported as a way to provide short-term oxygenation and cardiovascular support [71,72]. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

ECMO is most likely to be effective as a temporizing measure in patients for whom bleeding has been stopped and erythropoietin (EPO) and iron have been administered, while waiting for a few days for these therapies to begin raising the hemoglobin level. ECMO is not a long-term solution for patients with little hope of recovering RBCs.

Blood substitutes (HBOCs) — Patients and members of the health care team often inquire about using "artificial blood" such as hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon emulsion. Resources for obtaining these products are discussed separately. (See "Oxygen carriers as alternatives to red blood cell transfusion", section on 'Resources and processes for obtaining OCs in the United States'.)

While HBOCs may not be equivalent in risk to RBCs in randomized trials, many have well-understood risks. If they can be obtained, some clinicians feel that the risk-benefit ratio favors HBOC use in certain individuals with severe anemia who cannot receive transfusions. This is because the comparison is between receiving the HBOC and not receiving any treatment to improve oxygenation. These oxygen therapeutic agents are described separately [73]. (See "Oxygen carriers as alternatives to red blood cell transfusion".)

The position of Witnesses with respect to solutions containing human or animal hemoglobin leaves the decision up to the individual; it may be useful to point out that these are "subfractions" of RBCs [74]. However, some Witnesses will not accept HBOCs, so it is critical to find out in advance if these are acceptable before pursuing them.

While HBOCs have been doggedly investigated, none has yet reached the market in the United States or Europe, despite some having a history of successful use in patients who cannot receive transfusion [75-80]. A 25-year summary of clinical trials and case reports using HBOC-201 was published in 2021 [81].

After discouraging communications from the US Food and Drug Administration (FDA), several manufacturers abandoned attempts to obtain approval for their blood substitute products as equivalent to RBC. However, two review articles from 2019 reached strong conclusions about the value:

●"It is imperative that we reexamine the possibility of using HBOCs when red blood cell transfusion is not an option" [82].

●"The use of HBOC-201 should be considered when blood is unavailable or cannot be given, as oxygen delivery can be sustained in such circumstances by HBOC-201, and this has been demonstrated by phase 3 clinical trials showing transfusion-sparing properties" [83].

One company that is still pursuing approval by the FDA is the maker of HBOC-201 (Hemopure), a product made from bovine hemoglobin. (See "Oxygen carriers as alternatives to red blood cell transfusion", section on 'Hemoglobin-based oxygen carriers'.)

In addition to the issues of low hemoglobin content and short half-life, there are known risks associated with HBOCs that are discussed separately. (See "Oxygen carriers as alternatives to red blood cell transfusion", section on 'HBOC-associated side effects'.)

A 2022 subset analysis of a randomized, controlled trial of 688 elective orthopedic surgery patients compared those who received HBOC-201 versus RBC transfusions [80,84]. A portion of the increased adverse events in the HBOC-201 arm were related to the consistently lower total hemoglobin levels of patients in that arm. The authors suggested avoiding HBOC-201 in the following patients:

●Age >80 years

●Volume overload

●HBOC-201 dosing that did not lead to a high enough hemoglobin.

Reports suggest that the risk-benefit ratio changes and can favor HBOC when blood is not an option or is significantly delayed [85].

●An analysis carried out by the Naval Medical Research review of HBOC-201 in 1108 individuals determined that 48 fewer deaths would be expected with HBOC-201 infusion at the possible expense of 34 to 43 serious adverse events (SAE) [83]. The number of patients that would need to be treated with HBOC-201 to save a life was predicted to be 11.5 and the number needed to harm (experience ≥1 SAE) was estimated to be 13 to 17. Conservatively equating death and SAEs still provided a favorable benefit: risk ratio of 1.1 to 1.5 for infusion of HBOC-201.

●An analysis from 2020 identified 41 patients treated with HBOC-201 through the expanded access program in the United States from 2014 through 2017 [86]. Ten of these individuals received more than 10 units of the HBOC for severe anemia (mean hemoglobin 3.3 g/dL; range, 1.8 to 4.4 g/dL). In nine cases, the product was used because the patient declined transfusion; the exception was an individual with sickle cell disease for whom compatible blood was not available. Administration occurred two to five days after initial presentation (within 24 hours of signing consent), with an average of 16.2 units of HBOC administered, which was estimated to replace approximately 80 percent of blood volume on average.

All 10 patients survived and were discharged from the hospital, with a mean hemoglobin at the end of treatment of 7.3 g/dL (range, 4.8 to 10 g/dL) [86]. By comparison, the mortality in similar populations not treated with an HBOC was 50 to 75 percent. The authors acknowledged that the remarkable survival rate in these 10 individuals may have been biased towards being healthy enough to receive multiple doses of the product. The most common adverse events were methemoglobinemia requiring treatment with ascorbic acid and/or methylene blue, and elevated blood pressure that required antihypertensive therapy in some cases. Methemoglobinemia had no discernable adverse effects on any of the patients and did not require cessation of HBOC-201 administration.

●A multicenter randomized controlled trial showed no notable difference in mortality and serious adverse events compared with allogenic RBCs when up to 7 units of HBOC-201 were used in noncardiac surgery patients [87].

●In South Africa (where HBOC-201 is approved for use), a comprehensive review of 336 patients receiving the product found no pattern of HBOC-attributable significant adverse events. However, 5 percent of patients experienced a transient elevation in blood pressure greater than 30 mm Hg, all resolving after reducing the infusion rate or with treatment using standard medications. There were no deaths attributed as "probably" or "definitely" linked to the product [82].

Despite lack of routine availability of HBOCs, there are at least eight institutions in the United States with active expanded access ("compassionate use") protocols for using HBOC-201 (Hemopure) in patients with life-threatening anemia and for whom blood is not an option. These centers (and states) include:

●Duke University (NC)

●Englewood Hospital and Medical Center (NJ)

●John’s Hopkins University (MD)

●University of Florida (FL)

●University of Miami (FL)

●University of Michigan (MI)

●Vanderbilt University (TN)

In the USA, HBOC use outside of these centers would require a clinician to obtain an Emergency Investigational New Drug Application (IND) from the FDA and simultaneous emergency approval from the Institutional Review Board (IRB) where the product will be used, in addition to finding a company willing to provide the product. This approach is not encouraged because of the logistical difficulty and lack of institutional familiarity that can contribute to inconsistency in the quality of patient care.

These products and mechanisms to obtain them are discussed in detail separately. (See "Oxygen carriers as alternatives to red blood cell transfusion", section on 'Resources and processes for obtaining OCs in the United States'.)

OTHER INTERVENTIONS — All patients should benefit from a patient blood management (PBM) program that seeks to minimize blood loss, optimize hematopoiesis, maximize tolerance of anemia, and thus avoid unnecessary transfusions [88-92]. (See 'Importance of a hospital-wide policy to address blood product refusal' below.)

PBM programs are likely to benefit from a close and continuing consultation among hematologists, intensivists, surgeons, anesthesiologists, and transfusion medicine specialists, as well as the patient care team and the patient decision maker [31,93,94]. Some centers report that a comprehensive PBM program results in similar or better outcomes in patients who decline blood transfusion at equivalent or lower costs [95,96]. (See "Perioperative blood management: Strategies to minimize transfusions".)

A 2022 retrospective cohort study of 1111 adult inpatients who declined transfusion (compared with 137,009 other patients at the same hospital) concluded that patients receiving bloodless care and standard care had similar clinical outcomes and that bloodless care is cost-effective [96].

The interventions described below may entail taking risks that would not be taken in an individual willing to accept transfusion. Individuals who decline transfusion should be informed of these risks (see 'Components of shared decision-making' above). However, refusing transfusion does not intrinsically justify taking these risks. As an example, the use of erythropoietin (EPO) in a patient with a hemoglobin in the normal range who is preparing for a surgery with little expected blood loss and would decline blood transfusion has an unfavorable risk-to-benefit ratio, while it might be considered favorable in a patient with a low hemoglobin who is facing a procedure with the potential of significant blood loss.

Minimize blood loss — Major sources of blood loss include diagnostic phlebotomies and bleeding (surgical, traumatic, or due to a bleeding lesion).

Reduce blood draws (phlebotomy) — Studies have found mean daily phlebotomy losses in medical-surgical intensive care units (ICUs) of approximately 29 to 41 mL/day [97,98]. Practices to reduce these losses include decreased testing, small-volume sampling (using pediatric collection tubes), closed sampling circuits, point-of-care micro-testing, invasive monitoring using inserted sensors, and noninvasive testing (eg, pulse oximetry) [14,97,99]. It is estimated that four times more blood is discarded after testing by laboratories than is transfused into patients [100]. The need for pediatric collection tubes should be documented so the information is easily accessible to phlebotomists and others involved in the patient's care. (See 'Document well, including advance directives' above.)

Delaying less important procedures that may lead to bleeding (peripherally inserted central catheter [PICC] placement, Swan-Ganz catheterization) is also an option.

Minimize bleeding risk — General practices to reduce bleeding risk include close attention to the degree of anticoagulation (if employed), correcting coagulopathy and/or treating severe thrombocytopenia (platelet count <50,000/microL) if acceptable, and minimizing agents with antiplatelet activity (aspirin, nonsteroidal antiinflammatory drugs, clopidogrel).

●Hormonal therapy to reduce menstrual blood loss may be appropriate. (See "Hormonal contraception for menstrual suppression".)

●Surgical interventions to reduce bleeding risk may be appropriate. Risk-benefit calculations for patients who decline blood transfusions may be different from those in patients willing to accept transfusions. In some cases, an intervention may be performed earlier in the clinical course than it would be in a patient who would accept transfusions. Examples include:

•Some obstetricians might consider cesarean delivery sooner in patients with abnormal labor progression. (See "Labor: Overview of normal and abnormal progression".)

•Some obstetricians might have a lower threshold for performing a hysterectomy for potentially life-threatening postpartum hemorrhage. (See "Postpartum hemorrhage: Management approaches requiring laparotomy", section on 'Role of hysterectomy'.)

•Some oncologists might choose an alternative chemotherapy regimen (or alternative dosing) that is less likely to suppress the bone marrow, as might rheumatologists, nephrologists, and neurologists. (See "Causes of anemia in patients with cancer", section on 'Anemia from effects of cancer treatment'.)

Optimize red blood cell production — Production of new blood cells requires iron, folate, vitamin B12, other trace nutrients, erythropoietin (EPO), and a functioning bone marrow. Although the effects may take days to weeks, one or more of the medications discussed in the following sections may be given if indicated.

Use of a preoperative anemia clinic has been shown to reduce perioperative transfusion and possibly also length of stay [101].

For bone marrow dysfunction, the best approach depends on the underlying disorder, which may require additional evaluations to diagnose. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Treatment of aplastic anemia in adults".)

Iron/folic acid/vitamin B12 — For patients who are deficient in iron, folate, or vitamin B12, these should be provided. Compared with oral iron formulations, intravenous iron formulations are equally effective, and the entire dose can be delivered in one or a few infusions, shortening the time to full repletion. Folic acid and vitamin B12 can be administered parenterally if there are any concerns about oral absorption. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron' and "Treatment of vitamin B12 and folate deficiencies", section on 'Treatment of vitamin B12 deficiency' and "Treatment of vitamin B12 and folate deficiencies", section on 'Treatment of folate deficiency'.)

Erythropoiesis-stimulating agents (ESAs/EPO)

●Rationale – Erythropoietin (EPO) levels may be low in individuals with chronic kidney disease and/or chronic inflammatory states. In individuals with normal EPO levels and anemia, an erythropoiesis-stimulating agent (ESA, typically epoetin alfa) can be used to increase the hemoglobin to a safe range. In individuals with normal EPO levels and hemoglobin in the normal range who would not accept a transfusion and are at risk for significant blood loss, an ESA can be used to increase the hemoglobin and reduce the likelihood of life-threatening anemia. Recombinant human erythropoietin (rhEPO) and iron are acceptable to most Witnesses.

An ESA should be discussed early in treatment planning due to the time needed for a hemoglobin response [14]. The onset of action of rhEPO is at least four to six days, provided stores of vitamin B12, folate, and iron are sufficient [90,102,103]. A full response may take up to two weeks.

●Indications – A decision to use rhEPO must take into account the risk of thrombotic cardiovascular events seen in patients with kidney failure.

Administration of high-dose EPO is recommended for the following:

•Patients who have chronic kidney disease, anemia, and low EPO levels, typically in combination with iron, as discussed separately. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in patients on dialysis".)

•Patients who cannot receive transfusions who have normal EPO production but currently have, or are at high risk for developing, severe anemia [14,104-106]. Usually this is administered along with other necessary treatments to replete any deficiencies, such as iron or vitamin B12; if one of these deficiencies is the cause of anemia, then the fastest way to treat the anemia is to replete the deficient vitamin or mineral.

Our approach generally agrees with the Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists [107]. We believe it is reasonable to use preoperative rhEPO plus iron for patients undergoing elective surgery who are at high risk for postoperative anemia.

●Dosing – The FDA-approved dose for epoetin alfa to reduce the need for allogeneic RBC transfusion in patients undergoing elective, noncardiac, nonvascular surgery is based on the time interval before surgery [108]; published reports of the off-label use of ESAs in Witnesses show widely divergent dose regimens [109]. Both standardized and weight-based dosing have been used.

•Surgery in ≥3 weeks – If at least three weeks before surgery, give epoetin alfa or biosimilar 600 units/kg subcutaneously once per week, for a total of four doses (the last dose is given the day of surgery). For a 70 kg patient, each dose would be approximately 40,000 units.

•Surgery in <3 weeks – If less than three weeks before surgery, give epoetin alfa or biosimilar 300 units/kg subcutaneously once per day for a total of 15 daily doses, starting 10 days before surgery and continuing through post-op day 4. For a 70 kg patient, each dose would be approximately 20,000 units.

Most clinicians administer rhEPO at least three times per week for one to two weeks, along with intravenous iron; approximately half also give vitamin B12 and folic acid. Oral iron may be used preoperatively when time permits; however, intravenous iron allows for faster correction [103]. It is reasonable to round ESA doses up to the nearest vial size (eg, 20,000 units for rhEPO) to avoid waste.

Darbepoetin alfa is similar to epoetin alfa but has been modified so that it has a half-life that is three times greater; it has not been as widely used as epoetin alfa in this population.

●Target hemoglobin

•Anemic patient – In critical situations where a patient has a low hemoglobin, the goal is to provide a safe hemoglobin level. A safe hemoglobin level is one that will provide a buffer for potential blood loss due to recurrent bleeding (eg, menses, recurrent GI bleed) or planned surgery. This level must be determined on a case-by-case basis and is usually in the lower end of the reference range [110].

•Non-anemic patient – In patients who do not have anemia but have a high risk of significant blood loss and wish to receive an ESA to reduce the likelihood of life-threatening anemia, the hemoglobin target is also individualized, targeting the lowest possible value to reduce the risk of life-threatening anemia during or after surgery. Generally, the upper limit of the normal range is targeted.

●Risks – Clinicians should be aware of Boxed Warnings from the FDA regarding erythropoiesis-stimulating agents (ESAs) such as EPO and an increased risk of thrombosis and increased mortality or tumor progression in some individuals with cancer [108].

•Thrombosis and hypertension risk – The concern regarding thrombosis was originally raised in individuals with chronic kidney disease for whom ESAs were used to raise the hemoglobin level into the normal or near-normal range. This risk must be balanced with the risk of hemorrhagic death during surgery or in the intensive care unit. The risks of thrombosis and hypertension are discussed in more detail separately. (See "Treatment of anemia in patients on dialysis", section on 'Adverse effects of ESAs' and "Role of ESAs in adults with non-hematologic cancers", section on 'Risks and adverse events'.)

•ESA considerations in individuals with cancer – There is also a concern regarding decreased survival in individuals with cancer undergoing curative intent therapy. (See "Role of ESAs in adults with non-hematologic cancers", section on 'Use caution in patients treated with curative intent'.)

●Supporting evidence – Reports have described EPO administration as a component of successful management of individuals with severe bleeding who would not accept transfusions, especially in critical situations where bleeding has been stopped but the hemoglobin is very low [102,111-113].

A 2019 Cochrane Review of 12 studies with 1880 participants determined that giving EPO with iron supplementation reduced the need for RBC transfusions and that higher doses of EPO with iron increased hemoglobin before surgery, but at lower doses, any effect was unclear [114].

While not always cost-effective in patients for whom allogeneic transfusion is an option, using rhEPO in Witnesses to increase the hemoglobin and allow acute normovolemic hemodilution (ANH) and/or other blood conservation techniques has been viewed as a prudent measure [31,103]. (See "Surgical blood conservation: Acute normovolemic hemodilution".)

Studies of EPO and iron to reduce blood transfusion suggest that high-dose EPO is needed to see an adequate response [106,114]. The following reports of ESA use in Witnesses also support the need for higher doses of EPO:

•A protocol from a Korean bloodless surgery program for moderate-risk operations (<500 mL expected blood loss) used rhEPO intravenously at 200 units per kg three times per week or subcutaneous darbepoetin at 240 mcg once per week in the weeks preceding surgery, with the duration of treatment determined by the preoperative hemoglobin level [115]. In this protocol, preoperative screening tests included a complete blood count (CBC) with differential and blood smear review, iron, total iron-binding capacity (TIBC), ferritin, reticulocyte count, and total bilirubin. If there was macrocytosis (mean corpuscular volume [MCV] >95 fL), folate and vitamin B12 levels were also ordered and these vitamins replaced if deficient. If the ferritin was <200 mg/dL, iron (intravenous or oral) was administered. The authors commented that the 3 percent mortality at their institution with anemic patients undergoing bloodless surgery was far lower than that in other series, although it is not clear how much (if any) of this benefit was due to the use of ESAs.

•A "severe anemia protocol" for JW patients outlined in a 2014 document described the use of EPO and iron in individuals with symptomatic critical anemia with the hemoglobin <7 g/dL [79]. EPO (40,000 units) is given daily until the hemoglobin is >7 g/dL. Iron sucrose (100 mg) is given daily for 10 days, along with vitamin C, vitamin B12, and folate.

•A 2018 retrospective observational study in Witnesses encompassing over 10,000 admissions suggested that "low-dose" EPO (<600 units per kg per week) was not effective in shortening the duration of anemia, decreasing morbidity, or increasing survival [116]. The authors' recommendation was that if EPO is used, doses should be >600 units per kg per week (eg, for a 70 kg patient, >42,000 units per week).

Optimize preprocedure patient preparation — In addition to the blood management principles discussed above, certain preprocedure interventions may be helpful for obstetric patients and those undergoing surgery or invasive procedures. For certain procedures, it may be advisable to refer the patient to a center that routinely cares for patients who do not accept transfusions, especially if there is any doubt as to whether the procedure may be performed safely without blood.

Ideally, individuals who will not accept transfusion and are undergoing elective surgery with the potential for clinically significant blood loss should have testing with a CBC (and in some cases a ferritin level) approximately four to six weeks before the procedure to allow identification and treatment of iron deficiency [14,117]. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

This model has been formulated into useful algorithm for preoperative/preprocedural patient optimization based on the risk of significant blood loss [14,118]. However, these guidelines should not supersede the clinical judgment of the clinicians caring for the patient.

Another useful optimization algorithm published by a team from Johns Hopkins University was tested prospectively on 48 patients and resulted in a median hemoglobin increase of 2.3 g/dL [119]. All patients who had surgery were alive 30 days later, and there were no thromboembolic complications associated with use of EPO.

A German hospital with frequent surgery on JWs (approximately 100 surgeries annually) retrospectively analyzed severely anemic JW surgical patients over an 11-year period and concluded that, "Given optimal management, JW patients can undergo major surgery without an excessive risk of death" [35].

Guidance for estimating bleeding risk is presented in the table (table 5) and separately. (See "Perioperative management of patients receiving anticoagulants", section on 'Estimating procedural bleeding risk'.)

Four to six weeks in advance of the procedure, patient wishes regarding transfusion are documented and appropriate blood work is drawn based on anticipated blood loss:

●Minimal risk of blood loss – Obtain a CBC and proceed to surgery/intervention if anemia is absent (or only minimal anemia is present).

●Intermediate risk – Obtain a CBC and ferritin level. If the ferritin is <100 ng/mL, give intravenous iron (eg, 1 gram of low molecular weight iron dextran or equivalent). Preprocedure erythropoietin (EPO) may be appropriate, and/or an intraoperative antifibrinolytic agent such as tranexamic acid or aminocaproic acid. (See 'Erythropoiesis-stimulating agents (ESAs/EPO)' above and 'Optimize red blood cell production' above.)

●High risk – Obtain a CBC and ferritin level; test for vitamin B12 deficiency if the patient history or CBC suggests possible deficiency. If the ferritin is <100 ng/mL, give intravenous iron. If vitamin B12 is deficient, give one dose of intramuscular vitamin B12 and supplement with folic acid if needed (see "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency"). Preoperative EPO and/or an intraoperative antifibrinolytic agent may be appropriate.

Postoperative considerations — Postoperatively, minimize the number of blood draws and the amount of blood drawn and provide supplemental iron if the ferritin level remains low. EPO may also be used in selected individuals who may not have received it previously and/or who have severe anemia. It is also critical that patient handoffs are timely and complete; they must include the patient wishes concerning blood and the treatment plan [2]. (See 'Reduce blood draws (phlebotomy)' above and "Treatment of iron deficiency anemia in adults" and 'Erythropoiesis-stimulating agents (ESAs/EPO)' above.)

Venous thromboembolism (VTE) prophylaxis is used in most patients; refusal of blood transfusion is not a reason to avoid VTE prophylaxis. Conversely, anticoagulation or antiplatelet therapy that is inappropriate or no longer needed should be discontinued. Prophylaxis against gastrointestinal (GI) bleeding should be used if indicated. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'Prophylaxis'.)

REPORTS OF SUCCESSFUL OUTCOMES — A number of case reports and series have described successful outcomes in patients with serious medical and surgical conditions who were treated without transfusion, although serious risk exists:

●Surgical conditions:

•Aortic dissection, ruptured abdominal aortic aneurysm [120,121]

•Cardiothoracic surgery and/or cardiopulmonary bypass [33,122-137]

•Cardiac left ventricular assist device [138]

•Substernal goiter [139]

•Transcatheter aortic valve replacement [140,141]

•Organ transplantation (liver, kidney, pancreas, heart) [31,142-148]

•Liver resection and other abdominal surgery [149-152]

•Lung resection [106,153-155]

•Trauma [75,156]

•Genitourinary surgery/urology [77,157-159]

•Head and neck/orthognathic (including free flap reconstruction) [160-163]

•Plastic surgery (free tissue transfer) [164]

•Neurosurgery [37,165]

•Necrotizing fasciitis [166]

•Orthopedic surgery (including spinal deformity) [101,167-173]

●Obstetric conditions [174]:

•Obstetric emergencies (eg, placenta accreta, placenta percreta, placenta previa, uterine rupture, postpartum hemorrhage) [23,36,111,175-182].

•Gynecologic conditions [18,27]

•Severe anemia in pregnancy [101,183]

•Specific interventions related to uterine fibroid surgery are discussed separately. (See "Techniques to reduce blood loss during abdominal or laparoscopic myomectomy".)

●Medical conditions:

•Gastrointestinal (GI) bleeding [42,184,185]

•Hematologic malignancies/CAR T-cell therapy [1,186-192]

•Hematopoietic stem cell transplantation [193-200]

•Solid organ tumors [70,201]

•Hemorrhagic shock [111,202]

•Thrombotic thrombocytopenic purpura (TTP) [203-208]

•Extracorporeal membrane oxygenation (ECMO) [72,209,210]

•Benign hematology (including severe autoimmune hemolytic anemia, red cell aplasia, severe pernicious anemia, sickle cell anemia/acute chest syndrome) [1,68,86,211-214]

•Severe pancreatitis (treated by interventional radiology) [215]

•Radiation therapy [216]

IMPORTANCE OF A HOSPITAL-WIDE POLICY TO ADDRESS BLOOD PRODUCT REFUSAL — A hospital-wide policy for addressing refusal of blood transfusion may provide important clinical guidance, especially in an emergency situation when there is insufficient time to address the complex issues that arise [217]. The policy should address emergency situations where patient desires have not been adequately established (eg, a trauma victim presenting to an emergency department or a pediatric patient with acute life-threatening anemia) [160]. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Hospital-wide oversight programs/patient blood management'.)

Many Jehovah's Witnesses (JW; Witnesses) carry "Durable Power of Attorney" documents on their person that detail their wishes (or they make their wishes known in the medical record or to a family member) [32]. However, this information may not be immediately available in an emergency situation such as a trauma, acute bleeding event, or obstetric emergency.

The clinician should follow the patient's wishes. However, if there is any doubt in a clinician's mind concerning the wishes of a patient or what is legally appropriate, the prudent course in an emergency would be to treat according to the accepted standard of care. This would be without regard to special requests from parents on behalf of their children or relatives on behalf of incapacitated adults until reliable legal documentation (as judged by the treating clinician) is available. The treating clinician also must be able to leave the patient's bedside to review any new documentation (this is sometimes not possible until after the patient is stabilized) [218,219].

Patients who refuse transfusion are not usually refusing all care, and it is incumbent on clinicians caring for the patient to maintain respect and open communication with the patient and family as much as possible, even in emergencies [220]. It is also worthwhile to confirm from the medical record and/or the patient (if awake and coherent) that specific plans have been discussed regarding their wishes in the event of life-threatening hemorrhage and that these plans are being followed. This is discussed in more detail above. (See 'Components of shared decision-making' above and 'Discuss contingency plans for life-threatening situations' above.)

ETHICAL AND LEGAL ISSUES

Competence and informed consent — Many hospitals have an ethics committee that can provide consultation and a risk management group that can give advice for legal protection; however, when dealing with an adult Jehovah's Witness (JW; Witness) who is competent to make an informed decision, involvement of these groups is rarely needed. Court cases have upheld the validity of advance directives, even when a patient later loses decisional competency due to mental illness and still refuses blood [26,221,222].

One survey of South American physician attitudes found that only 128 of 564 cardiologists (23 percent) would be willing to commit to not performing blood transfusion under any circumstance for patients who refuse transfusions [223]. Nevertheless, in most countries, the right of a competent adult to refuse consent for medical treatment is well accepted by the majority of clinicians, and a number of legal cases have dealt specifically with Witnesses. Additional legal and ethical issues related to informed consent are discussed separately. (See "Informed procedural consent".)

Children, newborns, and fetuses — Conflicts may emerge between the guardians of a child younger than the legal age of consent and clinicians attempting to provide the best possible care. Minor children cannot legally give informed consent, and it is the duty of the clinician to seek legal intervention in cases where the child is placed at "clear and substantial" risk by parental decisions [224]. Candid discussion about the clinician's obligation before the law may help parents understand that the clinician may have no alternative than to transfuse in a life-threatening situation. In such situations, prompt consultation with legal specialists is recommended to clarify the laws of a particular state, province, or country.

Whenever possible, adolescents should be involved in the decision-making process. An adolescent may reject a transfusion that is acceptable to their guardians. In the United States, individual states have differing criteria for the age of majority (independent choice), and minors may be emancipated by the courts or through such events as marriage.

Specific variations regarding pediatric transfusion and the competency of children have been published in some countries:

●Japan [225]

●Great Britain [226]

●Canada [227]

For an acute, life-threatening situation that requires blood transfusion, a court order is not needed to transfuse a minor child in the United States and many other countries. In some settings, a court order allowing transfusion of a minor child is obtained in anticipation of a possible need. Although transfusing the child may be legally supportable, it does not mean that a transfusion must be given. Transfusing against the will of the parents and/or child may have psychological consequences.

If a clinician is legally bound to provide transfusions, they should communicate in a straightforward way with both the guardian and child (if old enough) to explain the situation and the intention to transfuse. Criteria that will be used to make the decision to transfuse and the use of transfusion as a last resort should also be clearly communicated. This will help the guardian understand the legal reality faced when conscience forbids consenting to a transfusion and a court order is sought.

Although the courts may overrule parental decision regarding transfusion, parents still have the legal right to be informed about their child's condition and the desire to be involved in other medical decisions. The clinician should remain sensitive to the possible feelings of guilt or distress associated with transfusion in the young patient and family, despite a court order. The health care team should not underestimate the child's awareness and concerns about being transfused.

A court order should not be written in a way that classifies the parents as negligent and removes the child totally from parental custody. As an example, the judge might "authorize" the treatment requested by the clinician, avoiding the harsher term "order" [7]. If transfusion is authorized by a judge, a JW family will not be considered to be acting against church teaching by allowing transfusion, since the official position of the faith on this point is that "Christians agree with laws or court actions to prevent child abuse or neglect." Additional information on this difficult subject is available on the JW website, section on medical information for clinicians (www.jw.org/en/medical-library/).

For a fetus, it has been accepted in courts in many countries that the mother has control over her own body. This suggests that she can legally refuse transfusion of herself. However, when a mother's life will likely be lost unless transfused, leaving behind a healthy newborn, the father or a designated guardian should be available to care for the child. If no parent or guardian will be available to care for the newborn after the mother's death, the question has been raised as to whether the transfusion should be given to save the life of the infant's sole caregiver. This controversial possibility must be weighed carefully by the hospital ethics committee and in the court system, which differs greatly from state to state in the United States [176]. A fetus that needs transfusion before birth to save its life is also legally and ethically controversial and should be approached similarly.

Requests from family members — Legal entanglement from individuals other than guardians or health care decision makers may be a concern. Witnesses are not, as a group, litigious; however, other family members who are not practicing Witnesses may have strong feelings about watching a loved one die after declining blood transfusion.

If family members, caregivers, or friends strongly disagree with the patient's decision to accept or refuse blood products, the clinician may be asked to provide additional explanation. In such cases, it may be wise to involve the medical center's ethics committee, legal department, and risk management group to balance the need between protecting confidentiality and providing effective communication of the treatment plan and its rationale. If the patient consents to a group meeting to discuss care with all of the concerned parties, this may have the best chance of diffusing the tension [13].

The decision-making process becomes complicated when the patient is incapacitated and the health care agent must balance the needs for patient autonomy and preservation of life (beneficence). Typically, a health care agent cannot override the patient's autonomy if it is known what the patient would have wanted in a given situation and the information is documented. (See 'Document well, including advance directives' above.)

Autonomy should be understood as simple competence, not rationality [228]. In a perfect world, a truly informed consent process would enable a clinician to know precisely what the patient would have wanted under any set of circumstances. In the real world, the clinician sometimes needs to determine if the consent was given under duress (even religious pressure might count), and whether the patient grasped the gravity and scope of the decision. Either of these might move the balance from autonomy toward beneficence, allowing the clinician to honor the request of the health care agent to transfuse [229,230].

Effect on the treatment team — Clinicians should be prepared for the psychological strain that may accompany a seemingly preventable death. This may involve sorrow and/or anger over losing a patient who they feel could have been saved. In certain cases, this has led to psychological disturbance that might have been avoided with appropriate counseling and support [7,78,231]. Providers must be prepared to seek emotional support, if necessary, both for themselves and other team members including nursing staff.

Hospitals that establish bloodless medicine and surgery programs should be prepared to provide support to the health care delivery team members. Although rare, despite a solid legal foundation, there may also be the stress of threatened litigation from the patient and/or family members who do not share the same views about transfusion as the patient. Respecting the wishes of competent, informed patients who refuse blood requires high standards of ethics and professionalism [7,26].

Declining to provide care — Some clinicians may not be comfortable with a patient's choices or may question their ability to care for the patient without providing transfusions [232]. In this case, the clinician may need to consider referring nonemergency patients to another competent provider. In this instance, the patient is also under an obligation to respect the conscience of the health care provider.

Withdrawal from such a case does not constitute malpractice if the clinician arranges for transfer of a nonemergency patient to another caregiver. The patient, family members/caregivers, and receiving clinician should understand the reason for transfer. Other caregivers who may be directly involved (anesthesiologists, intensivists, nurses) should be aware of the patient's decision to refuse blood products and should be capable of providing the alternative care necessary and willing to accept the possible consequences.

RESOURCES FOR CLINICIANS — Resources are available to support decision-making for patients declining transfusion, including other clinicians who have had experience in similar situations.

●Transfusion medicine specialists are available for consultation at major centers, particularly those with blood conservation programs.

●Many larger cities have a Hospital Liaison Committee of Jehovah's Witnesses (JW; Witnesses) that is capable of addressing patient questions, helping clinicians to obtain pertinent medical literature, and putting them in touch with clinicians experienced in their specific situations.

A local representative may be identified using one of the following methods:

•In the United States, call (718) 560-4300

•Outside the United States, call (718) 560-4700

•Email – [email protected]

•Website for clinicians – www.jw.org/en/medical-library/

●A number of review articles are available that discuss management of specific clinical scenarios [2,7,11,88,115,233,234].

●The Society for the Advancement of Blood Management (www.sabm.org; membership required for access) and the Association for the Advancement of Blood & Biotherapies (www.aabb.org), which are not affiliated with the JW faith, provide information about patient blood management programs.

●The Network for the Advancement of Blood Management, Haemostasis, and Thrombosis (www.nataonline.com) provides information and articles from the literature.

●Englewood Health (www.englewoodhealth.org/service/bloodless-medicine-and-surgery) provides information about bloodless surgery and has a referral line that offers phone consultation for physicians with their bloodless medicine providers at (888) 766-2566.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)

SUMMARY AND RECOMMENDATIONS

●Reasons for declining – Shared decision-making can ensure the needs and wishes of the patient are considered when they decline transfusions. Jehovah's Witnesses (JW; Witnesses) avail themselves of modern medical care, with the exception of certain forms of blood transfusion. Acceptable and unacceptable blood components and purified fractions can vary among Witnesses (table 1). Less common reasons include concerns about safety of the blood supply and previous severe transfusion reactions. (See 'Understand patient beliefs and reasons for declining transfusion' above.)

●How to discuss – Discussions should address the patient's wishes in the event of a life-threatening situation (if they would likely die without transfusion). A sample checklist is provided (table 3). The clinician should seek to understand, develop good rapport, provide non-adversarial support, serve as the patient's advocate, preserve confidentiality, and carefully document the patient's wishes. (See 'Be clear about the patient's wishes regarding consent' above and 'Discuss contingency plans for life-threatening situations' above and 'Maintain patient rapport' above.)

●How to document – Patient desires concerning transfusions have the same life-or-death importance as code status. A brief statement such as "some blood products are not acceptable per patient preference" might be kept with the documentation of a patient's allergies to prompt caregivers to review complete documentation kept with "Urgent Clinical Documents" or in a note in the medical record. (See 'Discuss contingency plans for life-threatening situations' above and 'Document well, including advance directives' above.)

●Emergencies – In an emergency, if there is any doubt concerning the patient's wishes or legal considerations, the prudent course is to follow the accepted standard of care. However, if a competent, well-informed patient wishes not to receive transfusion, care should be focused on other lifesaving interventions. (See 'The actively bleeding patient' above and 'Reports of successful outcomes' above.)

●PBM – Principles of patient blood management (PBM) focus on reducing blood transfusion:

•Reduce blood loss – Aggressive treatment of bleeding, meticulous surgical technique, correction of coagulopathy, attention to medications. Minimize blood loss by reducing phlebotomies and using pediatric collection tubes. (See 'Aggressively treat bleeding' above and 'Minimize blood loss' above.)

•Increase red blood cell production – Provide supplemental iron, vitamin B12, and folic acid if needed. Erythropoietin (EPO) may be used with iron in patients at high risk for postoperative anemia or those who are undergoing preoperative autologous blood donation, if acceptable. (See 'Optimize red blood cell production' above.)

•Maximize oxygenation – Maximize tolerance of anemia by reducing oxygen demand (control fever, use sedation) and providing oxygen as needed (table 4). A "blood substitute" such as a hemoglobin-based oxygen carrier (HBOC) may be used if available. (See 'Maximize tolerance of anemia' above.)

A hospital-wide policy for addressing refusal of blood transfusion may provide important guidance. (See 'Importance of a hospital-wide policy to address blood product refusal' above.)

●Elective interventions – Obstetric patients and those undergoing elective procedures may benefit from preoperative testing and possible treatment with EPO (and iron, vitamin B12, and folate if needed). Autologous cell salvage and/or acute normovolemic hemodilution (ANH) may also be used. The patient can be referred to a center that routinely cares for patients who decline transfusions. (See 'Optimize preprocedure patient preparation' above.)

●Ethical considerations – Minor children cannot legally give informed consent, and the clinician must seek legal intervention when a child is at "clear and substantial" risk from parental/caregiver decisions. In a life-threatening emergency, clinicians should not wait for legal intervention; they should transfuse according to standard of care. This also applies to adults for whom there is insufficient documentation to determine their preferences. A clinician may decline to provide care for a nonemergency patient who refuses transfusion if they arrange transfer to another caregiver. (See 'Ethical and legal issues' above.)

●Resources – Resources include transfusion medicine specialists, the local Jehovah's Witness Hospital Liaison Committee, and publications from various societies. (See 'Resources for clinicians' above.)

ACKNOWLEDGMENT — We are saddened by the death of Arthur J Silvergleid, MD, who passed away in April 2024. The UpToDate editorial staff gratefully acknowledges the extensive contributions of Dr. Silvergleid to earlier versions of this and many other UpToDate topics.