Analysis of early treatment of multiple injuries combined with severe pelvic fracture.

PURPOSE: To summarize and analyze the early treatment of multiple injuries combined with severe pelvic fractures, especially focus on the hemostasis methods for severe pelvic fractures, so as to improve the successful rate of rescue for the fatal hemorrhagic shock caused by pelvic fractures. METHODS: A retrospective analysis was conducted in 68 cases of multiple trauma combined with severe pelvic fractures in recent 10 years (from Jan. 2006 to Dec. 2015). There were 57 males and 11 females. Their age ranged from 19 to 75 years, averaging 42 years. Causes of injury included traffic accidents in 34 cases (2 cases of truck rolling), high falling injuries in 17 cases, crashing injuries in 15 cases, steel cable wound in 1 case, and seat belt traction injury in 1 case. There were 31 cases of head injury, 11 cases of chest injury, 56 cases of abdominal and pelvic injuries, and 37 cases of spinal and limb injuries. Therapeutic methods included early anti-shock measures, surgical hemostasis based on internal iliac artery devasculization for pelvic hemorrhage, and early treatment for combined organ damage and complications included embolization and repair of the liver, spleen and kidney, splenectomy, nephrectomy, intestinal resection, colostomy, bladder ostomy, and urethral repair, etc. Patients in this series received blood transfusion volume of 1200-10,000 mL, with an average volume of 2850 mL. Postoperative follow-up ranged from 6 months to 1.5 years. RESULTS: The average score of ISS in this series was 38.6 points. 49 cases were successfully treated and the total survival rate was 72.1%. Totally 19 patients died (average ISS score 42.4), including 6 cases of hemorrhagic shock, 8 cases of brain injury, 1 case of cardiac injury, 2 cases of pulmonary infection, 1 case of pulmonary embolism, and 1 case of multiple organ failure. Postoperative complications included 1 case of urethral stricture (after secondary repair), 1 case of sexual dysfunction (combined with urethral rupture), 1 case of lower limb amputation (femoral artery thrombosis), and 18 cases of consumptive coagulopathy. CONCLUSION: The early treatment of multiple injuries combined with severe pelvic fractures should focus on pelvic hemostasis. Massive bleeding-induced hemorrhagic shock is one of the main causes of poor prognosis. The technique of internal iliac artery devasculization including ligation and embolization can be used as an effective measure to stop or reduce bleeding. Consumptive coagulopathy is difficult to deal with, which should be detected and treated as soon as possible after surgical measures have been performed. The effect of using recombinant factor VII in treating consumptive coagulopathy is satisfactory.

A Phase 1, Open-Label, Dose-Escalation Trial to Investigate Safety and Tolerability of Single Intravitreous Injections of ICON-1 Targeting Tissue Factor in Wet AMD.

BACKGROUND AND OBJECTIVE: This phase 1 study evaluated the safety and tolerability of single intravitreous injections (IVIs) of ICON-1 (Iconic Therapeutics, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). ICON-1 is a modified factor VIIa protein linked with the Fc portion of a human immunoglobulin G1. The molecule binds tissue factor overexpressed on choroidal neovascularization (CNV) in AMD. PATIENTS AND METHODS: Open-label, interventional, dose-escalation trial in 18 patients with CNV due to AMD, with six patients per dose cohort. Patients received a single IVI of ICON-1 at baseline in one of three escalating doses: 60 µg, 150 µg, or 300 µg. Standard anti-vascular endothelial growth factor treatment was allowed at the investigator's discretion at least 2 weeks after the ICON-1 injection; patients were followed up to 24 weeks. Dose escalation was based on the absence of significant safety events. At each study visit, best-corrected visual acuity (BCVA), ophthalmic examination (intraocular pressure, slit-lamp, and dilated fundus examination), and ophthalmic imaging (color fundus photography, fluorescein angiography, and optical coherence tomography) assessments were performed. The systemic pharmacokinetics of ICON-1 and presence of anti-ICON-1 antibodies were also assessed. RESULTS: ICON-1 was safe and well-tolerated up to the highest dose administered, which was 300 µg. Commonly reported adverse events were considered related to the IVI procedure or to the underlying nAMD. No significant systemic levels of ICON-1 or anti-ICON-1 antibodies were detected. Preliminary evidence of biological activity (improved BCVA, reduced central retinal thickness, decreased CNV size, and leakage) was most evident with the 300 µg dose at 1 to 2 weeks after the single ICON-1 injection. CONCLUSION: Intravitreous administration of ICON-1 in single doses up to 300 µg in eyes with neovascular AMD was safe and well-tolerated. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:336-345.].

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).

[CORRECTION OF HEMOSTASIS WITH BLOOD PRODUCTS IN THE SURGICAL TREATMENT OF CONGENITAL HEART DISEASE IN INFANTS AND YOUNG CHILDREN].

The article deals with the safety and efficiency of recombinant activated factor VII (Coagil VII, Russia) and prothrombin complex concentrate (protromplex-600, Baxter Austria) in the neonatal and pediatric cardiac surgery. The study included 56 children aged from 7 days to 5.5 years underwent surgery with cardiopulmonary bypass for congenital heart defects repair. Clinical and laboratory evidences suggest that Coagil VII and protromplex-600 effective for bleeding stop. The drugs have no negative impact on hemodynamics. We did not identify allergic reactions and thrombosis associated with the introduction of drugs in the pen operative period.

Integrative Approach in Haemophillic Arthropathy of The Knee: a Case Report.

Haemophilic arthropathy is the most prevalent joint disorder in haemophilia. This disorder is characterized by chronic synovitis and progressive destruction of joint cartilage. We report a case of arthroscopic synovectomy to reduce bleeding frequency in haemophilic arthropathy of the knee. Patient was a 15 years old male with haemophilic arthropathy of the left knee. We performed an arthroscopic synovectomy under tightly regulated factor VIII replacement therapy. There were villous synovial hypertrophy at all part of the joint, multiple bone and cartilage defect, and also anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) deficiency found intraoperatively. After 6 month follow up, subjective complain and bleeding frequency decreased significantly. The visual analog scale improved from 5-6 to 1-2, and the International Knee Documentation Committee Score increased from 49 to 66. Bleeding frequency decreased from 4-8 times per month to less than 1 time per month. Arthroscopic synovectomy performed in this case could reduce the pain, decrease the frequency of bleeding, and improve patient's functional outcome.

Interconnections between autophagy and the coagulation cascade in hepatocellular carcinoma.

Autophagy has an important role in tumor biology of hepatocellular carcinoma (HCC). Recent studies demonstrated that tissue factor (TF) combined with coagulation factor VII (FVII) has a pathological role by activating a G-protein-coupled receptor called protease-activated receptor 2 (PAR2) for tumor growth. The present study aimed to investigate the interactions of autophagy and the coagulation cascade in HCC. Seventy HCC patients who underwent curative liver resection were recruited. Immunohistochemical staining and western blotting were performed to determine TF, FVII, PAR2 and light chain 3 (LC3A/B) expressions in tumors and their contiguous normal regions. We found that the levels of autophagic marker LC3A/B-II and coagulation proteins (TF, FVII and PAR2) were inversely correlated in human HCC tissues. Treatments with TF, FVII or PAR2 agonist downregulated LC3A/B-II with an increased level of mTOR in Hep3B cells; in contrast, knockdown of TF, FVII or PAR2 increased LC3A/B. Furthermore, mTOR silencing restored the impaired expression of LC3A/B-II in TF-, FVII- or PAR2-treated Hep3B cells and activated autophagy. Last, as an in vivo correlate, we administered TF, FVII or PAR2 agonist in a NOD/severe combined immunodeficiency xenograft model and showed decreased LC3A/B protein levels in HepG2 tumors with treatments. Overall, our present study demonstrated that TF, FVII and PAR2 regulated autophagy mainly via mTOR signaling. The interaction of coagulation and autophagic pathways may provide potential targets for further therapeutic application in HCC.

Prospective study of continuous infusion with Beriate® P in patients with severe haemophilia A undergoing surgery - a subgroup analysis.

INTRODUCTION: Inhibitor development in severe haemophilia A patients is currently the most serious complication of factor VIII (FVIII) treatment. Although continuous infusion (CI) of FVIII concentrate during surgical procedures in haemophilia A patients has been shown to be beneficial, some publications suggest that CI increases the risk of inhibitor generation. We conducted a prospective subgroup analysis to investigate if CI of the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate(®) P during surgery increases the risk of inhibitor formation. MATERIALS AND METHODS: Patients with severe haemophilia A (FVIII:C <1%) were included if they presented with a negative history of previous inhibitors, had ≥ 50 exposure days, and had been scheduled for a planned surgical procedure. A bolus infusion (30-50 IU/kg body weight) of Beriate(®) P was administered intravenously and followed by CI at a rate of 3-4 IU/kg body weight/hour. Dose adjustments were subsequently made based on daily measurements of plasma FVIII activity. RESULTS: Five patients (aged 8-34 years) with severe haemophilia A were included. The surgical procedures ranged from teeth extraction to internal fixation of a fracture. There was no inhibitor generation with CI of Beriate(®) P in patients undergoing surgery, and we did not observe any complications due to re-bleeding or virus transmission. CONCLUSION: Beriate(®) P was efficacious, safe, and well tolerated during CI.

Recombinant activated factor VII administration after pulmonary embolectomy: case report.

Bleeding management in cardiac surgery could be a great challenge for the surgeon and a life-threatening moment for the patient. Despite the fact that recombinant activated factor VII is now widely accepted as a useful adjunct in the management of postcardiotomy coagulopathy, its use in the course of recent thromboembolic event is rarely described. We hereby present a case of rescue recombinant activated factor VII administration to manage a severe coagulation disorder during surgical pulmonary embolectomy performed under cardiopulmonary bypass.

Factor VII light chain-targeted lidamycin shows intensified therapeutic efficacy for liver cancer.

The overexpression of tissue factor (TF) observed in numerous cancer cells and clinical samples of human cancers makes TF an ideal target for cancer therapy. The purpose of this study is to develop a TF-targeting energized fusion protein hlFVII-LDP-AE, which is composed of a human Factor VII light chain (hlFVII) as the targeting domain conjugated to the cytotoxic antibiotic lidamycin (LDM, LDP-AE) as the effector domain. The potential efficacy of hlFVII-LDP-AE for cancer therapy was tested in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and in vivo with a BALB/c nude mouse xenograft model of human liver cancer line HepG2. The inhibitory concentration (IC(50)) value of hlFVII-LDP-AE varied from 0.15 to 0.64 nM for the various human tumor lines. hlFVII-LDP-AE showed a tumor growth inhibition rate of 90.6% at the dose of 0.6 mg/kg in in vivo animal experiments. The mechanism through which hlFVII-LDP-AE inhibits tumor growth also was determined by Hoechst 33342 staining and Tdt-mediated dUTP nick-end labeling (TUNEL) assay. hlFVII-LDP-AE causes tumor cell death through inducing chromatin condensation and cleavage of genomic DNA. These findings suggest that the hlFVII-LDP-AE protocol is efficacious and tolerated in the mouse model of human liver cancer HepG2 and has clinical applicability for treating cancer patients.

Congenital FVII deficiency and thrombotic events after replacement therapy.

Thrombosis has been occasionally described in congenital FVII deficiency. This report deals with patients with FVII deficiency who presented thrombotic events after substitution therapy. At least 12 patients are reported in the literature. In all but two cases thrombosis occurred after prothrombin complex concentrates or plasma derived FVII concentrates. In two instances pulmonary embolism occurred after the administration of large amounts of whole blood. Concomitant prothrombotic risk factors were present in most of these cases (surgery, immobilization, old age, etc.). Personal files allowed us to add another patient who developed bilateral pulmonary embolism after two vials of an aFVII concentrate. In this case also, concomitant risk factors were present, namely surgery for hysterectomy, immobilization. The pulmonary embolism occurred in spite of the congenital FVII deficiency indicating that no sure antithrombotic protection is assured by this defect. The actual needs of substitution therapy in patients with some variants of FVII deficiency is discussed, together with comments on the therapeutic management of the thrombotic events in these patients.

Total hip replacement in a patient with acquired haemophilia A: a case report and literature review.

Acquired hemophilia A (AHA) is a very rare disease of idiopathic type, or secondary to neoplastic disease, the use of some drugs, or pregnancy. Owing to the rarity of the disease, no comparative clinical studies are currently available on the results of different intraoperative and postoperative pharmacological preventive strategies in arthroplasty surgery. We report the first case of a total hip replacement procedure for a fracture of the femoral neck performed in a patient affected by AHA. Treatment with recombinant factor VII was administered, at the dosage of 170 µg/kg preoperatively and continued postoperatively at 120-90 µg/kg every 2-6 h. The outcome described supports the use of the protocol adopted, demonstrating that the treatment duration was well adapted to this highly invasive surgical procedure.

[Anesthetic management of a patient with acquired factor V inhibitor].

A 74-year-old man was scheduled for laparoscopic low anterior resection of rectal cancer. Preoperative blood coagulation test showed his prothrombin time (PT) and activated partial thromboplastin time (APTT) remarkably prolonged. However, he experienced only slight epistaxis. Further examination suggested the presence of acquired factor V inhibitor. Plasmapheresis was carried out before surgery to eradicate inhibitors, but improvement of PT and APTT was temporary. We prepared platelet transfusion and recombinant activated factor VII (rFVIIa) for acute intraoperative bleeding, but there were no abnormal episodes during the surgery. On postoperative day 15, the patient suddenly passed blood in his stool, and received platelet transfusion. For the majority of patients with acquired factor V inhibitor, bleeding is usually mild, but fatal bleeding complications have also been reported. Platelet transfusion was effective in the patient described here.

[A Jehovah's Witness child with hemophilia B and factor IX inhibitors undergoing scoliosis surgery].

PURPOSE: To describe the successful perioperative hemostatic management of a Jehovah's Witness patient with hemophilia B and anaphylactic inhibitors to factor IX, undergoing scoliosis surgery. CLINICAL FEATURES: A 14 (1/2)-yr-old boy with severe hemophilia B who had a history of anaphylactic inhibitors to factor IX was scheduled to undergo corrective scoliosis surgery. He was initially started on epoetin alfa and iron supplementation to maximize preoperative red cell mass. Additionally, he was placed on a desensitization protocol of recombinant coagulation factor IX (rFIX) and was then treated with activated recombinant coagulation factor VII (rFVIIa) during the postoperative period. Tranexamic acid was given concomitantly. The intraoperative blood loss was approximately 350 mL. The nadir hemoglobin concentration was 111 g.L(-1) on postoperative days one and two. On postoperative day 11, the patient was stable and discharged home with a hemoglobin of 138 g.L(-1). He did not require blood transfusion and no adverse events were observed. CONCLUSIONS: The use of rFIX, rFVIIa, erythropoetin, iron, and tranexamic acid before, during and after scoliosis surgery may be a viable and safe option for hemophilia patients with inhibitors, who refuse blood products.

Recombinant activated factor VII in spinal surgery: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial.

STUDY DESIGN: Randomized, placebo-controlled, double-blind, multicenter, Phase IIa study. OBJECTIVE: To assess the safety and efficacy of recombinant-activated Factor VII (rFVIIa) in major spinal surgery. SUMMARY OF BACKGROUND: Spinal fusion surgery can cause substantial blood loss and blood product transfusions. Recombinant FVIIa is approved for treatment of bleeding in patients with coagulation abnormalities and has been shown to reduce blood loss and transfusion requirements in surgery in patients with no underlying coagulopathy. METHODS: Forty-nine patients undergoing fusion of 3 or more vertebral segments were randomized and treated on losing 10% of their estimated blood volume (with total expected surgical blood loss > or = 20%) and received 3 doses (2-hour intervals) of placebo (n = 13) or 30, 60, or 120 microg/kg rFVIIa (n = 12 per group). The primary endpoint was safety. A priori-defined efficacy endpoints included blood loss and transfusion requirements between placebo and each rFVIIa dose group, adjusted for surgery duration, number of segments fused, and estimated blood volume. RESULTS: Serious adverse events did not occur at any greater frequency in any of the treatment groups. One patient (3 x 30 microg/kg rFVIIa) with advanced cerebrovascular disease (undiagnosed, trial exclusion criterion) died 6 days after surgery due to an ischemic stroke. Mean blood loss was as follows: 2270 mL for placebo; 1909, 1262, and 1868 mL for 3 x 30, 3 x 60, and 3 x 120 microg/kg rFVIIa, respectively (differences not statistically significant). Mean adjusted surgical blood loss was as follows: 2536 mL for placebo; 1120, 400, and 823 mL for 3 x 30, 3 x 60, and 3 x 120 microg/kg rFVIIa, respectively (P < or = 0.001). Mean surgical transfusion volume was reduced by 27% to 50% with rFVIIa treatment (not significant). The mean adjusted surgical transfusion volume was reduced by 81% to 95% with rFVIIa treatment (P < or = 0.002). CONCLUSION: No safety concerns were indicated for the use of rFVIIa in patients at all doses tested; rFVIIa reduced adjusted blood loss and adjusted transfusions during spinal surgery.

Experience with recombinant-activated factor VII in 30 patients with congenital factor VII deficiency.

Recombinant-activated factor VII (rFVIIa) represents a therapeutic advance for the treatment and prevention of haemorrhage in patients with the rare bleeding disorder, congenital FVII deficiency. Thirty-nine cases of the use of rFVIIa in 30 patients with congenital FVII deficiency were identified from the international, internet-based registry haemostasis.com, which is a repository of case reports on the investigational use of rFVIIa that have been voluntarily submitted by physicians worldwide. These registry data have limitations compared with clinical-trial data but give valuable insights into a treatment for a rare disease that is virtually impossible to assess in conventional clinical trials. rFVIIa was used in: elective surgery (13 cases); haematoma (9 cases); emergency surgery (6 cases); epistaxis (4 cases); menorrhagia (2 cases); cover during childbirth (2 cases); disseminated intravascular coagulation (1 case; premature infant); removal of intradermal stitches (1 case); and haematuria (1 case). In 22/39 cases, rFVIIa was used prophylactically. Total dose and dosing schedules varied; median individual dose was 13.3 mug/kg body weight (bw) (range 1.2-223.8 mug/kg bw), median total dose was 38 microg/kg bw (range 1.2-758 microg/kg bw) and median number of doses was 3 (range 1-55). rFVIIa was generally associated with bleeding cessation or markedly reduced bleeding. Two adverse events were reported, but neither was regarded as being related to rFVIIa. These 39 cases support data confirming the safety and efficacy of rFVIIa in its EU-licensed indications, including that for preventing and/or controlling haemorrhage in patients with congenital FVII deficiency.

[Recombinant factor VII (NovoSeven) in intraoperative blood saving during neurosurgical treatment of the brain arteriovenous malformation].

BACKGROUND: Cerebral arteriovenous (AV) malformation causes, due to the increased blood flow through a malformation, a massive intraoperative bleeding complicating, so, surgical treatment. The use of intraoperative blood saving apparatus during surgery and a recombinant factor VII-a (NovoSeven) significantly reduce complications during surgical treatment. CASE REPORT: We reported a case of surgical treatment of the patient with AV malformation of IV stage according to the Spetzler-Martin scale, in the brain. Due to a possible heavy bleeding we used a apparatus for intrasurgical blood recovery, Cell Saver, Sequestra 1 000, Medtronic, U.S.A., and recombinant human factor VIIa (rFVIIa--NovoSeven, NovoNordisk, Denmark) to control bleeding and restore an adequate hemostasis. CONCLUSION: The use of an apparatus for intraoperative blood saving, as well as the NovoSeven preparation in the management of AV malformation of IV stage, showed to be successful.

Is the use of rFVIIa safe and effective in bleeding neonates? A retrospective series of 8 cases.

BACKGROUND: Recombinant activated factor VII (rFVIIa), originally developed for the treatment of life-threatening bleeding in hemophilic patients with inhibitors to factors VIII or IX, has been increasingly used to control hemorrhage unresponsive to conventional treatment, in the absence of a defined coagulopathy or thrombocytopathy. To date, clinical experience of rFVIIa administration in neonates, especially preterms, is rather limited, because of the lack of controlled studies and based solely on some published case reports and 1 prospective pilot study. The objective of this study was to retrospectively evaluate the clinical outcome of newborns treated with recombinant activated factor VII for intractable bleeding or severe coagulation disturbances, resistant to conventional hemostatic therapy. METHODS: The medical records of 8 neonates treated with rFVIIa (100 micro g/kg) were retrospectively reviewed for the course of hemorrhage and the hemostatic interventions performed before and up to 24 hours after the administration rFVIIa. Coagulation parameters of 3 different time-points were assessed and compared: before administration of any blood product (time-point 1), before administration of the first dose of rFVIIa (time-point 2), and 4 hours after the administration of the last dose of rFVIIa (time-point 3). The safety and tolerability profile of rFVIIa in bleeding neonates was also evaluated. RESULTS: Six preterm and 2 term patients were included in the study. Seven patients presented with refractory bleeding and 1 was diagnosed with severe coagulopathy unresponsive to the conventional treatment. Prompt hemostasis was achieved in half of the patients with their coagulation profile being restored within 4 hours after the administration of the first dose of rFVIIa. Improvement in prothrombin time, activated partial thromboplastin time, and fibrinogen after rFVIIa administration was statistically significant, as compared with that observed after conventional treatment. No major safety issues were observed during the study. All 8 patients survived and had their hemorrhage or coagulopathy controlled within 4 hours after transfusion of the last dose of rFVIIa. CONCLUSIONS: In this study, the hemostatic agent rFVIIa was well-tolerated and behaved in a safe and efficacious manner in all infants treated for life-threatening bleeding and coagulation disorders. Future prospective controlled trials are needed to determine the efficacy, safety, tolerability, and possibly the optimal dose and timing of rFVIIa administration.