Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received freshfrozen plasma. Prophylactic schedules clustered into "frequent" courses (three times weekly, n=23) and "infrequent" courses (≤2 times weekly, n=15). Excluding courses for menorrhagia, "frequent" and "infrequent" courses produced 18/23 (78%) and 5/12 (41%) "excellent" outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long-term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 mg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency (clinicaltrials.gov: NCT01269138). Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER)

Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition—even in homozygous subjects—to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency.

Aim:There is a paucity of data on the clinical presentation and management of cancer patients with acquired haemophilia (AH), we here report a systematic literature review on acquired haemophilia in the context of cancer.Methods: Treatment outcomes of AH were defined as complete response (CR), partial response (PR) or no response (NR), based on inhibitor eradication, coagulation factor VIII levels and bleeding control. Reported deaths were either related to cancer or bleeding.Results: Overall, 105 cases were collected and analyzed according to classification of cancer and efficacy of treatments for inhibitor and malignancy. The mean age was 68 years for both males (range 37-86 years) and females (range 43-89 years), 39 patients were female subjects and 66 were males. A solid cancer was diagnosed in 60 subjects, while 45 patients suffered a haematological malignancy. Solid cancers affected mainly males; however, the incidence of solid tumours vs haematological malignancies was not statistically significant (P = .09). Not all patients were treated for their underlying cancer, bleeding and/or inhibitor, in two cases outcome is unavailable. CR was reported in 62.1% (64/103) cases, PR in 9.7% (10/103) cases, NR with or without death was reported in 28.1% (29/103) cases. Conclusion:CR was best achieved when successful and complete elimination of autoantibodies occurred contemporaneously with the successful treatment of the underlying malignancy. In some cases, recurrent autoantibodies were harbingers of relapsed cancer. Type of cancer, inhibitor titer, treatments administered for bleeding control and inhibitor eradication did not significantly affect clinical outcome of analyzed cases. K E Y W O R D Sacquired haemophila, bleeding, cancer, diagnosis, haematological malignancy, inhibitor, treatment

SummaryExcessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi-centre, prospective, observational, webbased study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Fortyone surgical operations (24 'major' and 17 'minor') were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30-d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 lg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.

Background Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH‐BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups. Objectives The aim of the present study was to test the utility of the ISTH‐BAT in a large cohort of patients with a well‐defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type‐1 von Willebrand disease (VWD‐1) and one of healthy controls (HC). Patients/Methods We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries. Results IPFD patients had significantly higher bleeding score (BS; median 9) than VWD‐1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH‐BAT showed excellent discrimination power between IPFD and HC (0.9 < area under the curve [AUC] < 1), moderate (0.7 < AUC < 0.9) between IPFD and VWD‐1 and between IPFD and inherited thrombocytopenia (IT), while it was inaccurate (AUC ≤ 0.7) in discriminating IT from HC. Conclusions The ISTH‐BAT allows to efficiently discriminate IPFD from HC, while it has lower accuracy in distinguishing IPFD from VWD‐1. Therefore, the ISTH‐BAT appears useful for identifying subjects requiring laboratory evaluation for a suspected IPFD once VWD is preliminarily excluded.

In patients with cancer with a first DVT, treated for 6 months with LMWH, absence of RVT identifies a population at low risk for recurrent thrombotic events. Continuation of LMWH in patients with RVT up to 1 year did not reduce recurrent VTE.

Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.

In women of fertile age, iron loss consequent to excessive menstrual discharge is by far the most frequent cause of iron-deficient anemia. However, the relationship between menstrual discharge and iron loss is poorly understood. In this prospective study, total menstrual and iron losses were assayed in a large cohort of non-anemic women and women with excessive menstrual blood losses (menorrhagia) in order to provide data useful for intervention. One hundred and five Caucasian women aged 20-45 years were recruited. Blood cell count and serum ferritin (SF) levels were determined in each case before menses. Menstrual Fluid Losses (MFL) were determined using a standardized pads' weight method. Hematin concentration was assayed by a variant of the Alkaline Hematin Method from which iron concentration was calculated. Mean SF levels were 36.2 (range 8.6-100) ng/ml in healthy women and 6.4 (range 5-14) ng/ml in patients with menorrhagia. Median values of iron lost/cycle were 0.87 mg in healthy women and 5.2 mg in patients with menorrhagia (ranges: 0.102-2.569 and 1.634-8.665 mg, respectively, p<0.001). In women with menorrhagia, iron lost/cycle strongly correlated (0.789, p<0.001) with MFL. In conclusion, healthy women with normal menses lose, on average, 1 mg iron/cycle. Average iron losses in patients with menorrhagia are, at least in our cohort, on average, 5-6 times higher than normal. Most women with menorrhagia had totally depleted iron stores. Indirect, quantitative evaluation of iron lost with menses may be useful to assess the risk of developing iron-deficient anemia in individual patients. 3 IntroductionIron is a vital element of metabolism, with the most obvious and known role played in erythropoiesis, and important functions in other intracellular processes in all tissues of the body. The uptake of iron is finely regulated (1). For physiologic iron losses, no known mechanisms of maintaining iron homeostasis have been identified, and losses appear to be related mainly to cell exfoliation (2).