Dental surgery in patients with severe factor XI deficiency without plasma replacement.

Bleeding following dental extraction is frequently the first manifestation of severe factor XI deficiency. Safe oral surgery has previously been performed in such patients by using plasma replacement therapy with or without concomitant administration of antifibrinolytic agents. The aim of this study was to determine whether such patients can undergo safe dental extractions using only an antifibrinolytic agent. The study group consisted of 19 patients with severe factor XI deficiency (factor XI:C level less than 14 U/dl) who had previously bled following dental extractions (14 patients) or other trauma (five patients). Tranexamic acid, 1 g q.i.d., was given from 12 h before surgery, until 7 days afterwards. No excessive bleeding was observed following dental extractions. One patient had slight oozing after 3 days which ceased spontaneously. Thus, plasma replacement no longer appears necessary for patients with severe factor XI deficiency requiring dental extractions.     

The in-vitro effect of fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor on clot formation and susceptibility to tissue plasminogen activator-induced fibrinolysis in hemodilution model

Patients suffering major traumatic or surgical bleeding are often exposed to hemodilution resulting in dilutional coagulopathy. The aim of this study was to evaluate in vitro the effects of fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor (TAFI) on clot formation and resistance to fibrinolysis in hemodilution conditions. Citrated whole blood from 36 healthy volunteers was diluted to 30 and 60% with lactated Ringer's solution. Blood samples were subsequently supplemented with fibrinogen, FXIII, TAFI or their combinations. Rotation thromboelastometry (ROTEM) in whole blood and thrombin generation in plasma were performed in the presence of CaCl? and tissue factor/EXTEM reagent, and fibrinolysis was induced by tissue plasminogen activator (tPA). Hemodilution was expressed by decrease of peak height in thrombin generation and α-angle and maximum clot firmness (MCF) in ROTEM. Fibrinogen, FXIII or TAFI did not correct the decrease in thrombin generation peak height. In ROTEM, spiking of diluted blood with fibrinogen stimulated clot propagation. In tPA-treated blood fibrinogen, FXIII and TAFI increased clot firmness and inhibited fibrinolysis. Stronger protection against fibrinolysis was achieved combining FXIII with TAFI. Hemodilution was associated with inhibition of thrombin generation; however, this effect was not sensitive to blood spiking with fibrinogen, FXIII and TAFI. In ROTEM, these hemostasis agents improved clot strength and decreased clot susceptibility to tPA in nondiluted and to more extent in diluted blood. The maximal protection against fibrinolysis was caused by TAFI. Combining FXIII with TAFI exerted synergistic inhibitory effect on fibrinolysis.     

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX,in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double‐blind, non‐inferiority, cross‐over study conducted in participants aged ≥12 years weighing ≥40 kg, with severe or moderately severe haemophilia B (FIX activity ≤2 IU dL ^?1). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4–18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8–59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg^?1 or nonacog alfa. The lower limit of the one‐sided 95% confidence interval for the ratio of AUC_0‐t and AUC_0‐∞ (IB1001/nonacog alfa) was 0.90, establishing non‐inferiority. Terminal phase half‐lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non‐inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.     

Anaerobic power and muscle strength in young hemophilia patients

PURPOSE: The purpose of this study was to evaluate muscle strength and anaerobic power in young boys with hemophilia compared with healthy boys. METHODS: Thirteen boys with severe hemophilia (H) (mean (+/- SD) age = 12.0 +/- 3.17 yr) and 16 control (C) boys (age = 11.9 +/- 2.8 yr) performed elbow and knee flexion and extension on the Biodex System II dynamometer at two angular velocities. They also performed a Wingate Anaerobic Test (WAnT) for the legs and for the arms. All H subjects received prophylactic factor VIII treatment in the 24 h pretesting, and no test was performed in the presence of hemorrhage. RESULTS: C were consistently stronger than H in all dynamic strength measures (e.g., elbow flexors: 0.47 +/- 0.15 vs 0.36 +/- 0.08 N x m x kg(-1) for C and H, respectively, P < 0.05). Anaerobic mean power was also higher in C compared with H in both upper and lower extremities (arms: 3.08 +/- 0.99 vs 2.22 +/- 0.46 W x kg(-1) for C and H, respectively; legs: 6.94 +/- 1.62 vs 5.54 +/- 1.03 W x kg(-1) for C and H, respectively, P < 0.05). Upper and lower extremity strength, as well as anaerobic power, increased with age in C but not in H. By using the Godin Leisure-Time Exercise Questionnaire, H were found to be much less active, especially in intense activities, compared with C. CONCLUSION: Children and adolescents with hemophilia are characterized by lower muscle strength and anaerobic power compared with age-matched controls. This may be related to their lower leisure-time activity.     

Expanding portal haematomata as a complication of knee arthroscopies in persons with haemophilia

Recurrent haemarthroses stimulate the hypertrophy of synovial tissues that if left in situ will eventually cause joint destruction. Synovectomies have been the cornerstone of joint preservation and a number of different methods exist. We report two patients who suffered complications after an arthroscopic procedure. No previous complications of this nature have been reported in the literature.     

Updates in the management of severe coagulopathy in trauma patients

Coagulopathy is the major cause of bleeding-related mortality in patients who survive the operating room. Its association with hypothermia and metabolic acidosis is common and constitutes a vicious cycle. Usually, post-traumatic coagulopathy is an early event and may be present during surgery. The pathogenesis of severe post-traumatic coagulopathy is complex and multifactorial. Virtually every aspect of the normal coagulation cascade is affected in the cold, acidotic, exsanguinating trauma patient. In the last decade many surgeons have emphasized the role of prevention or early treatment of this vicious cycle. Damage control surgery with planned re-operations has demonstrated superiority over the traditional approach in cases where the patients' condition is deteriorating. Early control of surgical bleeding and significant contamination, together with vigorous correction of hypothermia and continuous resuscitation, has improved the survival of these patients. Recently, a new adjunct to the treatment of coagulopathy in trauma patients has been reported and is undergoing controlled animal trials. Recombinant activated factor VII (rFVIIa) was originally developed as a pro-hemostatic agent for the treatment of bleeding episodes in hemophilia patients. rFVIIa has been successfully used in moribund trauma patients in whom standard procedures had failed to correct bleeding. Preliminary preclinical and clinical studies are under way.     

Administration off label of recombinant factor-VIIa (rFVIIa) to patients with blunt or penetrating brain injury without coagulopathy

Summary  Traumatic brain contusions may increase in size over time or may develop at a delay after injury. This may lead to neurological deterioration, long term morbidity or even death. Coagulation disorders after injury can contribute to progression of haemorrhage. Recombinant activated factor VII (rFVIIa) was used in 12 patients with a severe head injury who had no systemic coagulopathy but who were considered to be at risk of progression of their intracranial lesion. Twelve consecutive patients suffering from life-threatening acute head injuries from blunt (3 cases) and penetrating mechanisms were given with rFVIIa, either to prevent the expected development of brain contusion or to assist in bleeding control during surgery. In 11 patients, rFVIIa was given by the attending neurosurgeon. Two of the patients died of their severe penetrating injuries one of whom had severe vasospasm 2 days after administration of rFVIIa. The other 11 patients did not appear to suffer any treatment-related adverse effects. When the drug was given prophylactically to prevent brain resection (6 cases) or to limit the need for widening resection (5 cases), marked control was achieved in seven cases, and a lesser effect was observed in the other 4 cases. We conclude that, in a small and highly individually selected series of patients with severe head injury, the administration of rFVIIa did not lead to adverse effects. Although the majority of patients were considered to be at high risk of progression of their lesions, this occurred in only one. The early use of rFVIIa in head injured patients without systemic coagulopathy may reduce the occurrence of enlargement of contusions, the requirement of further operation, and adverse outcome. Prospective randomised controlled studies are required to investigate this. Correspondence: L. Levi, Ramban Medical Centre, POB 9602, Haifa 31096, Israel.     

Elbow joint, crutches and locomotion: special reference to persons with haemophilia

A 52-year-old, trans-femoral amputee with haemophilia was hospitalized because of ambulatory problems arising from the osteo-arthropathic involvement of other major articulations. Reduced function in the upper limbs, caused by the effects of recurrent haemarthroses, resulted in additional problems concerning the usage of auxiliary ambulatory aids. The advantages and disadvantages of traditional and experimental crutches highlight the functional problems of ambulation in persons with concomitant upper limb pathologies.     

Stability of factor VIII concentrates after reconstitution

Adjusted-dose continuous infusion of factor VIII (FVIII) has recently been shown to reduce the doses of the factor in patients undergoing surgery by 50-75%. The main limitation of this method has been the instability of factor concentrates. All manufacturers are recommending infusion of the concentrate within hours after reconstitution. We studied the stability of 15 different lyophillzed F VIII products. Reconstituted samples were stored for periods of 4, 24, and 72 hr and 1, 2, 3, and 4 weeks at temperatures of WC, 20-23°C, and 37°C in their original glass containers and in plastic tubes and then frozen. Assays were performed in duplicate, using a one-stage clotting method and a chromoge nlc assay for F VIII, wlth all samples from a single concentrate In the same run. Activation of the coagulation factor occurred In some concentrates, more often at 44°C than at 20-23°C or 3PC. The stability of all products was substantially better than that declared by the manufacturers. Several concentrates maintained factor activities above 80% of baseline for the entlre period of 4 weeks at 44°C or at 20-23°C. The results demonstrate that many of the F VIII concentrates may be used for continuous infusion. © 1994 Wiley-Liss, Inc.     

Adjusted dose continuous infusion of factor VIII in patients with haemophilia A

Surgical interventions in patients suffering from haemophilia A require infusions of large doses of factor VIII (F VIII) concentrates. These are expensive and may pose a burden on the immune system, which is already compromised in many haemophiliacs. F VIII is usually given as bolus injections, although there are reports on fixed dose continuous infusion. We have developed a continuous infusion programme with dosage adjusted according to daily calculation of the clearance of F VIII. Twenty-four haemophiliacs received a total of 205 d of continuous infusion with F VIII (168 d in hospital, 37 d home therapy). Eighteen patients underwent surgeries (11 elective, seven emergency) and six were treated for serious haemorrhages. We observed a significant, progressive decrease of the clearance of F VIII over the first 5 d from 3.2 (2.8-3.5) to 1.7 (1.3-1.9) ml/kg/h (median and interquartile range). The decrease of the clearance together with the fact that a continuous infusion requires less drug than bolus injections to keep the same minimal concentration, contributed to much lower doses of F VIII than reported in the literature or than required by historical controls, matched for the type of operation. Other advantages of our method are improved safety with stable activities of F VIII, lack of hazardous troughs below the haemostatic range, and the convenience, which permits ambulant therapy even when high doses of F VIII are required.