R K Chakraverty’s research while affiliated with Queen Elizabeth Hospital Birmingham and other places

Five patients with ITP were treated with 2 gram intravenous infusions of intramuscular human non specific immunoglobulin (IMIg). Increased platelet counts similar to those achieved with intravenous Rhesus anti D immunoglobulin were observed in four patients. 5000 iu anti D immunoglobulin contain up to 2 g of IMIg, and the clinical responses seen in ITP patients treated with anti D may therefore be attributed to this non specific fraction. This was supported by the in vitro finding that adsorption of the rhesus specific IgG from anti D immunoglobulin did not reduce its inhibitory effect on monocyte Fc receptor function. The dose of intravenous IMIg which produced a response in ITP was less than 2% of the recommended standard dose of intravenous immunoglobulin. This correlated with the higher concentration of IgG polymers in IMIg, and we suggest therefore that the mechanism of action of this material is due to the inhibitory effect of its polymeric IgG fraction on low affinity monocyte/phagocyte Fc receptors.

Summary Anti-Rho(D) immunoglobulin (anti-D) contained more high molecular weight (HMW) IgG polymers than intravenous non-specific immunoglobulin (i.v. Ig). The low-dose anti-D and high-dose i.v. Ig regimens used to treat idiopathic thrombocytopenic purpura (ITP) therefore contained similar total amounts of HMW IgG. In vitro, the HMW IgG polymers were more effective competitive inhibitors of monocyte phagocyte Fc receptors than monomeric IgG. The IgG subclass composition of anti-D and i.v. Ig were both similar to normal human plasma. We conclude that the HMW IgG content but not the IgG subclass composition of anti-D may explain its low-dose therapeutic efficacy in ITP.

Five patients with ITP were treated with 2 gram intravenous infusions of intramuscular human non specific immunoglobulin (IMIg). Increased platelet counts similar to those achieved with intravenous Rhesus anti D immunoglobulin were observed in four patients. 5000 iu anti D immunoglobulin contain up to 2 g of IMIg, and the clinical responses seen in ITP patients treated with anti D may therefore be attributed to this non specific fraction. This was supported by the in vitro finding that adsorption of the rhesus specific IgG from anti D immunoglobulin did not reduce its inhibitory effect on monocyte Fc receptor function. The dose of intravenous IMIg which produced a response in ITP was less than 2% of the recommended standard dose of intravenous immunoglobulin. This correlated with the higher concentration of IgG polymers in IMIg, and we suggest therefore that the mechanism of action of this material is due to the inhibitory effect of its polymeric IgG fraction on low affinity monocyte/phagocyte Fc receptors.

A patient with chronic ITP relapsed after conventional therapy but following an infusion with low dose anti D (Rho) immunoglobulin, she entered a remission which has now lasted 10 months. This is difficult to explain on the basis of long term macrophage Fc receptor blockade and suggests an alternative mechanism of action.

Twenty-three courses of i.v. anti-D (Rho) immunoglobulin were administered to 13 Rh D-positive patients with chronic idiopathic thrombocytopenia (ITP). Clinically significant responses were seen in a proportion of patients treated with 500-2500 i.u. anti-D, but all those treated with 12,500 i.u. (180 i.u./kg) responded. Patients refractory to other forms of treatment responded well to anti-D, and previous splenectomy did not influence the clinical response. No adverse reactions were observed. The anti-D response was preceded by a lag period of 3-16 days and was maintained for 14-145 days. Platelet-associated IgG was increased after treatment, due to improved survival of immunosensitized platelets or platelet Fc receptor binding of high molecular weight IgG in the therapeutic material. There was no clinical or biochemical evidence of haemolysis. The erythrocyte direct Coombs' test remained positive for 3-45 days, and histological examination of splenic material showed no erythrophagocytosis. We conclude that anti-D (Rho) immunoglobulin is a safe and effective treatment for chronic ITP and that the therapeutic dose is now established in standardized units. The mechanism of action appears to be complex and is probably not due to macrophage Fc receptor blockade with immunosensitized red cells.