Increase In Bleeding Episodes Research Articles

The common VTE-protective G haplotype of F5 increases factor V-short, TFPI function, and risk of bleeding

AbstractThe G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Although 7% of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA sequencing data from 4651 blood donors in the INTERVAL study, we detected a rare excision event at the factor V (FV)-short splice sites in 5% of F5-G/Gs carriers as compared with 2.16% of homozygotes for the F5 reference sequence (F5-ref; P = .003). Highly elevated (∼10-fold) FV-short, an FV isoform that lack most of the B-domain, has been linked with increased tissue factor inhibitor α (TFPIα) levels in rare hemorrhagic diathesis, including East Texas bleeding disorder. To ascertain whether the enhanced FV-short splicing seen in F5-G/G INTERVAL participants translated to increased plasma FV-short levels, we analyzed plasma samples from 7 F5-G/G and 13 F5-ref individuals in a recall-by-genotype study. A ∼2.2-fold higher amount of FV-short was found in a plasma pool from F5-G/G participants when compared with the pool of F5-refs (P = .029), but there was no difference in the total FV levels. Although no significant difference in TFPI levels were found, F5-G/Gs showed a ∼1.4-fold TFPI-dependent increase in lag time to thrombin generation than F5-refs (P = .0085). Finally, in an analysis of 117 699 UK Biobank participants, we discovered that, although being protective against VTE, the G haplotype also confers an increase in bleeding episodes (P = .011). Our study provides evidence that the effect of the common G haplotype is mediated by the FV-short/TFPI pathway.

COVID-19 infections and vaccination in patients with hereditary hemorrhagic telangiectasia – a cohort study

Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant orphan disease, leading to malformations of blood vessels. Regarding the pandemic, both, the course of COVID-19 infection and the response to the vaccination and its pos- sible side effects, such as increased bleeding episodes, are still poorly investigated. Methodology: Retrospective single-center cohort study at the Department of Otolaryngology / Head & neck Surgery (University Hospital of Zurich, Switzerland) between February 14th and March 21th 2022. Among the 32 eligible adult patients with HHT, we collected patient- and disease-specific characteristics. The course of a COVID-19 infection including severity of the disease and symptoms were noted. We assessed changes in the Hereditary Hemorrhagic Telangiectasia Epistaxis Severity Score (HHT-ESS) before and after vaccination. Results: Out of the 32 patients, 5 patients suffered a COVID-19 infection, thereby mainly experiencing loss of taste and smell and cough. No significant change of the HHT-ESS before and after vaccination was observed. The median HHT-ESS before and after the vaccination was 4.06. Conclusions: There was no significant change in bleeding severity (HHT-ESS) before and after COVID-19 vaccination. Based on these findings, the vaccination for HHT patients does not seem to worsen the further course of the disease. The overall symptoms, risks and complications after Sars-CoV-2 vaccination and infection seem to be comparable to the general population.

Prophylaxis for venous thromboembolism in liver disease: a narrative literature review

Background: Patients with liver disease have traditionally been regarded as auto-anticoagulated against developing blood clots due to haemorrhage being regarded as the most significant haemostatic complication. More recently, there has been increasing recognition that hypercoagulability is a prominent aspect of cirrhosis, with an increasing number of patients developing thromboembolisms. When prescribing prophylactic low molecular weight heparin for prevention, clinicians are often concerned about the risk of bleeding, including gastrointestinal bleeding, specifically in those with decompensated liver disease and cirrhosis, due to the altered coagulopathy associated with these patients. Aim: The aim of this review was to assess if the use of prophylaxis in patients with liver disease is effective in the prevention of venous thromboembolism (VTE) and whether its use is related to an increase in bleeding episodes. Methods: A review of the literature was conducted to identify the incidence of VTE and bleeding in liver patients when given prophylactic VTE treatment. Results: The majority of evidence was inconclusive; however, the main emerging theme was that administering prophylaxis to patients with decompensated liver disease results in an increased risk of bleeding, while having little effect on reducing the risk of VTE development. Conclusion: The bleeding risk associated with VTE prophylaxis treatment and liver disease remains uncertain. Thus the ideal methods of medical prophylactic VTE prevention and monitoring in this patient population have not yet been determined. It is suggested that additional consideration should be given to serum albumin, platelet count and international normalised ratio, as well as renal function, in conjunction with risk assessment tools, when deciding whether to prescribe VTE prophylaxis or not.

Effect of Alteplase Administration on International Normalized Ratio in Patients With Acute Ischemic Stroke.

Alteplase may elevate international normalized ratio (INR) results, although the exact rate of elevation occurrence is not firmly established in the literature. The purpose of this study is to determine the occurrence rate of INR elevation following alteplase administration. We also aimed to determine what factors are independently associated with the development of elevated INR following alteplase administration for ischemic stroke. We conducted a multicenter, retrospective, cohort study of patients who received alteplase for acute ischemic stroke. Patients were screened for baseline INR measurement and a repeat value within 24 hours of alteplase administration. The primary outcome was the percent of patients who experienced ≥0.4-point increase in INR. Secondary outcomes included the rate of adverse bleeding events and identification of factors independently associated with elevated INR following alteplase administration. Two hundred and sixty-one patients were included, with 44 (16.9%) patients having an INR increase of 0.4 or more. Patients with an INR increase ≥0.4 experienced a nonstatistically significant increase in bleeding episodes (8.8% vs 18.2%; P = .10). We identified African American race (odds ratio, 3.48, 95% confidence interval, 1.5-7.6; P = .002) as an independent predictor of INR increase ≥0.04. An INR elevation is common following receipt of alteplase for ischemic stroke. Those of African American race were at increased risk of INR elevation; however, more studies are needed to determine whether these patients are at a higher bleeding risk as a result of INR elevation.

Measuring adherence in pediatric hemophilia patients: French-language adaptation of the VERITAS-Pro and VERITAS-PRN and psychometric properties

Veritas-Pro and Veritas-PRN are instruments to assess adherence to treatment of people with hemophilia. Low adherence can limit treatment effectiveness and result in increased bleeding episodes and...

Celery Plus Anise Versus Metformin for Treatment of Oligomenorrhea in Polycystic Ovary Syndrome: A Triple-Blind Randomized Clinical Trial

Background: Polycystic ovary syndrome (PCOS)-induced oligomenorrhea can leave psychological and non-psychological impacts on women. Among the proposed strategies for its treatment, herbal medications are of importance due to favorable effect profiles. Objectives: We planned a study to compare the effects of Celery and Anise combination (CAC) and metformin (met.) on oligomenorrhea in PCOS patients. Methods:We conducted a triple-blind, Randomized clinical trial on 72 patients that were randomly allocated into two equal groups to receive six capsules of either CAC (750mgeach) or met. (250mgeach) at three separate doses for 15 days beginning from the follicular phase. If the bleeding occurred, three capsules of either placebo or met. would be administered daily during the menstruation phase, and then the follicular phase step with six capsules would be repeated. If the bleeding did not occur, three capsules of either placebo or met. would be administered each day for 15 days. The regularity of menstrual bleeding as the primary outcome, as well as testosterone, luteinizing hormone/follicular stimulating hormone ratio (LH/FSH), and complications, was assessed before and after the three cycles. Results: The mean agestandard deviation of patients was 26.56.1. The mean Body Mass Index was 26.43.5. CAC significantly improved oligomenorrhea (58.3% vs. 25%, P < 0.01), increased bleeding episodes (P = 0.003), and reduced testosterone (mean difference: 0.16 vs. -0.02, P = 0.005) and LH/FSH (mean difference: 0.75 vs. -0.08, P = 0.002) without any major side effects compared to met. Conclusions:We showed that Celery and Anise combination could regulate menstrual cycles and improve oligomenorrhea in polycystic ovary syndrome patients superiorly to metformin.

Effect of an Active Phosphatidylserine Species on Antigen‐Specific Tolerance Induction Towards Factor VIII in Hemophilia A Mice

PurposeThe development of antibodies towards Factor VIII (FVIII) in Hemophilia A (HA) patients is a clinical complication that could lead to the loss of efficacy of treatment and increased bleeding episodes. Therefore, a reduction in immunogenicity to FVIII is an unmet clinical need. Our lab has previously shown that pre‐exposure of Factor VIII (FVIII) in the presence of phosphatidylserine (PS) is able to induce immunological tolerance or hypo‐responsiveness to FVIII in Hemophilia A mice by converting an immunogen to a tolerogen (Gaitonde et al, 2013). The PS that was previously used was derived from an animal source and was heterogeneous in its structure. The identification of an active synthetically‐derived PS species with optimal biophysical and structural requirements for an effective tolerance is critical. This work investigated the ability of a synthetic PS species (s‐PS) with acyl chain oxidation and unsaturation in antigen‐specific tolerance induction towards FVIII in HA mice.MethodsIn vivo studies were carried out in FVIII KO mice and all protein doses were 0.4 μg. Mice received weekly subcutaneous (SC) injections of FVIII in the absence and presence of PS and s‐PS liposomes. On week 6, mice received four weekly intravenous re‐challenge injections of FVIII 24 hours after SC liposome treatment. Two weeks after the last re‐challenge, all animals were sacrificed and plasma collected for titer analysis. To investigate the antigen specificity, mice received four weekly SC injections of FVIII in the presence and absence of s‐PS liposomes. Two weeks after the last injection, half the animals were re‐challenged with four weekly SC injections of FVIII alone while the other half received OVA, an irrelevant antigen. Two weeks after the last re‐challenge, all animals were sacrificed and plasma analyzed for anti‐FVIII and anti‐OVA antibody development.ResultsAnimals that received the s‐PS treatment displayed a significant reduction in both the total anti‐FVIII titers and neutralizing titers compared to animals that received free FVIII alone. Animals that received PS liposomes displayed a significant reduction in only the neutralizing titers compared to animals that received free FVIII alone. In the antigen specificity study, mice treated with s‐PS liposomes displayed a significant reduction in anti‐FVIII titers compared to those treated with free FVIII alone at baseline. Mice treated with s‐PS liposomes displayed a trend towards lower antibody development towards FVIII at the end of the study compared to mice treated with free FVIII alone. All mice, irrespective of treatment with s‐PS liposomes or free FVIII, displayed a robust immune response to the irrelevant antigen, OVA.ConclusionReduction in immunogenicity and tolerance induction towards FVIII was observed when mice were treated with s‐PS liposomes. This tolerance induction strategy using s‐PS liposomes was shown to be antigen‐specific and not general immunosuppression. The identification of a single PS species that could be responsible for the PS‐mediated effects observed is important to allow for further optimization and clinical translation.Support or Funding InformationThis work was supported by the National Institute of Health grant (R01 HL‐70227) to Dr. Sathy V. Balu‐Iyer.

Strategies to Optimize Dual Antiplatelet Therapy After Coronary Artery Stenting in Acute Coronary Syndrome.

The use of aspirin and a P2Y12 receptor antagonist as dual antiplatelet therapy (DAPT) has become the treatment of choice in patients with acute coronary syndrome (ACS) and percutaneous coronary intervention to prevent recurrent thrombotic events. Although DAPT is beneficial for most patients, few patients still experience recurrent thrombotic events and increased bleeding episodes. This article reviews current literature to identify various approaches that may enhance the DAPT benefit-risk ratio in patients with ACS. Three strategies addressed in this article include the following-(1) use of more potent antiplatelet agents other than clopidogrel; (2) addition of direct oral anticoagulants (DOACs) to DAPT; and (3) optimizing DAPT duration. Although the use of prasugrel or ticagrelor improves treatment efficacy, their use has been associated with increased risk of bleeding compared to clopidogrel. The combination of DOACs and DAPT may not be the most viable strategy because of its limited cardiovascular benefits and increased bleeding risks. The optimal duration of DAPT duration remains controversial. Most guidelines recommend 6 to 12 months of DAPT, whereas emerging studies have shown benefit for both shorter and longer duration of treatment. Risk stratification tools such as the DAPT score may play a role in individualizing DAPT duration according to patient's ischemic and bleeding risks.

Antiplatelet therapies: An overview

The role of blood components including platelets, in initiating inflammation, endothelial dysfunction, atherosclerosis, thrombus formation, thrombus growth, and acute vascular ischemic events, is well established. Given this recognized role played by platelets, there is a considerable interest in understanding the physiology and function of platelets, as well as in the development of novel platelet function-inhibitory drugs. The generation of the second messengers, calcium mobilization, shape change, adhesion, aggregation, contraction, release of granule contents, thrombus development, thrombus growth, and formation of hemostatic plug at the injured vessel surfaces, in brief, constitute platelet activation. Some of the known compounds that inhibit platelet activation include inhibitors of arachidonic metabolism (cyclooxygenase-1 inhibitors; aspirin, ibuprofen, etc.), adenosine diphosphate receptor antagonists (P2Y 12 inhibitors), adenylyl and guanylyl cyclase stimulators, calcium antagonists, and GP11b/111a receptor antagonists. Since platelets have multiple mechanisms of achieving in vivo activation, it is difficult to design a novel drug that offers total protection for developing acute ischemic vascular events, without compromising coagulation mechanisms. Given this complexity, any aggressive antiplatelet therapy results in increased bleeding episodes. Having said that, we feel that there is a great window of opportunity for developing novel antiplatelet therapies. There is also scope for the development of fixed-dose combinations for the primary and secondary management of chronic diseases such as hypertension, heart disease, and type-2 diabetes.

Efficacy and safety of antithrombotic regimens after coronary intervention in patients on oral anticoagulation: Traditional and Bayesian meta-analysis of clinical trials

ObjectiveTo perform a systematic review and meta-analysis to assess the efficacy and safety of diverse antithrombotic regimens in patients on long-term anticoagulation after percutaneous coronary intervention (PCI). MethodsAfter searching electronic database (up to 27 June 2015), we included trials comparing dual antiplatelet therapy (aspirin plus clopidogrel), oral anticoagulant (OAC) plus clopidogrel, OAC plus aspirin, or triple therapy (OAC with clopidogrel and aspirin). Efficacy outcomes were major adverse cardiovascular event (MACE), ischemic stroke, myocardial infarction (MI), and all-cause mortality; safety outcomes included major bleeding and any bleeding. We conducted both traditional and Bayesian network meta-analysis, computing pooled odds ratio (OR) with 95% confidence intervals (CI) to compare diverse antithrombotic therapies simultaneously. ResultsEighteen trials were included in the quantitative analysis. OAC plus clopidogrel and triple therapy were associated with a lower risk of MACE, ischemic stroke, MI and all-cause mortality compared with dual antiplatelet or OAC plus aspirin regimens. OAC plus clopidogrel was ranked the most efficacious option without an increase in bleeding episodes. However, triple therapy improved the efficacy outcomes at the expense of increasing hemorrhage. For the initial short-term outcomes, OAC plus clopidogrel inconclusively reduced the risk of MACE and had a significantly lower risk of any bleeding. ConclusionsOAC plus clopidogrel may be the optimal antithrombotic therapy in patients on oral anticoagulation undergoing PCI, which has equal or better efficacy outcomes without increasing the rates of bleeding episodes. Moreover, we found initial triple therapy to be unnecessary as it increased the risk of bleeding.

The Bleeding Tendency In Relation To Predicted FVIII Activity Levels In Severe Hemophilia A Patients Treated With Recombinant Factor VIII Fc Fusion Protein

IntroductionProphylactic regimens with coagulation factor in patients with hemophilia A have been designed to maintain FVIII activity above 1 IU/dL, based on previous studies demonstrating that joints can be preserved and bleeding is minimized when circulating factor levels remain above this level (Nilsson IM, et al. J Intern Med 1992). Collins and colleagues confirmed this observation and demonstrated that increasing time spent under 1 IU/dL FVIII activity in patients on prophylaxis with recombinant FVIII (rFVIII) was associated with an increase in bleeding episodes and hemarthroses (Collins PW, et al. J Thromb Haemost 2009). The pharmacokinetics (PK), safety, and efficacy of rFVIII Fc fusion protein (rFVIIIFc) have been evaluated in the A-LONG study and recently reported (Mahlangu J, et al. J Thromb Haemost 2013). Briefly, previously treated male patients, ≥12 years old with severe hemophilia A, were enrolled in A-LONG and allocated to 1 of 3 treatment arms: Arm 1) individualized prophylaxis with dose and dosing interval adjustments (25–65 IU/kg every 3–5 days) based on PK and clinical indications, Arm 2, fixed dose (65 IU/kg) weekly prophylaxis, and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. The median annualized bleeding rates for individualized prophylaxis and weekly prophylaxis were 1.6 and 3.6, respectively, and 33.6 for episodic treatment. In this analysis, we evaluated the bleeding tendency in relation to predicted FVIII activity levels in 163 subjects in the A-LONG study. MethodsA 2-compartment population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12 – 65 years old (16 from a Phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment) (Neelakantan S, et al. J Thromb Haemost 2013). Individual post-hoc PK parameters were derived to construct continuous FVIII activity-time profiles for each dose administered over the course of the study for 163 subjects in A-LONG. The cumulative time under 1IU/dL FVIII levels for each individual on study was calculated and normalized to obtain annualized time under 1IU/dL. Negative binomial regression models were used to evaluate associations between the number of bleeding episodes (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1IU/dL FVIII activity. Models were adjusted for age, body mass index, baseline HIV and HCV status, baseline von Willebrand factor, number of bleeding episodes in the 12 months prior to study entry, and each subject's time on study. ResultsThe predicted median annualized time under 1IU/dL FVIII activity for subjects on episodic treatment was 224.81 days, which was shortened to 51.55 days in subjects on a fixed prophylactic dose of 65 IU/kg of rFVIIIFc once weekly, and further reduced to 2.17 days in subjects on tailored prophylactic regimens (25 – 65 IU/kg, every 3 – 5 days). Multivariable negative binomial regression analysis showed that the number of overall bleeding episodes increased with increased time spent under 1IU/dL of FVIII activity level (p<0.001). A significant association was also observed for the time under 1IU/dL and the individual bleed types (spontaneous, traumatic, and joint) when analyzed separately. In addition, across all subtypes of bleeding, there was a significant decrease in the odds of being bleed-free for each one day increase in the time spent under 1IU/dL of FVIII activity. ConclusionsIn subjects treated with rFVIIIFc in the A-LONG study, there was a significant association between increased time spent under 1IU/dL of FVIII activity and increased bleeding tendency, as well as decreased odds of being bleed-free. The findings reinforce the importance of a therapeutic threshold of 1 IU/dL of FVIII activity as reported previously, and contribute to building a stronger foundation for designing effective rFVIIIFc prophylactic dosing regimens based on population PK simulations of FVIII activity. Disclosures:Pasi:Bayer: Membership on an entity's Board of Directors or advisory committees; Bio Products Laboratory Ltd: Membership on an entity's Board of Directors or advisory committees; OctaPharma : Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Wang:Biogen Idec: Employment. Kulke:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.

Efficacy and safety of the use of heparin as thromboprophylaxis in patients with liver cirrhosis: A systematic review and meta-analysis

Venous thromboembolism is a common cause of morbidity and mortality. Although cirrhosis has classically been considered as an acquired bleeding diathesis, there is increasing evidence that rejects the traditional belief that these patients are naturally protected against venous thromboembolism. However, antithrombotic prophylaxis in this setting is still underused. The aim of this review is to assess if the use of heparin in cirrhotic patients is effective in the prevention of venous thromboembolism and whether its use is related to an increase in bleeding episodes. We searched in MEDLINE and EMBASE, using the terms "liver cirrhosis", "heparin", "low molecular weight heparin," "venous thrombosis", "deep venous thrombosis", "hemorrhage" and "bleeding". We sought for clinical trials and observational studies performed in patients with liver cirrhosis to evaluate the efficacy or the safety of the heparin. It was used the Mantel-Haenszel method with a random effects model. Odd Ratio was the main measure of effect. The results of the pooled OR and its 95% confidence intervals were expressed in forest plots. The heterogeneity was assessed by the I(2) statistic. The statistical software RevMan was used. The current review found that, although the use of heparin was not related to higher rates of bleeding in cirrhotic patients (pooled OR 0.87 95% CI (0.34-2.18)), it doesn´t decrease the risk of venous thromboembolism in patients receiving prophylaxis, with a pooled OR 1.65 95% (0.36 to 7.54). However, further prospective studies are needed to assess this issue.

Factor VIII prophylaxis for adult patients with severe haemophilia A: results of a US survey of attitudes and practices

The emergence of a population of relatively healthy adults with severe haemophilia A presents a unique challenge for haemophilia care in the 21st century. Understanding how best to continue, restart, initiate or modify prophylaxis in younger and older adult patients is essential to optimizing their care. To elucidate practice and outcome data, a survey was sent to 23 US hemophilia treatment centers (HTCs); 10 centers responded, providing data concerning up to 145 adults (mean age of 34 years). Forty-eight patients (33%) were on regular prophylaxis when first seen at the HTC; the prophylactic regimen was modified for 22/48 (46%), often because of breakthrough bleeding. Five of 21 patients (24%) for whom data were available discontinued prophylaxis. Three of those five patients (60%) experienced increased bleeding episodes and the other two (40%) subsequently resumed regular prophylactic infusions because of the increased bleeding. Of the 77 patients not initially receiving prophylaxis for whom data were available, prophylaxis was started or resumed in all. The prophylactic regimen was modified in 57/77 patients (74%) at some point during treatment, often because of breakthrough bleeding. Of the 55 patients whose prophylactic regimens were modified for whom data were available, 22 (40%) discontinued prophylaxis. Thirteen of 20 patients (65%) for whom data were available experienced an increase in bleeding episodes and 7/18 patients (39%) who had discontinued prophylaxis and for whom data were available subsequently resumed regular prophylactic infusions because of bleeding. These findings suggest that prophylaxis prevents bleeding in adults with severe haemophilia A and that discontinuation of the prophylactic regimen is associated with increased bleeding events.

Treatment of hepatitis C in patients with haemophilia – the Israeli National Hemophilia Center experience

Treatment with pegylated interferon (Peg-IFN) and ribavirin, now the standard of care, has been shown to achieve sustained viral response (SVR) in up to 60% of patients with hepatitis C (HCV). Studies of response to this combination in HCV-infected haemophilia patients are scarce. The aim of the study was to report the results and safety of interferon/ribavirin treatment in HCV and HCV-/HIV-infected patients at the Israeli National Hemophilia Center. A retrospective observational cohort study was conducted on haemophilia patients infected with HCV or HCV/HIV. Patients received combination of Peg-IFN and ribavirin. Few were still treated with standard interferon. The primary end-point was sustained viral response (SVR). The secondary end-point was safety, with emphasis on increased bleeding episodes. Some 18/43 (42%) HCV mono-infected haemophilia patients achieved SVR. Relapse occurred in 14 (33%), while 11 patients (25%) were non-responders. SVR was achieved among 17/37 (46%) naïve patients receiving Peg-IFN and ribavirin. Among patients with genotype-1, SVR was achieved in 12/36 (33%) and 11/30 (37%) in the whole group and Peg-IFN treated naïve patients, respectively. In HCV/HIV co-infected patients only 1 patient achieved SVR. Severe anaemia occurred in 14/50 (28%) patients, four received erythropoietin. None maintained stable haemoglobin levels. Two patients had significant bleeding episodes. In our cohort of haemophilia patients, SVR was achieved in a lower than expected rates. A relatively high relapse rate in the HCV mono-infected patients and a very high non-response rate in the HCV/HIV co-infected patients were observed as anticipated. Anaemia was a major side effect and the use of growth factors seemed unrevealing.

Contraception with Levonorgestrel Subdermal Implants ($Norplant^R$) in Benin-City, Nigeria: A 12-year Review

The case notes of 377 clients who accepted Norplant out of 11961 acceptors of family planning methods in the Department of Obstetrics and Gynaecology University of Benin Teaching Hospital, between January 1985 and December 1996 were retrieved and analysed at the end of 2004, for socio-demographic characteristics of the clients, side effects and complications reported and reasons for discontinuation in relation to duration of use. The daily register of the acceptors were analysed for new acceptors of other methods during the same period and confirmed with their case notes. The acceptance incidence of Norplant was 3.2%. The mean age and parity of the acceptors were 32.2 +/- 4.5 years and 3.9 +/- 1.8 respectively. The duration of use ranged between 6 months and 13 years. 65% of the acceptors reported menstrual abnormalities. 48% of them reported reduced bleeding pattern, while 7.5% (25) discontinued method under 4 years of use because of increased bleeding episodes. Other side effects reported were headache 6%, weight gain 3%, mastalgia 1.8%, decreased libido 1.8%, abdominal pain 1.5% and hypertension 1.2%. 20.4% (68) discontinued the use under 4 years because of desire to have another baby. 38.6% (129) had implants removed at 5 years, while 20.1% (67) continued the use for 6-13 years before removal and replacement with another set. Husband's request for removal constituted 7.2% (24). The effectiveness was 100% as no pregnancy was reported during the study period. The continuation rate at 5 years was 58.7%. 43 clients were however lost to follow up. Norplant was found to be an effective and acceptable method of long-term reversible contraception with minimal side effects. The low incidence was attributed to the fact that the implants were donor driven and not included in the country contraceptive logistic system. Norplant acceptors who continued the use after 5 years did so, because they enjoyed it and did not want to part with them without replacement of new sets.

Contraception with levonorgestrel subdermal implants (Norplant) in Benin-City, Nigeria: a 12-year review.

The case notes of 377 clients who accepted Norplant out of 11961 acceptors of family planning methods in the Department of Obstetrics and Gynaecology University of Benin Teaching Hospital, between January 1985 and December 1996 were retrieved and analysed at the end of 2004, for socio-demographic characteristics of the clients, side effects and complications reported and reasons for discontinuation in relation to duration of use. The daily register of the acceptors were analysed for new acceptors of other methods during the same period and confirmed with their case notes. The acceptance incidence of Norplant was 3.2%. The mean age and parity of the acceptors were 32.2 +/- 4.5 years and 3.9 +/- 1.8 respectively. The duration of use ranged between 6 months and 13 years. 65% of the acceptors reported menstrual abnormalities. 48% of them reported reduced bleeding pattern, while 7.5% (25) discontinued method under 4 years of use because of increased bleeding episodes. Other side effects reported were headache 6%, weight gain 3%, mastalgia 1.8%, decreased libido 1.8%, abdominal pain 1.5% and hypertension 1.2%. 20.4% (68) discontinued the use under 4 years because of desire to have another baby. 38.6% (129) had implants removed at 5 years, while 20.1% (67) continued the use for 6-13 years before removal and replacement with another set. Husband's request for removal constituted 7.2% (24). The effectiveness was 100% as no pregnancy was reported during the study period. The continuation rate at 5 years was 58.7%. 43 clients were however lost to follow up. Norplant was found to be an effective and acceptable method of long-term reversible contraception with minimal side effects. The low incidence was attributed to the fact that the implants were donor driven and not included in the country contraceptive logistic system. Norplant acceptors who continued the use after 5 years did so, because they enjoyed it and did not want to part with them without replacement of new sets.

Reply to Letter from Drs. O’Beirne and Auzinger regarding article, “First Use of the Molecular Adsorbent Recirculating System Technique on Patients with Hypoxic Liver Failure after Cardiogenic Shock”, ASAIO J 50; 332–337, 2004.

Thank you for your comments concerning our article. In this first interim analysis of our study, we did not claim that the survival benefit of the Molecular Adsorbent Recirculating System (MARS) group was statistically significant. Nonetheless, an improvement in survival was shown in this patient cohort of the most critically ill patients that one may find in cardiothoracic surgery. Despite the use of mechanical circulatory support, these patients have mortality rates of usually up to 80% after persistent cardiogenic shock.1 To improve survival in these patients is an extremely difficult task. The better survival rate in the MARS group is raising hope and certainly has clinical significance. The study end-point was survival to hospital discharge, which usually was beyond 30 days. As clearly expressed in the Study Methods section, sepsis was an exclusion criteria for our study. Why MARS, though, should not be used, or even the role of it assessed for this patient cohort remains unclear from the reasoning of Drs. O’Beirne and Auzinger. The cardiac performance was comparable at the time of enrollment in both groups and afterwards treated according to necessity. Whether and to which extent continuous veno-venous hemofiltration (CVVH) can clear cytokines is, to our knowledge, disputable. The in vivo study by Kellum et al. cited by our critical readers could only demonstrate a reduction in tumor necrosis factor (TNF)-α and not of any other cytokines; moreover, the study was performed upon septic patients in whom the levels of cytokines might be different from our patients. It is, on the other hand, an accepted fact that MARS therapy does eliminate cytokines. Within the interim analysis, six of the non-MARS group patients were cross-over patients. The total study included 20 patients in each group, with a total of 9 cross-over patients. The overall MARS frequency was 10.5 times per patient and, thus, indeed similar in both groups (8.6 times for the non-MARS group compared with 8.2 times for the MARS group). The untreated patients in the non-MARS group died during the first 48 hours after study inclusion (because of multiple organ failure). The complete study analysis showed, within the surviving group, an average MARS frequency of 4.8 times. Patients requiring more than 14 settings of MARS therapy all died. This supports our initial results that MARS should be used early, and as this became obvious fairly soon in our study, it was the reason for allowing a cross-over group. The increase in bleeding episodes that might be related with MARS therapy and were described by other investigators are more or less observational findings in studies including a very small number of patients, and again their patient cohorts were essentially different from ours. Doria et al.2 performed a study on 10 patients with cirrhosis and described several observations from which they assume that MARS caused a coagulopathy. We did not perform thromboelastogram (TEG) examinations on all of our patients included in the MARS study, but we regularly apply this method now for our mechanical circulatory support patients. Up to now, in case these patients undergo MARS therapy again, we have not observed a relationship between MARS and a worsening of the TEG, but we are certainly keen to verify this in a further MARS study. Hartl et al. applied MARS to five postsurgical patients, of whom two had primary liver disease, two others had pancreatic carcinoma, and the last one had persistent biliary leak and cholangitis. All patients were only included in the study if they presented septic multiple organ dysfunction. Again, we would not apply MARS in septic patients, and we do not think that the patient cohorts are comparable. In our patients, no bleeding complications occurred and no coagulopathy developed. Maybe our primarily cardiac patients do react differently than those with primary liver or abdominal disease. Nevertheless, we still think that there is a chance for selected patients to benefit from MARS therapy. All nonevidence based therapies need to be applied with caution and respect but should be given a chance to become evidence based. Aly El-Banayosy Dagmar Cobaugh Department of Cardiothoracic Surgery, Heart Center NRW, Ruhr University Bochum, Georgstrasse, Oeynhausen, Germany.

Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in the management of ischemic stroke.

The only drug approved by the US FDA for use in patients with acute ischemic stroke is the thrombolytic, alteplase. Whereas alteplase rapidly restores blood flow, the drug has to be administered within 6 hours after symptom onset and is associated with an increased incidence of intracerebral hemorrhage (ICH). Moreover, transient and permanent re-occlusions associated with increased mortality continue to occur after thrombolysis with alteplase. Platelets are believed to play a pivotal role in the pathogenesis of atherothrombosis and the binding of the platelet glycoprotein (GP) IIb/IIIa receptor to fibrinogen is the final common pathway leading to platelet aggregation and thrombus formation. Antiplatelet agents such as platelet GP IIb/IIIa receptor antagonists have been studied in numerous multicenter, randomized clinical trials in patients with acute coronary symptoms (ACS). The intravenous GP IIb/IIIa receptor antagonists abciximab, eptifibatide and tirofiban are approved by the FDA for use in patients with ACS, and intravenous tirofiban is also approved for use during coronary intervention. Oral GP IIb/IIIa receptor antagonists such as lotrafiban, xemilofiban, sibrafiban and orbofiban have failed to provide myocardial protection in patients with ACS. Compared with ACS, few trials have evaluated the efficacy and tolerability of platelet GP IIb/IIIa receptor antagonists in patients with cerebrovascular syndromes. Agents such as SM-20302, TP201, ME3277, murine 7E3 F(ab')(2 )and SDZ-GPI 562 have been reported to preserve microvascular patency in different animal models of acute ischemic stroke and they may have neuroprotective properties. Platelet GP IIb/IIIa receptor antagonists may be suitable as a single therapeutic or as an adjunct therapeutic to thrombolysis with alteplase for the treatment of stroke. Platelet GP IIb/IIIa receptor antagonists may enhance the efficacy of thrombolytics and reduce potentially fatal adverse effects such as ICH. Preliminary results from the Abciximab in Emergent Stroke Treatment Trial (AbESTT) indicate that abciximab, administered as a bolus dose 0.25 mg/kg followed by 12-hour infusion, was associated with significant improvement in clinical rating scores and no significant increase in bleeding episodes in patients with acute stroke. The tolerability of argatroban in patients with acute stroke is currently being assessed in the multicenter Argatroban in Ischemic Stroke (ARGIS-1) trial.

Changes in menstrual and haematological indices among norplant® acceptors

A longitudinal study of women using Norplant® was conducted to determine the effects of levonorgestrel implants on menstrual and haematological indices among the acceptors. Packed cell volume (PCV), white blood cell (WBC) concentrations (total and differential), and platelet concentration were performed at pre-insertion and at the 12-month follow-up. Each acceptor received a menstrual calendar to chart all bleeding, and spotting events. The mean PCV was 40.5 ± 2.4 at insertion and had a statistically significant (p <0.01) rise to a mean value of 42.2 ± 2.6 at 12 months. The mean WBC concentration had a significant decrease at 12 months (p <0.001) when compared with the pre-insertion value. Similarly, the neutrophil and lymphocyte concentration had a statistically significant decrease (p <0.05 and p <0.01, respectively) at 12 months of use. The reduced values in the concentrations of monocytes, eosinophils and basophils did not reach significant levels. The mean value of the platelet concentrations had a significant decline at 12 months of use (p <0.001). Reduced bleeding patterns were more commonly reported compared to increased bleeding episodes. This pattern was associated with increased PCV, a change that may prevent anaemia in developing countries. The decline in the platelet concentration at 12 months of study was, however, a source of concern that will require follow-up.

Successful use of protease inhibitors in HIV-infected haemophilia patients.

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group. Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 x 10(6)/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.