Heparin-induced thrombocytopenia: the female factor

Comment on Warkentin et al, page 2937

HIT, which may be one of the most common and potentially devastating of the immune-mediated drug reactions, is induced when antibodies that are directed against a complex of platelet factor 4 (PF4) and heparin bind to FcγRII receptors on platelets, thereby inducing activation and removal of the platelets from the circulation.

In this issue of Blood, Warkentin and colleagues have provided convincing data, beginning with large databases and continuing on to analyses of published studies, to show that women are more likely than men to develop heparin-induced thrombocytopenia (HIT) when exposed to unfractionated heparin; the risk is increased and the sex difference maintained in the surgical compared with the medical setting. The authors have shown that for both men and women, low-molecular-weight heparin (LMWH) has minimal risk for HIT, regardless of use in the medical or surgical setting.

The list of autoimmune disorders that are expressed preferentially in women over men is long and includes such hematologic disorders as the antiphospholipid syndrome, idiopathic thrombocytopenic purpura, and thrombotic thrombocytopenic purpura.^1,2  However, a sex difference with respect to a drug-induced immune disorder hasnot previously been highlighted in the literature. The information provided in this report will increase the sensitivity of consultants and critical care personnel to the likelihood of the development of HIT in women in the surgical setting and eventually may lead to specific targeted practices to reduce the frequency of this disorder.

The recognition of the increased likelihood for HIT in women may shed some insights on pathophysiology, although multiple pieces of information concerning the immune system will need to be integrated. We know that inflammation is associated with an increased incidence of HIT; presumably, this is due in part to the release of the PF4 from platelets, but it may also be due to the up-regulation of the immune system. PF4 may up-regulate T-cell activation by impairing the suppressive capacity of the CD4⁺CD25⁺ T regulatory cells.³  In women, the immune system generates a response that is dominated by cytotoxic T cells when exposed to an antigen.⁴  In contrast, the male immune system produces a milder response (T-helper 2 response). Could this partially explain why the present report found that in the surgical situation, which is essentially an inflammatory environment, women were about 4 times more likely than men to develop HIT? In pregnancy, women's immune response shows a pattern similar to that of men. Could this explain the relative paucity of reports about HIT in pregnancy, especially considering that some women have had months of treatment with unfractionated heparin? All of these questions will eventually be answered; they have in part been stimulated by the reporting of clinical data, such as that which the current study provides. The information on sex has not been easy to obtain, clearly demonstrating the perseverance and ingenuity on the part of the authors. In the future, such investigations could be made much simpler if authors were to include the data on sex when reporting their studies, no matter how large or small. ▪