Hyperhaemolysis Syndrome

Hyperhaemolysis syndrome is a severe transfusion complication, mostly in sickle cell disease and less often in thalassaemia, in which both the transfused and the patient's own red cells are destroyed. Haemoglobin falls to a level lower than before transfusion, with a very low reticulocyte count, and further transfusion worsens haemolysis.

Epidemiology. It occurs in about 1 to 4% of transfused patients with sickle cell disease. It may be acute (within 7 days of transfusion) or delayed (7 to 30 days after transfusion). Many patients have had previous uncomplicated transfusion, and recurrence on re-transfusion is frequent.

Triggers. Transfusion for pain crisis, acute chest syndrome, surgery or pregnancy, and previous transfusion with alloimmunisation.

Pathophysiology. Proposed mechanisms are macrophage activation, bystander destruction of the patient's red cells by complement activation, suppressed erythropoiesis from cytokines and haem toxicity. Free haem promotes endothelial injury and vaso occlusion.

Presentation is fever, severe pain (crisis), dark urine, jaundice, dyspnoea, rapid fall in haemoglobin to a level lower than before transfusion, and acute chest syndrome, stroke, renal failure or shock in severe cases. The direct antiglobulin test is often negative, and a new alloantibody may not be found.

Red flags.

• Haemoglobin falling to a level lower than before transfusion.
• Reticulocytopenia, dark urine and rapidly rising lactate dehydrogenase.
• Pain crisis or acute chest syndrome after transfusion.

Full blood count and film, reticulocyte count (low or falling), bilirubin, lactate dehydrogenase, haptoglobin, plasma haemoglobin, direct antiglobulin test, antibody screen and identification, haemoglobin electrophoresis or high performance liquid chromatography (a rapid fall in percentage of haemoglobin A, showing destruction of donor cells), renal function and urinalysis. Search for infection (parvovirus B19, malaria).

Differential diagnosis. Delayed haemolytic transfusion reaction, aplastic crisis, splenic or hepatic sequestration, acute chest syndrome, sepsis, G6PD-related haemolysis and autoimmune haemolysis.

Avoid further transfusion unless life threatening anaemia or end organ ischaemia, since it fuels haemolysis. If essential, use extended phenotype matched blood with specialist advice, accompanied by immunomodulation.

First line immunomodulation.

• Methylprednisolone 1 g IV daily for 2 to 3 days, or prednisolone 1 mg/kg daily.
• Intravenous immunoglobulin 1 g/kg daily for 2 days (or 0.4 g/kg daily for 5 days), given slowly, with renal function monitoring.

Erythropoiesis support. Epoetin alfa (dose directed by specialist, commonly 100 to 300 units/kg daily or three times weekly) with IV iron, folic acid 5 mg daily, and vitamin B12 as needed.

Refractory or life threatening disease. Specialist use of rituximab 375 mg/m2 weekly for 4 doses and complement inhibition (eculizumab, dose and schedule set by the haematology team).

Supportive care. Oxygen, hydration, analgesia for crisis (morphine titrated), treatment of infection, folic acid, and monitoring for acute chest syndrome, stroke and acute kidney injury.

Prevention. Avoid unnecessary transfusion, use extended phenotype matched blood, record prior episodes in a patient alert, and consider prophylactic immunomodulation (steroid and intravenous immunoglobulin) before essential transfusion in patients with a previous episode.

Monitoring. Haemoglobin and reticulocytes daily, bilirubin and lactate dehydrogenase, creatinine, oxygen saturation and neurological state.

Referral and escalation. Haematology, intensive care and transfusion medicine at once.

Special groups. In pregnancy, involve obstetrics and haematology. In children, weight based dosing and stroke vigilance.