Intravenous immunoglobulin given to lymphoma patients with recurrent haemolytic transfusion reactions after transfusion of compatible blood

Accelerated destruction of red cells after transfusion of compatible blood has been reported in both sickle cell disease (SCD) and non-SCD patients. We report three patients with lymphoma, all of whom had recurrent haemolytic transfusion reactions after receiving compatible red cell units. The direct antiglobulin test (DAT) was negative and there were no detectable red cell alloantibodies in either pre-transfusion or post-transfusion samples. As there was no evidence of red cell antibody-mediated haemolysis and response to oral steroids, a trial of intravenous immunoglobulin (IVIg) was given. Immediate cessation of haemolysis with sustained haemoglobin level was achieved in all cases. The response to IVIg in these cases suggests that IVIg should be tried when recurrent non-antibody mediated haemolytic transfusion reactions occur in patients with a lymphoid malignancy.     

Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease

Hyperhaemolysis syndrome (HS), a syndrome in which there is destruction of both donor and recipient red cells after transfusion, is well recognised in patients with sickle cell disease and beta-thalassaemia. It has also been reported in a patient with myelofibrosis. In acute forms of HS, evidence of red cell antibody-mediated haemolysis is lacking, and it has been proposed that the transfused and the patient's own red blood cells were destroyed by hyperactive macrophages. Continuation of transfusion may be lethal as this can further exacerbate haemolysis. We report two cases of HS successfully treated with IVIg and IV methylprednisolone. The cessation of haemolysis following administration of IVIg and IV methylprednisolone supports the view that hyperactive macrophages contribute to the RBC destruction. IVIg and methylprednisolone appear to have a synergistic effect on suppressing the activity of macrophages.     

Use of Intravenous Immunoglobulin and Intravenous Methylprednisolone in Hyperhaemolysis Syndrome in Sickle Cell Disease

Hyperhaemolysis syndrome (HS), a syndrome in which there is destruction of both donor and recipient red cells after transfusion, is well recognised in patients with sickle cell disease and β-thalassaemia. It has also been reported in a patient with myelofibrosis. In acute forms of HS, evidence of red cell antibody-mediated haemolysis is lacking, and it has been proposed that the transfused and the patient's own red blood cells were destroyed by hyperactive macrophages. Continuation of transfusion may be lethal as this can further exacerbate haemolysis. We report two cases of HS successfully treated with IVIg and IV methylprednisolone. The cessation of haemolysis following administration of IVIg and IV methylprednisolone supports the view that hyperactive macrophages contribute to the RBC destruction. IVIg and methylprednisolone appear to have a synergistic effect on suppressing the activity of macrophages.     

Delayed haemolytic transfusion reaction due to anti-M antibody

A female patient with delayed haemolytic transfusion reaction due to anti-M antibody is described. Diagnosis was based on laboratory evidence of haemolysis and on characteristic serological findings. Anti-M was detected in the recipient's serum 7 d after the last transfusion episode. This alloantibody had not been present in the pretransfusion serum. In addition, the direct antiglobulin test was positive on post-transfusion testing and the implicated antibody was eluted from post-transfused red cells.
Delayed haemolytic transfusion reactions have long been recognized as a potencial hazard of transfusion therapy, but such cases due to anti-M are extremely rare.     

Delayed haemolytic transfusion reaction in paediatric patients with sickle cell disease: A retrospective study in a French national reference centre

Delayed haemolytic transfusion reaction (DHTR) is a life-threatening haemolytic anaemia following red blood cell transfusion in patients with sickle cell disease, with only scarce data in children. We retrospectively analysed 41 cases of DHTR in children treated between 2006 and 2020 in a French university hospital. DHTR manifested at a median age of 10.5 years, symptoms occurred a median of 8 days after transfusion performed for an acute event (63%), before surgery (20%) or in a chronic transfusion programme (17%). In all, 93% of patients had painful crisis. Profound anaemia (median 49 g/L), low reticulocyte count (median 140 ×10⁹/L) and increased lactate dehydrogenase (median 2239 IU/L) were observed. Antibody screening was positive in 51% of patients, and more frequent when there was a history of alloimmunisation. Although no deaths were reported, significant complications occurred in 51% of patients: acute chest syndrome (12 patients), cholestasis (five patients), stroke (two patients) and kidney failure (two patients). A further transfusion was required in 23 patients and corticosteroids were used in 21 to reduce the risk of additional haemolysis. In all, 13 patients subsequently received further transfusions with recurrence of DHTR in only two. The study affords a better overview of DHTR and highlights the need to establish guidelines for its management in children.     

Red cell ABO incompatibility and production of tumour necrosis factor-alpha

Tumour necrosis factor-alpha (TNF) is a major mediator of diverse pathophysiological events similar to those of haemolytic transfusion reactions (HTR), such as fever, intravascular coagulation and organ failure. However, the possible role of TNF in HTR has not been investigated. We have constructed an in vitro whole blood model of HTR to examine whether TNF may be produced in red cell ABO incompatibility. TNF was observed in plasma, in a dose dependent manner, when ABO incompatible red cells were added, but not with compatible (group O) cells. Plasma TNF levels were maximal at 2 h, and declined to control levels by 24 h. Haemolysis of incompatible red cells was accompanied by TNF production. Immune haemolysis induced TNF gene expression by buffy coat leucocytes, as determined by Northern blot analysis. Heat inactivation of plasma abolished TNF production, whereas prior treatment with interferon-gamma augmented the response. These results demonstrate that a major cytokine is produced in response to red cell incompatibility, and suggest that TNF may play a role in the pathogenesis of haemolytic transfusion reactions.     

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.     

A physician's guide to transfusion in autoimmune haemolytic anaemia

Patients with autoimmune haemolytic anaemia (AIHA) frequently have anaemia of sufficient severity as to require a blood transfusion. However, it is impossible to find compatible blood when, as is frequently the case, the autoantibody in the patient's serum reacts with all normal red blood cells. Further, the autoantibody may mask the presence of a red cell alloantibody capable of causing a haemolytic transfusion reaction. Optimal patient management in this clinical setting requires special compatibility test procedures in the transfusion service laboratory. Equally important is that clinicians must understand the principles of the compatibility tests performed. Provided appropriate compatibility tests are performed, the indications for transfusion in patients with AIHA are not significantly different than for similarly anaemic patients without AIHA. Communication between clinicians and laboratory personnel are important to review the urgency of transfusion and the compatibility test methods used to select the optimal unit of red blood cells for transfusion.     

Novel uses for recombinant erythropoietin therapy in unlicensed indications

Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.     

Experimental Transfusion Reactions in Monkeys: Haemolytic, Coagulant and Renal Effects of Transfused Isoimmune IgG and IgM

S ummary . IgG and IgM fractions were purified from plasmas of six pairs of monkeys cross-immunized with each others' red cells. Essentially all haemolytic activity was found in IgG fractions. Immune IgG or IgM was transfused into incompatible recipients. A dose of immunoglobulin equivalent to that present in 10 ml of plasma per kg of recipient body weight was used. Red cell mass decreased in direct proportion to quantitative haemolysin content of IgG during the first 4 hr after transfusion. A small decrease was also noted after one IgM transfusion. Parallel increases in plasma and urinary haemoglobin were observed. Disseminated intravascular coagulation (DIC) and anuria or oliguria were seen after every immune IgG infusion. DIC, characterized by falls in platelet count, fibrinogen content, levels of factors V and VIII, and fibrin clots at autopsy varied in severity with the extent of the haemolysis. The amount of haemolysis in vivo was accurately predictable by the QH₅₀, a sensitive in vitro assay of antibody haemolytic activity. No coagulation changes or decreases in urinary volume were noted after immune IgM or control immunoglobulin infusions. These immune IgG infusions in monkeys provide a model for the study of the pathophysiology and therapy of human transfusion reactions.     

A prospective study of the incidence of delayed haemolytic transfusion reactions following peri-operative blood transfusion

Delayed haemolytic transfusion reactions (DHTRs) are a recognized sequel of blood transfusion. The true incidence and importance of this complication have been difficult to estimate due to the lack of any prospective studies. We have carried out such a study by testing 530 patients who were transfused during cardiac surgery. 2% of the patients had new red cell alloantibodies detectable 1 week following transfusion. Despite this finding, and the fact that at the time the study was performed pre-transfusion antibody screening of recipients was not routine practice, no DHTRs were diagnosed on clinical or laboratory criteria. These results indicate that the reported incidences, based on retrospective recognition of DHTRs, are not a serious underestimate of the frequency of the complication.     

Thrombopoietin Activity in Idiopathic Thrombocytopenic Purpura

S ummary . A phenothiazine derivative (chlorpromazine hydrochloride) was investigated as a possible means of reducing the transfusion requirement of patients with paroxysmal nocturnal haemoglobinuria. Results of in-vitro studies have indicated that the drug has both beneficial and detrimental effects on the PNH red cell. Thus, while the osmotic haemolysis time is increased and the degree of acid haemolysis (Ham's test) is decreased, the osmotic fragility is increased on incubation. An in-vivo survival study of ficin-treated rabbit red cells showed no beneficial effect when the rabbits were primed with phenothiazine. It is therefore suggested that whenever drugs of the phenothiazine family are used, it should be with an awareness of potential haemolytic side effects in PNH and possibly in other haemolytic disorders.     

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.     

Delayed intravascular haemolysis following multiple asymptomatic ABO‐incompatible red blood cell transfusions in a patient with hepatic failure

ABO‐incompatible red blood cell (RBC) transfusions have rarely been associated with delayed haemolysis. However, we report the case of a 75‐year‐old man (blood type O) with hepatic disease, who received 5 units of incompatible type B RBCs over 8 days. The patient did not develop symptomatic or biochemical evidence of haemolysis until 7–8 days after the first incompatible RBC unit. The patient had a low anti‐B antibody titre (1 : 64) prior to the first transfusion. The onset of haemolysis was temporally associated with an increase in anti‐B and the infusion of fresh‐frozen plasma. In conclusion, a patient with hepatic failure experienced a delayed haemolytic transfusion reaction after receiving multiple ABO‐incompatible RBC transfusions that were initially well‐tolerated. We speculate that the delayed haemolysis may have resulted from an anamnestic antibody response to the initial incompatible transfusion, or possibly as a result of the transfusion of fresh‐frozen plasma, which might have repleted low complement levels.     

Anti-T haemolysins: the effects of sialic acid removal and 2-aminoethylisothiouronium bromide treatment of erythrocytes on immune lysis

Background and Objectives Intravascular haemolytic reactions are reported in red‐cell T‐activated patients after blood transfusion. The relationship between T antigen antibodies present in normal plasma and these reactions remains unclear. In this study, we assessed the haemolytic activity of T antibodies in vitro in comparison with anti‐A/B antibodies. Materials and Methods We established a haemolysis assay based on treating target red‐blood‐cells (RBCs) with 2‐aminoethylisothiouronium bromide (AET). Two hundred and seven blood donor sera were analysed for anti‐T, anti‐A/B haemolysins and anti‐T agglutinins. Results Anti‐T haemolysins were found in 4 (1·9%) blood donor sera using a standard haemolysis method and in 174 (84%) samples using AET‐treated RBCs. Haemolysis correlated with agglutination titres (P < 10^?7). With both methods, anti‐T haemolysins were much weaker than anti‐A and anti‐B haemolysins. Gradual desialylation of RBCs showed a correlation between sialic acid level as indicated by agglutination with Sambucus nigra lectin and anti‐T mediated haemolysis that was significantly increased (fold 2·4) independently of T antigen expression. Conclusion These data indicate that, in vitro, anti‐T‐mediated haemolysis depends primarily on the degree of desialylation of target RBCs. They suggest that the haemolytic activity of T antibodies‐containing human sera is usually weak and may only become significant in the very rare setting of a profound desialylation of RBCs.     

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.     

Histopathological evidence for macrophage activation driving post-transfusion hyperhaemolysis syndrome

Post-transfusion hyperhaemolysis syndrome (PTHS) is a rare life-threatening transfusion complication reported mainly in sickle cell patients. Its pathogenesis is poorly understood. Antibody-mediated haemolysis and bystander effect have been proposed as putative mechanisms, but in half of cases, red cell antibodies are undetectable, and PTHS develops despite transfusion of cross-matched compatible RBC. An alternate hypothesis proposes activated macrophages as the main drivers of red cell destruction through direct phagocytosis. We report the histopathological findings of two patients with PTHS showing extensive macrophage expansion and erythrophagocytosis, supportive of macrophage activation driving PTHS. This supports a possible role for novel therapies that target macrophage activation.     

Passenger lymphocyte syndrome in liver transplant recipients: a description of 12 cases

BackgroundPassenger lymphocyte syndrome is an important cause of immune haemolysis after solid organ transplantation. It mainly occurs in minor ABO and Rh mismatched transplants. The haemolysis is usually mild and self-limited. We present our experience in passenger lymphocyte syndrome and liver transplantation and review the literature.ResultsA total of 1,217 liver transplants were performed and 12 passenger lymphocyte syndromes were detected: of the 56 cases with minor ABO incompatibility, ten patients developed passenger lymphocyte syndrome (17.9%) and of 147 cases with minor Rh incompatibility, two patients developed the syndrome (1.40%). All patients with passenger lymphocyte syndrome had haemolysis, a decrease of haemoglobin (median 6.8 g/dL) and an increase of bilirubin (median 5.15 mg/dL). The treatment of passenger lymphocyte syndrome consisted of increasing the dose of corticosteroids that the patients were receiving as post-transplantation immunosuppressive therapy and, in the majority of cases, transfusion of donor compatible red blood cells.DiscussionPassenger lymphocyte syndrome in liver transplantation has significant clinical consequences. It is, therefore, important to make the diagnosis rapidly, performing pre-transfusion direct antiglobulin tests, and manage the problem correctly with donor compatible red blood cell transfusions and/or immunosuppressive treatment.     

Effects on erythropoiesis of alemtuzumab-containing reduced intensity and standard conditioning regimens

Haemopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) has been associated with delayed disappearance of host anti-A and anti-B isohaemaglutinins and hindrance of donor erythropoiesis in major ABO mismatched transplants. Erythroid recovery, disappearance of recipient type and appearance of donor-type isohaemaglutinins was compared in 84 patients undergoing RIC and 50 patients with standard-conditioning (SCo) HCT. All patients received alemtuzumab as part of their conditioning. The incidence of immune-mediated anaemia and red cell transfusion usage were also compared. Immune factors affecting post-transplant erythroid kinetics showed little variance between different conditioning regimens. Disappearance of recipient isohaemaglutinins and emergence of donor red cells proceeded at similar rates in RIC and SCo transplants; the effects of ABO mismatch were marginal. Pure red cell aplasia, alloimmune haemolysis and autoimmune haemolytic anaemia were not more common in RIC transplants. We believe that alemtuzumab played a critical role in dampening immune reactions of both the host and the donor. Patients in both conditioning groups had similar post-transplant erythroid burst-forming unit (BFU-E) counts; BFU-E chimaerism analysis showed that 90–100% progenitors were of donor origin. However, transfusion requirements were significantly higher in the SCo group, due at least partly to earlier onset of bone marrow hypoplasia.     

Hereditary non-spherocytic haemolytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain: clinical and molecular studies

In four unrelated patients with chronic haemolysis and markedly reduced red blood cell (RBC) glutathione (49.5%, 12.6%, 11.5% and 15% of the normal concentration respectively), a severe glutathione synthetase (GSH-S, EC 6.3.2.3) deficiency was found. One case exhibited a neonatal haemolytic anaemia associated with oxoprolinuria, but without neurological manifestations. The family study revealed GSH-S activity in both parents to be around half the normal level, a finding consistent with the presumed autosomal recessive mode of inheritance of this enzymopathy. Two cases exhibited a well-compensated haemolytic syndrome without anaemia or splenomegaly at steady state. One of these cases was diagnosed after an episode of acute haemolytic anaemia after fava bean ingestion. The remaining patient suffered from moderate to severe chronic non-spherocytic haemolytic anaemia and splenomegaly, and required occasional blood transfusion for a haemolytic crisis associated with drug ingestion. In this patient, the anaemia was corrected by splenectomy. In addition to GSH-S, a panel of 16 other RBC enzyme activities was also studied in all the patients. Hexokinase, aldolase, glucose-6-phosphate dehydrogenase and pyruvate kinase activities all increased; these increases were to be expected, given the rise in the number of circulating reticulocytes. In two patients, the incubation of RBCs with hydrogen peroxide revealed an enhanced production of malonyldialdehyde. DNA analysis showed a homozygous state for 656 A-->G mutation in patients 2 and 3. The GSH-S gene of patient 1, studied elsewhere, revealed an 808 T-->C. The GSH-S gene of patient 4 was not available for study. The present study demonstrates that GSH-S deficiency is also present in Spain and further supports the molecular and clinical heterogeneity of this enzymopathy