Iron deficiency and fatigue among adolescents with bleeding disorders.

Iron deficiency anemia is associated with heavy menstrual bleeding (HMB) and, by extension, a bleeding disorder (BD). It is unknown if iron deficiency without anemia is associated with a BD in adolescents. Moreover, the threshold of ferritin associated with fatigue in adolescents with HMB is unclear. In this multicenter study, we enrolled adolescents with HMB without BD. Participants underwent BD and anemia work-up in Young Women's Hematology Clinics and completed the Peds QL™ fatigue scale. BDs were defined as von Willebrand Disease, platelet function defect, clotting factor deficiencies, and hypermobility syndrome. Two hundred and fifty consecutive adolescents were enrolled, of whom 196 met eligibility criteria. Overall, 43% (95% confidence interval: 36%-50%) were diagnosed with BD. A total of 61% (n = 119) had serum ferritin levels < 15 ng/mL, 23.5% (n = 46) had iron deficiency only, and 37% (n = 73) had iron deficiency anemia. Low ferritin or ferritin dichotomized as < 15 or ≥ 15 ng/mL was not associated with BD on univariable analysis (p = .24) or when accounting for age, race, ethnicity, body mass index, and hemoglobin (p = .35). A total of 85% had total fatigue score below the population mean of 80.5, and 52% (n = 102) were > 2 SD (or < 54) below the mean, the cut-off associated with severe fatigue. A ferritin threshold of < 6 ng/mL had a specificity of 79.8% but a sensitivity of 36% for severe fatigue. In conclusion, iron deficiency without anemia is not a predictor of BD in adolescents with HMB in a specialty setting. Severe fatigue, especially sleep fatigue, is prevalent in adolescents with BD. Ferritin of < 6 ng/mL has ~80% specificity for severe fatigue in adolescents with HMB.

Screening hemostatic defects in Saudi University students with unexplained menorrhagia: a diagnosis, which could be missed.

Bleeding disorders are a common cause of unexplained menorrhagia in adolescents. However, there is lack of information provided on Arab girls. To estimate the prevalence of coagulation factor deficiencies and platelet dysfunction among Saudi university students with unexplained menorrhagia. In this cross sectional study, 463 adolescent girls surveyed for having heavy menses for further evaluation of underlying bleeding tendencies using screening standardized questionnaire. Only 109 girls out of the total 463 girls reported menorrhagia and were included in the evaluation. All girls with menorrhagia were evaluated by Pictorial blood assessment chart (PBAC) for precise evaluation of menstrual blood loss (PBAC score >100), had underwent pelvic ultrasonography and screening of hemostatic abnormalities (complete blood count, PFA-100, PT, aPTT, vWF:RCo, vWF:Ag, coagulation factors assay). On the basis of the score of PBAC more than 100, 25.6% (28/109) of adolescent women (age ranged: 17-25 years old) had confirmed menorrhagia. In 30.8% of them, an ultimate diagnosis of bleeding tendency or hemostatic abnormality was detected [five cases of probable von Willebrand disease (vWD) or low level of vWF:Ag and/or vWF:RCo, two cases of probable platelet dysfunction, and one case of factorV (FV) deficiency]. Anemia was found in 39.28% (11/28) of them; however, only 4 (36%) had received iron supplements. Our study demonstrated that hemostatic defects are not uncommon in Saudi adolescent women presenting with menorrhagia but mostly unrecognized and untreated. It is probably advisable to screen women with menorrhagia for these defects.

Management of heavy menstrual bleeding on anticoagulation.

Heavy menstrual bleeding (HMB) is a common complication of anticoagulation, affecting ∼70% of menstruating women receiving oral anticoagulants. The risk of HMB is lower with apixaban and/or dabigatran than with rivaroxaban. HMB can result in iron deficiency with or without anemia, increased need for medical interventions, decreased quality of life, and missed school/work. Mainstays of treatment include hormone therapies such as the levonorgestrel intrauterine system, subdermal implant, and other progesterone-based therapies, which can result in decreased blood loss and, in some cases, amenorrhea. Combined hormone therapies can be used while patients continue receiving anticoagulation and are also highly effective for decreasing menstrual blood loss. Rarely, procedure-based interventions such as endometrial ablation may be required. Patients should be evaluated for iron deficiency and anemia and offered supportive therapies as needed. Abbreviating the course of anticoagulation or skipping doses can increase the risk of recurrent venous thromboembolism by as much as fivefold, but switching oral anticoagulants may be considered. Awareness of HMB and careful history taking at each visit are crucial to avoid a missed diagnosis.

Less common hemorrhagic coagulopathies in women.

Congenital coagulopathies are a group of hereditary conditions associated with significant hemorrhagic complications. Women with congenital coagulopathies tend to experience higher bleeding rates resulting from physiological processes and pregnancy and delivery. In these women, it is essential to recognize the symptoms and work in a coordinated way between hematologists and gynecologists.

Elagolix Treatment for Up to 12 Months in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas.

OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.

Prolonged use of finasteride-induced gonadal sex steroids alterations, DNA damage and menstrual bleeding in women.

The aim of the present study was to examine the effect of prolonged use of finasteride on serum levels of dihydrotestosterone (DHT), estradiol (E2), progesterone, testosterone and androstenedione in women during the menstrual period. Further, to screen and compare the 5α-reductase activities through the expression of SRD5A1, SRD5A2 and AR gene and to determine the level of VEGF, VKOR and SAA gene expression and DNA damage. A total of 30 Saudi women aged between 25 and 35 years were enrolled in the study. The selected women were divided into two groups. The first group (n = 15) received 5 mg finasteride/day for prolonged period of one year and second group (n = 15) was taken as a healthy control. ELISA technique was used for measuring the serum levels of the targeted hormones, and Comet assay was used for checking the DNA integrity. Our findings revealed significant decrement of DHT, E2, progesterone and androstenedione levels and elevated levels of testosterone in group treated with daily oral doses of 5 mg finasteride/day compared with the control subjects. mRNA expression suggested that finasteride has concrete effects on the gene expression of the selected genes from the treated group in comparison with the control group. In addition, finasteride induced DNA damage, and heavy menstrual bleeding was noted in women treated with finasteride. In conclusion, the present findings revealed that finasteride has adverse health effects in women associated with gonadal sex steroids alterations, DNA damage and heavy menstrual bleeding with no consensus in the treatment of androgenetic alopecia in women.

Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for the treatment of preoperative anemia in patients with menorrhagia: An open-label, multicenter, randomized study.

AIM: To compare ferric carboxymaltose (FCM) with iron sucrose (IS) for the effective and timely treatment of preoperative iron deficiency anemia (IDA) in women with menorrhagia. METHODS: This open-label, multicenter, two-arm study randomized patients to receive either a single dose of FCM or multiple doses of IS. The primary endpoint was the proportion of patients who achieved hemoglobin (Hb) levels ≥10 g/dL within 2 weeks after the first administration. Secondary endpoints included mean Hb levels, time to reach Hb ≥10 g/dL and quality of life (QoL). RESULTS: In total, 101 patients (FCM n = 52; IS n = 49) were randomized to the study treatments. FCM was as effective as IS in achieving Hb ≥10 g/dL within 2 weeks after the first administration (78.8% vs 72.3%). The time to reach Hb ≥10 g/dL was significantly shorter in the FCM group than in the IS group (7.7 days vs 10.5 days). Mean Hb levels were higher in the FCM-treated patients than in the IS-treated patients with borderline significance. QoL scores did not differ between the two groups. CONCLUSION: Ferric carboxymaltose is as effective as IS in correcting preoperative IDA among patients with menorrhagia. The added benefits of FCM over IS included significant rapid correction of IDA, replenishment of iron stores and reduced hospital visits.

Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas. METHODS: This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density. RESULTS: From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate. CONCLUSION: Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.

Significant gynecological bleeding in women with low von Willebrand factor levels.

Gynecological bleeding is frequently reported in women with von Willebrand disease (VWD). Low von Willebrand factor (VWF) may be associated with significant bleeding phenotype despite only mild plasma VWF reductions. The contribution of gynecological bleeding to this phenotype has yet to be described. The optimal clinical bleeding assessment tool (BAT) to evaluate bleeding remains unclear. Using a standardized approach to phenotypic assessment, we evaluated gynecological bleeding and directly compared the Condensed Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD (Condensed MCMDM-1 VWD) and International Society on Thrombosis and Haemostasis (ISTH) BAT scores in 120 women enrolled in the Low von Willebrand in Ireland Cohort study. Heavy menstrual bleeding (HMB) was reported in 89% of female participants; 45.8% developed iron deficiency. Using identical data, Condensed MCMDM-1 VWD menorrhagia domain scores were significantly lower than ISTH BAT scores (2 vs 3; P < .0001), the discrepant results related to 40% of women not seeking medical consultation for HMB, reducing the sensitivity of the Condensed score. For those who reported HMB to physicians, the low VWF diagnosis was not expedited (age at diagnosis 34.2 vs 33.4 years in women failing to present; P = .7). Postpartum hemorrhage (PPH) was self-reported in 63.5% of parous women (n = 74); 21.6% required transfusion, critical care, radiological, or surgical intervention. Our data demonstrate that gynecological bleeding is frequently reported in women with low VWF; despite pregnancy-related increases in plasma VWF levels, these women may experience PPH. Defining the optimal management approach for these patients requires further research. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

Efficacy and Safety of Estradiol Valerate/Dienogest for the Management of Heavy Menstrual Bleeding: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase III Clinical Trial.

BACKGROUND: To investigate the efficacy and safety of estradiol valerate (EV)/dienogest (DNG) for the management of heavy menstrual bleeding (HMB) in Asian and non-Asian women desiring contraception. MATERIALS AND METHODS: In this multicenter, double-blind, phase III study, women were randomized 2:1 to receive EV/DNG or placebo tablets daily for seven 28-day cycles. The primary endpoint was the absolute change in menstrual blood loss (MBL) volume between the run-in and efficacy phases (90 days each). Secondary endpoints included the proportion of women with successful treatment (i.e., no episodes of MBL ≥80 mL and a decrease of <50% in MBL), percent change in MBL from the run-in phase, and change in hemoglobin and serum ferritin levels. Adverse events (AEs) were monitored throughout the study. RESULTS: Of the 341 women (mean age 34.7 ± 7.7 years; 309 Asians, 32 non-Asians) randomized, 270 completed the study. Mean reduction in MBL volume from run-in phase was significantly greater with EV/DNG than placebo (366.75 mL vs. 149.14 mL; p < 0.0001), with ∼52% and 12% of women, respectively, experiencing successful treatment. Percent decrease in MBL volume from the run-in phase was significantly greater with EV/DNG than placebo (63.5% vs. 24.8%; p < 0.0001). Hemoglobin and serum ferritin levels were increased with EV/DNG compared with placebo. Study drug-related AEs were reported in 16.3% and 8.2% of women with EV/DNG and placebo, respectively, none of which were of severe intensity. CONCLUSIONS: EV/DNG may be a safe and effective option in the treatment of HMB in Asian and non-Asian women who desire contraception.

Endometrial vascular development in heavy menstrual bleeding: altered spatio-temporal expression of endothelial cell markers and extracellular matrix components.

STUDY QUESTION: Are there any phenotypic and structural/architectural changes in the vessels of endometrium and superficial myometrium during the normal menstrual cycle in healthy women and those with heavy menstrual bleeding (HMB)? SUMMARY ANSWER: Spatial and temporal differences in protein levels of endothelial cell (EC) markers and components of the extracellular matrix (ECM) were detected across the menstrual cycle in healthy women and these are altered in HMB. WHAT IS KNOWN ALREADY: HMB affects 30% of women of reproductive age with ~50% of cases being idiopathic. We have previously shown that the differentiation status of endometrial vascular smooth muscle cells (VSMCs) is altered in women with HMB, suggesting altered vessel maturation compared to controls. Endometrial arteriogenesis requires the co-ordinated maturation not only of the VSMCs but also the underlying ECs and surrounding ECM. We hypothesized that there are spatial and temporal patterns of protein expression of EC markers and vascular ECM components in the endometrium across the menstrual cycle, which are altered in women with HMB. STUDY DESIGN, SIZE, DURATION: Biopsies containing endometrium and superficial myometrium were taken from hysterectomy specimens from both healthy control women without endometrial pathology and women with subjective HMB in the proliferative (PP), early secretory (ESP), mid secretory (MSP) and late secretory (LSP) phases (N = 5 for each cycle phase and subject group). Samples were fixed in formalin and embedded in paraffin wax. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serial sections (3µm thick) were immunostained for EC markers (factor VIII related antigen (F8RA), CD34, CD31 and ulex europaeus-agglutinin I (UEA-1) lectin), structural ECM markers (osteopontin, laminin, fibronectin and collagen IV) and for Ki67 to assess proliferation. Immunoreactivity of vessels in superficial myometrium, endometrial stratum basalis, stratum functionalis and luminal region was scored using either a modified Quickscore or by counting the number of positive vessels. MAIN RESULTS AND THE ROLE OF CHANCE: In control samples, all four EC markers showed a dynamic expression pattern according to the menstrual cycle phase, in both endometrial and myometrial vessels. EC protein marker expression was altered in women with HMB compared with controls, especially in the secretory phase in the endometrial luminal region and stratum functionalis. For example, in the LSP expression of UEA-1 and CD31 in the luminal region decreased in HMB (mean quickscore: 1 and 5, respectively) compared with controls (3.2 and 7.4, respectively) (both P = 0.008), while expression of F8RA and CD34 increased in HMB (1.4 and 8, respectively) compared with controls (0 and 5.8, respectively) (both P = 0.008). There was also a distinct pattern of expression of the vascular structural ECM protein components osteopontin, laminin, fibronectin and collagen IV in the superficial myometrium, stratum functionalis and stratum basalis during the menstrual cycle, which was altered in HMB. In particular, compared with controls, osteopontin expression in HMB was higher in stratum functionalis in the LSP (7.2 and 11.2, respectively P = 0.008), while collagen IV expression was reduced in stratum basalis in the MSP (4.6 and 2.8, respectively P = 0.002) and in stratum functionalis in the ESP (7 and 3.2, respectively P = 0.008). LIMITATIONS, REASONS FOR CAUTION: The protein expression of vascular EC markers and ECM components was assessed using a semi-quantitative approach in both straight and spiral arterioles. In our hospital, HMB is determined by subjective criteria and levels of blood loss were not assessed. WIDER IMPLICATIONS OF THE FINDINGS: Variation in the protein expression pattern between the four EC markers highlights the importance of choice of EC marker for investigation of endometrial vessels. Differences in expression of the different EC markers may reflect developmental stage dependent expression of EC markers in endometrial vessels, and their altered expression in HMB may reflect dysregulated vascular development. This hypothesis is supported by altered expression of ECM proteins within endometrial vessel walls, as well as our previous data showing a dysregulation in VSMC contractile protein expression in the endometrium of women with HMB. Taken together, these data support the suggestion that HMB symptoms are associated with weaker vascular structures, particularly in the LSP of the menstrual cycle, which may lead to increased and extended blood flow during menstruation. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Wellbeing of Women (RG1342) and Newcastle University. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Pilot study of novel lab methodology and testing of platelet function in adolescent women with heavy menstrual bleeding.

BackgroundApproximately 40% of adolescent women experience heavy menstrual bleeding (HMB), and 10-62% of them have an underlying bleeding disorder (BD). Diagnosing a BD remains challenging because of limitations of available clinical platelet function assays. The aim of this study was to characterize platelet function in a population of adolescent women with HMB using small-volume whole-blood assays.MethodsAnticoagulated whole blood was used to assess platelet GPIIbIIIa activation, α-granule secretion, and aggregation in response to multiple agonists. Platelet adhesion on collagen or von Willebrand Factor (VWF) under static and shear flow was also assessed.ResultsFifteen participants with HMB were included in the study, of which eight were diagnosed with a clinically identifiable BD. Platelet activation was blunted in response to calcium ionophore in participants without a BD diagnosis compared with that in all other participants. Impaired GPIIbIIIa activation was observed in response to all GPCR agonists, except adenosine diphosphate (ADP), in participants with qualitative platelet disorders. Our assays detected platelet aggregation in the majority of participants with a BD in response to ADP, collagen-related peptide (CRP), thrombin receptor activator 6 (TRAP-6), or U46619. Platelet adhesion and aggregation on collagen and VWF was decreased for participants with VWD.ConclusionParticipants with and without BD exhibited aberrant platelet function in several assays in response to select agonists.

Factor 11 single-nucleotide variants in women with heavy menstrual bleeding.

In a previous study it was shown that lower factor XI (FXI) levels in women with heavy menstrual bleeding (HMB). Our aim was to determine the single-nucleotide variants (SNVs) in the F11 gene in women with HMB. In addition, an extensive literature search was performed to determine the clinical significance of each SNV. Patients referred for HMB (PBAC-score >100) were included. With direct sequencing analysis of all 15 exons and flanking introns of the F11 gene, 29 different non-structural SNVs were detected in 49 patients with HMB. Interestingly, most of these SNVs have previously been associated with venous thrombosis instead of bleeding. These findings have not helped to elucidate the molecular basis of HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB. IMPACT STATEMENT Women with mild deficiencies of factor XI (FXI) (< 70%) are prone to excessive bleeding during menstruation. Bleeding manifestations are not well correlated with plasma FXI levels and bleeding episodes can vary widely among patients with similar low FXI levels. In a previous study we showed that women with heavy menstrual bleeding (HMB) had normal, but on average, lower levels of FXI than controls. In light of these findings, we performed F11 gene analysis to determine the single-nucleotide variants (SNVs) in women with HMB and performed an extensive literature search to determine the clinical significance of each SNV. By direct sequencing analysis of the F11 gene we found 29 different non-structural SNVs in 49 women with heavy menstrual bleeding. Remarkably, a number of these SNVs have previously been implicated in thrombosis. These findings have not helped to elucidate the molecular basis of lower FXI levels in HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB.

Heavy menstrual bleeding: An update on management.

Heavy menstrual bleeding (HMB) is defined as excessive menstrual blood loss (MBL) >80 mL per cycle, that interferes with a woman's physical, emotional, social wellbeing and quality of life. Aetiology is due to underlying uterine pathologies, coagulopathy, ovulation dysfunction, or iatrogenic. Up to 20% of women with HMB will have an underlying inherited bleeding disorder (IBD). Assessment of HMB should entail a menstrual and gynaecological history and a bleeding score to distinguish those women who require additional haematological investigations. A pelvic examination and ultrasound scan help to rule out presence of any underlying pathology. Management depends on the underlying cause and the woman's preference and her fertility wishes. Medical therapies include hormonal treatments; levonorgestrel-releasing intrauterine system (LNG-IUS) and combined hormonal contraceptives are most commonly used. Ulipristal acetate is an approved preoperative treatment for uterine fibroids, and has demonstrated efficacy in reducing MBL. Haemostatic therapies include tranexamic acid and DDAVP (1-deamino-8-D-arginine). DDAVP is used for HMB associated with certain IBDs. These therapies can be used in isolation or in combination with hormonal treatments. HMB associated with certain severe IBDs may require factor concentrate administration during menses to alleviate symptoms. Endometrial ablation is a minor surgical procedure that is associated with low operative morbidity and can be performed as an outpatient. Hysterectomy remains the definitive treatment of choice when medical therapies have failed and endometrial ablation is not suitable.

Angiogenesis mediators in women with idiopathic heavy menstrual bleeding.

OBJECTIVE: To assess the relationship between stromal cell-derived factor 1 (SDF-1) and mature endothelial cells in patients with heavy menstrual bleeding (HMB). METHODS: In a prospective observational study, women with idiopathic HMB and control individuals attending Menoufia University Hospital, Egypt, between August 2015 and January 2016 were enrolled. The inclusion criteria were a regular menstrual cycle, a normal coagulation study, and no anomalous ultrasonographic or hysteroscopic findings. Blood samples were collected during different phases of the menstrual cycle (day 5, ovulation, day 24) for measurement of the SDF-1 plasma level (by enzyme-linked immunosorbent assay) and for quantification of mature endothelial cells (by flow cytometry). RESULTS: Overall, 20 women with HMB and 10 control individuals were enrolled. The SDF-1 level was significantly lower in the HMB group than in the control group during all phases of the menstrual cycle (P≤0.05 for all). The percentage of mature endothelial cells was significantly higher in the HMB group than among controls (P<0.001 for all). The SDF-1 level and the percentage of endothelial cells were negatively correlated throughout the cycle (P<0.001 for all). CONCLUSION: Some mediators of angiogenesis, such as SDF-1 and endothelial cells, are disturbed in women with idiopathic HMB.

Iron Deficiency Anemia in Adolescents Who Present with Heavy Menstrual Bleeding.

STUDY OBJECTIVE: To assess the clinical severity and initial treatment of iron deficiency anemia (IDA) in female adolescents with heavy menstrual bleeding (HMB) in our center. DESIGN: Retrospective cohort study of electronic medical records via search of administrative records using International Classification of Diseases Ninth Revision codes for IDA or unspecified anemia and disorders of menstruation. SETTING: Children's Medical Center in Dallas, Texas. PARTICIPANTS: One hundred seven patients with HMB and concomitant IDA (median age, 14.4 years) who presented to the outpatient, emergency department, and/or inpatient settings. RESULTS: The median initial hemoglobin concentration for all patients (n = 107) was 7.4 g/dL, and most (74%, n = 79) presented to the emergency department or via inpatient transfer. Symptomatic IDA was treated with blood transfusion in 46 (43%, n = 46). Ferrous sulfate was the most commonly prescribed oral iron therapy. Seven patients received intravenous iron therapy either initially or after oral iron treatment failure. Combined oral contraceptives were commonly prescribed for abnormal uterine bleeding, yet 10% of patients (n = 11) received no hormonal therapy during their initial management. Evaluation for underlying bleeding disorders was inconsistent. CONCLUSION: Severe anemia because of IDA and HMB resulting in urgent medical care, including hospitalization and blood transfusion, is a common but underemphasized problem in adolescent girls. In addition to prevention and early diagnosis, meaningful efforts to improve initial management of adolescents with severe HMB and IDA are necessary.

Dysfunctional coagulation and fibrinolysis systems due to adenomyosis is a possible cause of thrombosis and menorrhagia.

OBJECTIVE: To study the effects of adenomyosis on the coagulation and fibrinolysis system during menstruation and the relationship between dysfunction of the coagulation and fibrinolysis system and the symptoms and complications of adenomyosis. STUDY DESIGN: Concentrations of thrombin-antithrombin complex (TAT) and soluble fibrin (SF) as markers of coagulation, D-dimer (DD) as a marker of both coagulation and fibrinolysis, and plasmin-alpha 2-plasmin inhibitor complex (PIC) as a marker of fibrinolysis in the peripheral blood of eight patients with adenomyosis were measured daily from the first to fifth day of menstruation. Associations between levels of these markers during menstruation and patient characteristics, history of thrombotic disorder, and hemoglobin loss during menstruation were investigated. RESULTS: TAT, SF, DD and PIC increased in 5, 2, 3 and 1 of the 8 patients, respectively. TAT increased in 5 of the 6 patients with an adenomyotic uterus ≥100 cubic centimeters. Patients with elevated DD, SF and/or PIC were among patients with elevated TAT. DD was only increased in 3 patients with a past history of small cerebral infarction or pulmonary thromboembolism and/or hemoglobin loss >2.0g/dl during menstruation. SF was increased only in 2 patients with a past history of cerebral infarction or pulmonary thromboembolism. PIC increased in 1 of the 2 patients with hemoglobin loss >2.0g/dl during menstruation. CONCLUSION: Adenomyosis patients with a uterus volume ≥100 cubic centimeters are at risk of having an activated coagulation system. These patients, particularly those with elevated SF and DD, may be at risk of thrombotic disorders. Fibrinolysis is activated in a portion of patients with activated coagulation during menstruation. Activated fibrinolysis during menstruation may contribute to menorrhagia in patients with adenomyosis, as only patients with activated fibrinolysis suffered menorrhagia, even though patients with an adenomyotic uterus ≥100 cubic centimeters without activated fibrinolysis did not. These results suggest extensive adenomyosis confers a potential risk of infarction and thrombosis and exacerbates menorrhagia via activation of coagulation and fibrinolysis during menstruation.

Iron Deficiency without Anemia: A Common Yet Under-Recognized Diagnosis in Young Women with Heavy Menstrual Bleeding.

STUDY OBJECTIVE: To assess the proportion of iron deficiency that is not detected with a screening hemoglobin or complete blood count (CBC) alone in young women with heavy menstrual bleeding. DESIGN: Retrospective review of electronic medical records. SETTING: Nationwide Children's Hospital in Columbus, Ohio. PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: One hundred fourteen young women aged 9-19 years consecutively referred to a young women's hematology clinic with a complaint of heavy menstrual bleeding. RESULTS: Fifty-eight (50.9%) of all patients had ferritin <20 ng/mL indicating iron deficiency. Of the 58 patients with iron deficiency, only 24 (41.4%) were anemic and 25 (46.3%) were microcytic. The sensitivity of hemoglobin alone and CBC alone for identifying women with ferritin <20 ng/mL was 41.4% (95% confidence interval [CI], 28.7-54.1) and 46.3% (95% CI, 33.0-59.6), respectively. Both tests had reasonable specificity at 91.1% (95% CI, 83.6-98.5) for hemoglobin and 83.9% for CBC (95% CI, 74.3-93.6). Patients had significantly higher odds of having iron deficiency if they were overweight or obese (odds ratio, 2.81; 95% CI, 1.25-6.29) compared with patients with normal body mass index. Age at presentation for heavy menstrual bleeding, presence of an underlying bleeding disorder, and median household income were not significantly associated with iron deficiency. CONCLUSION: In adolescents with heavy menstrual bleeding, fewer than half of iron deficiency cases are detected when screening is performed with hemoglobin or blood count alone. Measuring ferritin levels in at-risk patients might allow for earlier implementation of iron therapy and improvement in symptoms.

Plasma factor XIII level variations during menstrual cycle.

Factor XIII (FXIII) has an important role in the control of bleeding through fibrin cross-linking; however, its effect within the menstrual cycle is not fully understood. The aim of this study was to examine changes in FXIII activity during the normal menstrual cycle and correlate FXIII activity with menstrual blood loss. A total of 32 healthy normal women of reproductive age were recruited. Menstrual blood loss was measured using the pictorial blood-assessment chart (PBAC). A bleeding score questionnaire was also completed. Blood samples were taken during the menstrual, proliferative, periovulatory, secretory and premenstrual phase for assessment of FXIII level. The mean ±â€ŠSD FXIII level was lowest during menstrual and periovulatory phases (114 ±â€Š23 and 114 ±â€Š21 IU/dl, respectively). Mean FXIII level during the secretory and premenstrual phases were higher than the menstrual phase (P = 0.036). Mean secretory phase FXIII was also significantly higher compared with the periovulatory phase (P = 0.02). There was no significant correlation between FXIII level during the menstrual phase and age (P = 0.53) or PBAC score (P = 0.53). There were no significant differences in FXIII level during the menstrual phase between women with PBAC scores of at least 100 (n = 14; mean 116 IU/dl) and women with PBAC scores less than 100 (n = 18; mean 113 IU/dl). There was no correlation between FXIII level and bleeding score. FXIII activity was lower during menstrual and periovulatory phases of the cycle. However, the small difference between mean values (8 IU/dl) would be unlikely to have a significant impact on diagnosis of FXIII deficiency and clinical management.

Mild factor XIII deficiency and concurrent hypofibrinogenemia: effect of pregnancy.

Factor XIII (FXIII) deficiency is a rare bleeding disorder. Patients with mild congenital FXIII deficiency tend to be asymptomatic, but may demonstrate significant bleeding symptoms with surgery, trauma, and pregnancy. Postpartum hemorrhage has been described in mild FXIII deficiency. We present a case of mild FXIII deficiency and concurrent hypofibrinogenemia manifested by recurrent postpartum hemorrhage, menorrhagia, and miscarriage. Mutational analysis identified a previously unreported heterozygous mutation of the FXIIIA subunit (p.Trp315Arg). No mutation was noted in the fibrinogen gene. FXIII levels decreased approximately 50% from nonpregnant levels to their nadir during labor, whereas fibrinogen levels rose approximately 1.5-fold from decreased nonpregnant levels to their peak at the time of labor. This case illustrates the course of mild FXIII and fibrinogen deficiencies during pregnancy, labor, and postpartum, and raises possible management options for prevention of antepartum and postpartum hemorrhage in women with these deficiencies.