Non-Intuitive Medicine: Using Anti-D to Treat ITP

Most people are aware of the consequences of Rhesus incompatibility. It's usually the 2nd pregnancy. The mother is Rhesus negative. The father is Rhesus positive and has the D antigen. The foetus inherits the D antigen from the father. The mother's immune system mounts an attack on the D iso-antigens in the child's blood, resulting in haemolysis, sometimes ending fatally in erythroblastosis foetalis.

Now countenance this. Would you consider infusing a patient known to be Rhesus positive with pre-formed antibodies to the Rhesus(D) antigen, deliberately risking haemolysis?

No, I thought not.

Yet, that is exactly what happens in in subjects with severe Idiopathic Thrombocytopenic Purpura (ITP) who have life threatening haemorrhage. If the patient is D+, he/she is infused with anti-D containing immunoglobulin. IgG antibodies to the D antigen agglutinate the subjects' RBCs. Macrophages, mainly in the spleen, recognise the Fc portion of the anti-D immunoglobulins to bind to the D antigen on RBC and take them up actively. In so doing, the reticulo-endothelial system becomes saturated with millions of antibody-agglutinated RBC and is no longer free to bind to and destroy the platelets.

Medicine in reverse.

Of course, a better known agent for treating ITP is intravenous immunoglobulin (IVIG). It was from observing the small incidence of haemolysis in subjects receiving IVIG that the idea of using anti-D arose. Anti-D has a number of advantages over IVIG. These include a substantially shorter infusion time, markedly smaller infusion volume, longer duration of response demonstrated in HIV-infected patients with ITP, lower cost, and exposure to 1/100th as many donors per dose. Increased platelet count is seen in 70-80% of patients receiving anti-D. The dose is 50-75 ug/kg. It is licensed for this purpose in the USA but not in Europe, where plasmapheresis and romiplostim (thrombopoetin agonist) are used in addition to IVIG for treating major bleeding (intracranial or gastrointestinal) in severe ITP.

Anti-D is not without its dangers with such usage. Approximately 1 in 1000 patients develop severe transfusion reactions, with extravascular haemolysis, and increased risk of DIC and acute renal failure. This has resulted in a Black Box warning being issued by the FDA for such usage. However, in most patients, the degree of haemolysis is mild, with Hb dropping by 0.5-2g within a week, and recovering by 3 weeks.

Understandably, anti-D should not be used in those with pre-existing haemolysis, in those with a positive Coomb's test or those with renal impairment. It is ineffective in those who have had a splenectomy. Some haematologists never use anti-D despite its advantages, and prefer IVIG instead.

IgG anti-D does not bind complement. There is therefore no intravascular haemolysis. Haptoglobin and haemopexin do not fall.

References:

1. Despotovic JM, Lambert MP, Herman JH et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy. Transfusion 2012;52:1125-6.