Progestin-only Injectables Research Articles

The relationship between hormonal contraception and cervical dysplasia/cancer controlling for human papillomavirus infection: A systematic review

ObjectiveStudies on the effect of long-term use of combined oral contraceptives (COCs) on cervical dysplasia and/or cancer risk have been inconsistent. Less is known about the effects of other forms of hormonal contraception (HC). We examine whether HC use increases the risk of incident cervical intraepithelial neoplasia (CIN) 2, 3 and/or cancer after accounting for preexisting human papillomavirus (HPV) infection. Study DesignSystematic review of prospective studies on HC use as risk factor for cervical dysplasia with HPV infection documented prior to outcome assessment including PubMed and EMBASE records between January 2000 and February 2020 (Prospero #CRD42019130725). ResultsAmong nine eligible studies, seven described recency and type of HC use and therefore comprise the primary analysis; two studies limit comparisons to ever versus never use and are summarized separately. All seven studies explored the relationship between oral contraceptive (OC) use and cervical dysplasia/cancer incidence: two found increased risk (adjusted odds ratio, aOR = 1.5–2.7), one found no association but decreased risk when restricted to women with persistent HPV (adjusted hazard ratio = 0.5), and four found no association. None of the seven studies differentiated between COC and progestin-only pills (POPs) by use recency or duration. The only study that included injectable progestin-only contraception (DMPA) found increased CIN3 incidence among current versus never users (aOR = 1.6). The one study that included Norplant found no association. Two studies included intrauterine device (IUD) use, but did not differentiate between hormonal and copper IUDs, and found no association. ConclusionWe found no consistent evidence that OC use is associated with increased risk for cervical dysplasia/cancer after controlling for HPV infection. There were too few studies of progestin-only injectables, implants or IUDs to assess their effect on cervical dysplasia/cancer risk. ImplicationsUse of single self-reported HC measures and insufficient distinction by hormonal constituent cloud our understanding of whether some HCs increase risk for cervical cancer. Methodologically rigorous studies with distinct HCs measured as time-varying exposures are needed to inform cervical cancer prevention efforts and improve our understanding of cervical cancer etiology.

Intake of Lycopene and other Carotenoids and Incidence of Uterine Leiomyomata: A Prospective Ultrasound Study

BackgroundUterine leiomyomata (UL) are the leading indication for hysterectomy in the United States. Dietary supplementation with lycopene was associated with reduced size and incidence of oviduct leiomyoma in the Japanese quail. Two US prospective cohort studies of women reported little association between intake of lycopene, or other carotenoids, and UL incidence. However, these studies relied on self-reported physician-diagnosed UL, which is prone to misclassification. ObjectiveThis study examines the association between dietary intake of carotenoids and UL incidence. DesignData were derived from the Study of the Environment, Lifestyle, and Fibroids, a prospective cohort study. Women completed self-administered baseline questionnaires on demographic characteristics, reproductive history, and lifestyle, including a 110-item validated food frequency questionnaire, from which dietary intakes of carotenoids—including alpha carotene, beta carotene, cryptoxanthin, lutein-zeaxanthin, and lycopene—and vitamin A were estimated. Participants/settingOne thousand two hundred thirty Black women aged 23 to 35 years who did not have a previous diagnosis of UL, cancer, or autoimmune disease were eligible for enrollment (2010-2012). Participants were residents of the Detroit, MI, metropolitan area. Main outcome measuresTransvaginal ultrasound was used to assess UL at baseline and 20, 40, and 60 months of follow-up. Statistical analyses performedCox regression was used to estimate hazard ratios and 95% CIs, adjusted for energy intake, age at menarche, education, body mass index, parity, age at first birth, years since last birth, current use of oral contraceptives or progestin-only injectables, alcohol intake, and cigarette smoking. ResultsAmong 1,230 women without prevalent UL at baseline, 301 incident UL cases during follow-up were identified. Intakes of lycopene, other carotenoids, and vitamin A were not appreciably associated with UL incidence. Hazard ratios comparing quartiles 2 (2,376 to 3,397 μg/day), 3 (3,398 to 4,817 μg/day), and 4 (≥4,818 μg/day) with quartile 1 (<2,376 μg/day) of lycopene intake were 1.03 (95% CI 0.72 to 1.47), 1.22 (95% CI 0.86 to 1.72), and 0.95 (95% CI 0.67 to 1.36), respectively. ConclusionsStudy findings do not support the hypothesis that greater carotenoid intake is associated with reduced UL incidence.

Human papillomavirus infection and cervical dysplasia in HIV-positive women: potential role of the vaginal microbiota.

To assess the associations between microbiological markers of vaginal dysbiosis and incident/cleared/type-swap/persistent high-risk human papillomavirus (hrHPV) infection; and incident/cured/cleared/persistent high-grade cervical intraepithelial neoplasia (CIN2+) while controlling for persistent hrHPV infection. Two nested case-control studies (N = 304 and 236) within a prospective cohort of HIV-positive women in Johannesburg, South Africa. Participants were examined for hrHPV type (INNO-LiPA), cervical dysplasia (histology), and vaginal microbiota (VMB) composition (V3-V4 Illumina HiSeq 2x300 bp) at baseline and endline, a median of 16 months later. Women with incident hrHPV compared to those who remained hrHPV-negative were less likely to have an optimal Lactobacillus crispatus or jensenii-dominated VMB type at end-line [relative risk ratio (RRR) 0.125, P = 0.019], but not at baseline. Having different hrHPV types at both visits was associated with multiple anaerobic dysbiosis markers at baseline (e.g. increased bacterial vaginosis-associated anaerobes relative abundance: RRR 3.246, P = 0.026). Compared to women without CIN2+, but with hrHPV at both visits, women with incident CIN2+ had increased Simpson diversity (RRR 7.352, P = 0.028) and nonsignificant trends in other anaerobic dysbiosis markers at end-line but not baseline. These associations persisted after controlling for age, hormonal contraception, and CD4 cell count. Current hormonal contraceptive use (predominantly progestin-only injectables) was associated with increased CIN2+ risk over-and-above persistent hrHPV infection and independent of VMB composition. hrHPV infection (and/or increased sexual risk-taking) may cause anaerobic vaginal dysbiosis, but a bidirectional relationship is also possible. In this population, dysbiosis did not increase CIN2+ risk, but CIN2+ increased dysbiosis risk. The CIN2+ risk associated with progestin-only injectable use requires further evaluation.

Side Effects and Health Benefits of Depot Medroxyprogesterone Acetate: A Systematic Review.

Counseling about potential side effects and health benefits of contraceptive methods could facilitate continued method use and method satisfaction, yet no evidence-based compilation of side effects and benefits exists to aid such counseling. Among contraceptive methods in the United States, depot medroxyprogesterone acetate (DMPA) injectables have the highest discontinuation rates, and most discontinuation is attributable to side effects. This review examines the side effects and health benefits of DMPA to inform counseling. We searched PubMed, POPLINE, EMBASE, Web of Science, Campbell Collaboration Library of Systematic Reviews, the Cochrane Database of Systematic Reviews, the Cochrane Center Register of Controlled Trials, and ClinicalTrials.gov. We included English-language studies published from 1985 to 2016 that enrolled healthy, nonbreastfeeding females aged 13-49 years at risk of unintended pregnancy, compared intramuscular or subcutaneous progestin-only injectables to a contemporaneous comparison group, and addressed at least one key question: 1) What side effects are associated with progestin-only injectable contraceptive use? 2) What health benefits are associated with progestin-only injectable contraceptive use? Study quality was assessed using criteria from the U.S. Preventive Services Task Force. Twenty-four studies met inclusion criteria. None were randomized controlled trials. There were 13 prospective cohort, five retrospective cohort, four case-control, and two cross-sectional studies. Studies of moderate or high risk of bias suggest an association between DMPA use and weight gain, increased body fat mass, irregular bleeding, and amenorrhea. Inconsistent evidence exists for an association between DMPA use and mood or libido changes. Limited evidence exists for an association between DMPA use and decreased risk of cancers and tubal infertility. Higher-quality research is needed to clarify DMPA's side effects and benefits. In absence of such evidence, patient-centered counseling should incorporate the available evidence while acknowledging its limitations and recognizing the value of women's lived experiences.

Pharmacokinetic, biologic and epidemiologic differences in MPA- and NET-based progestin-only injectable contraceptives relative to the potential impact on HIV acquisition in women

Access to safe and effective contraceptive choices is a reproductive right and contributes tremendously to improvements in maternal and child health. Progestin-only injectables, particularly intramuscularly injected depot medroxyprogesterone acetate (DMPA-IM), have received increased attention given findings suggesting a potential association with increased HIV risk. For women at high risk of HIV, the World Health Organization's Medical eligibility criteria for contraceptive use currently aggregate recommendations for all progestin-only injectables, including DMPA-IM, subcutaneously injected DMPA (DMPA-SC) and intramuscularly injected norethindrone/ norethisterone enanthate (NET-EN), except in the case of some drug interactions. We considered whether published data indicate differences or similarities between these injectables relevant to risk of acquiring HIV. In vitro data confirm different biological activities of these distinct progestins, including that MPA, and not NET, binds and activates the glucocorticoid receptor resulting in different biological effects relevant to immune function. Limited clinical data suggest changes in immunologic activity following DMPA-IM and NET-EN initiation, but interstudy variation and study design differences diminish ability to determine clinical relevance and the degree to which DMPA-IM and NET-EN could act differentially. The highest-quality epidemiologic studies suggest a potential 40% increase in HIV incidence in users of DMPA-IM relative to women not using hormonal contraception but no significant increase in risk in users of NET-EN. In our opinion, most of the available biologic activity and epidemiologic data indicate that DMPA and NET-EN are likely to act differently, and data remain too limited to evaluate differences between DMPA-IM and DMPA-SC.

Re-Evaluating the Possible Increased Risk of HIV Acquisition With Progestin-Only Injectables Versus Maternal Mortality and Life Expectancy in Africa: A Decision Analysis.

The association between increased risk of HIV acquisition and use of progestin-only injectables (POIs) is controversial. We sought to compare the competing risks of maternal mortality and HIV acquisition with use of POIs using updated data on this association and considering an expanded number of African countries. We designed a decision-analytic model to compare the benefits and risks of POIs on the competing risks of maternal mortality and HIV acquisition on life expectancy for women in 9 African countries. For the purposes of this analysis, we assumed that POIs were associated with an increased risk of HIV acquisition (hazards ratio of 1.4). Our primary outcome was life-years and the population was women of reproductive age (15-49 years) in these countries, who did not have HIV infection and were not currently planning a pregnancy. Probabilities for each variable included in the model, such as HIV incidence, access to antiretroviral therapy, and contraceptive prevalence, were obtained from the literature. Univariate and multivariate sensitivity analyses were performed to check model assumptions and explore how uncertainty in estimates would affect the model results. In all countries, discontinuation of POIs without replacement with an equally effective contraceptive method would result in decreased life expectancy due to a significant increase in maternal deaths. While the removal of POIs from the market would result in the prevention of some new cases of HIV, the life-years gained from this are mitigated due to the marked increase in neonatal HIV cases and maternal mortality with associated life-years lost. In all countries, except South Africa, typical-use contraceptive failure rates with POIs would need to exceed 39%, and more than half of women currently using POIs would have to switch to another effective method, for the removal of POIs to demonstrate an increase in total life-years. Women living in sub-Saharan Africa cope with both high rates of HIV infection and high rates of pregnancy-related maternal death relative to the rest of the world. Based on the most current estimates, our model suggests that removal of POI contraception from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality under a variety of scenarios.

Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2016: Revised Recommendations for the Use of Hormonal Contraception Among Women at High Risk for HIV Infection.

CDC's U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) (first published in 2010 and updated in 2016) provides evidence-based guidance for the safe use of contraceptive methods among U.S. women with certain characteristics or medical conditions (1), and is adapted from global guidance from the World Health Organization (WHO) and kept up to date based on continual review of published literature (2).* CDC recently evaluated the evidence and the updated WHO guidance on the risk for human immunodeficiency virus (HIV) acquisition among women using hormonal contraception.† After careful review, CDC adopted the updated WHO guidance for inclusion in the U.S. MEC guidance; this guidance states that the advantages of progestin-only injectable contraceptive use (including depot medroxyprogesterone acetate [DMPA]) by women at high risk for HIV infection outweigh the theoretical or proven risks (U.S. MEC category 2). The guidance also includes an accompanying updated clarification, which states that "there continues to be evidence of a possible increased risk of acquiring HIV among progestin-only injectable users. Uncertainty exists about whether this is due to methodological issues with the evidence or a real biological effect. In many settings, unintended pregnancies and/or pregnancy-related morbidity and mortality are common, and progestin-only injectables are among the few types of methods widely available. Women should not be denied the use of progestin-only injectables because of concerns about the possible increased risk. Women considering progestin-only injectables should be advised about these concerns, about the uncertainty over whether there is a causal relationship, and about how to minimize their risk of acquiring HIV." Recommendations for other hormonal contraceptive methods (including combined hormonal methods, implants, and progestin-only pills) remain the same; there is no restriction for their use among women at high risk for HIV infection (U.S. MEC category 1).

Contraceptive method and self-reported HIV status among women in Malawi

ObjectivesWe aimed to describe contraceptive methods used by women in Malawi and determine whether contraceptive use differed by self-reported HIV status. Effective contraception is a primary method of preventing mother-to-child transmission of HIV. Study designAnalysis is based on 12,658 nonpregnant, sexually debuted women ages 15–49 years in the 2010 Malawi Demographic and Health Survey. Analysis was restricted to respondents with contraceptive need (i.e., fecund and did not want a child in the next 12 months) who reported their last HIV test result. We accounted for the two-stage cluster sampling design by applying cluster, stratum and sample weights. We assessed differences in contraceptive method use by HIV status with χ2 tests and multivariable logistic regression. ResultsA total of 893 (7.0%) of respondents reported being HIV positive. Use of long-acting reversible contraception (LARC) was low and did not differ between HIV-positive (1.4%) and HIV-negative (1.9%) women [adjusted odds ratio (aOR)=0.7, 95% confidence interval (CI), 0.4–1.4]. HIV-positive women (15.6%) were less likely than HIV-negative women (30.4%) to use progestin-only injectable contraception (aOR, 0.7; 95% CI, 0.5–0.8). Prevalence of female sterilization was higher among HIV-positive women (17.9%) compared to HIV-negative women (9.2%; aOR=1.7; 95% CI, 1.2–2.3). ConclusionsLARC use was low among adult women with contraceptive need in Malawi. HIV-positive women were less likely to report progestin-only injectable use but more likely to report having undergone female sterilization compared to their HIV-negative counterparts. Noncoercive interventions that provide highly effective methods of contraception to HIV-positive women with contraceptive need are valuable methods of vertical transmission prevention in Malawi. ImplicationsContraceptive use differed by self-reported HIV status among adult women with contraceptive need in Malawi. Female sterilization was significantly higher, and use of progestin-only injectables was significantly lower, among HIV-positive women compared to their HIV-negative counterparts. Use of long-acting reversible contraception was low among both HIV-positive and HIV-negative women.

Ectopic Pregnancy With Use of Progestin-Only Injectables and Contraceptive Implants

Background Use of contraception lowers a woman's risk of experiencing an ectopic pregnancy. In the case of method failure, however, progestin-only contraceptives may be more likely to result in ectopic pregnancies than some other methods such as combined hormonal and barrier contraceptives. Objective To describe ectopic pregnancy risk associated with use of implants and progestin-only injectable contraceptives through a systematic review of published studies. Data sources We searched electronic databases for articles in any language published through May 2015 describing studies of progestin-only injectables and implants. We also searched bibliographies and review articles for additional studies. Study selection and extraction Studies that reported any pregnancies were included in the review. Independent data extraction was performed by two authors based on predefined data fields, and where possible, we calculated the proportion of pregnancies that were ectopic and the ectopic pregnancy incidence rate per 1000 woman-years. Results Fifty-three studies of implants and 28 studies of injectables were identified; 79% reported pregnancy location. The proportion of ectopic pregnancy ranged from 0 to 100% with an incidence of 0-2.9 per 1000 woman-years in studies of marketed levonorgestrel implants. Studies of etonogestrel implants and the injectables, depot-medroxyprogesterone acetate and norethisterone enanthate, reported few ectopic pregnancies. Conclusion Progestin-only contraceptive implants and injectables protect against ectopic pregnancy by being highly effective in preventing pregnancy overall; however, the absolute risk of ectopic pregnancy varies by type of progestin. Risk of ectopic pregnancy should not be a deterrent for use or provision of these methods.

Injectable Contraception: Current Practices and Future Trends

Injectable contraception includes progestin-only and combined estrogen and progestin agents that provide safe and highly effective birth control for one to three months. Injectable agents are widely available and play an important role in family planning programs worldwide. Depot medroxyprogesterone acetate, available for intramuscular injection and subcutaneous injection, is the best known and most broadly distributed injectable contraceptive agent, and is an ideal agent for women who have contraindications to estrogen use. Despite their effectiveness, progestin-only injectables are associated with high rates of discontinuation due to bothersome side effects including abnormal bleeding, health controversies including decreased bone mineral density, and increased risk of human immunodeficiency virus acquisition. Injectables do offer non-contraceptive benefits including symptom control related to endometriosis and fibroids, and decreased risk of endometrial cancer. Research is ongoing to determine new injectable hormone formulations that provide longer-acting contraceptive protection and fewer side effects.

Contraceptive counselling and self-prescription of contraceptives of German gynaecologists: Results of a nationwide survey

Objective To evaluate the attitude toward contraceptive methods of gynaecologists who, in Germany, are the sole prescribers of contraceptives.Methods An anonymous questionnaire was sent to 9545 gynaecologists inquiring about factors involved in their prescription of contraceptives, the contraceptives they preferred, and those they would recommend to their daughter, if they had one.Results The response rate of this survey was 21% (N = 2016). The combined oral contraceptive (COC) was the most commonly prescribed method followed by the levonorgestrel-releasing intrauterine system (LNG-IUS), the vaginal ring, the progestin-only pill (POP), the patch, and the progestin-only injectables. Of the respondents 51% would never prescribe the patch and 45% would never prescribe the hormonal implant at all; 61% would choose the LNG-IUS for themselves/for their partner; 18% would opt for a COC and 8% for the vaginal ring. Concerning their imaginary daughter, 71% would prefer a COC, 26% the ring, and 9% the LNG-IUS. The first counselling session lasted 13.8 ± 4.9 min, and the provision of information on the occasion of following visits 6.6 ± 3.2 min.Conclusion The contraceptives most prescribed by German gynaecologists were COCs, followed by the LNG-IUS, the vaginal ring, and POPs. The spectrum of contraceptives preferred for personal use differed in some ways from those prescribed to patients. Reasons for this discrepancy should be investigated.Chinese 摘要 目的 评估德国妇科医生对避孕方法的态度，在德国这些医生具有独自处方权。方法 共计9545名妇科医生参与了匿名问卷调查，问题包括避孕药具处方的相关因素、他们更愿意选择的避孕药具、他们会推荐给自己女儿（如果有）的避孕药具。结果 调查的有效反馈率为21%（N = 2016）。复方口服避孕药（COC）在处方中应用最普遍，其次为左炔诺孕酮宫内缓释系统（LNG-IUS）、阴道环、单孕激素片剂（POP）、贴片以及单孕激素注射。数据显示，有51%的医生不会处方激素贴片，45%不会处方激素埋植；61%倾向于为自己或伴侣选择LNG-IUS；18%选择COC，8%选择阴道环。若有女儿，71%的妇科医生会为其选择COC，26%选择避孕环，9%选择LNG-IUS。第一次咨询会平均时长13.8±4.9分钟，随后的信息补充访问时长6.6±3.2分钟。结论 德国妇科医生处方中最常选用的避孕方式为COCs，之后依次为LNG-IUS、阴道环和POPs。但医生在个人选择避孕药时与给患者的处方建议有所不同，这一差异的原因需要进一步研究。

Progestin-only contraception: Injectables and implants

Progestin-only contraceptive injectables and implants are highly effective, longer-acting contraceptive methods that can be used by most women in most circumstances. Globally, 6% of women using modern contraception use injectables and 1% use implants. Injectables are the predominant contraceptive method used in sub-Saharan Africa, and account for 43% of modern contraceptive methods used. A lower-dose, subcutaneous formulation of the most widely used injectable, depot-medroxyprogesterone acetate, has been developed. Implants have the highest effectiveness of any contraceptive method. Commodity cost, which historically limited implant availability in low-resource countries, was markedly lowered between 2012 and 2013. Changes in menstrual bleeding patterns are extremely common with both methods, and a main cause of discontinuation. Advice from normative bodies differs on progestin-only contraceptive use by breastfeeding women 0-6 weeks postpartum. Whether these methods are associated with HIV acquisition is a controversial issue, with important implications for sub-Saharan Africa, which has a disproportionate burden of both human immunodeficiency virus (HIV) and maternal mortality.

Use of hormonal contraceptives and HIV acquisition in women: a systematic review of the epidemiological evidence

Whether or not the use of hormonal contraception affects risk of HIV acquisition is an important question for public health. We did a systematic review, searching PubMed and Embase, aiming to explore the possibility of an association between various forms of hormonal contraception and risk of HIV acquisition. We identified 20 relevant prospective studies, eight of which met our minimum quality criteria. Of these eight, all reported findings for progestin-only injectables, and seven also reported findings for oral contraceptive pills. Most of the studies that assessed the use of oral contraceptive pills showed no significant association with HIV acquisition. None of the three studies that assessed the use of injectable norethisterone enanthate showed a significant association with HIV acquisition. Studies that assessed the use of depot-medroxyprogesterone acetate (DMPA) or non-specified injectable contraceptives had heterogeneous methods and mixed results, with some investigators noting a 1·5-2·2 times increased risk of HIV acquisition, and others reporting no association. Thus, some, but not all, observational data raise concern about a potential association between use of DMPA and risk of HIV acquisition. More definitive evidence for the existence and size of any potential effect could inform appropriate counselling and policy responses in countries with varied profiles of HIV risk, maternal mortality, and access to contraceptive services.

Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: a prospective study.

The authors assessed the risk of uterine leiomyomata in relation to reproductive factors and hormonal contraception in a prospective cohort study of US Black women. From March 1997 through March 2001, the authors followed 22,895 premenopausal women with intact uteri and no prior self-reported diagnosis of uterine leiomyomata. The authors used age- and time-stratified Cox regression models to estimate incidence rate ratios for self-reported uterine leiomyomata, confirmed by ultrasound or hysterectomy, in association with selected reproductive and hormonal factors. During 76,711 person-years of follow-up, 2,279 new cases of ultrasound- or hysterectomy-confirmed uterine leiomyomata were self-reported. After adjustment for age, body mass index, smoking, alcohol intake, and other reproductive covariates, the risk of ultrasound- or hysterectomy-confirmed leiomyomata was inversely associated with age at menarche, parity, and age at first birth and positively associated with years since last birth. Overweight or obesity appeared to attenuate the inverse association between parity and uterine leiomyomata. Current use of progestin-only injectables was inversely associated with risk. No consistent patterns were observed for other forms of hormonal contraception. Reproductive history is an important determinant of leiomyomata risk in premenopausal US Black women. Progestin-only injectables may reduce risk.

Steroidal contraceptives and changes in individual plasma phospholipids: possible role in thrombosis

The changes in the levels of individual phospholipids were studies in women during prolonged use of three types of steroidal contraceptive preparation: high-dose combined pills (Noriday 1 + 50 Fe); low-dose combined pills (Nominest Fe) and progestin-only injectables (Depo-Provera). Women on high-dose combined pills had significantly higher (p less than 0.05) mean lysophosphatidylcholine (LPC), sphingomyelin (SPH), phosphatidylserine (PS) and phosphatidylethanolamine (PE) levels, respectively, than the women on low-dose combined pills, progestin-only injectables and the controls, respectively. Women on low-dose combined pills had significantly lower (p less than 0.01) mean LPC and PS levels, respectively, than the controls, while women on progestin-only injectables had significantly lower (p less than 0.01) mean PS and PE levels, respectively, than the controls. Based on the reported high activities of PS and PE in hemostasis, the PE/total plasma phospholipids, PS/total plasma phospholipids and the sum of PE and PS/total plasma phospholipids ratios were calculated to assess the possible overall effect of the changes in plasma phospholipids in steroidal contraceptive users. The results obtained using these indices agree with some earlier reports of an estrogen dose-dependent risk/incidence of thrombosis in steroidal contraceptive users. It is concluded that the observed dose-dependent estrogen-induced alterations in phospholipids, and, most especially, the PE and PS fractions may bear a relationship with thrombotic conditions.