8%) achieving eradication [46]. As a third-line agent, bismuth also may be selleck chemicals llc useful. In one multicenter study from Spain published recently, an eradication rate of 65% was observed for third-line bismuth-based quadruple therapy when standard therapy with clarithromycin and levofloxacin

had failed [47]. Studies on the role of probiotics as an adjunct to H. pylori eradication treatment have again been somewhat equivocal this year. The most frequently studied agents have been Lactobacillus sp. strains. In one study where 70 naïve patients were treated, Lactobacillus reuteri increased eradication rate by 8.6% and reduced the reported side effects when compared with placebo-supplemented triple therapy [48]. A meta-analysis of nine studies on probiotic use as an adjunct to triple therapy found that when specific Lactobacillus strains were used, eradication rates raised significantly by 17%, but when multistrain probiotics were used, eradication rates enhanced click here by

only 2.8% [49]. This also was reflected in two other trials from Iran and Brazil where multistrain probiotics as adjunct therapy failed to show a benefit for eradication [50, 51]. Another study examined the role of L. reuteri without antibiotic therapy, finding a cure rate of 13.6% (3/22) when it was used with PPI [52]. Bifidobacterium infantis has also been proposed as having anti-H. pylori activity, and in a study this year from MCE Asia, it was observed that adding it to standard triple therapy increased the cure rate from 68.9% to 83%, and when pretreatment with 2 weeks of B. infantis was given as well, the success rate of eradication increased to 90.5% [53]. There were many studies on H. pylori resistance levels in the last year. These studies on resistance over the last

year are summarized in Table 2 [54-62]. One of the most significant of these was a systematic review of studies on resistance in Latin American countries [54]. This found that antibiotic resistance rates varied significantly by drug and by country, but not by year of sample collection [54]. This was corroborated by a Brazilian study [56]. However, it was in contrast to other studies from outside the Latin America region that showed rising resistance rates to certain antibiotics over time, especially with regard to levofloxacin resistance [55, 57-60]. Regarding secondary resistance, a large German study of over 5000 strains found this to be also a major problem, especially with reference to fluoroquinolones. In this study, from 2006 onward, a steady annual increase was noted in the level of levofloxacin/ciprofloxacin, and triple resistance (quinolone, clarithromycin, and metronidazole) was noted, peaking in 2011 with 29.1% for fluoroquinolone resistance and 18.6% for triple resistance.

To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors)

to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors. Atezolizumab research buy “
“Therapy with fresh frozen plasma (FFP) confers serious

risks, such as contraction of blood-borne viruses, allergic reaction, volume overload and development of alloantibodies. The aim of this study was to apply principles MAPK Inhibitor Library of pharmacokinetic (PK) modelling to individual factor content of FFP to optimize individualized dosing, while minimizing potential risks of therapy. We used PK modelling to successfully target individual factor replacement in an 8-month-old patient receiving FFP for treatment of a severe congenital factor V (FV) deficiency. The model fit for the FV activity vs. time data was excellent (r = 0.98) and the model accurately predicted FV activity during the intraoperative and postoperative period. Accurate PK modelling medchemexpress of individual factor activity in FFP has the potential to provide better targeted therapy, enabling clinicians to more precisely dose patients requiring coagulation products, while avoiding wasteful and expensive product overtreatment, minimizing potentially life-threatening complications due

to undertreatment and limiting harmful product-associated risks. “
“Summary.  All UK patients with bleeding disorders treated with any UK-sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt–Jakob disease (vCJD). We describe a study to detect disease-associated, protease-resistant prion protein (PrPres) in 17 neurologically aysmptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrPres. The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrPres by Western blot analysis. This tissue came from a 73-year-old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene.

To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors)

to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors. selleck products “
“Therapy with fresh frozen plasma (FFP) confers serious

risks, such as contraction of blood-borne viruses, allergic reaction, volume overload and development of alloantibodies. The aim of this study was to apply principles Trichostatin A solubility dmso of pharmacokinetic (PK) modelling to individual factor content of FFP to optimize individualized dosing, while minimizing potential risks of therapy. We used PK modelling to successfully target individual factor replacement in an 8-month-old patient receiving FFP for treatment of a severe congenital factor V (FV) deficiency. The model fit for the FV activity vs. time data was excellent (r = 0.98) and the model accurately predicted FV activity during the intraoperative and postoperative period. Accurate PK modelling MCE公司 of individual factor activity in FFP has the potential to provide better targeted therapy, enabling clinicians to more precisely dose patients requiring coagulation products, while avoiding wasteful and expensive product overtreatment, minimizing potentially life-threatening complications due

to undertreatment and limiting harmful product-associated risks. “
“Summary.  All UK patients with bleeding disorders treated with any UK-sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt–Jakob disease (vCJD). We describe a study to detect disease-associated, protease-resistant prion protein (PrPres) in 17 neurologically aysmptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrPres. The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrPres by Western blot analysis. This tissue came from a 73-year-old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene.

2 Impressively, fra-1tg mice developed hepatic inflammatory infiltrates mainly confined to the portal tracts (Fig. 1). Infiltration of cells in fra-1tg mice was evident at 6 weeks of age (mean inflammatory area 6.33 ± 1.14 mm2). At 18 weeks we observed bridging inflammatory infiltrates between neighboring portal tracts. However, at 23 weeks of age inflammatory infiltrates covered large areas of the liver of fra-1tg mice (mean inflammatory area fra-1tg 21.08 ± 5.47 mm2 versus wildtype 1.48 ± 0.71 mm2; P < 0.05; Fig. 1B). Selleckchem Copanlisib Even more interesting, we observed a ductular reaction in fra-1tg mice, assessed by staining for cytokeratine 19 (CK19) protein (Fig. 1A). Although we could

not detect major changes in the morphology of the larger bile ducts, the small bile ducts were increased in their numbers (Fig. 2). At 10 weeks of age the mean number of bile ducts

per portal tract was 1.38 ± 0.05 and 3.24 ± 0.22 for wildtype and fra-1tg mice (mean ± SEM; P < 0.05), respectively. This further increased up to 4.90 ± 1.44 bile ducts in fra-1tg mice at 23 weeks of age, whereas it remained unchanged in wildtype mice (1.32 ± BMS-354825 research buy 0.07; P < 0.05). We next investigated the activity of ALP of fra-1tg and control mice (Fig. 2). ALP is an enzyme presented in bone and liver. As mentioned, fra-1tg mice develop osteosclerosis. For our study we investigated the activity of ALP directly in liver tissue. Increased medchemexpress ALP activity was observed in fra-1tg mice at almost all timepoints, as seen at week 10 (wildtype 1.90 ± 0.74 versus fra-1tg 3.73 ± 1.48; P < 0.05) and 23 (wildtype 0.98 ± 0.14 versus fra-1tg 3.66 ± 1.53; P < 0.05). Thus, specific increase of intrahepatic ALP points to the presence of biliary and liver abnormalities. As we observed a strong infiltration of immune cells into the portal tracts, we next asked whether increased chemokine and cytokine expression

mediates this cell influx. We found a dramatic induction of distinct chemokines, such as CXCL5 (22-fold), CCL1, CCL5, and CCL7 (about 3.5-fold), CCL-8 (10-fold), and CCL20 (10-fold). We also observed an up-regulation of chemokine receptors such as CCR4 (9-fold) and CCR2 (4-fold) in the liver of fra-1tg mice (Supporting Fig. 1). To determine the composition of the inflammatory infiltrates, we first performed IHC on liver sections of wildtype and fra-1tg mice. The infiltrate in fra-1tg mice is mainly composed of neutrophils and cluster of differentiation 3 (CD3+) T-cells. B cells and macrophages are less frequently found at the site of liver inflammation. This pattern was consistent in fra-1tg mice at all ages investigated (week 6, 10, and 18). Thus, overexpression of fra-1 causes a progressive infiltration of the liver by cells belonging to the innate and adaptive immune system (Supporting Fig. 2).

2 Impressively, fra-1tg mice developed hepatic inflammatory infiltrates mainly confined to the portal tracts (Fig. 1). Infiltration of cells in fra-1tg mice was evident at 6 weeks of age (mean inflammatory area 6.33 ± 1.14 mm2). At 18 weeks we observed bridging inflammatory infiltrates between neighboring portal tracts. However, at 23 weeks of age inflammatory infiltrates covered large areas of the liver of fra-1tg mice (mean inflammatory area fra-1tg 21.08 ± 5.47 mm2 versus wildtype 1.48 ± 0.71 mm2; P < 0.05; Fig. 1B). selleck products Even more interesting, we observed a ductular reaction in fra-1tg mice, assessed by staining for cytokeratine 19 (CK19) protein (Fig. 1A). Although we could

not detect major changes in the morphology of the larger bile ducts, the small bile ducts were increased in their numbers (Fig. 2). At 10 weeks of age the mean number of bile ducts

per portal tract was 1.38 ± 0.05 and 3.24 ± 0.22 for wildtype and fra-1tg mice (mean ± SEM; P < 0.05), respectively. This further increased up to 4.90 ± 1.44 bile ducts in fra-1tg mice at 23 weeks of age, whereas it remained unchanged in wildtype mice (1.32 ± DNA Synthesis inhibitor 0.07; P < 0.05). We next investigated the activity of ALP of fra-1tg and control mice (Fig. 2). ALP is an enzyme presented in bone and liver. As mentioned, fra-1tg mice develop osteosclerosis. For our study we investigated the activity of ALP directly in liver tissue. Increased MCE ALP activity was observed in fra-1tg mice at almost all timepoints, as seen at week 10 (wildtype 1.90 ± 0.74 versus fra-1tg 3.73 ± 1.48; P < 0.05) and 23 (wildtype 0.98 ± 0.14 versus fra-1tg 3.66 ± 1.53; P < 0.05). Thus, specific increase of intrahepatic ALP points to the presence of biliary and liver abnormalities. As we observed a strong infiltration of immune cells into the portal tracts, we next asked whether increased chemokine and cytokine expression

mediates this cell influx. We found a dramatic induction of distinct chemokines, such as CXCL5 (22-fold), CCL1, CCL5, and CCL7 (about 3.5-fold), CCL-8 (10-fold), and CCL20 (10-fold). We also observed an up-regulation of chemokine receptors such as CCR4 (9-fold) and CCR2 (4-fold) in the liver of fra-1tg mice (Supporting Fig. 1). To determine the composition of the inflammatory infiltrates, we first performed IHC on liver sections of wildtype and fra-1tg mice. The infiltrate in fra-1tg mice is mainly composed of neutrophils and cluster of differentiation 3 (CD3+) T-cells. B cells and macrophages are less frequently found at the site of liver inflammation. This pattern was consistent in fra-1tg mice at all ages investigated (week 6, 10, and 18). Thus, overexpression of fra-1 causes a progressive infiltration of the liver by cells belonging to the innate and adaptive immune system (Supporting Fig. 2).

5D). After UVC treatment, in the more sensible cells lines (RKO and HepG2), a robust caspase-3 activity increase was observed at 5 and 8 hours, respectively, in the presence of H(3KR)V5 mutant, in comparison to HuR-V5. Similar results were

obtained in MLP29 and SAMe-D cells at 16 and 36 hours after UVC treatment (Fig. 5D). These data highlight the proapoptotic phenotype associated with the H(3KR)V5 mutant and therefore to the lack of HuR NEDDylation. To further explore the mechanism by which HuR gets NEDDylated, we examined the interaction between Mdm2 and HuR by IP. Mdm2 interacts with both WT and H(K326R)V5 mutant (Fig. 6A), Also, HuR-V5 was cotransfected with Mdm2 WT and Mdm2 mutants (nuclear localization signal [NLS] and C464A). NLS, a Mdm2 mutant characterized by its exclusively cytoplasmic localization,29, 30 produced buy Galunisertib the same stabilization of HuR, compared to Mdm2 WT (Fig. 6B), suggesting that Mdm2-mediated HuR NEDDylation PLX-4720 chemical structure takes place in the cytoplasm. The C464A Mdm2 mutant, residue required for Mdm2 function as an E3 Ub ligase,27 had the same effect as WT MdM2 (Fig. 6B). In summary, these data indicate that Mdm2 interacts with HuR in the cytoplasm and participates in its stabilization independently of Mdm2 Ub ligase activity.

HuR is, predominantly, a nuclear protein.31 Using immunofluorescence, we observed that HuR-V5 expression was mostly nuclear, similar to the endogenous protein, whereas HuR mutants

had a more diffuse expression, with a predominantly cytoplasmic 上海皓元医药股份有限公司 localization in the case of H(K326R)V5 (Fig. 6C, upper panel). These results were confirmed by western blotting analysis (Fig. 6C, lower panel). Interestingly, the cysteine protease (NEDP1), which specifically removes NEDD8 molecules from conjugated substrates, reduced, by approximately 50%, the nuclear localization of HuR-V5, having no effect on cytoplasmic content. These data emphasize the role of NEDDylation in HuR nuclear localization (Fig. 6D). Given that HuR plays a central role in the post-transcriptional regulation of many critical proteins involved in fundamental processes in tumorigenesis (e.g., cell cycle, apoptosis and survival, proliferation, proangiogenesis, etc.), we analyzed the mechanisms regulating HuR overexpression in HCC and colon cancer. It was previously reported that in gastric cancers, HuR is transcriptionally up-regulated via the NFκB-PI3K axis.8 In liver cells, we reported that HuR expression levels increased proportionately to their transformation status.22 Here, we observed a strong correlation in the levels of HuR and Mdm2 during the transformation from primary hepatocytes to hepatoma, in colon cancer cells, and, more important, in a cohort of human metastatic colon cancer and HCC samples. We report that HuR is a NEDDylation substrate, and that Mdm2 mediates this NEDDylation by acting as an E3 NEDD8 ligase in the cytoplasm.

5D). After UVC treatment, in the more sensible cells lines (RKO and HepG2), a robust caspase-3 activity increase was observed at 5 and 8 hours, respectively, in the presence of H(3KR)V5 mutant, in comparison to HuR-V5. Similar results were

obtained in MLP29 and SAMe-D cells at 16 and 36 hours after UVC treatment (Fig. 5D). These data highlight the proapoptotic phenotype associated with the H(3KR)V5 mutant and therefore to the lack of HuR NEDDylation. To further explore the mechanism by which HuR gets NEDDylated, we examined the interaction between Mdm2 and HuR by IP. Mdm2 interacts with both WT and H(K326R)V5 mutant (Fig. 6A), Also, HuR-V5 was cotransfected with Mdm2 WT and Mdm2 mutants (nuclear localization signal [NLS] and C464A). NLS, a Mdm2 mutant characterized by its exclusively cytoplasmic localization,29, 30 produced this website the same stabilization of HuR, compared to Mdm2 WT (Fig. 6B), suggesting that Mdm2-mediated HuR NEDDylation Navitoclax mouse takes place in the cytoplasm. The C464A Mdm2 mutant, residue required for Mdm2 function as an E3 Ub ligase,27 had the same effect as WT MdM2 (Fig. 6B). In summary, these data indicate that Mdm2 interacts with HuR in the cytoplasm and participates in its stabilization independently of Mdm2 Ub ligase activity.

HuR is, predominantly, a nuclear protein.31 Using immunofluorescence, we observed that HuR-V5 expression was mostly nuclear, similar to the endogenous protein, whereas HuR mutants

had a more diffuse expression, with a predominantly cytoplasmic 上海皓元医药股份有限公司 localization in the case of H(K326R)V5 (Fig. 6C, upper panel). These results were confirmed by western blotting analysis (Fig. 6C, lower panel). Interestingly, the cysteine protease (NEDP1), which specifically removes NEDD8 molecules from conjugated substrates, reduced, by approximately 50%, the nuclear localization of HuR-V5, having no effect on cytoplasmic content. These data emphasize the role of NEDDylation in HuR nuclear localization (Fig. 6D). Given that HuR plays a central role in the post-transcriptional regulation of many critical proteins involved in fundamental processes in tumorigenesis (e.g., cell cycle, apoptosis and survival, proliferation, proangiogenesis, etc.), we analyzed the mechanisms regulating HuR overexpression in HCC and colon cancer. It was previously reported that in gastric cancers, HuR is transcriptionally up-regulated via the NFκB-PI3K axis.8 In liver cells, we reported that HuR expression levels increased proportionately to their transformation status.22 Here, we observed a strong correlation in the levels of HuR and Mdm2 during the transformation from primary hepatocytes to hepatoma, in colon cancer cells, and, more important, in a cohort of human metastatic colon cancer and HCC samples. We report that HuR is a NEDDylation substrate, and that Mdm2 mediates this NEDDylation by acting as an E3 NEDD8 ligase in the cytoplasm.

Treatment endpoints depend on the monitoring used and the specialist clinic, but at least they have to cover two aspects: (1) cognitive performance (improvement in one accepted test as a minimum) and (2) daily life

autonomy (basic and operational abilities). Nutritional aspects: weight loss with sarcopenia may worsen HE, and, accordingly, the nutritional priority is to provide enough protein and energy to favor a positive nitrogen balance and increase in muscle mass, as recommended above. Portosystemic shunt: occlusion of a dominant shunt may improve HE in patients with recurring HE and good liver function.[114] Because the current experience is limited, the risks and benefits must be weighed before employing Smoothened Agonist datasheet Rucaparib nmr this strategy. This section deals with research into the management of HE. However, such research should always be based on research into the pathophysiology of HE. It is necessary to gain more insight into which liver

functions are responsible for maintenance of cerebral functions, which alterations in intestinal function and microbiota make failure of these liver functions critical, which brain functions are particularly vulnerable to the combined effects of the aforementioned events, and, finally, which factors outside this axis that result in the emergence of HE (e.g., inflammation, endocrine settings, or malnutrition). Therefore, the research fields into pathophysiology and clinical management should remain in close contact. Such collaboration should result in new causal and symptomatic treatment modalities that need and motivate clinical trials. There is a severe and unmet need for controlled clinical trials on treatment effects on all the different forms of HE. Decisive clinical studies are few, although the number of patients and their resource utilization medchemexpress is high. There are no data on which factors and patients represent the higher costs, and research is needed

to examine the effect of specific cirrhosis-related complications. At present, there is an insufficient basis for allocating resources and establishing priority policies regarding management of HE. Many drugs that were assessed for HE several decades ago were studied following a standard of care that, at present, is obsolete. Any study of treatment for HE should be reassessed or repeated using the current standard of care. It is critical to develop protocols to identify precipitating factors and ACLF. The benefit of recently assessed drugs is concentrated in the prevention of recurrence, and there is a large need for trials on episodic HE. There is also an unmet need for research into diagnostic methods that is necessary to form a basis for clinical trials. The diagnosis of MHE and CHE has received enormous interest, but it is still not possible to compare results among studies and the precision should be improved.

Treatment endpoints depend on the monitoring used and the specialist clinic, but at least they have to cover two aspects: (1) cognitive performance (improvement in one accepted test as a minimum) and (2) daily life

autonomy (basic and operational abilities). Nutritional aspects: weight loss with sarcopenia may worsen HE, and, accordingly, the nutritional priority is to provide enough protein and energy to favor a positive nitrogen balance and increase in muscle mass, as recommended above. Portosystemic shunt: occlusion of a dominant shunt may improve HE in patients with recurring HE and good liver function.[114] Because the current experience is limited, the risks and benefits must be weighed before employing Selleckchem MAPK Inhibitor Library Topoisomerase inhibitor this strategy. This section deals with research into the management of HE. However, such research should always be based on research into the pathophysiology of HE. It is necessary to gain more insight into which liver

functions are responsible for maintenance of cerebral functions, which alterations in intestinal function and microbiota make failure of these liver functions critical, which brain functions are particularly vulnerable to the combined effects of the aforementioned events, and, finally, which factors outside this axis that result in the emergence of HE (e.g., inflammation, endocrine settings, or malnutrition). Therefore, the research fields into pathophysiology and clinical management should remain in close contact. Such collaboration should result in new causal and symptomatic treatment modalities that need and motivate clinical trials. There is a severe and unmet need for controlled clinical trials on treatment effects on all the different forms of HE. Decisive clinical studies are few, although the number of patients and their resource utilization 上海皓元 is high. There are no data on which factors and patients represent the higher costs, and research is needed

to examine the effect of specific cirrhosis-related complications. At present, there is an insufficient basis for allocating resources and establishing priority policies regarding management of HE. Many drugs that were assessed for HE several decades ago were studied following a standard of care that, at present, is obsolete. Any study of treatment for HE should be reassessed or repeated using the current standard of care. It is critical to develop protocols to identify precipitating factors and ACLF. The benefit of recently assessed drugs is concentrated in the prevention of recurrence, and there is a large need for trials on episodic HE. There is also an unmet need for research into diagnostic methods that is necessary to form a basis for clinical trials. The diagnosis of MHE and CHE has received enormous interest, but it is still not possible to compare results among studies and the precision should be improved.

Women who have completed their childbearing, particularly those who have

failed medical management or endometrial Lumacaftor ic50 ablation, are candidates for hysterectomy. Because menorrhagia is often the primary symptom that women with bleeding disorders experience, hysterectomy does offer the possibility for significant improvement in quality of life and is a safer procedure than it was decades ago. Thirty-six years ago when Silwer et al. published the results of a comparison of the complications of hysterectomy in 18 women with VWD vs. 50 controls, 50% of the women with VWD received transfusion, but so did 30% of the controls [17]. In a recent study of United States hospital discharge data, only 7% of women with VWD received transfusions compared to 2% of controls [41]. Furthermore, in the last 20 years, the availability of recombinant or plasma-derived/virally inactivated clotting factor concentrates has reduced the chance of viral transmission with factor replacement. There are few data on management

of acute, severe menorrhagia, particularly in the adolescent or woman with a bleeding disorder. In November, 2009, a consensus conference sponsored by CSL Behring selleck compound was convened specifically to address this issue. A full report will be published in the future, but there was consensus that balloon tamponade, hormonal therapy (oestrogen) and antifibrinolytic treatment should be instituted while replacing clotting factor or platelets as indicated. It is recognized that normal pregnancy is accompanied by increased concentrations of various clotting factors. Despite improved haemostasis, however, women with bleeding disorders often do not achieve the same levels of clotting factors as other women and, therefore, are at an increased risk of bleeding complications with pregnancy. In the last 20 years, there have been several case reports and case series documenting the profoundly increased risk of miscarriage and placental

abruption resulting in foetal loss or premature delivery in women with deficiency of fibrinogen [42–51], or factor XIII [52–55] but whether there is an increased risk of miscarriage in women with other bleeding disorders is not clear [18]. Clotting factor replacement is used to reduce the risk of miscarriage, foetal loss and premature 上海皓元 delivery in women with deficiency of fibrinogen [43–45,47–51] and factor XIII [52–55], but whether any therapy is necessary or available to prevent miscarriage or foetal loss in women with other bleeding disorders has not been reported. Despite the primary role of uterine contractility in controlling postpartum blood loss, women with bleeding disorders are at an increased risk of postpartum haemorrhage. There are multiple case series documenting the incidence of postpartum haemorrhage in women with bleeding disorders [18] and four case-control studies comparing women with VWD and controls.