What Impact for Sex Difference on Immune Thrombocytopenic Purpura?

Emmanuel Andrès, MD, PhD

Professor Department of Internal Medicine Competence Center of Autoimmune Cytopenias University Hospital of Strasbourg Strasbourg, France; Tel. 33388115066; Fax: 33388116262; E-mail: emmanuel.andres@chru-strasbourg.fr

Despite the progress in medicine the impact of gender on many diseases remains unknown or unstudied. In this context, it seemed appropriate to us, with a bit of provocation, to study the impact of gender on Immune Thrombocytopenic Purpura (ITP).

ITP, currently also known as primary immune thrombocytopenia, is an autoimmune disorder that results in acute or chronic thrombocytopenia and that may potentially lead to a life-threatening hemorrhagic event.¹

Major advances in our understanding of the pathophysiology of ITP have been done last years (evidence of anti-platelet antibodies and the relative failure of bone marrow platelet production),2 but the diagnosis of ITP still is based on exclusion.¹

While ITP in childhood is usually an acute, self-limiting condition (the thrombocytopenia is transient and recovers spontaneously despite an initially severe presentation), ITP is more often a chronic disease in adults (at least 30% of cases) with an insidious onset requiring multiple therapeutic approache.¹

ITP mainly occurs in young adults, particularly women in their third or fourth decade, with an overall female to male ratio of 3-4 to 1. These figures suggest that sex hormones, as in other immune disorders (systemic lupus, multiple sclerosis, etc.) may play a role in the susceptibility to ITP..³ In addition to having an impact on the immune system, sex hormones may also alter the clinical picture and response to therapy.

In recent years, it has become clear that women and men may differ for drug response. There is an increasing recognition on the role of sex hormones on pharmacokinetics and pharmacodynamics as mechanism accounting for sex differences in drug effects. The available evidence suggests that sex hormones influence drug absorption, distribution, metabolism, pharmacodynamics, and adverse effects. For instance, many cardiovascular drugs are metabolized by enzymes of the cytochrome system, which is more expressed in females than in males, showing sex differences in drug response. A line of evidence also exists that posits that genetic variation among different genders may be responsible for the variability in therapeutic response.

We have previously reported such a gender-related analysis in 225 consecutive cases of established ITP followed up over a period of 1.7 to 112 in the Strasbourg University Hospital (Strasbourg, France).⁴

The analysis of the data revealed significant statistical differences between female and male for: 1) the bleeding score: 13±6.3 in females versus 8.4±4.1 in males (p=0.03); 2) the presence of a documented anemia: 7 % in females versus 4.3 % in males (p=0.04); and 3) the detection of antinuclear and/or antiphospholipid antibodies: 64.7 % versus 35.3 % (p<0.02) (Table 1). For the first 2 parameters, the difference may be related to the presence of meno- and/or metrorrhagia and hematuria in female patients.

No statistically significant difference was found regarding outcome for these 225 patients in relation to their gender (Table 2).

An abundance of recent research indicates that there are multiple differences between males and females regarding both the normal physiological processes and the pathophysiology of disease. Studies have addressed sex-based differences in the physiology and pathophysiology of the cardiovascular, musculoskeletal, and immune systems as well as the mechanism of action of sex steroid hormone actions on nonreproductive tissues.⁵

Thus, as is the case for several other autoimmune disorders, the role of patient gender in the course and outcome of ITP should be considered.

A strikingly common feature observed in many autoimmune diseases in both humans and animal models is that females are highly susceptible to autoimmune conditions as compared with males-regardless of the differences in disease pathology.⁵ This is the case in several documented studies of ITP.¹

In several animal models, estrogens promote, whereas androgens abrogate, B-cell-mediated autoimmune diseases.⁵ Estrogens are able to influence the immune response via several mechanisms, but recently, they have been shown (along with other sex hormones) to largely exert their effects on immune effector cells, modulating the expression and production of several cytokines.⁵ This is a potential explanation for the efficacy of danazol in ITP.⁴

Thus to date, the impact for sex difference on immune thrombocytopenic purpura or on primary immune thrombocytopenia is not known.

ACKNOWLEDGEMENT

Professor E. Andrès has received several grants for lectures, studies or expertise from laboratories (AMGEN, ROCHE, CHUGAI, GSK, VIFOR, BMS, PFIZER, FERRING), but this present work is free of any such association.

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2. Audia S, Lorcerie B, Godeau B, Bonnotte B. Pathophysiology of immune thrombocytopenia. Rev Med Interne. 2011; 32(6): 350- 357. doi: 10.1016/j.revmed.2009.05.017

3. Cines DB, Liebman HA. The immune thrombocytopenia syndrome: a disorder of diverse pathogenesis and clinical presentation. Hematol Oncol Clin North Am. 2009; 23(6): 1155-1161. doi: 10.1016/j.hoc.2009.09.003

4. Andrès E, Mecili M, Fothergill H, Zimmer J, Vogel T, Maloisel F. Gender-related analysis of the clinical presentation, treatment response and outcome in patients with immune thrombocytopenic purpura. Presse Med. 2012; 41(9 pt 1): e426-e431. doi: 10.1016/j. lpm.2012.02.010

5. Blair ML. Sex-based differences in physiology: what should we teach in the medical curriculum? Adv Physiol Educ. 2007; 31(1): 23-25. doi: 10.1152/advan.00118.2006