Thromboelastography in pre-surgery monitoring in Hemophilia A with high inhibitor titer: case report and literature review

AbstractThe development of factor VIII inhibitors (allo-antibodies) continues to be a major complication in the management of severe forms of hemophilia A, especially as far as treatment and treatment response monitoring is concerned. The need to implement a reliable laboratory assay is all the more obvious if major surgery occurs, when conventional tests (activated partial thromboplastin time APTT, prothrombin time PT, factor VIII level) are of no avail and there is a very fragile balance between bleeding and thrombosis.We report the case of a 32 year-old patient diagnosed with severe Hemophilia A, referred to the Comprehensive Center for the Diagnosis and Treatment of Hemophilia of the Fundeni Clinical Institute for a multidisciplinary assessment in view of a total left hip arthroplasty due to aseptic necrosis of the femoral neck.Workup showed a high inhibitor titer (>200 BU). Taking into consideration the interindividual variability of the response to bypassing agents, as well as the bleeding risk associated with a major orthopedic surgery, we used thromboelastography (TEG) to assess the patient’s response to aPCC (activated prothrombin complex concentrate) and rFVIIa (activated recombinant factor VII). The findings helped select the optimal replacement scheme to ensure perioperative hemostasis.

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Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China

Blood ◽

10.1182/blood-2021-145618 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4250-4250

Author(s):

Rong-Fu Zhou ◽

Yueyi Xu ◽

Wenjin Gao

Keyword(s):

Hemophilia A ◽

Conflicts Of Interest ◽

Clinical Manifestations ◽

Coagulation Factor ◽

Factor Vii ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Coagulation Factor Vii ◽

Prolonged Aptt ◽

Inhibitor Titer

Abstract Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment. Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed. Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection. Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time. Disclosures No relevant conflicts of interest to declare.

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Postpartum Acquired Hemophilia: A Rare Cause of Postpartum Hemorrhage

Case Reports in Hematology ◽

10.1155/2013/735715 ◽

2013 ◽

Vol 2013 ◽

pp. 1-2 ◽

Cited By ~ 1

Author(s):

Srikanth Seethala ◽

Sumit Gaur ◽

Elizabeth Enderton ◽

Javier Corral

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

Factor Vii ◽

Normal Vaginal Delivery ◽

Factor Viii Inhibitor ◽

Activity Levels ◽

Factor Viii Activity ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Viii Inhibitor

A 36-year-old female started having postpartum vaginal bleeding after normal vaginal delivery. She underwent hysterectomy for persistent bleeding and was referred to our institution. An elevation of PTT and normal PT made us suspect postpartum acquired hemophilia (PAH), and it was confirmed by low factor VIII activity levels and an elevated factor VIII inhibitor. Hemostasis was achieved with recombinant factor VII concentrates and desmopressin, and factor eradication was achieved with cytoxan, methylprednisolone, and plasmapheresis.

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Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa

Blood ◽

10.1182/blood.v95.4.1330.004k28_1330_1335 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1330-1335 ◽

Cited By ~ 98

Author(s):

Cornelis van 't Veer ◽

Neal J. Golden ◽

Kenneth G. Mann

Keyword(s):

Factor Viii ◽

Tissue Factor ◽

Thrombin Generation ◽

Hemophilia A ◽

Factor Viia ◽

Plasma Concentrations ◽

Factor Xa ◽

Factor Vii ◽

Lag Phase ◽

Single Chain

Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace (∼10-100 pmol/L) circulates as the 2-chain form, factor VIIa. Factor VII and factor VIIa were studied in a coagulation model using plasma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII both extended the lag phase of the reaction and depressed the rate of thrombin generation. The inhibition of factor Xa generation by factor VII is consistent with its competition with factor VIIa for TF. Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tissue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII significantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect.

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Hemophilia a Clots Generated with Recombinant Factor VIIa Differed in Structure and Composition from Those Formed with Factor VIII

Blood ◽

10.1182/blood.v128.22.3798.3798 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3798-3798

Author(s):

Lilley Leong ◽

Irina N. Chernysh ◽

Yifan Xu ◽

Cornell Mallari ◽

Billy Wong ◽

...

Keyword(s):

Factor Viii ◽

Whole Blood ◽

Neutralizing Antibodies ◽

Research Funding ◽

Thrombin Generation ◽

Hemophilia A ◽

Clot Formation ◽

Factor Vii ◽

Wild Type ◽

Independent Mechanism

Abstract Patients with severe factor VIII (FVIII) deficiency (hemophilia A [HemA]) develop neutralizing antibodies (inhibitors) against FVIII in up to ~30% of cases. For HemA patients with inhibitors, activated recombinant factor VII (rFVIIa) is a treatment option. High levels of rFVIIa are required for treating HemA patients with inhibitors to induce direct activation of factor X on the surface of activated platelets via a tissue factor (TF)-independent mechanism (Hoffman M, Monroe DM. Thromb Res. 2010;125(suppl 1):S16-S18). To assess how rFVIIa-mediated clot formation in HemA patients with inhibitors may differ from unaffected individuals, we compared the effect of rFVIIa on HemA versus control (or HemA supplemented with 100% FVIII) clot formation in human and/or mouse systems. By TF-induced thrombin generation assay, increasing rFVIIa from 5 nM to 100 nM did not appreciably alter the kinetics or extent of thrombin generation compared with the same human HemA plasma containing 100% FVIII. Confocal microscopy of human HemA plasma clots generated with 75 nM rFVIIa and TF showed few branching fibrin fibers and an open fibrin meshwork. In contrast, TF-induced coagulation of the same HemA plasma containing 100% FVIII formed fibrin clots with numerous branches, interconnecting to form a dense meshwork. To confirm that these findings reflect rFVIIa-mediated clot formation in vivo, we assessed the intrinsic coagulation of mouse HemA whole blood collected without anticoagulant and spiked with rFVIIa. Intrinsic coagulation with rFVIIa was assessed by T2 magnetic resonance (T2MR), a technique capable of monitoring the separation of whole blood into serum, loose-clot, and tight-clot compartments during coagulation (Skewis et al. Clin Chem. 2014;60:1174-1182; Cines et al. Blood. 2014;123:1596-1603). By T2MR, rFVIIa induced the separation of HemA whole blood into the serum and clot compartments, indicating that the reduced fibrin generation with rFVIIa did not interfere with whole blood coagulation. Furthermore, saphenous vein puncture of HemA mice treated with rFVIIa showed a dose-dependent decrease in clot times. Scanning electron microscopy of the clots extracted from these HemA mice indicated markedly different composition than clots extracted from wild-type mice. In wild-type clots, fibrin and polyhedral erythrocytes formed a large proportion of the total structures. In contrast, clots from rFVIIa-treated HemA mice consisted primarily of platelets and erythrocytes with forms intermediate between discoid and polyhedral but, surprisingly, low fibrin content. Taken together, these data suggest that rFVIIa-mediated clot formation may require greater activated platelet involvement, which would be consistent with the TF-independent mechanism of action proposed for rFVIIa in HemA. Finally, the compositional difference between clots from wild-type versus HemA mice dosed with rFVIIa suggest that evaluating HemA therapies for their ability to form more physiologic clots could be an approach to improve treatment options for patients with HemA. Disclosures Leong: Bayer: Employment. Xu:Bayer: Employment. Mallari:Bayer: Employment. Wong:Bayer: Employment. Sim:Bayer: Employment. Cuker:Stago: Consultancy; Genzyme: Consultancy; Amgen: Consultancy; Biogen-Idec: Consultancy, Research Funding; T2 Biosystems: Research Funding. Marturano:T2 Biosystems: Employment. Lowery:T2 Biosystems: Employment. Kauser:Bayer: Employment. Weisel:Bayer: Research Funding.

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Relationship between Factor VII Activity and Clinical Efficacy of Recombinant Factor VIIa Given by Continuous Infusion to Patients with Factor VIII Inhibitors

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616517 ◽

2001 ◽

Vol 86 (10) ◽

pp. 954-958 ◽

Cited By ~ 71

Author(s):

M. Morfini ◽

A. Rocino ◽

F. Baudo ◽

F. A. Scaraggi ◽

A. Gringeri ◽

...

Keyword(s):

Factor Viii ◽

Continuous Infusion ◽

Clinical Efficacy ◽

Surgical Procedures ◽

Factor Viia ◽

Factor Vii ◽

Major Surgery ◽

Spontaneous Bleeding ◽

Human Factor Viii ◽

Minor Surgery

SummaryA multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out.Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 μg/kg (median: 100) were followed by CI given at median rates of 20 μg/kg/h for major surgery and of 17 and 16 μg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 μg/kg/h, respectively; median FVII:C: 14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed.

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Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy

Blood ◽

10.1182/blood-2010-06-288001 ◽

2010 ◽

Vol 116 (26) ◽

pp. 5842-5848 ◽

Cited By ~ 100

Author(s):

Jonathan D. Finn ◽

Margareth C. Ozelo ◽

Denise E. Sabatino ◽

Helen W. G. Franck ◽

Elizabeth P. Merricks ◽

...

Keyword(s):

Gene Therapy ◽

Factor Viii ◽

Neutralizing Antibodies ◽

Viral Vectors ◽

Hemophilia A ◽

Major Complication ◽

Complete Disappearance ◽

Anamnestic Response ◽

Endogenous Expression ◽

Liver Gene

Abstract Inhibitory antibodies to factor VIII (FVIII) are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of patients. Current treatment for inhibitors is based on long-term, daily injections of large amounts of FVIII protein. Liver-directed gene therapy has been used to induce antigen-specific tolerance, but there are no data in hemophilic animals with pre-existing inhibitors. To determine whether sustained endogenous expression of FVIII could eradicate inhibitors, we injected adeno-associated viral vectors encoding canine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs. In 3 dogs, a transient increase in inhibitor titers (up to 7 Bethesda Units [BU]) at 2 weeks was followed by continuous decline to complete disappearance within 4-5 weeks. Subsequently, an increase in cFVIII levels (1.5%-8%), a shortening of clotting times, and a reduction (> 90%) of bleeding episodes were observed. Immune tolerance was confirmed by lack of antibody formation after repeated challenges with cFVIII protein and normal protein half-life. A fourth dog exhibited a strong early anamnestic response (216 BU), with slow decline to 0.8 BU and cFVIII antigen detection by 18 months after vector delivery. These data suggest that liver gene therapy has the potential to eradicate inhibitors and could improve the outcomes of hemophilia A patients.

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The Inhibitor Antibody Response Is More Complex in Hemophilia A Patients Than in Most Nonhemophiliacs With Factor VIII Autoantibodies

Blood ◽

10.1182/blood.v89.10.3663 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3663-3671 ◽

Cited By ~ 123

Author(s):

Richard Prescott ◽

Hiroaki Nakai ◽

Evgueni L. Saenko ◽

Inge Scharrer ◽

Inga Marie Nilsson ◽

...

Keyword(s):

Immune Response ◽

Antibody Response ◽

Factor Viii ◽

Light Chain ◽

Hemophilia A ◽

Epitope Specificity ◽

Extensive Analysis ◽

Number Of Patients ◽

Recombinant Fviii ◽

Inhibitor Titer

Abstract Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as ≥ 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

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Inhibitors in mild/moderate haemophilia A: An update

Thrombosis and Haemostasis ◽

10.1160/th06-02-0078 ◽

2006 ◽

Vol 96 (08) ◽

pp. 113-118 ◽

Cited By ~ 10

Author(s):

Gian Salvagno ◽

Giuseppe Lippi ◽

Massimo Franchini

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

Tolerance Induction ◽

Factor Vii ◽

Factor Viii Inhibitor ◽

Increased Risk ◽

Bypassing Agents ◽

The Many ◽

Activated Prothrombin Complex Concentrates ◽

Optimal Approach

SummaryThe development of inhibitors in patients with mild/moderate hemophilia A is an increasingly recognized occurrence and is manifested by the patients’ bleeding pattern becoming more severe. Inherited (hemophilia genetic mutations) and acquired (type and delivery of factor VIII replacement therapy) factors have been associated with an increased likelihood of developing factor VIII inhibitors. Although the use of bypassing agents (i.e. activated prothrombin complex concentrates and recombinant factor VII activated) has been demonstrated to be effective in controlling bleeding episodes in patients who develop factor VIII inhibitors, the limited data available in the literature are insufficient to determine the optimal approach to the eradication of inhibitors (i.e. immune tolerance induction, immunosuppression or both) for this group. Particular attention should be directed to the prevention of this complication in those patients with mild/moderate hemophilia recognized to be at increased risk of developing a factor VIII inhibitor. In conclusion, large prospective trials are warranted in order to elucidate the many still unclear pathogenic and therapeutic aspects of the development of inhibitors in patients with mild/moderate hemophilia A.

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Successful Orthotopic Liver Transplantation in Severe Hemophilia A with High Responding Inhibitor.

Blood ◽

10.1182/blood.v110.11.3968.3968 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3968-3968

Author(s):

Robert Chen ◽

Seligman Paul ◽

Justin Call ◽

Brenda Riske ◽

Ruth Ann Kirschman ◽

...

Keyword(s):

Liver Transplantation ◽

Factor Viii ◽

Orthotopic Liver Transplantation ◽

Immune Tolerance ◽

Hemophilia A ◽

White Male ◽

Factor Vii ◽

Severe Hemophilia ◽

Factor Viii Activity ◽

History Of

Abstract Orthotopic liver transplantation (OLT) is an effective treatment for both hepatitis C associated cirrhosis, hepatocellular carcinoma, and hemophilia A. Factor VIII activity usually increases into the normal range. Only a few patients with hemophilia complicated by an inhibitor have undergone OLT with both successful outcomes and uncontrolled bleeding being reported. We report early results of OLT in a middle-aged white male severe hemophilia A patient with a history of a high responding inhibitor (historical high - 70 Bethesda units) who had been on immune tolerance for greater than 10 years prior to transplant. A regimen of 40 u/kg of Factor VIII three times per week successfully suppressed inhibitor titers to less than 2 Bethesda units in the previous years. Hand surgery was managed with Factor VII infusions in the year prior to OLT with good results. At the time of transplantation, his inhibitor titer was 0.7 B.U. Due to his history of non-linear kinetics with factor VIII infusion, (5% of a dose remaining at 24 hours), frequent bolus dosing during surgery was employed. He received 10,500 units (116 units/kg) prior to the incision with smaller doses repeated every 2–4 hours. During the operation and the 24 hr immediately post op he required another 27,300 units (300 units/kg) of factor VIII infusion to maintain activity between 61–122%. On post op day 1 he required 46 units/kg to keep activity between 60.2–108%. On post op day 2 he required 35 units/kg to keep activity between 36.8–68.4%. His immunosuppresion included tacrolimus, mycophenolate, and solumedrol taper of 120 mg on day 2, 80 mg on day 3, 40 mg on day 4, and 20 mg day 5. From day 6 to day 8, his total bilirubin increased to 15 and his requirement for Factor VIII also increased to 70 units/kg daily for 3 days to keep his activity between 33.1% to 71.2%. His immunosuppression was increased because of possible acute rejection and solumedrol 500 mg IV was given daily for 3 days. On day 9 his requirement for factor decreased to 11.6 units/kg daily for 4 additional days. Solumedrol was tapered off to prednisone 10 mg po daily. On day 13 post operation, Factor VIII replacement was stopped and his activity was 56.8%, which gradually rose to 81% on day 25. We conclude: Orthotopic liver transplantation was successful in a hemophilia A inhibitor patient on long term immune tolerance. Factor VIII production by the transplanted liver suppressed the inhibitor and normalized Factor VIII activity up to 4 weeks post transplant. Close follow-up will be required.

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Long-Term Prophylaxis with Activated Recombinant FVII in Children with Hemophilia a and Inhibitor, Receiving Treatment with ITI Protocol

Blood ◽

10.1182/blood.v128.22.4980.4980 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4980-4980 ◽

Cited By ~ 1

Author(s):

Ekaterina Shiller ◽

Victor Petrov ◽

Pavel Svirin ◽

Vladimir Vdovin ◽

Igor Koltunov ◽

...

Keyword(s):

Quality Of Life ◽

Factor Viii ◽

Hemophilia A ◽

Treatment Time ◽

Conflicts Of Interest ◽

Factor Vii ◽

Treatment Level ◽

Factor Viii Inhibitor ◽

Bleeding Episodes

Abstract Background: Recent studies have shown that addition of bypassing agents to immuno-tolerance induction (ITI) protocol for patients with hemophilia A and inhibitor results in better control of bleeding episodes and improves quality of life. Few publications have addressed prophylactic usage of recombinant factors VIIa in these settings. Due to relatively low infusion volume, convenience of administration and high efficacy rFVIIa - Coagil-VII seems to be especially reasonable for ITI protocol. Aim: To assess the efficacy and safety of rFVIIa - Coagil-VII (SJC "GENERIUM", Russia) for prophylactic use during ITI protocol in patients with hemophilia A and inhibitor. Methods: Seven patients aged between 2 to 7 years with severe hemophilia A and inhibitor have been treated with ITI protocol using plasma derived factor VIII with von Willebrand factor. Seven of them simultaneously received treatment with Coagil-VII in individual doses (100-250 mkg/kg) and regimens (every 12 - 48 hours). When inhibitor reached level of 3 BU (Bethesda Unit) either dose or frequency of Coagil-VII administration were gradually reduced. After 1 BU the patients were given factor VIII only. Number and severity of bleeding events were assessed. Results: Five patients with high responding inhibitors and poor prognosis (history of high titer of factor VIII inhibitor, prolonged time between first inhibitor appearance and the beginning of ITI) received Coagil-VII in high doses 150 - 250 mkg/kg every 12-24 hours in 1-4 years. At time of booster effect titer of inhibitors reached 92 -16 000 BU. One of patients had ITI failure because of interruption of protocol, while 4 patients continue treatment. Level of 3 BU was reached by 4 patients at 40, 12, 35, and 3 months of treatment. Level of 1 BU was reached by 2 patients at 6 and 42 months of treatment. Significant clinical effect was achieved after 6 months of treatment. Time of bleeding episode was decreased from 7 (±2) to 2 (±1) days. Total number of hemorrhagic events, including hemarthrosis, hematomas and bleedings decreased by 3,7 fold (3,7 events per patient-month during first 6 months versus 1,0 events per patient-month). Only 1 hospital admission with bone fracture was recorded. All children have an active lifestyle and attend school. Two patients with low responding inhibitor and good prognosis received Coagil-VII in low doses 90 - 170 mkg/kg every 24-48 hours. Maximal titer of inhibitor was 1.3 - 1.9 BU. Both patients completed treatment with Coagil-VII in 2 and 4 months and continue ITI protocol and both achieved undetectable level of inhibitor. No bleeding episodes were recorded in these patients since the beginning of treatment. There was no clinical or laboratory evidence of thrombosis, thrombocytopenia, or disseminated intravascular coagulation. Conclusion: We report our experience of prolonged (2 months - 4 years) prophylactic treatment with recombinant activated factor VII (rFVIIa) - Coagil-VII in patients with hemophilia A and inhibitor. This prophylaxis is efficacious when doses and treatment regimens are individually determined. This approach results in reduction of bleeding episodes in all patients, as well as increase of quality of life. No any adverse events (AE and SAE) with prolonged use of Coagil-VII have been registered so far. Disclosures No relevant conflicts of interest to declare.

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