Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients

Beriplex, a prothrombin complex concentrate (PCC), was administered to 42 patients requiring immediate reversal of their oral anticoagulant therapy. The dose administered was determined using the pretreatment International Normalized Ratio (INR). Blood samples were obtained before treatment and at 20, 60 and 120 min after treatment. The following investigations were performed on all samples - INR, clotting factors II, VII, IX and X, coagulation inhibitors protein C (PC) and antithrombin (AT), and other markers of disseminated intravascular coagulation, plasma fibrinogen, D-dimer and platelet count. Immediate reversal of the INR, the vitamin K-dependent clotting factors and PC was achieved in virtually all patients. Reduced AT levels were present in 18 patients before treatment. Further slight AT reductions occurred in four patients, but other associated abnormalities of haemostasis were observed in only one of the four patients. One patient with severe peripheral vascular disease, sepsis and renal and cardiac failure died of a thrombotic stroke following leg amputation, 48 h after receiving Beriplex. No other arterial and no venous thromboembolic events occurred within 7 d of treatment. Beriplex is effective in rapidly reversing the anticoagulant effects of warfarin, including PC deficiency, without inducing coagulation activation. Caution should continue to be exercised in the use of these products in patients with disseminated intravascular coagulation, sepsis or liver disease.     

Complications of warfarin therapy monitored by the international normalized ratio versus the prothrombin time ratio

The objective of our study was to determine the rates of bleeding complications and thromboembolic events in patients receiving oral anticoagulant therapy monitored with the prothrombin time (PT) ratio versus therapy monitored with the International Normalized Ratio (INR) using a retrospective time-series study design. Over 650 patients enrolled in a large anticoagulation clinic were studied during two time periods corresponding to the use of the PT ratio versus the INR to guide anticoagulant therapy, with over 400 patient-years of follow-up for each time period. The rate of bleeding complications using the PT ratio to guide therapy was 6.7% (1.2% major, 5.5% minor) per patient-year, compared with 2.9% (0% major, 2.9% minor) using the INR (p = 0.02). The rate of thromboembolic complications was 1.0% using the PT ratio, compared with 0.2% using the INR (p = NS). Therapy monitored with the INR required 19.8 visits per year, compared with 20.7 visits per year using the PT ratio. We conclude that the INR should be used to monitor oral anticoagulant therapy in an effort to reduce bleeding complications while maintaining an acceptable rate of thromboembolic events.     

Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin

A cohort of patients with an INR >7.0 were identified prospectively and compared with a group of patients with stable anticoagulant control. During the study 15 100 INR measurements were recorded and 31 (0.2%) were >7.0. Odds ratios of patient characteristics were calculated as an estimate of relative risk for the development of a high INR. The highest risk factor was a target INR of 3.5 (OR 7.3, 95% CI 2.6–20.2). The second highest risk factor was antibiotic therapy in the 4 weeks preceding the high INR (OR 6.2, 95% CI 1.4–27.7). Bleeding was reported more frequently in the high INR group (OR 5.4, 95% CI 2.1–13.9). Five major bleeds occurred in this group compared to none in the stable group. This analysis identifies risk factors for over-anticoagulation and hence when to intensify monitoring and when to consider pre-emptive warfarin dose reductions.     

Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation

Background: Prothrombinex‐VF (a three‐factor prothrombin complex concentrate) contains little factor VII. Therefore, the Warfarin Reversal Consensus Guidelines from 2004 published by The Australasian Society of Haemostasis and Thrombosis recommend that it be administered with fresh frozen plasma to reverse warfarin anticoagulation. Aim: To evaluate the efficacy and safety of Prothrombinex‐VF used alone in warfarin reversal. Methods: Adult patients requiring urgent reversal of warfarin anticoagulation were defined as having achieved complete (target international normalized ratio (INR) <1.4) or partial reversal (target INR 1.4–2.0) of their anticoagulation. Prothrombinex‐VF was given at doses of between 25 and 50 IU/kg based on the intent of reversal and an INR was obtained 30 min post infusion. Results: A total of 50 patients (mean age 72 years, range 32–85 years) was included. The median initial INR in the complete reversal arm (n= 35) was 3.5 (range 1.7–20) with 91% achieving the target INR (mean 1.1, range 0.9–1.4). In the partial reversal arm (n= 15) the mean initial INR was 5.6 (range 2.5–12) with 93% achieving the target INR (mean 1.6, range 1.4–2.2). There were no adverse effects attributed to Prothrombinex‐VF. Conclusions: Prothrombinex‐VF is very effective and safe when used alone to reverse warfarin anticoagulation. The supplementary use of fresh frozen plasma in these patients is not required. A review of the current Warfarin Reversal Consensus Guidelines is needed.     

The cost-effectiveness of different management strategies for patients on chronic warfarin therapy

OBJECTIVE: To examine the cost-effectiveness of moving from usual care to more organized management strategies for patients on chronic warfarin therapy. DESIGN: Using information available in the scientific literature, supplemented with data from a large health system and, when necessary, expert opinion, we constructed a 5-year Markov model to evaluate the health and economic outcomes associated with each of three different anticoagulation management approaches: usual care, anticoagulation clinic testing with a capillary monitor, and patient self-testing with a capillary monitor. PATIENTS: Three hypothetical cohorts of patients beginning long-term warfarin therapy were used to generate model results. MAIN RESULTS: Model results indicated that moving from usual care to anticoagulation clinic testing would result in a total of 1.7 thromboembolic events and 2.0 hemorrhagic events avoided per 100 patients over 5 years. Another 4.0 thromboembolic events and 0.8 hemorrhagic events would be avoided by moving to patient self-testing. When direct medical care costs and those incurred by patients and their caregivers in receiving care were considered, patient self-testing was the most cost-effective alternative, resulting in an overall cost saving. CONCLUSIONS: Results illustrate the potential health and economic benefits of organized care management approaches and capillary monitors in the management of patients receiving warfarin therapy.     

Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000–4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47–759) and 159 ng/ml (45–255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9–15·4) and 1·2 (1·0–1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.     

Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study

Background Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) reverse oral anticoagulants. We compared PCC and FFP intraoperative administration in patients undergoing heart surgery with cardiopulmonary bypass (CPB). Methods Forty patients [with international normalized ratio (INR) ≥ 2·1] assigned semi‐urgent cardiac surgery were randomized to receive either FFP (n = 20) or PCC (n = 20). Prior to CPB, they received either 2 units of FFP or half of the PCC dose calculated according to body weight, initial INR and target INR (≤ 1·5). After CPB and protamine administration, patients received either another 2 units of FFP or the other half PCC dose. Additional doses were administered if INR was still too high (≥ 1·5). Results Fifteen minutes after CPB, more patients reached INR target with PCC (P = 0·007): 7/16 patients vs. 0/15 patients with FFP; there was no difference 1 h after CPB (6/15 patients with PCC vs. 4/15 patients with FFP reached target). Fifteen minutes after CPB, median INR (range) decreased to 1·6 (1·2–2·2) with PCC vs. 2·3 (1·5–3·5) with FFP; 1 h after CPB both groups reached similar values [1·6 (1·3–2·2) with PCC and 1·7 (1·3–2·7) with FFP]. With PCC, less patients needed additional dose (6/20) than with FFP (20/20) (P < 0·001). Both groups differed significantly on the course of factor II (P = 0·0023) and factor X (P = 0·008) over time. Dilution of coagulation factors was maximal at CPB onset. Safety was good for both groups, with only two related oozing cases with FFP. Conclusion PCC reverses anticoagulation safely, faster and with less bleeding than FFP.     

Anticoagulation with anisindione in patients who are intolerant of warfarin

Patients who require oral anticoagulation usually receive warfarin. We used an indanedione drug, anisindione, in two patients who were intolerant of warfarin but who needed long-term oral anticoagulation. The use of this alternative oral anticoagulant is reviewed. © 1994 Wiley-Liss, Inc.     

The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation

Of 125 patients aged 65 years or over, with atrial fibrillation taking warfarin for at least 12 months, with a standard deviation (SD) of prothrombin time, expressed as the International Normalized Ratio (INR) >0.5 over the previous 6 months, 40 were randomized to continue with usual clinic care and 85 to receive education about warfarin. Of these, 44 were randomized to self-monitor their INR and 41 returned to clinic. Compared with the previous 6 months there was a significant increase in percentage time within the therapeutic range for the 6 months following education [61.1 vs. 70.4; mean difference 8.8; 95% confidence interval (CI): -0.2-17.8; P = 0.054] and following education and self-monitoring (57 vs. 71.1; mean difference 14.1; 95% CI: 6.7-21.5; P < 0.001), compared with those patients following usual clinic care (60.0 vs. 63.2; mean difference 3.2; 95% CI: -7.3-13.7). Using the same comparative periods, the INR SD fell by 0.24 (P < 0.0001) in the group allocated to education and self-monitoring, 0.26 (P < 0.0001) in the group receiving education alone and 0.16 (P = 0.003) in the control group. Inter-group differences were not statistically significant (intervention groups 0.26 +/- 0.30 vs. control 0.16 +/- 0.3, P = 0.10). Quality-of-life measurements and health beliefs about warfarin were unchanged (apart from emotional role limitation) with education or education and self-monitoring. Patient education regarding anticoagulation therapy could be a cost-effective initiative and is worthy of further study.     

Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 outpatients

Abstract. Objective. The aim of the study was to compare the incidence of bleeding complications in patients receiving warfarin alone and those receiving warfarin in combination with acetylsalicylic acid. Subjects and methods. This retrospective study comprises all outpatients in our hospital receiving warfarin (n = 3166) in the period 1 January 1986 to 31 December 1990. Of these, 2026 patients received warfarin alone, aiming at an international normalized ratio level of 4.2-2.5, whereas the combination of warfarin and acetylsalicylic acid (150 mg daily) was given to 1140 patients, aiming at an international normalized ratio level of 2.8-2.2. Total observation time represents 4420 treatment years. Results. A total of 175 bleeding episodes was observed, 18 of which were fatal, and 96 were serious (requiring hospitalization). The incidence of minor bleedings was significantly higher in the combined therapy group than in the group receiving warfarin alone, 2.9% and 1.4% respectively (P < 0.003). However, there was no difference in the therapy groups regarding the incidence of serious and fatal bleedings. The overall incidence of gastrointestinal bleedings was equal in the two groups. Conclusions. The combination of warfarin and aspirin 150 mg daily aiming at a less intense level of anticoagulation than in warfarin therapy alone does not increase the risk of major or fatal haemorrhage.     

Workshop: Special problems in anticoagulation therapy: Cancer and venous thromboembolism-temporary discontinuation of warfarin for surgery and invasive procedures

Health care providers monitoring anticoagulated patients are often asked to make recommendations regarding anticoagulant management during periods when illness or treatment may complicate anticoagulant therapy. Two particularly difficult clinical problems concern the indications for and management of anticoagulant therapy in patients with cancer and the management of anticoagulated patients who must undergo some type of surgical procedure. Cancer is a significant risk factor for a variety of thromboembolic disorders, particularly venous thromboembolism. Venostasis from immobility, vessel wall damage from tumor invasion, and especially tumor-mediated activation of the coagulation system are important contributors to the prethrombotic state in cancer patients. The risk of venous thromboembolism is greatest during surgery, chemotherapy, and long-term use of central venous catheters. For selected patients, prophylaxis with subcutaneous heparin, low-intensity warfarin, or very low-intensity warfarin may substantially reduce this risk. A related concern for primary care clinicians is the increasing evidence that idiopathic venous thromboembolism may be the first manifestation of occult cancer. Whether and how these patients should be screened for malignancy is currently uncertain. Prior to surgical procedures in anticoagulated patients, clinicians must compare the risk of bleeding if anticoagulation is continued with the risk of recurrent thrombosis if anticoagulation is stopped. Bleeding risk is influenced by how a specific procedure affects the ability to assess and control bleeding and the intensity of anticoagulation at the time of the procedure. Thromboembolism risk is determined by the specific indication for the anticoagulation and the length of time during which anticoagulant therapy must be discontinued. Guidelines are suggested for perioperative anticoagulant management of patients with different thromboembolic disorders undergoing a variety of surgical procedures.     

华法令在肺栓塞抗凝治疗中的剂量与使用方法

目的探讨华法令抗凝治疗肺血栓栓塞症（PTE）时尽快达到国际标准化比值（INR）在2—3之间时的剂量及方法。方法分析94例接受华法令口服抗凝治疗的PTE患者的临床资料；比较起始量3mg组与6mg组在华法令治疗第3、5、10天时INR达标情况；计算达标者每日人均华法令用量。结果94例患者中56例有明确达标剂量，占59．6％；所有达标者每日人均华法令用量为4．097mg；3mg组达标25例，6mg组达标22例；抗凝第3、5、10天时6mg组达标人数及百分比均明显高于3mg组（P〈0．05），两组达标时所用的华法令总量平均数皆为29mg左右；6mg组平均达标天数为第5—6天，3mg组为第8～9天（P〈0．05）；随年龄增大华法令需求量下降；94例PTE患者在华法令抗凝期间无一例发生出血，6mg组有1例出现再栓塞。结论使用6mg负荷量的给药方法可使PTE患者在第5～6天尽快达标同时又能避免早期再栓及出血；本组华法令平均个体维持量在4mg／d左右。     

A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin

The role of oral Vitamin K administration in the reversal of anticoagulation is not yet clear because of a paucity of data on the early effects of treatment, apparent differences in efficacy between preparations and a lack of data comparing oral with intravenous administration. We have compared the effects on the International Normalized Ratio (INR) and activities of the Vitamin K-dependent clotting factors II, VII, IX and X at 4 h and 24 h after administration of three oral Vitamin K preparations and of intravenous Vitamin K in 64 anticoagulated patients who required non-urgent partial correction of anticoagulation. Our data confirm that correction of anticoagulation is more rapid after intravenous administration of Vitamin K than after oral administration of similar or larger doses. At 24 h, satisfactory correction of INR can be achieved using low-dose Vitamin K given by either the intravenous or oral route. Our data, and that from previous studies, suggest that there may be differences in efficacy between orally administered products. Administration of Vitamin K by either route was accompanied by changes in the activities of the Vitamin K-dependent clotting factors that reflected their respective biological half-lives. In the 24 h after treatment, the relationship between the INR and the individual Vitamin K-dependent clotting factors was similar to that described previously in stable anticoagulated patients. We conclude that the reversal of anticoagulation with warfarin is achieved more rapidly by intravenous administration of Vitamin K. Satisfactory, but slower, reversal of anticoagulation can be effected using oral Vitamin K, but there may be differences in efficacy between the products tested in our study.     

Maintenance of ribosomal protein S19 in plasma by complex formation with prothrombin

We have demonstrated that the cross-linking of ribosomal protein S19 (RP S19) on platelets by activated factor XIII provides chemotactic potency to monocytes/macrophages for a resolution of coagulum. Factor XIII is activated by an active form of prothrombin, thrombin. We here report that RP S19 is present as a complex with prothrombin in the blood stream. Formation of this complex was blocked by a mutation of the glycosaminoglycan-binding basic cluster (Lys(23) -Lys(29) ) in RP S19. Prothrombin-RP S19 interaction was enhanced by an absence of Ca(2+) and the plasma RP S19 concentration was significantly low in the patient treated with warfarin, indicating participation of the γ-carboxyl glutamic acid domain of prothrombin making a salt bridge with the basic cluster. The complex formation likely explains why a protein as small as RP S19 can prevent from a filtering system of renal glomeruli at a steady state. The translocation of RP S19 from prothrombin to platelets during blood coagulation seems to be also advantageous for RP S19 from the perspective of oligomerisation by activated factor XIII, which should have been activated by thrombin.     

Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding

In an open non-randomized study, 10 patients with major bleeding and an Internationalized Normal Ratio (INR) greater than 14 were treated with 5 mg of intravenous vitamin K and 30 iu/kg of a single concentrate containing factors II, VII, IX and X (Beriplex P/N; Aventis Behring). The levels of these factors before and immediately after treatment were 4.7, 1.6, 8.5 and 1.1 iu/dl and 94, 30, 66 and 91 iu/dl respectively. The median INR before treatment was greater than 20 and, after treatment, 1.1. All patients had a satisfactory clinical response with immediate cessation of bleeding, and no thromboembolic complications occurred.     

On the mechanism of action of recombinant activated factor VII administered to patients with severe thrombocytopenia and life-threatening haemorrhage: focus on prothrombin activation

We report the ex vivo effect of recombinant activated factor VII (rFVIIa) on prothrombin activation after whole blood clotting. Two patients with severe thrombocytopenia and life-threatening haemorrhage were successfully managed using a single dose of rFVIIa (90 microg/kg). Western blotting using antiprothrombin antibody showed that rFVIIa did not induce thrombin generation in citrated platelet-poor plasma. Patient sera showed significantly impaired prothrombin activation before and after rFVIIa administration. rFVIIa administration shortened the prothrombin time, activated partial thromboplastin time and Ivy bleeding time, and normalized the clot retraction. These data indicate that rFVIIa accelerated thrombin generation without significant increase of generated thrombin.     

Dietary factor VII activation does not increase plasma concentrations of prothrombin fragment 1+2 in patients with stable angina pectoris and coronary atherosclerosis

Studies in healthy subjects showed that blood coagulation factor VII (FVII) is activated postprandially after consumption of high-fat meals, but accompanying thrombin formation has not been demonstrated. In patients with coronary atherosclerosis, the arterial intima is supposed to present more tissue factor, the cofactor of FVII, to circulating blood; therefore, thrombin formation in response to FVII activation is more likely to occur in such patients. This hypothesis was tested in a randomized crossover study of 30 patients (aged 43 to 70 years) with stable angina pectoris and angiographically verified coronary atherosclerosis. They were served a low-fat (5% of energy from fat) breakfast and lunch and a high-fat (40% of energy from fat) breakfast and lunch on 2 different days. Venous blood samples were collected at 8:15 AM (fasting), 12:30 PM, 2:00 PM, 3:30 PM, and 4:45 PM and analyzed for triglycerides, activated FVII (FVIIa), FVII protein concentration (FVII:Ag), prothrombin fragment 1+2 (F1+2), and soluble fibrin. Triglyceride levels increased from fasting levels on both diets, but they increased most markedly on the high-fat diet. FVIIa and FVIIa/FVII:Ag increased with the high-fat diet and decreased with the low-fat diet. For both diets, FVII:Ag and F1+2 decreased slightly. No postprandial changes were observed for soluble fibrin. Postprandial mean values of triglycerides, FVIIa, FVII:Ag, and FVIIa/FVII:Ag were significantly higher for the high-fat diet than for the low-fat diet. Our findings confirm that high-fat meals cause immediate activation of FVII. The clinical implication is debatable because FVII activation was not accompanied by an increase in plasma F1+2 concentrations in patients with severe atherosclerosis. However, a local thrombin generation on the plaque surface cannot be excluded.     

Advances in the monitoring of oral anticoagulation: Point-of-care testing, patient self-monitoring, and patient self-management

Oral anticoagulation with warfarin sodium has proven to be an effective therapy for patients at risk for thromboembolic disease, but due to its high risk/benefit ratio, many physicians are reluctant to prescribe the drug. The development of capillary whole-blood prothrombin time (PT) monitors provides a potential means to decrease this risk/benefit ratio and to encourage the use of warfarin. Studies show that this technology is accurate, precise, and correlates closely with standard laboratory methods. Given that these monitors are simple and portable, investigators have conducted studies to determine their suitability for patient self-testing and home monitoring. Investigations show that patients can accurately and precisely perform the PT test at home, and that this mode of therapy appears to be at least as safe and effective as standard management. Furthermore, limited studies also suggest that patients can also manage their own dosing based on personalized guidelines designed by a physician. Given the theoretical potential for improved patient outcomes and overall cost reduction, patient self-monitoring and self-management are not far off. Large randomized prospective trials are now needed to confirm that the future of anticoagulation management should include patient self-monitoring and patient self-management of therapy.     

Comparative efficacy and safety of low‐intensity warfarin therapy in preventing unprovoked recurrent venous thromboembolism: A systematic review and meta‐analysis

Background

Although there exists potential risk of bleeding, extended ‘lifelong’ conventional‐intensity [international normalized ratio (INR): 2.0‐3.0] warfarin anticoagulation is recommended for unprovoked venous thromboembolism (VTE) patients because of risk of recurrent VTE. Whether long‐term low‐intensity (INR: 1.5‐2.0) warfarin therapy reduced the risk of major bleeding without substantially lowered antithrombotic efficacy is not well understood. The aim of this study was to perform a systematic review and meta‐analysis to evaluate the risk‐benefits of low‐intensity warfarin therapy.

Methods

We conducted a comprehensive search of electronic databases and included randomized control trials (RCTs) that reported efficacy (recurrent VTE) and safety (bleeding episodes) of low‐intensity warfarin therapy compared with conventional‐intensity warfarin or placebo from inception through Jun 2016.

Results

Four RCTs reporting high GRADE quality evidence were included. Although the relative risk of recurrent VTE with low‐intensity therapy was significantly increased [2.96 (95% CI: 1.40 to 6.24), P < .004] compared to conventional‐intensity warfarin, there was significant decrease of relative risk when compared with placebo [0.37 (95% CI: 0.24 to 0.56), P < .00001]. As per included publications, no significant major bleeding episodes were observed in low‐intensity warfarin group.

Conclusions

Although less effective than conventional‐intensity warfarin therapy this meta‐analysis indicates that long‐term low‐intensity warfarin therapy is highly effective for preventing recurrent VTE than placebo, along with reduced risks of major bleeding and minimizing potential complications.     

Prophylaxis and therapy with factor VII concentrate (human) immuno,vapor heated in patients with congenital factor VII deficiency: A summary of case reports

Hereditary factor VII deficiency is a rare autosomal recessive condition, usually associated with normal or reduced levels of a functionally defective molecule. The available means of treating this condition in North America presents serious health risks to the patient. Transfusion with fresh frozen plasma carries a risk of volume overload and a significant risk for viral transmission. Sustained prothrombin complex therapy is associated with a high risk for thrombogenic complications. This communication describes the use of Factor VII Concentrate (Human) Immuno, Vapor Heated—an intermediate purity factor VII concentrate from Immuno A.G.—for the treatment of 13 patients with factor VII deficiency. Treatment regimens described include those for long-term prophylaxis (three children), acute hemorrhages (two children, one adult), peripartum prophylaxis (one patient), and surgical coverage (two children, four adults). Prophylaxis and therapy were successful in all cases, the medication was well-tolerated, and there were no complications. In the three cases of long-term prophylaxis in children, doses of 10-50 lU/kg were given one to three times a week; one patient has undergone long-term prophylaxis for approximately 8 years, one patient for 1 year, and one patient for 1 1/2 years. Three cases in which Factor VII Concentrate was principally used for treatment of acute episodes of bleeding are described. One infant received Factor VII Concentrate on about 50 occasions for treatment of mucosal bleeding; a correction to 40–100% resulted in cessation of bleeding within 15 min in all cases. For treatment of an episode of intracranial bleeding, an 8-year-old boy received a dose of 37 IU/kg Factor VII Concentrate every 6 hr for peak factor VII levels of approximately 100% and troughs as low as 4% over the 11-day treatment period. A 37-year-old adult male with intracranial bleeding received alternating doses of 16 IU/kg and 8 IU/kg every 6 hr for 10 days with peak factor VII levels in the upper thirties (%). The peak favor VII level during surgical coverage with Factor VII Concentrate (neurosurgery, open reduction of ankle bones, dental surgery, pituitary adenoma surgery, closed liver biopsy) was approximately 100% in all cases, with trough levels ranging from 8 to 65% over treatment periods of 24 hr to 16 days using treatment intervals of 6–12 hr.