A transient decrease in hemoglobin is to be expected following IV RhIG therapy in D-positive patients. In a large study of 272 patients,3 hemolysis was the main adverse event but decreases in hemoglobin values averaged less than 1 g/dL(10 g/L). The anemia was transient and never severe enough to require a transfusion. No patient group was particularly susceptible to therapy-induced hemolysis and there was no correlation between the dose of anti-D, ranging from 20 to 60 µg/kg (100 to 300 IU/kg), and the degree of hemolysis
In four clinical trials of patients treated with the recommended initial IV dose of 50 µg/kg (250 IU/kg), the mean maximum decrease in hemoglobin was 1.7 g/dL (17 g/L) with a range of+0.4 to ?6.1 g/dL (+4 to ?61 g/L).9 Only 5/137 (3.7%) of patients had a decrease in hemoglobin of greater than 4 g/dL (40 g/L).
Severe complications such as sudden hemoglobinemia or hemoglobinuria were known to occur rarely, but warnings were not present in the product?s package insert.
2000 FDA Report 12
In 2000 the FDA reported the first case series involving 15 patients experiencing IV RhIG-associated acute hemolysis occurring between September 1995and March 1999, four of whom died.12 The author noted that both the follow-up and the literature suggested that physicians and health care professionals who manage ITP patients treated with IV RhIG might be relatively unaware of what appears to be an uncommon but a potentially serious complication.12
Of the 15 patients, 4 experienced no symptoms but most exhibited classic symptoms associated with acutehemolytic transfusion reactions. Of the available data,
The most consistentsign was hemoglobinuria (n=14).
When provided, the urine color rangedfrom pink to red to brown to black.
In the 8 patients in whom hemoglobin was not confounded by RBCtransfusion, the mean decrease was 3.7 g/dL (37 g/L) with a range of 0 to 7.6 g/dL (0 to 76 g/L).
In the patient with the most dramatic drop in hemoglobin,the maximum decrease of 7.6 g/dL (76 g/L) occurred 8 days after treatment and she experienced ongoing hemolysis for at least 20 days, as evidenced by persistent hemoglobinuria.
Of the four patients who died, one refused transfusion and succumbed to pulmonary edema and respiratory distress resultingfrom anemia. Threepatients died from other primary causes, however, the extent to which the hemolysis may have contributedto their deaths isunknown.12
Between May 1999and October 1999,subsequent to initial review, the FDA received an additional 26IV RhIG adverse event reports of possible or probable hemoglobinemia and/or hemoglobinuria in ITP patients, bringing the total to 41 at that time.12
The incidence of acute hemolysis associated with IV RhIG is unknown. Estimates include a 1.5% incidence rate from published clinical trial data and a 0.1% reporting rate from FDA and drug utilization data.12 Reporting rates typically underestimate the incidence. 12
The cause of the acute hemolysis associated with IV RhIG is unknown.
Although the severe sequelae of IV RhIG are not proven to involve intravascular hemolysis (IVH), rapid onset of hemoglobinuria is usually associated with C9-binding antibodies such as anti-A and anti-B and not the non-complement-binding anti-D. Multiple mechanisms may occur or interact and different mechanisms or explanations may account for hemoglobinemia and/or hemoglobinuria in different patients.12 For example, possible additional mechanisms that could be responsible for potentiating hemoglobinemia and/or hemoglobinuria include
- concomitant unreported or undiagnosed diseases such as autoimmune hemolytic anemia and Evan's syndrome;
- plenic saturation resulting in diminished ability to clear anti-D-sensitized red cells;
- IgGaggregates and/or anti-idiotype antibodiesin IV RhIG that may form complement-fixing immune complexesin vivo
- and more.
DIC Case Series (added 5 Sept. 2005)16
In September 2005 the FDA published thefirst case series of DIC associated with acute hemoglobinemia or hemoglobinuria following IV RhIG administered for ITP. The report was based on continued post-marketing surveillance of adverse event reports submitted to the FDA.The case series consisted of 6 patients: 1 child, who recovered without sequelae, and 5 adults, all of whom died. The review concludes:
This review reinforces the suggestion that patients should be closely monitored for signs and symptoms of acute hemoglobinemia or hemoglobinuria, clinically compromising anemia, and renal insufficiency following anti-D IGIV administration for ITP or other thrombocytopenias.It further suggests that it may be prudent to monitor patients experiencing those events for signs and symptoms of DIC. It should also be noted that previous uneventful administration of anti-D IGIV does not preclude the occurrence of acute hemoglobinemia or hemoglobinuria following subsequent administration of anti-D IGIV.
1. What are anti-idiotype antibodies?
Subsequent to the FDA case series, the manufacturer altered the package insert and monograph to alert users to the risk of acute hemolysis. It wasrecommended that patients be monitored for signs and/or symptoms of IVH, clinically compromising anemia, and renal insufficiency, and that serious adverse events should be reported to The manufactureror to the FDA's MedWatch reporting system.14
Given that patients will develop positive antibody screen results after infusions of IV RhIG, the question arises as to what type of RBCs to transfuse:
- type-specific but crossmatch-incompatible D+ RBCs
- crossmatch-compatible D? RBCs
Standard practice in transfusion medicine is to issue crossmatch-compatible RBCs that lack corresponding antigens to which patients have clinically significant antibodies in order to prevent red cell destruction. Therapy with IV RhIG for ITP breaks this principle in that the purpose is to sensitize and destroy autologous red cells and thereby block destruction of IgG-sensitized platelets.
During the Rushin study13 4 patients were transfused with crossmatch-incompatible RBCs on at least one occasion and no adverse effects were observed.
- The authors used the rationale that the primary goal of treatment was to increase the platelet count as quickly as possible and selecting D-positive RBCs would theoretically increase the availability of incompatible red cells and support the primary treatment objective.
- Conversely, they reasoned that selecting crossmatch-compatible D-negative RBCs would circumvent the intent of infusing IV RhIG and may not be the optimal choice, unless anemia (and not platelet count) was the main concern.
In the FDA review of 15 patients who experienced severe sequelae, only 6patients were transfused.12 The mean number of RBCs transfused within hours to days of IV RhIG therapy was 3and, when specified, patients were transfused with D-negative RBCs.
- The author suggests that when transfusing RBCs in the presence of ongoing hemoglobinemia and/or hemoglobinuria, physicians may wish to consider transfusing D-negative RBCs and using caution if platelets are required, since platelet concentrates and apheresis platelets may contain 0.5to 5.0mL of red cells.
The manufacturer of IV RhIG recommends that patients who require transfusion to treat anemia following IVH caused by IV RhIG therapy should receive D-negative RBCs so as not to exacerbate ongoing IVH. They also caution against transfusing D-positive platelets in such circumstances.9