Administration Of Recombinant Factor VII Research Articles

Immune gene polymorphisms associated with poor response to platelet transfusion and recombinant factor VII administration in Glanzmann thrombasthenia.

Poor response to platelet and recombinant factor VII administration is a major problem in patients with Glanzmann Thrombasthenia (GT). The risk factors associated with poor response to treatment in these patients are unknown. Some genetic variations of cytokines may contribute to therapy resistance. We evaluated, for the first time, whether genetic polymorphisms on cytokine genes are related to poor treatment response in GT patients. We enrolled 30 patients with GT (15 resistant and 15 non-resistant) and 100 healthy controls. Gene polymorphisms of IL-10 and TNF-α were analysed using TaqMan Realtime PCR, and IL-1, IL-1R1 and IL-1RN were investigated with the RFLP method. In-silico analyses were performed to predict the potential impact of these polymorphisms. In the resistant group, all patients had a variant of the IL-10 gene at the -1082 position (rs1800896), with a GG genotype that was significantly more frequent than the non-resistant group. Analysis between healthy controls and GT patients revealed a probable correlation between rs3783550, rs3783553, rs3917356 and rs2234463 and GT. The In-silico study indicated that TNF-α rs1800629 and IL-10 rs1800896 polymorphisms result in different allelic expressions which may contribute to poor response to therapy. These findings suggest that polymorphisms in the IL-10 and IL-1 receptor antagonist genes may play a role in poor therapy response in GT patients. In addition, some polymorphisms in IL-1α, IL1-β, IL-1R1 and IL-R antagonists might be involved in the GT progression.

Initiation of Emicizumab Therapy in an Adult Patient With Hemophilia A With Inhibitors and Associated Drug Cost Savings

Objective: To report the utilization of emicizumab in a patient with severe hemophilia A with inducible inhibitors and the reduction of drug costs related to decreased on-demand recombinant factor VIIa use. Case Summary: A 65-year-old African American man with established hemophilia A with an inducible factor VIII inhibitor presented with a bleeding hematoma from the right posterior thigh. The patient was historically managed on frequent administration of recombinant factor VIIa to achieve hemostasis and was started on every 2-hour dosing during this admission. Emicizumab, a new therapy for hemophilia A, became available during this admission, and the patient discontinued recombinant factor VIIa and transitioned to weekly emicizumab injections. The patient did not require any recombinant factor VIIa during the following 12 months resulting in substantial drug cost savings. Discussion: After initiation of emicizumab therapy, the patient no longer required on-demand treatment with recombinant factor VIIa for bleeds. Through this reduction in recombinant factor VIIa, there was a large decrease in inpatient drug costs and inpatient admissions for bleeding events. Conclusion: The potential reduction in drug costs and inpatient admissions should be considered when determining if emicizumab therapy is appropriate for hemophilia A patients with inhibitors. Further research is needed to confirm that continued long-term use of emicizumab remains associated with a reduction in on-demand treatment.

Acquired factor V inhibitor

Since acquired factor V inhibitor (FV-INH) has been first reported in Germany in 1955, about 200 cases have been recorded globally. The incidence of FV-INH is extremely low, with a rate of 0.023-0.09 per million persons per year. FV-INH formation is caused by infection, use of antibiotics and other drugs, surgery, and diseases, including malignancy and autoimmune disorder. Some patients with FV-INH present with abnormal clinical laboratory test results but have no hemorrhagic symptoms. Others experience life-threatening bleeding. Moreover, thrombosis can sometimes occur. The diagnosis is based on prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), an inhibitor pattern shown by a cross-mixing test of PT and APTT, decreased factor V activity, and detection of FV-INH. Treatment includes hemostatic and immunosuppressive therapy. However, in some cases, the monitoring of progression alone is appropriate. In terms of hemostatic therapies, infusion of platelet concentrates and administration of recombinant factor VIIa are highly useful. However, no definitive treatment strategy has been established. In about 50% of cases, FV-INH is eliminated spontaneously. Therefore, immunosuppressive therapy is recommended only for hemorrhagic patients or those at high risk of hemorrhage. Prednisolone is generally used for the management of immunosuppression. However, some reports have shown that the administration of rituximab, cyclophosphamide, and intravenous immunoglobulin and plasma-exchange can be utilized as treatments.

Timing of Recombinant Factor VIIa Administration for Severe Bleeding in Cardiac Surgery: Does It Make Any Differences?

Timing of Recombinant Factor VIIa Administration for Severe Bleeding in Cardiac Surgery: Does It Make Any Differences?

A novel protocol for accurate and reliable postoperative bolus administration of recombinant factor VIIa using an automated mini-pump system.

Recombinant FVIIa (rFVIIa) is widely used to manage bleeding risk during and after surgery in patients with haemophilia complicated by inhibitors. In the postoperative period, rFVIIa must be delivered frequently and regularly to maintain haemostasis, considering its short half-life. Preparation and manual administration of bolus doses of rFVIIa at regular intervals may place a strain on available nursing resources. A programmable mini-pump may offer an approach to facilitate regular administration of bolus doses of rFVIIa at specified intervals. To investigate if a mini-pump is a practical and effective way to deliver rFVIIa in the postoperative period. It was first necessary to establish that rFVIIa remains stable and sterile in the mini-pump reservoir for an extended period. Four days after loading the mini-pump under sterile conditions no evidence of bacterial or fungal growth was observed and in vitro procoagulant activity of rFVIIa remained stable. The mini-pump was used to deliver rFVIIa as bolus doses to two patients with inhibitors who had undergone surgery. Nurses were asked to report their satisfaction with the use of the mini-pump using a specific questionnaire. Haemostasis was evaluated as excellent in both cases; nurses were satisfied with use of the mini-pump. This pilot study shows that intermittent delivery of rFVIIa at fixed intervals using an automated mini-pump offers accurate and reliable administration in the postoperative setting. This approach may reduce burden on nursing staff, potentially minimize the risk of human error and avoid delay in administration of rFVIIa.

Evaluation of Recombinant Factor VIIa Utilization and Development of a Cost-Effective Dose Minimization Protocol in Adult Cardiac Surgery Patients at an Academic Medical Center

Background: Although recombinant factor VIIa is often utilized to mitigate critical bleeding following cardiac surgery, the optimal dosing strategy in this population is not well-established. At our institution, hospital guidelines recommend administration of recombinant factor VIIa 60 mcg/kg for all off-label indications. However, available data suggest doses as low as 17 mcg/kg have been efficacious in cardiac surgery patients with critical bleeding. Additionally, although low-dose recombinant factor VIIa (< 40 mcg/kg) and high-dose (50-109 mcg/kg) dosing strategies have been reported equally efficacious according to retrospective, observational studies, higher doses may be associated with increased incidence of adverse events. Therefore, we aimed to evaluate the safety of recombinant factor VIIa in cardiac surgery patients with critical bleeding, and estimate potential cost-savings associated with implementation of a low-dose recombinant factor VIIa protocol in this population.Methods: All adult cardiac surgery patients who received one or more doses of recombinant factor VIIa during a 1-year period (July 1, 2016 to June 30, 2017) were included. Thromboembolic event rates documented within 14 days following recombinant factor VIIa administration were evaluated in patients alive at discharge. An average wholesale price of 2.59 USD per mcg was utilized for recombinant factor VIIa cost calculations.Results: A total of 16 patients received 24 doses of recombinant factor VIIa during the study period. The median weight-based dose administered was 55 mcg/kg (utilizing actual body weight), and the median dose was 5 mg. The median cost per recombinant factor VIIa dose was 12,950 USD, resulting in a total expenditure of 277,174 USD. Nine of sixteen patients (56%) survived to hospital discharge. Five of nine (56%) patients alive at discharge experienced thromboembolic complications following recombinant factor VIIa administration, three (60%) of which were central nervous system (CNS) thromboembolic events. Based on data supporting low-dose strategies, a proposed weight-based recombinant factor VIIa dose-minimization protocol was developed by leadership in the departments of pharmacy, hematology, cardiac surgery, and cardiac anesthesia (Table 1). Implementation of this protocol would result in an estimated annual cost-avoidance of 168,376 USD.Conclusions: Recombinant factor VIIa administration at a dose of 55 mcg/kg in adult cardiac surgery patients with critical bleeding is associated with a high rate of thromboembolic events, including CNS thromboembolism. Additionally, this recombinant factor VIIa dosing strategy is associated with significant cost, which can be substantially reduced with implementation of a low-dose recombinant factor VIIa protocol in the cardiac surgery population. DisclosuresNo relevant conflicts of interest to declare.

Pediatric trauma transfusion and cognitive aids.

Trauma is the most common cause of pediatric mortality. Much of the research that led to life-saving interventions in adults, however, has not been replicated in the pediatric population. Children have important physiologic and anatomic differences from adults, which impact hemostasis and transfusion. Hemorrhage is a leading cause of death in trauma, and children have important differences in their coagulation profiles. Transfusion strategies, including the massive transfusion protocol and use of antifibrinolytics, are still controversial. In addition to the blood that is lost from the injury itself, trauma leads to inflammation and to a dysfunction in hemostasis, causing coagulopathy. In one study in which children suffered from mainly blast and penetrating injuries in a combat setting (PEDTRAX trial), the early administration of tranexamic acid was associated with decreased mortality. Some authors suggest that this result may not apply to blunt trauma, which is much more common in children in noncombat settings. Using thromboelastography to guide the administration of recombinant Factor VIIa has been done in selected cases and may represent a future avenue of research. This article explores new research from the past year in pediatric trauma, starting with the physiologic differences in pediatric red blood cells and coagulation profiles. We also looked at the dramatic change in thinking over the past decade in the tolerable level of anemia in critically ill pediatric patients, as well as scales for determining the need for massive transfusion and exploring if the concepts of damage control resuscitation apply to children. Other strategies, such as avoiding hypothermia, and the selective administration of antifibriniolytics, are important in pediatric trauma as well. Future research that is pediatric focused is needed for the optimal care of our youngest patients.

Protocol based invasive intracranial pressure monitoring in acute liver failure: feasibility, safety and impact on management

BackgroundAcute liver failure (ALF) may result in elevated intracranial pressure (ICP). While invasive ICP monitoring (IICPM) may have a role in ALF management, these patients are typically coagulopathic and at risk for intracranial hemorrhage (ICH). Contemporary ICP monitoring techniques and coagulopathy reversal strategies may be associated with a lower risk of hemorrhage. Our objective was to evaluate the safety, feasibility, impact on clinical management and outcomes associated with protocol-directed use of IICPM in ALF.MethodsAdult patients admitted between June 2011 and October 2016, with ALF and grade-4 encephalopathy with a reasonable likelihood of survival, were eligible for IICPM. The coagulopathy reversal protocol included administration of recombinant Factor VIIa (rFVIIa) and desmopressin, a goal platelet count >50,000/mm3 and fibrinogen >100 mg/dL. Monitor insertion was performed within an hour of the rFVIIa dose. Only intraparenchymal monitors were used. Computed tomography of the brain was performed prior to and within 24 hours of monitor placement. Outcomes of interest included ICH, sustained intracranial hypertension, therapeutic intensity level (TIL) for ICP management, mortality and functional outcome on the Glasgow Outcome Scale (GOS) at discharge and 6 months.ResultsA total of 24/37 patients (65%) with ALF underwent IICPM. The most common reason for exclusion was encephalopathy grade <4. Four patients underwent liver transplantation. There was one asymptomatic ICH following IICPM, in a patient who had an excellent outcome. Sustained intracranial hypertension occurred in 13/24 monitored patients (54%), 5/24 (21%) required extreme measures (TIL-4) for ICP control, which were successful in 4 patients: 12/24 patients (50%) died but only 4 deaths (17%) were attributed to intracranial hypertension. Six of the 8 survivors with 6-month follow up had good functional outcome (GOS >3).ConclusionsProtocol-directed use of IICPM in ALF is feasible, associated with a low incidence of serious complications and has a significant impact on clinical management.

High Dose, Prolonged Epsilon Aminocaproic Acid Infusion, and Recombinant Factor VII for Massive Postoperative Retroperitoneal Hemorrhage following Splenectomy.

The antifibrinolytic agent ε-aminocaproic acid is used to decrease procedural blood loss in a variety of high risk surgeries. The utility of recombinant factor VII administration in massive hemorrhage has also been reported in a variety of settings, though the impact in a surgical context remains unclear. We describe the case of a patient who underwent massive open splenectomy and developed diffuse retroperitoneal bleeding on postoperative day one. Massive transfusion was initiated, but attempts to control hemorrhage with surgical and interventional radiology approaches were unsuccessful, as was recombinant factor VII administration. Commencement of a high dose aminocaproic acid infusion was followed by a prominent rise in fibrinogen levels and stabilization of the hemorrhage. Indications, dosages, and adverse effects of ε-aminocaproic acid as described in the literature are reviewed.

Mysterious bruises

A 69-year-old man presented with multiple spontaneous bruises in the past 2 weeks. Several large-sized hematomas were found on examination. The initial investigation revealed a prolonged activated partial thromboplastin time (aPTT) with normal platelet count and international normalized ratio. Further investigation revealed a low factor VIII activity secondary to presence of factor VIII inhibitor, making the diagnosis of acquired hemophilia A. Further work-up revealed that pernicious anemia was present and acted as an associated disease. After steroids therapy, his aPTT was normalized and the factor VIII inhibitor titer became undetectable. 2 months later, a relapse occurred and new hematomas appeared at his retropharyngeal space and left arm. His bleeding was controlled by administration of recombinant factor VIIa, and a combined therapy of intravenous steroids and rituximab was given to eradicate the inhibitor. The approach to workup of bleeding disorders as well as treatment of acquired hemophilia A are herein discussed.

Possible Anaphylaxis Due to Recombinant Factor VIIa Administration During Thoracic Aortic Surgery

Possible Anaphylaxis Due to Recombinant Factor VIIa Administration During Thoracic Aortic Surgery

Risk of Bleeding and Inhibitor Development After Circumcision in Minimally Treated Severe Hemophilia A Patients: A One Year Prospective Study,

Abstract 4653 BackgroundCircumcision is a cultural practice for males in the Middle-East during first weeks of life. All parents of hemophilics are eager to do circumcision to their sibs, however, it may carry a risk for development of factor VIII inhibitors as well as risk of excessive bleeding. ObjectiveTo evaluate post-circumcision bleeding and assess incidence and time of inhibitor development over 12 months follow-up period of minimally treated severe hemophilia A patients. Patients and methodsThis prospective analysis has been conducted on eighteen minimally treated patients with severe hemophilia A (age range 8–36 months) with a median age of 18 months, who underwent circumcision during 2009 and twenty four age matched non circumcised patients minimally treated severe hemophilia A. Both groups were followed up for12 months from study entry and all were treated on demand therapy with a single plasma-derived factor VIII product. Hemophilic patients who underwent circumcision were inhibitor negative except two with low- titer inhibitor(3.3 and 4.4 BU/ml) respectively. One hour before the operation, intravenous tranexamic acid (25 mg/ kg) and first dose of factor concentrate (25 unit / Kg) were given to the patients. After reaching a trough plasma factor level more than 90%, patients underwent circumcision using general anesthesia and same surgical technique for all. Bolus injections of factor VIII concentrate were repeated in a dose of (25 units / Kg ) twenty four hours after operation. However, the two patients with inhibitors were given factor VIII concentrate in a dose of (50 units /Kg) with an extra dose at forty-eight hours. Another dose of factor concentrate (25 units/ Kg) was given just before removal of gauze dressing at 5th −7th day post operative. Follow up for inhibitor development was assessed every 8 exposure days (EDs) for 12 months or 100 EDs whichever comes first. Results:Of the eighteen patients enrolled, only one of the 2 patients with low- titer inhibitor had postoperative bleeding at day 5 and 7 respectively. First attack responded to a single dose of factor administration (50 units/Kg), whereas haemostasis was achieved in the second episode after a single dose of Recombinant Factor VIIa (90 microgram/kg) and applying absorbable haemostatic agent (gelatin sponge) and binding. None of the other patients had any bleeding or infection at site of surgery. High -titer inhibitors developed in three patients (16.6 % ) during the follow-up; after 8, 16 and 40 EDs respectively in contrast to four patients (16.6 %) developed high titer inhibitor in the non circumcised group; after a median of 16 exposure days (range 8– 60 EDs). Conclusion:Our study has shown that bleeding following circumcision was absent except in low- titer inhibitor patient necessitating administration of Recombinant Factor VIIa. Moreover, circumcision was not a risk for development of inhibitor where the incidence of high- titer inhibitors during12 months follow up was low in this cohort of minimally treated patients and comparable to non circumcised group. Disclosures:No relevant conflicts of interest to declare.

Safety of Recombinant Activated Factor VII in Patients With Warfarin-Associated Hemorrhages of the Central Nervous System

Recombinant Factor VIIa decreases hematoma growth after spontaneous intracerebral hemorrhage (ICH) and rapidly decreases international normalized ratios in patients on warfarin but is also associated with an increased risk for thromboembolic complications. In this study, we assessed the risk of thromboembolic events in patients receiving recombinant Factor VIIa after ICH associated with warfarin treatment. We reviewed the medical charts, laboratory data, and radiological findings of consecutive patients with anticoagulation-related hemorrhages of the central nervous system who received recombinant Factor VIIa at Mayo Clinic Rochester and Mayo Clinic Florida between 2002 and 2009. The primary end point was the frequency of new thromboembolic events, including myocardial infarction, deep vein thrombosis, ischemic stroke, and pulmonary embolism. We identified 101 patients; 54% had ICH and 30% subdural hematomas. The most common indications for anticoagulation were atrial fibrillation, deep vein thrombosis, and prosthetic valve. Thirteen patients (12.8%) had new thromboembolic events (10 deep vein thromboses and 3 ischemic strokes) within 90 days after recombinant Factor VIIa administration. Eight of these adverse events occurred within 2 weeks of treatment. In patients with ICH, the rate of thromboembolic complications was 5% and all events were venous. The risk of thromboembolic events in patients who received recombinant Factor VIIa for anticoagulation-associated ICH was not higher than that seen in patients treated for spontaneous ICH in the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Spontaneous deep vein thrombosis was the most common complication in our series.

The Acute Management of Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating disease with high rates of mortality and morbidity. The major risk factors for ICH include chronic arterial hypertension and oral anticoagulation. After the initial hemorrhage, hematoma expansion and perihematoma edema result in secondary brain damage and worsened outcome. A rapid onset of focal neurological deficit with clinical signs of increased intracranial pressure is strongly suggestive of a diagnosis of ICH, although cranial imaging is required to differentiate it from ischemic stroke. ICH is a medical emergency and initial management should focus on urgent stabilization of cardiorespiratory variables and treatment of intracranial complications. More than 90% of patients present with acute hypertension, and there is some evidence that acute arterial blood pressure reduction is safe and associated with slowed hematoma growth and reduced risk of early neurological deterioration. However, early optimism that outcome might be improved by the early administration of recombinant factor VIIa (rFVIIa) has not been substantiated by a large phase III study. ICH is the most feared complication of warfarin anticoagulation, and the need to arrest intracranial bleeding outweighs all other considerations. Treatment options for warfarin reversal include vitamin K, fresh frozen plasma, prothrombin complex concentrates, and rFVIIa. There is no evidence to guide the specific management of antiplatelet therapy-related ICH. With the exceptions of placement of a ventricular drain in patients with hydrocephalus and evacuation of a large posterior fossa hematoma, the timing and nature of other neurosurgical interventions is also controversial. There is substantial evidence that management of patients with ICH in a specialist neurointensive care unit, where treatment is directed toward monitoring and managing cardiorespiratory variables and intracranial pressure, is associated with improved outcomes. Attention must be given to fluid and glycemic management, minimizing the risk of ventilator-acquired pneumonia, fever control, provision of enteral nutrition, and thromboembolic prophylaxis. There is an increasing awareness that aggressive management in the acute phase can translate into improved outcomes after ICH.

Von Willebrand disease, angiodysplasia and atorvastatin

We read with interest the report of a patient with severe type I von Willebrand disease (VWD) and angiodysplasia responding to atorvastatin (Sohal & Laffan, 2008). As a direct result of this report we reviewed the case of a 59-year-old man with Type 2A VWD. During the period 1992–2003 he required a total of 235 units of blood to be transfused for anaemia due to bleeding from angiodysplasia of the small and large intestine. Subsequently, he was admitted to hospital on 30 occasions in 2007, receiving a total of 70 units of blood; in 2008 there were a further 18 admissions with 52 units of blood transfused. Unsurprisingly, he has developed a number of red cell antibodies, including Anti-Fya, Anti-K and Anti-Kpa. In addition to supportive blood transfusions we have tried to manage his symptoms with intermediate purity factor replacement in the form of Haemate P. However, he has struggled with peripheral venous access and recurrent portocath thromboses followed by failure of a surgically created arteriovenous fistula in the arm. He has also received adjunctive therapy in the form of ethinyloestradiol in 2004 and thalidomide in 2005, but these were stopped due to intolerant side effects. He also suffered a myocardial infarction in 2004 following the administration of recombinant factor VIIa during an acute bleeding episode. We commenced our patient on atorvastatin 10 mg nocte in August 2008, increasing the dose by 10 mg per month until November 2008. He was maintained on 40 mg nocte for 3 months, with a noticeable reduction in blood transfusion requirements. In January 2009, the dose of atorvastatin was increased to 80 mg nocte. The patient has now been on this dose for the past 9 months and has not required hospital admission or a single unit of blood to be transfused during this period (Fig 1). Effect of atorvastatin dose on blood transfusion requirements. A downward trend in bleeding episodes and the need for blood transfusion was observed as the dose of atorvastatin was increased from 10 to 40 mg. At a dose of 80 mg atorvastatin there have been no bleeding episodes and no blood transfusions during the past 9 months.

The contemporary role of blood products and components used in trauma resuscitation

IntroductionThere is renewed interest in blood product use for resuscitation stimulated by recent military experience and growing recognition of the limitations of large-volume crystalloid resuscitation.MethodsAn editorial review of recent reports published by investigators from the United States and Europe is presented. There is little prospective data in this area.ResultsDespite increasing sophistication of trauma care systems, hemorrhage remains the major cause of early death after injury. In patients receiving massive transfusion, defined as 10 or more units of packed red blood cells in the first 24 hours after injury, administration of plasma and platelets in a ratio equivalent to packed red blood cells is becoming more common. There is a clear possibility of time dependent enrollment bias. The early use of multiple types of blood products is stimulated by the recognition of coagulopathy after reinjury which may occur as many as 25% of patients. These patients typically have large-volume tissue injury and are acidotic. Despite early enthusiasm, the value of administration of recombinant factor VIIa is now in question. Another dilemma is monitoring of appropriate component administration to control coagulopathy.ConclusionIn patients requiring large volumes of blood products or displaying coagulopathy after injury, it appears that early and aggressive administration of blood component therapy may actually reduce the aggregate amount of blood required. If recombinant factor VIIa is given, it should be utilized in the fully resuscitated patient. Thrombelastography is seeing increased application for real-time assessment of coagulation changes after injury and directed replacement of components of the clotting mechanism.

Incidence and Risk Factors for Venous Thromboembolism in Critically Ill Children After Trauma

Venous thromboembolism (VTE) causes major morbidity in adults after trauma, occurring in up to 50% of patients without prophylaxis. The incidence of VTE after trauma is lower in children. No study has measured the incidence of and risk factors for VTE in critically ill children after trauma. Nested case-control study of children, younger than 18 years, admitted to the pediatric intensive care unit at a level I trauma center. Three controls were selected for each identified VTE case. Nine of 144 children admitted to the pediatric intensive care unit after trauma developed VTE (incidence 6.2%, 95% confidence interval [CI] 2.3-10.2), with a median age of 8.6 years (range, 2.3-17.9). VTE was diagnosed at a median of 9 days after admission, with 67% of VTE located at the site of previous or existing central venous line (CVL). Significant risk factors for thrombosis included parenteral nutrition (odds ratio [OR] 20, 95% CI 1.9-227), CVL (OR 19, 95% CI 2-178), deep sedation (OR 13, 95% CI 1.6-48), neuromuscular blockade (OR 10, 95% CI 1.4-70), inotropic support (OR 10, 95% CI 1.7-59), and recombinant factor VIIa administration (p = 0.012, OR not calculable). Logistic analysis found a 7.9-fold increase in the odds of developing VTE for each additional CVL (p = 0.005), a threefold increase with each additional risk factor present (p = 0.009), and a 1.3-fold increase for an increase in injury severity (p = 0.03). VTE was not associated with sepsis, spinal cord injury, fracture, or elevated D-dimer level. VTE is not a rare event in critically ill children after trauma. Most patients developing thrombosis have multiple risk factors, including poor perfusion, immobility, and presence of a CVL.

Activated recombinant factor VII for refractory bleeding during extracorporeal membrane oxygenation*

To determine the frequency of adverse events with the use of activated recombinant factor VII during extracorporeal membrane oxygenation support and to quantify the effect on bleeding parameters. Retrospective case series from January 1999 to August 2006. Pediatric intensive care unit at a tertiary academic children's hospital. Seventeen patients received a total of 26 doses of activated recombinant factor VII while supported on extracorporeal membrane oxygenation or within 3 hrs of initiation of extracorporeal membrane oxygenation support from February 2003 to August 2006, and 23 historical controls from January 1999 to December 2002 with bleeding complications reported to the Extracorporeal Life Support Organization database while supported on extracorporeal membrane oxygenation before the use of activated recombinant factor VII. None. No significant difference in the rate of thromboembolic complications, extracorporeal membrane oxygenation circuit failures, or mortality was found between the patients and historical controls. No trend toward increased survival was found, and a significant number of circuit complications was seen in both groups. In patients treated with activated recombinant factor VII, a significant reduction in chest tube output and blood product transfusion rates was seen within 5 hrs of activated recombinant factor VII administration. Activated recombinant factor VII administration during extracorporeal membrane oxygenation support was associated with a decrease in bleeding severity (indicated by chest tube output and blood product transfusion rates) and was not associated with an increased rate of thromboembolic complications.

Recombinant Factor VIIa for Treatment of Gastrointestinal Hemorrhage Following Rattlesnake Envenomation

North American rattlesnakes possess venom with primarily cytotoxic and hemotoxic properties. When persons are envenomated by these snakes, thrombocytopenia and coagulopathy commonly occur, yet patients rarely develop severe bleeding. This report describes a 44-year-old Native American man bitten on the index finger by an unknown species of rattlesnake. The man developed massive gastrointestinal hemorrhage that was ultimately treated with recombinant factor VIIa. He presented to an emergency department with a depressed level of consciousness, a blood pressure of 60/20 mm Hg, and heart rate of 148 beats per minute. He was diaphoretic and vomiting bright red blood. Initial laboratory results revealed thrombocytopenia and coagulopathy. Despite aggressive fluid resuscitation and administration of blood and antivenom in the emergency department, the patient continued to have profuse upper gastrointestinal bleeding, with hemoglobin as low as 1.8 g/dL. He received fluids, antivenom, and multiple blood products, with cessation of bleeding after administration of recombinant factor VIIa. Esophagogastroduodenoscopy revealed a single Mallory-Weiss tear as the source of hemorrhage. The patient stabilized after 6 hours of aggressive resuscitation but over the next several days developed several complications, including acute renal failure and gram-negative sepsis. The patient died on hospital day 5. In cases of life-threatening hemorrhage after rattlesnake envenomation in which traditional therapy with antivenom and aggressive supportive measures fail, recombinant factor VIIa should be considered as an additional therapeutic option to achieve hemostasis.

Emergency reversal of antithrombotic treatment

The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be reversed by various specific strategies. Heparin and heparin derivatives can be counteracted by protamine sulphate, whereas the anticoagulant effect of vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates. The anti-hemostatic effect of aspirin and other anti-platelet strategies can be corrected by the administration of platelet concentrate or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors has been introduced and most of these agents are presently being evaluated in clinical studies. The new generation anticoagulants include specific inhibitors of factor IIa, factor Xa (including pentasaccharides) and agents that interfere with tissue factor activity. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although in some cases the administration of recombinant factor VIIa may be an option.