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Summary. Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven®, a plasma-derived FXI concentrate. The application required an investigator-initiated IRB-approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of ≤ 4 doses of 10-15 U/kg Hemoleven®; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients. [ABSTRACT FROM AUTHOR]

The prothrombin G20210A mutation is a common risk factor for thrombosis which increases the risk of deep vein thrombosis, stroke, and fetal loss. There are few publications of its clinical manifestations in children. Our objective was to determine the clinical manifestations of the prothrombin mutation in children. Via survey of pediatric hematologists, we collected data on children with thrombosis and the prothrombin mutation. Thirty-eight patients with a thrombotic event were identified as having the prothrombin mutation. Children with arterial thrombosis were younger, less than half had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and had thrombosis occur most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there. In all, 14/38 children (37%) had central nervous system thrombosis. Unlike factor V Leiden and deficiencies of proteins C and S which cause venous thromboembolism, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. In children with the prothrombin mutation and venous thrombosis, other risk factors are usually present. Therefore, children with arterial or venous thrombosis of any location should be evaluated for the presence of the prothrombin mutation.

Porcine factor VIII (pFVIII) is an effective haemostatic treatment for bleeding in selected patients with FVIII inhibitors. Its use is sometimes associated with a transient fall in platelet count and transfusion reactions, the risk of which may be related to the rate of administration. Theoretical considerations suggest that the administration of pFVIII by continuous infusion should be effective, and could have pharmacokinetic advantages that lead to an improvement in the side-effect profile. The results of a retrospective survey of continuous infusion of pFVIII with respect to clinical safety and efficacy are reported. Porcine FVIII stability and microbiological studies are included. It is concluded that pFVIII given by continuous infusion is safe and effective. The risk of transfusion reactions and fall in platelet count appears to be reduced, compared with bolus administration. Stability studies showed that pFVIII activity declined at room temperature, most rapidly in the dilute solution (5-10 U mL(-1)). More concentrated mixtures showed acceptable stability for up to 24 h using a variety of infusion devices. Various concentrations of pFVIII did not support the growth of Escherichia coli or Staphylococcus aureus. These observations suggest that the porcine factor is suitable for continuous infusion (CI).

Objective: This study was carried out to determine whether the routine use of low-dose heparin in umbilical catheter infusates increases the risk of intraventricular hemorrhage or alters the coagulation profile in premature infants., Methods: In a randomized, blinded trial, 113 infants born at less than 31 weeks' gestation were assigned to receive, in their umbilical catheter infusate, either 1 unit of heparin per milliliter (n = 55) or no heparin (n = 58). Prothrombin time, activated partial thromboplastin time, fibrinogen concentration, and antithrombin III activity levels were determined at the start and the completion of the study. Cranial ultrasonography was performed during the first week of life., Results: There was no difference in the incidence of intraventricular hemorrhage between the heparin and no heparin groups, 35.8% and 31.5%, respectively (p = 0.6). Similarly, no difference was detected in the incidence of severe intraventricular hemorrhage (grades III/IV). Prothrombin time, activated partial thromboplastin time, and fibrinogen levels were not significantly different between the two groups. However, the use of heparin was associated with a lower antithrombin III activity level. Antenatal indomethacin use was associated with a 2.9 increased risk of intraventricular hemorrhage (95% confidence interval, 1.15 to 7.17)., Conclusion: A low dose of heparin added to umbilical catheter infusates does not increase the incidence or severity of intraventricular hemorrhage or significantly alter the coagulation profile in premature infants.

Purpose: This case report represents a description of a hemorrhagic ovarian cyst in a patient with hemophilia A., Patient: An 18-year-old female patient with severe factor VIII deficiency presented with the acute onset of a hemorrhagic ovarian cyst, meeting the standard indications for surgical intervention. Instead, because of the underlying coagulopathy, factor VIII therapy was instituted., Result: Within 1 day of starting the factor VIII therapy, the hemorrhage had clinically resolved and surgical intervention was avoided., Conclusions: Hemorrhagic ovarian cysts in the setting of hemophilia may respond to factor VIII replacement therapy without the need for surgical intervention. Because the incidence of functional ovarian cysts is high in the general population, female patients with hemophilia should be counseled regarding its possibility of occurrence. Moreover, if a female patient with hemophilia displays a propensity toward the development of ovarian cysts, the administration of prophylactic oral contraceptive pills should strongly be considered.

Factor VIII (FVIII) replacement by continuous infusion has been advocated as a cost-effective method for maintaining stable plasma levels of FVIII in the hemophilia A patients during surgery or life-threatening hemorrhage. Continuous delivery of monoclonal or recombinant FVIII concentrates to our pediatric patients using a traditional delivery system (dilution in normal saline of 2-10 U/ml infused at a rate of 20 ml/hr) has frequently yielded higher than expected factor usage to achieve desired levels and unexpected variability in plasma levels under presumed steady-state conditions. To determine if diminished in vitro FVIII recovery was responsible for these observations, a study of four ultrapure concentrates during 8 hr of in vitro continuous delivery was performed using four delivery systems. When reconstituted concentrate was added to normal saline in polyvinylchloride bags at a concentration of 10 U/ml (method IA), monoclonal products showed a stable recovery of 84-109% of time 0 levels. Recombinant product recovery dropped to 57-76% of time 0 levels before reapproximating the time 0 level at 2 hr. The addition of 10 mg/ml human albumin to the bags (method IB) did not improve recoveries. When reconstituted concentrate was delivered undiluted (method IIA), the early drop in recombinant recovery was eliminated; stable recovery of 78-117% of time 0 level was achieved with all products. In using method IA, a large discrepancy was seen between the actual time 0 recoveries and those expected based on vial assays, most striking for recombinant products (49-57% of expected. Method IIA allowed 75-90% recovery; addition of 20 mg/ml albumin of reconstituted but undiluted concentrate (method IIB) maximized recovery at 85-98% of expected.

Twenty-one patients with prolonged bleeding times secondary to inherited disorders of platelet function and eight patients with prolonged bleeding times secondary to acquired platelet dysfunction were given 0.3 micrograms per kilogram of DDAVP, 1-deamino-8-D-arginine vasopressin, intravenously. Sixteen of twenty-two DDAVP trials in patients with inherited platelet dysfunction (73%) and seven of the nine DDAVP trials in patients with acquired platelet dysfunction (78%) resulted in normalization or shortening of the prolonged bleeding times by at least 4 min. The bleeding time response did not correlate with changes in the levels of von Willebrand factor (vWf) antigen or ristocetin cofactor activity, nor was it associated with changes in vWf multimeric analysis or in vitro platelet aggregations following the administration of DDAVP. Shortening of the bleeding time with DDAVP was seen in patients with a failure to release/storage pool type defect, thromboxane synthesis type defect, Bernard-Soulier syndrome, Glanzmann's thrombasthenia, the May-Hegglin anomaly, liver disease, nonuremic renal disease, myelofibrosis, and Tangier's disease.

Analysis of the multimeric structure of von Willebrand's factor (vWf) was compared with vWf-binding to collagen in subjects' plasma. The percentage binding of vWf to collagen was determined by both an enzyme-linked immunosorbent assay (ELISA) method and quantitative immunoelectrophoresis. Normal subjects, type I von Willebrand's disease (vWd), and type II vWd were studied. The authors have found by correlating collagen-binding results with multimeric analysis that normal controls exhibit 85.4 +/- 5.1% collagen absorption of their vWf, patients with type I vWd 80.8 +/- 5.3%, whereas patients exhibiting a deficiency of high molecular weight vWf have 32.3 +/- 16.6% collagen absorption of vWf. The results suggest that this functional assay of vWf can be used in the classification of vWd and in the detection of new dysfunctional forms of vWf.