Delayed haemolytic transfusion reaction in adults with sickle cell disease: a 5‐year experience

Delayed haemolytic transfusion reactions (DHTR) are potentially life‐threatening complications in patients with sickle cell disease (SCD). Between 1 August 2008 and 31 December 2013, 220 of 637 adult patients in our centre had at least one red blood cell (RBC) transfusion in 2158 separate transfusion episodes. Twenty‐three DHTR events occurred in 17 patients (13 female) including 15 HbSS, one HbSC and one HbSβ⁰ thalassaemia, equating to a DHTR rate of 7·7% of patients transfused. Mean interval from RBC transfusion to DHTR event was 10·1 ± 5·4 d, and typical presenting features were fever, pain and haemoglobinuria. Twenty of the 23 (87·0%) DHTR episodes occurred following transfusion in the acute setting. Notably, 11/23 (47·8%) of DHTRs were not diagnosed at the time of the event, most were misdiagnosed as a vaso‐occlusive crisis. 16/23 DHTRs had ‘relative reticulocytopenia’, which was more common in older patients. Seven of 23 episodes resulted in alloantibody formation, and three caused autoantibody formation. DHTRs are a severe but uncommon complication of RBC transfusion in SCD and remain poorly recognized, possibly because they mimic an acute painful crisis. Most of the DHTRs are triggered by RBC transfusion in the acute setting when patients are in an inflammatory state.     

Risk of alloimmunization and delayed hemolytic transfusion reactions in patients with sickle cell disease

Blood transfusion is an integral part of the supportive care of patients with sickle cell diseases. The hazards of red blood cell alloimmunization and delayed hemolytic transfusion reactions (DHTRs) complicate the treatment of patients with sickle cell diseases, particularly since such reactions may be misinterpreted as a pain crisis, and, as a result, specific transfusion serologic studies may not be performed. The frequency of alloimmunization in this population has been the subject of several reports; however, the frequency of DHTRs is unknown. To determine the frequency of this event, we retrospectively reviewed the medical and transfusion service records of all adult patients with sickle cell diseases transfused during the six-year period from January 1980 to December 1985. Seventy-three adult patients with sickle cell diseases received transfusions. The prevalence of recognized DHTR was three (4%) of 73. Red blood cell alloimmunization was seen in 22 (30%) of 73 of the patients. The calculated risk of alloimmunization was 3.1% per unit of blood. These observations suggest that alloimmunization and clinically apparent DHTRs occur more frequently in patients with sickle cell diseases and support pretransfusion testing for at least Rh and Kell red blood cell antigens in patients who are at high risk of such events (patients who have formed an alloantibody or who are being enrolled in a transfusion program).     

Delayed hemolytic transfusion reaction in adult sickle‐cell disease: presentations,outcomes, and treatments of 99 referral center episodes

Delayed hemolytic transfusion reaction (DHTR) is one of the most feared complications of sickle‐cell disease (SCD). We retrospectively analyzed the clinical and biological features, treatments and outcomes of 99 DHTRs occurring in 69 referral center patients over 12 years. The first clinical signs appeared a median of 9.4 [IQR, 3–22] days after the triggering transfusion (TT). The most frequent DHTR‐related clinical manifestation was dark urine/hemoglobinuria (94%). Most patients (89%) had a painful vaso‐occlusive crisis and 50% developed a secondary acute chest syndrome (ACS). The median [IQR] hemoglobin‐concentration nadir was 5.5 [4.5–6.3] g/dL and LDH peak was 1335 [798–2086] IU/L. Overall mortality was 6%. None of the patients had been receiving chronic transfusions. Among these DHTRs, 61% were developed in previously immunized patients, 28% in patients with prior DHTR. Among Abs detected after the TT in 62% of the episodes, half are classically considered potentially harmful. No association could be established between clinical severity and immunohematological profile and/or the type and specificity of Abs detected after the TT. Management consisted of supportive care alone (53%) or with adjunctive measures (47%), including recombinant erythropoietin and sometimes rituximab and/or immunosuppressants. Additional transfusions were either ineffective or worsened hemolysis. In some cases, severe intravascular hemolysis can be likely responsible for the vascular reaction and high rates of ACS, pulmonary hypertension and (multi)organ failure. In conclusion, clinicians and patients must recognize early DHTR signs to avoid additional transfusions. For patients with a history of RBC immunization or DHTR, transfusion indications should be restricted. Am. J. Hematol. 91:989–994, 2016. © 2016 Wiley Periodicals, Inc.     

Effectiveness of a protocol to improve transfusion practice in knee replacement surgery

BACKGROUND AND OBJECTIVES: The available guidelines on red cell transfusion are not clearly defined and therefore have had only a modest impact on transfusion practice. The aims of this study were to assess the rate of compliance with a transfusion algorithm and its effect on transfusion practice. MATERIALS AND METHODS: A prospective observational study was carried out on 101 patients who underwent primary elective total knee replacement surgery. RESULTS: Only 30% of the patients were transfused. An overall compliance rate of 77% was achieved with the transfusion algorithm. CONCLUSION: A transfusion algorithm, together with staff education, is effective in reducing both the number of patients transfused and inappropriate transfusions.     

Post-Transfusion Hyperhaemolysis in a Patient with Sickle Cell Disease: Use of Steroids and Intravenous Immunoglobulin to Prevent Further Red Cell Destruction

Delayed haemolytic transfusion reactions (DHTRs) are seen more frequently in patients with sickle cell disease (SCD) than in other groups of patients, and are characterised by a positive direct antiglobulin test and the appearance of previously undetected red blood cell (RBC) alloantibodies in the patient's serum. Recently a syndrome of post-transfusion hyperhaemolysis has been described in children with SCD, characterised by destruction of both autologous and transfused RBCs with negative serological findings: continuation of RBC transfusion exacerbated haemolysis further. We describe a case of life-threatening posttransfusion hyperhaemolysis in an adult patient with SCD in whom severe anaemia necessitated further RBC transfusion, which was successfully performed in conjunction with intravenous immunoglobulin. This approach may be useful in the management of post-transfusion hyperhaemolysis in SCD as well as in the management of severe DHTRs.     

Non-infectious complications of transfusion therapy.

Blood transfusion is considered safe when the infused blood is tested using state of the art viral assays developed over the past several decades. Only rarely are known viruses like HIV and hepatitis C transmitted by transfusion when blood donors are screened using these sensitive laboratory tests. However, there are a variety of transfusion risks which still remain that cannot be entirely eliminated, many of which are non-infectious in nature. Predominantly immune-mediated complications include the rapid intravascular or slow extravascular destruction (hemolysis) of transfused red cells or extravascular removal of platelets by pre-formed antibodies carried by the transfusion recipient. Alternatively, red cells can be damaged when exposed to excessive heat or incompatible intravenous fluids before or during the transfusion. Common complications of blood transfusion that at least partly involve the immune system include febrile non-hemolytic and allergic reactions. While these are usually not life-threatening, they can hamper efforts to transfuse a patient. Other complications include circulatory overload, hypothermia and metabolic disturbances. Profound hypotensive episodes have been described in patients on angiotensin-converting enzyme (ACE) inhibitors who receive platelet transfusions through bedside leukoreduction filters. These curious reactions appear to involve dysmetabolism of the vasoactive substance bradykinin. Products contaminated by bacteria during blood collection and transfused can cause life-threatening septic reactions. A long-term complication of blood transfusion therapy unique to chronically transfused patients is iron overload. Less common - but serious - reactions more specific to blood transfusion include transfusion-associated graft-versus-host disease and transfusion-associated acute lung injury. Many of these complications of transfusion therapy can be prevented by adhering to well-established practice guidelines. In addition, individuals who administer blood transfusions should recognize these complications in order to be able to quickly provide appropriate treatment.     

A diagnostic nomogram for delayed hemolytic transfusion reaction in sickle cell disease

Diagnosis of delayed hemolytic transfusion reactions (DHTR), one of the most dreaded complications of transfusion in patients with sickle cell disease (SCD), is challenging and not straightforward. Current diagnostic approaches are complex and not consensual; they are based on assessment of hemoglobin (Hb) drop and enhanced hemolysis, features also seen during classical vaso‐occlusive events. In this observational study, we tested the hypothesis that the rate of decline in HbA after an index transfusion is a surrogate marker for the destruction of transfused RBC, which could be used diagnostically. We examined 421 transfusion episodes (in 128 patients of a French referral center for SCD) for which an Hb electrophoresis was obtained within 1 week following an index transfusion and repeated within 2 months (before a subsequent scheduled transfusion or during an acute complication). Chart review found DHTR to be present in 26 cases (6.2%), absent in 389 cases (92.4%), and possible in six cases (1.4%). As expected, DHTR was associated with accelerated hemolysis (increased serum bilirubin and lactic dehydrogenase concentrations) and a decline in total Hb as compared to the early post‐transfusion value. However, the decline in HbA concentration appeared more effective in segregating between patients without DHTR and others. We propose a diagnostic nomogram for DHTR based on Hb A as a biologic marker of the survival of transfused RBCs. Am. J. Hematol. 91:1181–1184, 2016. © 2016 Wiley Periodicals, Inc.     

Refractoriness to platelet transfusion

This review discusses the causes of refractoriness to platelet transfusions and presents three options for its management. Platelet refractoriness is a complication of platelet transfusion that affects variable proportions of patients, mostly depending on their diagnosis, previous immunologic stimuli, and type of blood products used for transfusion. A large recent study showed that platelet refractoriness develops in 13% of patients with acute leukemia transfused with traditional blood products and in 3 to 4% of recipients of white cell-reduced blood components. Options to manage platelet refractoriness include platelets from HLA-typed donors, platelet cross-matching, and the antibody specificity prediction method. The selection of the most convenient approach depends on local skills and the available economic and organizational resources. Finally, emerging concepts are presented which could impact the management of platelet refractoriness.     

Would a National Antibody Register contribute to improving patient outcomes?

Despite stringent testing protocols, there always remains a chance of a delayed haemolytic transfusion reaction (DHTR) occurring as a result of an undetected or unknown antibody. In this systemic review and meta-analysis, we aimed to investigate improvements to patient outcomes that could be achieved through the implementation of a national antibody registry. A series of searches through PubMed and SCOPUS identified a collection of articles with relevant information, restricted to full text, English language articles available through the RMIT Library service. 25 articles were considered for the review, four of these found to have relevant, extractable data for use in the meta-analysis. Alloantibody evanescence rates were analysed for the potential for reducing DHTRs associated with transfusion services, returning significant results indicating antibody evanescence rates of up to 68.4% in one study, with p-values less than 0.001. Due to the small number of included studies however, the interference values were quite high for these analyses at greater than 90% for each. Additional, beneficial side-effects of such a system were also considered, along with reductions in DHTRs. In conclusion it was determined that a National antibody registry would contribute to improving patient outcomes, however further studies could be performed to determine a stronger correlation, and exact levels of improvement that could be achieved.     

Preoperative transfusion in sickle cell disease: a survey of practice in England

OBJECTIVES: To gather data on current preoperative transfusion practice and postoperative complications in sickle cell disease (SCD) as a prelude to a randomised trial. METHODS: A prospective one year survey of 114 SCD patients undergoing elective surgery in 31 English hospitals was undertaken. RESULTS: 43%, 39% and 23% of patients respectively [corrected] received no transfusion, top-up and exchange transfusion preoperatively. Overall postoperative complication rates were 18%, 26% and 17%, with SCD related complications of 12%, 8% and 0% respectively. 85% of patients with [corrected]HbSC/HbSss(+)thalassaemia and 71% of obstetric and gynaecology patients were not transfused preoperatively, whereas 59% patients undergoing ENT procedures and 83% of hip replacements had top-up and exchange transfusions respectively. Multivariable logistic regression analysis revealed that having moderate/high risk procedures was a predictor of postoperative complications (OR 4.9 (95% CL: 1.3 to 18), P = 0.017) [corrected] while preoperative transfusion was not (OR 1.7, (95% CL: [corrected] 0.5 to 6), P = 0.41). CONCLUSION: The lack of clear benefit of transfusion confirms the need for a randomised controlled trial of transfusion vs. no transfusion in patients with HbSS and HbSss(0)thalassaemia.     

Indications for red cell transfusion in sickle cell disease

Transfusion of red blood cells is an important therapeutic method employed in the care of people with sickle cell disease (SCD). There are several clinical situations in which patients with SCD clearly need red cell transfusion (RCT). In other situations, the indication for RCT is doubtful, controversial, or ill-advised. RCT is used on either an episodic or chronic basis in the management of SCD. Episodic transfusions are usually applied in a patient who has already developed a serious complication of SCD or are used to reduce the chances for the development of a complication. Chronic transfusion therapy is often used to prevent the recurrence of a major complication such as a stroke. Recently, chronic transfusion has been applied to patients with evidence of cerebrovascular disease to prevent the first occurrence of stroke.     

Incidence and predictive score for delayed hemolytic transfusion reaction in adult patients with sickle cell disease

Delayed hemolytic transfusion reaction (DHTR) is a life‐threatening complication of transfusion in sickle cell disease (SCD). The frequency of DHTR is underestimated because its symptoms mimic those of vaso‐occlusive crisis and antibodies (Abs) are often not detectable. No predictive factors for identifying patients likely to develop DHTR have yet been defined. We conducted a prospective single‐center observational study over 30 months in adult sickle cell patients. We included 694 transfusion episodes (TEs) in 311 patients, divided into occasional TEs (OTEs: 360) and chronic transfusion program (CTEs: 334). During follow‐up, 15 cases of DHTR were recorded, exclusively after OTEs. DHTR incidence was 4.2% per OTE (95% CI [2.6; 6.9]) and 6.8% per patient during the 30 months of the study (95% CI [4.2; 11.3]). We studied 11 additional DHTR cases, to construct a predictive score for DHTR. The DHTR mortality is high, 3 (11.5%) of the 26 DHTR patients died. The variables retained in the multivariate model were history of DHTR, number of units previously transfused and immunization status before transfusion. The resulting DHTR‐predictive score had an area under the ROC curve of 0.850 [95% CI: 0.780‐0.930], a negative‐predictive value of 98.4% and a positive‐predictive value of 50%. We report in our study population, for the first time, the incidence of DHTR, and, its occurrence exclusively in occasionally transfused patients. We also describe a simple score for predicting DHTR in patients undergoing occasional transfusion, to facilitate the management of blood transfusion in SCD patients.     

Principles and problems of transfusion in sickle cell disease

Sickle cell disease (SCD) is associated with red blood cell (RBC) abnormalities and moderate to severe anemia, and blood transfusion is naturally a mainstay of treatment. However, transfusion therapy for SCD may incur special and distinctive adverse effects. Thus, it is important to understand the indications for and goals of transfusion therapy and to be aware of the potential side effects of therapy. Years of unsystematic clinical observations, followed by more carefully designed and in some cases randomized studies, have contributed substantially to our knowledge of transfusion therapy in SCD. However, much remains unknown and areas of controversy persist. In addition, serologic barriers pose enduring roadblocks to the optimization of transfusion therapy for patients with SCD, and the syndrome of massive hemolytic transfusion reactions and hyperhemolysis in SCD persists as a life-threatening complication for which appropriate clinical management is not yet defined.     

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication.     

Effect of red cell exchange transfusion on plasma levels of inflammatory mediators in sickle cell patients with acute chest syndrome

Red cell exchange transfusion is the recommended therapy for patients with sickle cell disease (SCD) who have severe, progressive acute chest syndrome (ACS). A double-volume red cell exchange transfusion decreases the percentage of hemoglobin S (Hgb S) containing red blood cells to less than 20%, improving vascular perfusion. We speculated that reduction of pro-inflammatory mediators might also contribute to the therapeutic effect of an exchange transfusion. We measured white blood cell count (WBC), absolute neutrophil count (ANC), platelet concentration as well as plasma levels of interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in 8 sickle cell patients with 9 episodes of ACS who received a manual, double-volume exchange transfusion. Six patients with SCD seen during a routine clinic visit were used as controls. The mean number of hospitalization days was 6, with an average of 2 days in the intensive care unit. All patients recovered without complication. Sickle cell patients with ACS had a higher WBC and ANC at baseline but lower sVCAM-1 levels compared to controls. TNF-alpha, IL-1alpha, IL-1beta, and IL-8 levels were not significantly different from controls. WBC, ANC, platelet, and sVCAM-1 measurements were significantly decreased immediately post-exchange in patients with ACS; however, this effect was not persistent as levels trended towards pre-exchange values by 24 hr post-exchange. Due to wide inter-individual variability, a consistent pattern was not seen for TNF-alpha, IL-1alpha, IL-1beta, or IL-8. We conclude that in sickle cell patients with ACS, a manual, double-volume exchange transfusion lowers WBC, ANC, platelets, and sVCAM-1 levels, but the effect is short-lived.     

A prophylactic transfusion program for children with sickle cell anemia complicated by CNS infarction

CNS infarction is a devastating complication in sickle cell anemia. Episodes are frequently repetitive and often result in permanent neurologic abnormalities. In an attempt to prevent such recurences a periodic transfusion program was begun at the Children's Hospital of Michigan in 1969. Twenty-one children currently on the program receive buffy-coat poor transfusions on an out-patient basis every 3 weeks. Of 15 who have been on the program for periods of from 9 months to 5 ¾ years, none have had progression of neurologic abnormalities, and several have had definite improvement in neurologic function. One child who was not brought in regularly had recurrent CNS infarction. The only recognized complication has been one instance of serum hepatitis. While such a transfusion of neurologic abnormalities resulting from recurrent CNS infarction in sickle cell anemia.     

Transfusion-related alloimmune neutropenia: an undescribed complication of blood transfusion

Alloimmune neutropenia in neonates is rare. We describe severe and persistent neutropenia in a 4-week-old neonate, which arose within 2 h of a transfusion of blood that contained about 28 mL of plasma and in which strong antibodies against human neutrophil antigen 1b (HNA-1b) were subsequently identified. The infant was positive for HNA-1b. No other likely cause of neutropenia was discovered. We believe this complication of blood transfusion to be a previously unrecognised one, and have called the condition transfusion-related alloimmune neutropenia (TRAIN).     

Platelet transfusion improves clot formation and platelet function in severely thrombocytopenic haematology patients

Prophylactic platelet (PLT) transfusion is a common practice in severely thrombocytopenic patients that reduces mortality, but responses to platelet transfusions are variable and difficult to predict in individual patients. In this prospective study, we evaluated the outcome of PLT transfusions in 40 patients with haematological malignancies, linking corrected count increment (CCI) to clot formation and agonist-induced platelet activation after transfusion. The CCI was highly variable between patients and 34% showed no response (1-h CCI < 7,5). Short time since the last PLT transfusion and extended storage time of the PLT product were linked to poor transfusion response, while patient sex, C-reactive protein or the number of chemotherapy cycles prior to transfusion did not influence transfusion outcome. High CCI and good PLT responsiveness to agonist stimulation predicted efficient clot formation in rotational thromboelastometry, but transfusion did not restore poor PLT function in patients to the level of healthy controls. Our study provides new insights into factors affecting PLT transfusion outcome in haematology patients with severe thrombocytopenia, and suggests that the thrombocytopenic environment, or disease-associated factors, may hamper platelet responsiveness.     

Precautions surrounding blood transfusion in autoimmune haemolytic anaemias are overestimated

Background

It is very evident that many precautions are taken regarding transfusion of red blood cells in patients with autoimmune haemolytic anaemia. Frequently, considerable efforts are made to examine the indication and serological compatibility prior to transfusion in such patients. However, at times, this may unnecessarily jeopardize patients who urgently require a red blood cell transfusion.

Materials and methods

Thirty-six patients with warm-type autoimmune haemolytic anaemia were included in this study. All patients had reactive serum autoantibodies and required blood transfusion. Standard serological assays were employed for the detection and characterization of antibodies to red blood cells.

Results

A positive direct antiglobulin test was observed in all 36 patients, in addition to detectable antibodies in both the eluate and serum. Significant alloantibodies were detected in the serum samples of three patients (anti-c, anti-JK^a, and anti-E). In 32 patients, red blood cell transfusion was administered with no significant haemolytic transfusion reactions due to auto- and/or allo-antibodies. Due to overestimation of positive cross-matches three patients received no transfusion or delayed transfusion and died, and one patient died due to unrecognised blood loss and anaemia which was attributed to an ineffective red blood cell transfusion.

Discussion

Many of the reported recommendations regarding transfusion of red blood cells in autoimmune haemolytic anaemia are highly questionable, and positive serological cross-matches should not result in a delay or refusal of necessary blood transfusions.     

Guideline on the investigation and management of acute transfusion reactions Prepared by the BCSH Blood Transfusion Task Force

Although acute non‐haemolytic febrile or allergic reactions (ATRs) are a common complication of transfusion and often result in little or no morbidity, prompt recognition and management are essential. The serious hazards of transfusion haemovigilance organisation (SHOT) receives 30–40 reports of anaphylactic reactions each year. Other serious complications of transfusion, such as acute haemolysis, bacterial contamination, transfusion‐related acute lung injury (TRALI) or transfusion‐associated circulatory overload (TACO) may present with similar clinical features to ATR. This guideline describes the approach to a patient developing adverse symptoms and signs related to transfusion, including initial recognition, establishing a likely cause, treatment, investigations, planning future transfusion and reporting within the hospital and to haemovigilance organisations. Key recommendations are that adrenaline should be used as first line treatment of anaphylaxis, and that transfusions should only be carried out where patients can be directly observed and where staff are trained in manging complications of transfusion, particularly anaphylaxis. Management of ATRs is not dependent on classification but should be guided by symptoms and signs. Patients who have experienced an anaphylactic reaction should be discussed with an allergist or immunologist, in keeping with UK resuscitation council guidelines.