Global hemostasis assays in acute myeloid leukemia: results of an observational prospective study.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by a complex spectrum of coagulopathy ranging from hemorrhagic to thrombotic symptoms. To date, platelet count (PLT) and conventional coagulation tests (CCTs) cannot predict hemorrhagic events and thrombotic risk. Thromboelastography (TEG) measures the viscoelastic properties of the clot, thus providing information on the entire process of blood coagulation. The primary aim of the study was to assess the hemostatic balance from AML diagnosis to the end of chemotherapy (CHT) by TEG. MATERIAL AND METHODS: Here we present the results of a prospective study enrolling newly diagnosed AML patients treated with chemotherapy. Patients had complete blood counts (CBCs), TEG and CCTs performed at three time points: 1) diagnosis (T0); 2) during the first cycle of CHT (T1); and 3) at the end of CHT (T2). An algorithm of TEG indirectly calculated thrombin generation (TG). Patients underwent daily follow-up for bleeding and thrombotic episodes up to the time of hospital discharge or death. RESULTS: Eighty consecutive patients were evaluated; forty were eligible for the study, and 21 completed the entire study. At T1, maximum amplitude (MA), TG and K-time were significantly shifted toward a hypocoagulability state compared to T0 (p<0.05), while a hypercoagulable state at T2 was shown by changes in α-angle, MA and TG values. Otherwise, there were no statistically significant differences in CCTs between the evaluated time points. DISCUSSION: Overall, TEG revealed complex and dynamic coagulation abnormalities in patients with AML according to both the course of disease and therapy. Further studies are needed to investigate more fully the role of TEG in defining the hemostatic profile in patients with AML.

Buffy coat-derived platelets cryopreserved using a new method: Results from a pivotal clinical trial on thrombocytopenic patients with acute leukaemia.

The administration of cryopreserved platelets (PLTs) may overcome the limits of platelet shortage and availability, especially during some seasons or in specific contexts like rural areas. After in vitro validation studies, ad hoc prepared buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at -80 °C with a modified Valeri method, were transfused in patients with severe thrombocytopenia secondary to chemotherapy for acute leukaemia (AL). Five inpatients were enrolled in the pivotal clinical trial NCT02032134: 4 males and 1 female with a mean age of 71 years (range: 65-80). Four patients were diagnosed with acute myeloid leukaemia and 1 had acute lymphoblastic leukaemia.Transfusion of one Unit of CRY BC-PLTs resulted effective in active bleeding control in two patients without any adverse reaction or concomitant antihaemorrhagic therapies. CRY BC-PLTs met the currently accepted criteria for cryopreserved PLTs, their transfusion in patients with AL was safe. (Clinical trial: NCT02032134).

Role of clinical and laboratory parameters for treatment choice in patients with inherited FVII deficiency undergoing surgical procedures: evidence from the STER registry.

Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0·003) for a longer RT duration (3 days vs. 1 day, P = 0·001), with no difference in RT dose. Similarly, patients with a history of major bleeds received a higher number of RT doses (8·5 vs. 2-3, P = 0·013) for a longer RT duration (2 days vs. 1 day, P = 0·005) as compared to those with a history of minor bleeds or to asymptomatic patients. No difference in RT was found among major and minor surgical procedures. Overall, multivariate analysis showed that history of major bleeding was the only independent predictor of number of RT doses (ß = 0·352, P = 0·001) and RT duration (ß = 0·405, P = 0·018). Overall, a ≈20 µg/kg perioperative RT was efficacious in 95·5% of cases. The infusion should be repeated ≈8 times in high-risk subsets (i.e. patients with a history of major bleeding).

Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses.

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, five-to-six 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.

Recombinant, activated factor VII for surgery in factor VII deficiency: a prospective evaluation - the surgical STER.

Excessive 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, web-based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty-one 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 µg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.

Steps towards an effective treatment strategy in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is a consequence of a genetic polymorphism that can produce a wide spectrum of disease severity. Mildly affected patients may experience increased bleeding after surgery, trauma or mucosal bleeding, while spontaneous and life-threatening bleeding occurs in patients who are severely affected. Replacement therapy is the mainstay of treatment for patients with FVII deficiency. This has traditionally been achieved using fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), or plasma-derived FVII concentrates. However, recombinant activated FVII is now widely used for therapy in these patients. As cases of FVII deficiency tend to be encountered infrequently in most centers, no consolidated evidence-based therapeutic regimens have evolved and the side effects of the available treatments have not been comprehensively evaluated. Consequently, an online registry, the Seven Treatment Evaluation Registry (STER) has been set up. This is a prospective study that aims to evaluate the efficacy and safety of the different therapeutic options with which FVII-deficient patients may be treated. Recruitment of patients into the study is currently underway.