Menorrhagia and inherited disorders of coagulation

Menorrhagia, a common complaint among women, may be a manifestation of an underlying inherited disorder of coagulation. In this review, the most frequent hereditary bleeding disorders associated with menorrhagia are briefly analyzed. Particularly, the epidemiological, clinical and diagnostic characteristics of von Willebrand disease, factor VIII, factor IX and factor XI deficiencies are examined. The influence of external factors (age, phase of menstrual cycle and hormonal therapy) on coagulation factor levels is also analyzed. Finally, the main therapeutic options (such as hormonal therapy, tranexamic acid and desmopressin), for the treatment of menorrhagia in women with hereditary bleeding disorders are reviewed. Since inherited bleeding disorders are frequently associated with menorrhagia, the conclusion is drawn that an underlying congenital bleeding disorder should be ruled out in any woman with menorrhagia.     

PGD for X-linked and gender-dependent disorders using a robust,flexible single-tube PCR protocol

X-linked genetic diseases include a wide range of disorders such as the dystrophinopathies. Additionally in some rare genetic diseases, severity of expression is gender dependent. Prevention of such disorders usually involves prenatal diagnosis and termination of affected pregnancies, while preimplantation genetic diagnosis (PGD) represents a specialized alternative that avoids pregnancy termination. To preclude the rejection of unaffected male embryos that cannot be differentiated from those affected when using fluorescence in-situ hybridization, a flexible protocol based on multiplex fluorescence polymerase chain reaction (PCR) was standardized and validated for gender determination in single cells, which can potentially incorporate any disease-specific locus. The final panel of nine loci included four loci on the Y chromosome, two on the X chromosome plus up to three microsatellite markers to either support the gender diagnosis or to further monitor extraneous contamination. The protocol, standardized on single lymphocytes, established a PCR efficiency of >93% for all loci with maximum allele dropout rates of 4%. Microsatellite analysis excluded external contamination and confirmed biallelic inheritance. Proof of principle for the simplicity and flexibility of the assay was demonstrated through its application to clinical PGD cycles for lipoid congenital adrenal hyperplasia, which presents a more severe clinical course in males, and Duchenne muscular dystrophy.     

Medical and social perspectives of PGD for single gene disorders and human leukocyte antigen typing

Preimplantation genetic diagnosis (PGD) for single gene disorders combined with human leukocyte antigen (HLA) typing has recently emerged as a therapeutic tool. For couples who are at risk of passing on a genetic disease to their offspring, preimplantation embryos can be selected according to their genetic status as well as a possible HLA matching with the affected sibling. Stem cells from the resulting baby's umbilical cord blood have, therefore, a great therapeutic value for haematopoietic and other life threatening diseases, as stem cells in the cord blood from a HLA-compatible newborn can be used for transplantation without graft rejection, thus saving an affected child's life. However, apart from being a valuable treatment option, there exist several medical and social aspects that should be evaluated and discussed. From the ethical and the social aspects, although PGD for single gene disorders is well defined and accepted, application of PGD combined with HLA typing is less obvious and under extensive debate. This article is aimed at summarizing the current results and limitations of PGD with HLA typing that are related to the successful medical outcome. It further discusses the ethical and social issues that have recently been raised on the application of this technique.     

Factor V Leiden mutation: the most commonly inherited risk factor for venous thromboembolism

Factor V Leiden mutation is a common genetic risk factor for venous thrombosis. It has been documented in up to 65% of patients with unexplained venous thromboembolism. This genetic mutation is now known to be the most common inherited cause of activated protein C (APC) resistance. Recently, FV Leiden mutation has been associated with adverse pregnancy outcomes (including recurrent fetal loss, severe preeclampsia, placental abruption, intrauterine growth restriction and stillbirth), in addition to venous thromboembolic disorders. In this article, we discuss the genetic basis, diagnosis and clinical significance of FV Leiden mutation. Awareness of the clinical manifestations associated with FV Leiden mutation should ensure screening of appropriate populations and prophylaxis against thromboembolic disease when indicated.     

Gynaecological and obstetric management of women with inherited bleeding disorders.

OBJECTIVE: The prevalence of bleeding disorders, notably von Willebrand disease (vWD), among adult women with objectively documented menorrhagia is consistently reported to be 10% to 20% and is even higher in adolescents presenting with menorrhagia. This consensus document has been developed by a multidisciplinary committee consisting of an anesthesiologist, 2 hematologists, and an obstetrician/gynaecologist and has been endorsed by their relevant specialty bodies. It has been prepared with the express purpose of providing guidelines for both women with inherited bleeding disorders and for their caregivers regarding the gynaecological and obstetric management of these women, including appropriate anesthesia support where indicated. OPTIONS: Diagnostic tools and specific medical and, where appropriate, surgical alternatives to management are reviewed and evidence-based recommendations presented. EVIDENCE: A MEDLINE search of the English literature between January 1975 and November 2003 was performed using the following key words: menorrhagia, uterine bleeding, pregnancy, von Willebrand, congenital bleeding disorder, desmopressin/DDAVP, tranexamic acid, oral contraceptives, medroxyprogesterone, therapy, hysterectomy, anesthesia, epidural, spinal. Recommendations from other society guidelines were reviewed. RECOMMENDATIONS: 1. Inherited bleeding disorders should be considered in the differential diagnosis of all patients presenting with menorrhagia (II-2B). The graphical scoring system presented is a validated tool which offers a simple yet practical method that can be used by patients to quantify their blood loss (II-2B). 2. Because underlying bleeding disorders are frequent in women with menorrhagia, physicians should consider performing a hemoglobin/hematocrit, platelet count, ferritin, PT (INR) and APTT in women with menorrhagia. In women who have a personal history of other bleeding or a family history of bleeding, further investigation should be considered, including a vWD workup (factor VIII, vWF antigen, and vWF functional assay) (II-2B). 3. Treatment of menorrhagia in women with inherited bleeding disorders should be individualized (III-B). 4. An inherited bleeding disorder is not a contraindication to hormonal therapy (oral contraceptives [II-1B], depot medroxyprogesterone acetate (DMPA) [II-3B], danazol [II-2B], GnRH analogs [II-3B]) or local treatments (levonorgestrel-releasing IUS [II-1B]) and non-hormonal therapy (antifibrinolytic drug tranexamic acid [II-1B]) as well as desmopressin (II-1B). These therapies represent first line treatment. Blood products should not be used for women with mild bleeding disorders (III-A). 5. In women who no longer want to preserve their fertility, conservative surgical therapy (ablation) and hysterectomy may be options (III-B). Clinicians may consult the "SOGC Clinical Practice Guideline: Guidelines for the Management of Abnormal Uterine Bleeding" for an in-depth discussion of the available therapeutic modalities, both medical and surgical. To minimize the risk of intraoperative and post-operative hemorrhage, coagulation factors should be corrected preoperatively with post-operative monitoring (II-1B). 6. Girls growing up in families with a history of vWD or other inherited bleeding disorders should be tested pre-menarchally to determine whether or not they have inherited the disease to allow both the patient and her family to prepare for her first and subsequent menstrual periods (III-C). 7. In adolescents presenting with menorrhagia, an inherited bleeding disorder should be excluded (III-B). When possible, investigation should be undertaken before oral contraceptive therapy is instituted, as the hormonally induced increase in factor VIII and vWF may mask the diagnosis (II-B). 8. Pregnancy in women with inherited bleeding disorders may require a multidisciplinary approach. A copy of their recommendations should be given to the patient and she should be instructed to present it to the health care provider admitting her to the birthing centre. Women with severe bleeding disorders or with a fetus at risk for a severe bleeding disorder should deliver in a hospital (level three) or where there is access to consultants in obstetrics, anesthesiology, hematology, and pediatrics (III-C). 9. Vacuum extraction, forceps, fetal scalp electrodes, and fetal scalp blood sampling should be avoided if the fetus is known or thought to be at risk for a congenital bleeding disorder. A Caesarean section should be performed for obstetrical indications only (II-2C). 10. Epidural and spinal anesthesia are contraindicated if there is a coagulation defect. There is no contraindication to regional anesthesia if coagulation is normalized. The decision to use regional anesthesia should be made on an individual basis (III-C). 11. The risk of early and late postpartum hemorrhage is increased in women with bleeding disorders. Women with inherited bleeding disorders should be advised about the possibility of excessive postpartum bleeding and instructed to report this immediately (III-B). 12. Intramuscular injections, surgery, and circumcision should be avoided in neonates at risk for a severe hereditary bleeding disorder until adequate workup/preparation are possible (III-B). The quality of evidence reported in this document has been described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam (Table 1).     

The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is used commonly by gynaecologists as a contraceptive and to treat menorrhagia. However, its efficacy has not been examined in women with inherited bleeding disorders. DESIGN: A prospective pilot study. SETTING: A teaching hospital in north London with a designated haemophilia centre. POPULATION: Female patients with a known inherited bleeding disorder. METHODS: Sixteen women with subjective and objective menorrhagia caused by inherited bleeding disorders (13 von Willebrand's Disease, two factor XI deficiency and one Hermansky-Pudlak syndrome), who had previously undergone unsuccessful medical treatment were followed up for nine months after LNG-IUS insertion. Bleeding was measured by pictorial chart and haemoglobin concentration. RESULTS: All women reported that their periods were improved, pictorial chart scores were lower and 56% became amenorrhoeic. None reported side effects. CONCLUSION: The LNG-IUS is well tolerated and effective and improves quality of life.