Martinowitz U.


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Topical Hemostatic-Anesthetic Solution to Reduce Bleeding During Mohs Micrographic Surgery: A Case Control Study.

Wed, 20/07/2016 - 4:08am

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Topical Hemostatic-Anesthetic Solution to Reduce Bleeding During Mohs Micrographic Surgery: A Case Control Study.

J Drugs Dermatol. 2016 Jul 1;15(7):851-5

Authors: Zilinsky I, Barazani TB, Shenkman B, Weisman O, Farber N, Martinowitz U

Abstract
BACKGROUND: Between stages of Mohs micrographic surgery, the wound is dressed and the patient waits for the histopathological results.<br/>
OBJECTIVE: To investigate the efficacy of a hemostatic-anesthetic solution-impregnated gauze in decreasing bleeding between Mohs stages.<br/>
MATERIALS AND METHODS: Twenty patients were treated with a hemostatic-anesthetic solution composed of tranexamic acid, adrenaline, and lidocaine (TAL), and 20 others were treated with a saline solution for control. At the second Mohs stage, size measurements of the blood stain on a Telfa pad and the defect were recorded. The Rotation Thromboelastometry Method (ROTEM) was used to investigate a possible effect of lidocaine and adrenaline on the clot stability induced by tranexamic acid.<br/>
RESULTS: The ratio of blood stain size to Mohs defect size in the hemostatic anesthetic solution group was 1:1.47, whereas the ratio in the control saline group was 1:3.37 (P&lt;.001). Results of the ROTEM test showed that lidocaine and adrenaline did not interfere with the effect of tranexamic acid on clot formation and stability.<br/>
CONCLUSION: The application of gauze impregnated with tranexamic acid, adrenaline, and lidocaine on a surgical wound may be effective in reducing bleeding between Mohs stages. <br /><br /> <em>J Drugs Dermatol.</em> 2016;15(7):851-855.

PMID: 27391635 [PubMed - in process]

Categories: Publications list

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

Wed, 20/07/2016 - 4:08am

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Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

Blood. 2016 Apr 7;127(14):1761-9

Authors: Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger I, von Depka Prondzinski M, Altisent C, Castaman G, Yamamoto K, Álvarez-Roman MT, Voigt C, Blackman N, Jacobs I, PROLONG-9FP Investigators Study Group

Abstract
A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered atwww.clinicaltrials.govas #NCT0101496274.

PMID: 26755710 [PubMed - in process]

Categories: Publications list

Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage.

Wed, 20/07/2016 - 4:08am

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Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage.

J Thromb Haemost. 2015 Dec;13(12):2202-9

Authors: White NJ, Mehic E, Wang X, Chien D, Lim E, St John AE, Stern SA, Mourad PD, Rieger M, Fries D, Martinowitz U

Abstract
BACKGROUND: Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis.
OBJECTIVES: (i) To use a swine model of femoral artery bleeding to understand the perivascular hemostatic response to contained arterial hemorrhage. (ii) To directly confirm the association between hemodynamics and bleeding velocity. (iii) To observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach.
METHODS: Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery hemorrhage was also used to demonstrate the feasibility of local delivery of an activated clotting factor.
RESULTS: In this model, clots formed slowly within the peri-wound hematoma, but eventually contained the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated factor VII into the injured artery near the site of major internal hemorrhage in the pelvis and axillae was feasible.
CONCLUSIONS: We rediscovered that clot formation within the peri-wound hematoma is an integral component of hemostasis and a feasible target for the treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach.

PMID: 26414624 [PubMed - in process]

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The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency.

Wed, 20/07/2016 - 4:08am

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The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency.

Thromb Res. 2015 Aug;136(2):465-73

Authors: Livnat T, Shenkman B, Martinowitz U, Zivelin A, Dardik R, Tamarin I, Mansharov R, Budnik I, Salomon O

Abstract
The phenotype of bleeding in patients with severe FXI deficiency is unpredictable and unlike other bleeding disorders, it is not directly correlated with levels of FXI. In this study we analyzed whether the global coagulation assays can serve as a clinical tool in predicting bleeding tendency in patients with severe FXI deficiency undergoing surgery, taking into account the large inter-individual variability of FXI levels and genotypes. Thrombin generation (TG) was measured in 39 platelet-poor plasma with or without tissue factor (TF) and in the presence or absence of corn trypsin inhibitor (CTI). Rotation thromboelastometry (ROTEM) was performed with fresh whole blood of 26 patients applying NATEM and INTEM tests. TG induced by recalcification can distinguish between bleeding and non-bleeding patients with severe FXI deficiency particularly among those with FXI activity of 2-20IU/dl. The addition of TF or TF and CTI to the TG assay masked the ability to differentiate between XI activity, genotype as well as bleeding and non-bleeding patients. ROTEM assays failed to distinguish bleeding from non-bleeding patients but could do so between different FXI activity levels and genotypes. In conclusion, in the current study we found a sensitive tool to distinguish between bleeding and non-bleeding patients. In order to recommend TG as a predictive tool for treatment tailoring, a larger patient group is required.

PMID: 26160656 [PubMed - indexed for MEDLINE]

Categories: Publications list

Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients.

Wed, 20/07/2016 - 4:08am

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Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients.

Haemophilia. 2015 Nov;21(6):784-90

Authors: Martinowitz U, Lissitchkov T, Lubetsky A, Jotov G, Barazani-Brutman T, Voigt C, Jacobs I, Wuerfel T, Santagostino E

Abstract
INTRODUCTION: rIX-FP is a coagulation factor IX (recombinant), albumin fusion protein with more than fivefold half-life prolongation over other standard factor IX (FIX) products available on the market.
AIM: This prospective phase II, open-label study evaluated the safety and efficacy of rIX-FP for the prevention of bleeding episodes during weekly prophylaxis and assessed the haemostatic efficacy for on-demand treatment of bleeding episodes in previously treated patients with haemophilia B.
METHODS: The study consisted of a 10-14 day evaluation of rIX-FP pharmacokinetics (PK), and an 11 month safety and efficacy evaluation period with subjects receiving weekly prophylaxis treatment. Safety was evaluated by the occurrence of related adverse events, and immunogenic events, including development of inhibitors. Efficacy was evaluated by annualized spontaneous bleeding rate (AsBR), and the number of injections to achieve haemostasis.
RESULTS: Seventeen subjects participated in the study, 13 received weekly prophylaxis and 4 received episodic treatment only. No inhibitors were detected in any subject. The mean and median AsBR were 1.25, and 1.13 respectively in the weekly prophylaxis arm. All bleeding episodes were treated with 1 or 2 injections of rIX-FP. Three prophylaxis subjects who were treated on demand prior to study entry had >85% reduction in AsBR compared to the bleeding rate prior to study entry.
CONCLUSION: This study demonstrated the efficacy for weekly routine prophylaxis of rIX-FP to prevent spontaneous bleeding episodes and for the treatment of bleeding episodes. In addition no safety issues were detected during the study and an improved PK profile was demonstrated.

PMID: 25990590 [PubMed - in process]

Categories: Publications list

Rotation thromboelastometry analysis of clot formation and fibrinolysis in severe thrombocytopenia: effect of fibrinogen, activated prothrombin complex concentrate, and thrombin- activatable fibrinolysis inhibitor.

Wed, 20/07/2016 - 4:08am

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Rotation thromboelastometry analysis of clot formation and fibrinolysis in severe thrombocytopenia: effect of fibrinogen, activated prothrombin complex concentrate, and thrombin- activatable fibrinolysis inhibitor.

Int J Lab Hematol. 2015 Aug;37(4):521-9

Authors: Shenkman B, Einav Y, Livnat T, Budnik I, Martinowitz U

Abstract
INTRODUCTION: Bleeding symptoms in severe thrombocytopenia range from mild to severe. The aim of this in vitro study was to improve blood clotting and protect against fibrinolysis in reconstituted severe thrombocytopenia blood.
METHODS: Thrombocytopenia [(16 ± 4) × 10(6) /mL] was created by high-speed centrifugation of normal blood with subsequent mixing plasma with packed cells. The blood samples were subjected to clotting by CaCl2 and tissue factor and to fibrinolysis by the addition of tissue plasminogen activator. Blood was spiked with fibrinogen, activated prothrombin complex concentrate (FEIBA), thrombin activatable fibrinolysis inhibitor (TAFI), or their combinations. To mimic the situation that may occur in patients subjected to massive transfusion of plasma substitutes, blood was diluted by 40% of TRIS/saline buffer. Clotting time (CT), α-Angle, maximum clot firmness (MCF), and lysis onset time (LOT) were evaluated using rotation thromboelastometry.
RESULTS: Spiking thrombocytopenia blood with FEIBA led to reduction of CT. Fibrinogen and FEIBA enhanced α-Angle and MCF both in the absence and in the presence of tPA. LOT values were prolonged by TAFI and to less extent by FEIBA. Dilution of thrombocytopenia blood was followed by reduction of α-Angle and MCF compared to nondiluted blood which partly reversed by either fibrinogen or FEIBA being higher using fibrinogen and FEIBA together. Clot strength was enhanced, and fibrinolysis was inhibited by TAFI.
CONCLUSION: The results of this study suggest that combined spiking of blood with fibrinogen and FEIBA may be enough to correct the clot formation disorder in severe thrombocytopenia, whereas in thrombocytopenia and blood dilution, additive inhibition of fibrinolysis may be needed.

PMID: 25651468 [PubMed - indexed for MEDLINE]

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Survival of hepatitis C-infected haemophilia patients is predicted by presence of cirrhosis but not by anti-viral treatment.

Wed, 20/07/2016 - 4:08am

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Survival of hepatitis C-infected haemophilia patients is predicted by presence of cirrhosis but not by anti-viral treatment.

Ann Hepatol. 2014 Nov-Dec;13(6):753-61

Authors: Maor Y, Schapiro JM, Bashari D, Martinowitz U

Abstract
BACKGROUND/PURPOSE: Hepatitis C (HCV) is a major cause of morbidity and mortality in haemophilia patients who received clotting factor concentrates before the availability of virus-inactivated factors in the mid-1980s. Recently, it has been suggested that anti-HCV treated patients, particularly those achieving a sustained virological response (SVR) have an improved outcome. We sought to examine the survival of treated and untreated HCV-infected haemophilia patients.
MATERIAL AND METHODS: We studied overall and liver-related survival of patients with haemophilia and other congenital bleeding disorders between 2000 and 2010. The outcome was compared in 3 sub-groups: HCV mono-infected (N = 127), HCV/HIV co-infected (N = 28), and patients with either HCV-antibodies negative or persistent HCV RNA-negative (referred to as non-infected) (N = 45). Sixty-two (40%) (HCV and HCV/HIV) patients underwent anti-HCV treatment with an SVR rate of 40.3%.
RESULTS: Overall and liver-related 10-year survival were: 82.1 and 89.3%, 95.3 and 99.2 and 100% for HCV/HIV co-infected, HCV mono-infected and non-infected haemophilia patients, respectively (p = 0.015 and 0.023 for comparisons of HCV/HIV vs. HCV; p = 0.003 for comparison of HCV/HIV and non-infected). One HCV mono-infected and 3 co-infected patients died of end-stage liver disease (2 underwent liver transplantation). There was no survival benefit from anti-HCV treatment or from attaining of an SVR. Only clinically suspected cirrhosis remained as an independent predictor of survival.
CONCLUSION: The prognosis of haemophilia patients who acquired HCV/HIV co-infection is worse than that of HCV mono-infected or non-infected or haemophiliacs. This is mainly due to liver-related mortality. Anti-HCV treatment or SVR had no observable impact on survival rate.

PMID: 25332261 [PubMed - indexed for MEDLINE]

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Management of atrial fibrillation in people with haemophilia--a consensus view by the ADVANCE Working Group.

Wed, 20/07/2016 - 4:08am

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Management of atrial fibrillation in people with haemophilia--a consensus view by the ADVANCE Working Group.

Haemophilia. 2014 Nov;20(6):e417-20

Authors: Schutgens RE, Klamroth R, Pabinger I, Dolan G, ADVANCE working group

PMID: 25296569 [PubMed - indexed for MEDLINE]

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Patient characteristics that influence efficacy of prophylaxis with rFVIII-FS three times per week: a subgroup analysis of the LIPLONG study.

Wed, 20/07/2016 - 4:08am

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Patient characteristics that influence efficacy of prophylaxis with rFVIII-FS three times per week: a subgroup analysis of the LIPLONG study.

Haemophilia. 2014 May;20(3):354-61

Authors: Lalezari S, Coppola A, Lin J, Enriquez MM, Tseneklidou-Stoeter D, Powell J, Ingerslev J, LIPLONG Investigators

Abstract
Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose-formulated recombinant factor VIII [rFVIII-FS (control)] arm of the LIPLONG study, a randomized, double-blind, 52-week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79-4980 or rFVIII-FS. The per-protocol population of previously treated patients with severe haemophilia A without a history of inhibitors (n = 68 males; mean age, 34.4 years) received 25 IU kg−1 rFVIII-FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t-test. The annualized median (range) number of bleeds was 2.2 (0.0–23) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.0–17.1) vs. 4.2 (0.0–22.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.0–19.2) vs. 5.3 (0.0–22.8); P = 0.01]. Following randomization to prophylaxis with rFVIII-FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment.

PMID: 24847524 [PubMed - indexed for MEDLINE]

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Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect.

Wed, 20/07/2016 - 4:08am

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Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect.

Thromb Haemost. 2014 Aug;112(2):424-5

Authors: Morfini M, Batorova A, Mariani G, Auerswald G, Bernardi F, Di Minno G, Dolce A, Fede C, Giansily-Blaizot M, Ingerslev J, Martinowitz U, Napolitano M, Pinotti M, Schved JF, International FVII [IF7] and Seven Treatment Evaluation Registry [STER] Study Groups

PMID: 24763923 [PubMed - indexed for MEDLINE]

Categories: Publications list