Protamine–heparin complex antibodies raise concerns

By Lynda Williams, Senior medwireNews Reporter

mewireNews: Almost a third of patients treated with protamine (PRT) for heparin reversal during cardiopulmonary bypass (CPB) develop antibodies to circulating protamine-heparin (PRT/H) complexes, study findings suggest.

In the absence of further PRT treatment, there was no significant increased risk for thrombocytopenia, thrombosis, or long-term cardiovascular events in the 29% of patients with antibodies against PRT/H complexes at day 3, 7, and 30 after CPB compared with patients without antibodies.

However, the researchers note that the antibodies induce platelet activation and show heparin-dependent binding, similar to antibodies formed against platelet factor 4-heparin (PF4/H) complexes. These are associated with the development of heparin-induced thrombocytopenia and thrombosis.

"The lack of serious adverse outcomes in our study does not imply that PRT/H antibodies are inconsequential," say Gowthami Arepally and co-workers, from Duke University Medical Center in Durham, North Carolina, USA.

"The serologic and functional properties of these antibodies suggest that the antibodies could be pathogenic in the appropriate clinical context of re-exposure."

The study included 500 cardiac surgery patients given heparin and protamine during CBP. The patients were followed-up for thromboembolism for 90 days and then for major adverse cardiac events (death, repeat cardiac surgery, myocardial infarction, or revascularization) for a median of 765 days.

PRT/H antibodies were found in 2% of 101 controls, and 1% of patients at day 0, 2% of patients at day 3-7, and 31% of patients at day 30.

All high-titer PRT/H antibodies bound to PRT/H complexes and 47% of antibodies bound to protamine alone, but there was no reactivity to human (h)PF4 or hPF4/H complexes. PRT/H antibodies showed decreased binding in the presence of excess heparin, and analysis of plasma from three patients seropositive for PRT/H but not PF4/H showed "robust" platelet activation when exposed to PRT.

Analysis also showed that while 78% of the 154 patients with PRT/H antibodies also carried PF4/H antibodies, just 33% of PF4/H seropositive patients were also positive for PRT/H antibodies. Two percent of patients were seropositive for neither complex.

At baseline, patients seropositive for PRT/H were significantly more likely than seronegative patients to have insulin-dependent diabetes and a history of peripheral vascular disease or myocardial infarction. There was also a trend towards decreased event-free survival but this did not reach significance.

At 30 days after CPB, seropositive patients were more likely to have diabetes than seronegative patients, be smokers, and be of a younger average age.

The authors comment in Blood: "Future prospective studies are necessary to define populations at risk and to further characterize the physiologic consequences of protamine re-exposure in sensitized patients."

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