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Pulmonary hemorrhage (PHEM) complicates the hospital course of 3-5% of preterm infants with respiratory distress syndrome (RDS), and bears a high mortality rate. Impaired thrombin generation and poor clot formation in premature neonates affect PHEM severity.We evaluated the impact of surfactant upon in-vitro clot formation in order to assess the role of surfactant in the pathogenesis of PHEM.Blood samples were obtained from healthy volunteers for measuring complete blood count, PT, PTT, and platelet function. Surfactant at increasing concentrations was added to blood samples, and whole blood clotting assays were performed using rotation thromboelastogram (ROTEM®, Pentapharm Munich, Germany) and whole blood platelet adhesion and aggregation (Impact-R®, Diamed, Switzerland).The mean PT level increased from 10.05 ± 033 to 11.64 ± 0.85 sec (p=0.06) in the presence of surfactant. Platelet aggregation with the agonists adenosine diphosphate and epinephrine significantly decreased with escalating surfactant concentration (p0.001). Adhesion, manifested by surface coverage (SC), significantly decreased with increasing surfactant concentration: mean SC 9.25 ± 2.96 compared to 6.1 ± 0.96 and 0.05 ± 0.058 with 0/0.1/5mg/ml surfactant, respectively, p0.001 Whole blood ROTEM studies showed a trend towards lengthening of clotting time with increased surfactant concentration and lower clot strength.The presence of surfactant impairs coagulation in-vitro. The risk of PHEM may therefore be greater in extremely premature infants. Future studies are required to assess the clinical significance and relevance of our preliminary findings.

A 13-year-old boy with severe haemophilia presented at the National Centre with gross swelling of his foot and infrapatella area, and reported that several months previously he had kicked a football and had instantly developed a bleed in his foot. Despite replacement factor the swelling failed to subside. He had ambulated for a while using crutches and when he eventually presented himself the X-rays revealed two separate pseudotumours. The patient underwent a transfemoral amputation.

Carrier detection and prenatal diagnosis of haemophilia A, which was based in the last decade mainly on linkage polymorphism analysis, has been greatly facilitated by the recent discovery that two types of inversion disrupting the factor VIII gene are common mutations observed in 42-48% of severe haemophilia A cases. In this study DNA analysis was performed in 64 unrelated severe haemophilia A patients and 173 women belonging to their families, and in four women from a family with a deceased haemophilic relative whose DNA was unavailable (a total of 177 females from 65 unrelated families). Factor VIII gene inversions were found in 32 out of the 65 families (49%), 29 involving recombination with the distal A gene and three with the proximal A gene. Definitive information regarding carriership of haemophilia was provided to all 81 women belonging to the 32 inversion-positive families, among them one woman previously uninformative for any of the polymorphisms examined, five women who were informative only for extragenic polymorphisms, and four suspected carriers who were relatives of the deceased haemophiliac. In 33 inversion-negative families, 96 females were examined by analysis of the BclI restriction fragment length polymorphism (RFLP) in intron 18 and of the multiallelic dinucleotide repeats in introns 13 and 22, followed by analysis of other intragenic polymorphisms. This procedure yielded an informativity rate of almost 100%. Of the 96 females examined by linkage polymorphism analysis, 78 belonged to 25 families with more than one haemophiliac and 29 of them were obligate carriers. In 47 of the 49 suspected carriers linkage polymorphism analysis enabled definition of carriership based on intragenic polymorphisms. 18 of the 96 females belonged to eight families with sporadic haemophilia cases and only eight of the 18 suspected carriers could be diagnosed by exclusion. In nine pregnant women carrying factor VIII gene inversions, mRNA extracted from chorionic villus samples (CVS) was analysed for factor VIII gene inversion by reverse transcription/polymerase chain reaction (RT/PCR). This procedure enabled rapid prenatal diagnoses in six male fetuses. Taken together, our data indicate that a high rate of informativity and carrier definition is possible by the strategy of first screening for factor VIII gene inversions, and, if none are found, sequential use of highly informative intragenic polymorphisms, followed by less informative intragenic and extragenic polymorphisms.

Summary. Objectives: The hypothesis that the administration of fibrinogen concentrate enables restoration of impaired clot formation and increased bleeding in severe thrombocytopenia was tested. Methods: Thirty pigs were anesthetized, instrumented for blood sampling (routine coagulation tests, modified thrombelastography ROTEM®), hemodynamic monitoring and platelet apheresis to a target below 30 × 109 L−1 after splenectomy. Thereafter 10 each of the animals randomly received two apheresis platelet concentrates, 250 mg kg−1 fibrinogen concentrate or normal saline solution. A standardized liver injury was subsequently inflicted to induce uncontrolled hemorrhage. Results: Median (Q1, Q3) clot firmness increased significantly more in thrombocytopenic pigs after fibrinogen administration (42 mm (41, 43) to 60 mm (57, 63)) than following platelet transfusion (40 mm (37, 45) to 52 mm (48, 55), P = 0.0004) or placebo (45 mm (41, 48) to 45 mm (43, 46), P = 0.0002). Median blood loss velocity after liver injury was significantly less with fibrinogen (33 mL min−1, P = 0.005) than with platelets (62 mL min−1, P = 0.037) or saline (84 mL min−1, P = 0.005), and median survival time after liver injury was 55 min in the fibrinogen, 26 min in the platelet (P = 0.035) and 19 min in the saline group (P =

Summary Background Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis. Objectives (i) To use a swine model of femoral artery bleeding to understand the perivascular hemostatic response to contained arterial hemorrhage. (ii) To directly confirm the association between hemodynamics and bleeding velocity. (iii) To observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach. Methods Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery hemorrhage was also used to demonstrate the feasibility of local delivery of an activated clotting factor. Results In this model, clots formed slowly within the peri-wound hematoma, but eventually contained the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated factor VII into the injured artery near the site of major internal hemorrhage in the pelvis and axillae was feasible. Conclusions We rediscovered that clot formation within the peri-wound hematoma is an integral component of hemostasis and a feasible target for the treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach.

Summary. The development of pseudotumors represents one of the most challenging complications facing physicians who care for patients with hemophilia. The successful removal of the giant pseudotumor described in this case report was acheived by a multidisciplinary team and demonstrates that this approach, albeit associated with significant risk, may be curative.

The issue of platelet function in infants and neonates is of interest, and current data are debatable. A new method for assessing platelet function involves using the cone and plate(let) analyzer (CPA), applicable for small (0.2 ml) whole blood volumes. We used polystyrene surface-coated plates to evaluate cord blood neonatal platelet function under flow. One hundred and sixty full-term and 29 preterm infants born at the Sheba Medical Center between March 2003 and January 2004 were evaluated for platelet adhesion measured as surface coverage (SC; the percentage of total area covered by platelets) and platelet aggregation, defined as the average size (AS) of the aggregates. Platelets from preterm infants displayed less platelet adhesion than did those from full-term infants. Platelet SC correlated with gestational age in all infants (p < 0.05), and both groups exhibited similar aggregation (AS). AS values, however, were significantly lower than the normal adult range in our laboratory. Infants born to mothers with pregnancy-induced hypertension displayed significantly lower SC. No association was found between CPA and postnatal complications. Conclusion: CPA provides a rapid, feasible option for testing platelet function in neonates. Its potential predictive value deserves further attention, and more extensive studies are warranted.

Objective. The purpose of this study was to evaluate postoperative bleeding in patients treated with oral anticoagulant drugs who underwent dental extractions without interruption of the treatment and to compare the effect of 3 different hemostatic modalities. Study design. A total of 150 patients who underwent dental extractions were divided into 3 groups. Local hemostasis was carried out as follows: group 1 (119 extractions), with gelatin sponge and sutures; group 2 (117 extractions), with gelatin sponge, sutures, and mouthwash with tranexamic acid; group 3 (123 extractions), with fibrin glue, gelatin sponge, and sutures. Results. Of 150 patients, 13 (8.6%) presented with postoperative bleeding: 3 patients from group 1, 6 patients from group 2, and 4 patients from group 3. Conclusions. Dental extractions can be performed without interruption in patients treated with oral anticoagulant. Local hemostasis with gelatin sponge and sutures is sufficient. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:137-40)

Summary. Factor XI deficiency leads to a more variable bleeding tendency than haemophilia A or B. Although severely deficient individuals are likely to bleed excessively especially after surgery in areas of the body with increased fibrinolysis, there is evidence that some partially deficient individuals are at risk of excessive bleeding. This will entail careful planning for surgery. Several therapeutic modalities are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs and desmopressin. The advantages and risks of these are considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used, it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.

Summary. von Willebrand disease (vWD) is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (vWF). vWF is synthesized by endothelial cells and megakaryocytes and circulates in plasma as a multimeric high molecular weight glycoprotein. vWF plays a major role in the early phases of ostasis by promoting platelet-vessel wall and plateletplatelet interactions under high shear conditions. It is also the carrier of coagulation factor VIII (FVIII) in plasma. A deficiency of vWF results in impairment of both primary and secondary phases of ostasis. Therefore, patients with vWD manifest bleeding symptoms that are typical of defects of primary ostasis (mucocutaneous haemorrhages) but, in case of severe deficiency of vWF, there are also haemarthroses and haematomas, which are typical of those seen with coagulation defects. Several types and subtypes of vWD have been described with a high degree of heterogeneity. The diagnosis is based on measurements of plasma and platelet vWF, the ability of vWF to interact with its platelet receptor and the analysis of the multimeric composition of vWF. Due to the heterogeneity of vWF defects, a correct diagnosis of types and subtypes may be sometimes difficult but is very important for an appropriate treatment of patients with vWD.

Haemophiliacs, until recently, have been at risk of hepatitis B and C infection. Substantial numbers of patients remain persistently infected. Several lines of evidence suggest that these diseases will cause considerable morbidity unless therapy can successfully reduce viraemia and prevent disease progression. Cessation of viral replication may prevent progression to hepatic fibrosis.

Summary. The purpose of this presentation is to concentrate on three issues: Is there an explanation for the large difference in reported incidence rates of inhibitor formation in haemophiliacs? Why do not all severe patients develop inhibitors? And how on the contrary do some patients with mild haemophilia develop inhibitors?

Joint and muscle injury associated with direct damage to the tissues and muscle atrophy may ensue following immobility. Rehabilitation of the injury is linked with the return to normal functional values such as range of motion, muscle strength, and muscle tone. It is, however, likely that subtle changes or differences still exist in the site of injury or haemarthrosis. In particular proprioception may be distorted due to the direct injury of sensory receptors and to feedback systems. The implications of such damage are important, where proprioception plays an important part in the control, timing and organisation of coordinated bodily actions.

In an era of increasing constraints in health care expenditure, it has become necessary for the practising physician to utilise resources economically. Due to expenditure ceilings in many countries, the rational allocation of health care resources has become a central goal in health policy. Medical economics is the discipline which covers the issues of economic evaluation, policy and decision analysis and outcomes research. This paper discusses the fundamentals of this new type of research, highlighting the importance of such results in formulating health policy. Undoubtedly, medical economics will play a similar role as evidence-based medicine and clinical epidemiology in the continuous education within the medical community. This holds specially true for costly indications such as haemophilia and other coagulation disorders.

Summary. Results of assays of recombinant FVIII concentrates have been reviewed over a 10-year period. Initially there was wide variability between laboratories but this was minimised by the development of standardised assay methodology, in particular the use of haemophilic plasma for pre-dilution and 1% albumin in assay buffers. Using this standardised methodology and concentrate standards, there were no major diferences in potency between one-stage, two-stage, and chromogenic assays on the two full-length recombinant FVIII concentrates. However, using a plasma standard, the chromogenic method gave much higher potencies than the one-stage method on the same concentrates, and this explains a similar discrepancy found in patients' post-infusion samples after injection of recombinant concentrates. It is suggested that concentrate standards be used for such post-infusion samples in order to minimise this discrepancy.

At the haemophilia centre in Malmo, Sweden, regular prophylactic treatment is begun at 1-1 1/4 years of age, before the onset of joint bleeds. The dose and dose interval are optimised by means of pharmacokinetic studies to determine the individual patient's FVIII or IX metabolism, the goal of maintaining a level > 1% of normal being taken as a guideline which experience has shown to yield satisfactory control of bleeding diathesis. An optimal model for prophylactic treatment needs to be applicable to haemophiliacs and acceptable to health authorities in a majority of the countries in the world. To fulfill these criteria, the Swedish model, which has been shown to yield most satisfactory outcome, can hopefully be further refined in the future. Were continuous infusion, using a recombinate concentrate with a prolonged half-life, technically feasible and socially acceptable to the child, we would probably have attained the optimal model of prophylactic treatment. (Less)

Summary. The immunogenicity of factor VIII depends on the interaction of multiple parametres including host susceptibility and characteristics of the factor VIII preparations. We briefly review here the basic mechanisms by which tolerance to self is established, maintained, and possibly broken in the context of haemophilia A, with special emphasis on the severity of the disease. Reference is also made to the situation observed in healthy individuals and patients with autoantibodies to factor VIII.

Treatment of haemophilia A requires frequent infusion of plasma- or recombinant-derived factor VIII. This regimen is limited due to the high cost and inconvenient access to peripheral veins. In addition, patients frequently develop inhibitory antibodies that limit available therapeutic regimens. Two major advances in factor VIII research over the past 15 years were the ability to isolate homogeneous preparations of factor VIII and the isolation of the factor VIII gene that provided for a detailed biochemical and structural characterization of the factor VIII molecule. With an increased understanding of the requirements for factor VIII function, studies have attempted to produce improved factor VIII molecules for replacement therapy. These findings have produced forms of factor VIII that are more efficiently produced, that are less immunogenic, and that have higher specific activity. The future will see the engineering of novel factor VIII molecules with increased therapeutic efficiency while minimizing inhibitor antibody development. In addition, there are now structural models of factor VIII available that should in the future direct development of novel peptidomimetics that may eventually overcome the requirement for replacement therapy with factor VIII protein.

Inhibitors are an uncommon complication of mild haemophilia, occurring in 3-13% of patients and usually arising during adulthood. The risk of inhibitor development in this group appears to be associated with relatively few high-risk factor VIII genotypes clustered in the A2 and C2 domains, especially the Arg593-Cys and the Trp2229-Cys mutations. Kindreds with these mutations have an inhibitor incidence of up to 40%. These mutations may induce a stable conformational change in the factor VIII molecule rendering it antigenically distinct from wild-type factor VIII. Inhibitors in mild haemophilia usually cross-react with endogenous factor VIII reducing the basal VIIIC to < 0.01 IU/ml, and causing spontaneous bleeding. This bleeding is sometimes severe and life-threatening, two-thirds of patients developing a pattern of soft tissue, gastrointestinal (GI) and urinogenital bleeding reminiscent of acquired haemophilia. Bleeding has been treated with human and porcine factor VIII, bypass therapy and DDAVP. Recombinant factor VIIa and DDAVP have the advantage that they do not induce an anamnestic rise in inhibitor titre. About 60% of these inhibitors disappear in the remainder over a median of 9 months. Few of these inhibitors recur, suggesting that most such patients have become tolerant. The inhibitors persist long-term and remain troublesome in about 40% of patients. The limited data available on immune tolerance induction in this group indicate a generally poor response to this approach. Two of nine achieved tolerance, with a partial response in a further four. Inhibitors are an uncommon but life-threatening complication of haemophilia. This complication should be considered when selecting the treatment modality for patients with a family history of inhibitors, and DDAVP used whenever possible.

Musculoskeletal care is provided in many different settings by many different providers. Physicians are better prepared to treat acute diseases, acute manifestations and have problems in following chronic patients and to preventing losses of functional independence. Haematoma affecting muscles and joints is the most common musculoskeletal finding in haemophilic patients. Proper treatment is fundamental to prevent disability. Treatment aims at restoring the original muscle trophism and strength because joint stability is dependent on the uniform distribution of muscle power over different joint surfaces. Physical rehabilitation continues until complete anatomical and functional recovery is achieved. Coordination and proprioceptive stimulation complement the exercises to recover original muscle strength. Recurrent haemorrhages usually progress to chronic synovitis, the leading cause of motor disability and joint degeneration in haemophilic patients. Moreover, chronic synovitis is a predisposing factor for repetitive episodes of haemarthrosis, a leading cause of joint deformities and severe muscle atrophy. At this point, an efficient treatment alternative should be put into effect to restrain bleeding and prevent synovitis-related joint degeneration, which is synovectomy. Synovectomy is an effective alternative, less costly and easier to perform. Rifampicin synovectomy is advantageous because it is safe, not aggressive to the patient, can be repeated if necessary, and it does not prevent the use of either radiotherapy or surgery after, if necessary. Once the sequelae have set in, treatment tends to be conservative, and it aims at giving the patient functional independence for gait and other activities. The most common limb deformities seen in these patients are knee and elbow flexion, but the patient should also be assessed for compensatory scoliosis, hyperlordosis and lower limb length discrepancies. Chronic joint pain is a rather common complaint in this patient population with early arthrosis, and special drugs and physical treatment must be put into action. Rehabilitation is often inexpensive and very efficient.

Because of the increased morbidity and cost of care associated with inhibitor development, immune tolerance therapy (ITT) is of crucial value in the care of haemophilia. The 24-year experience with this modality, primarily in the treatment of factor VIII inhibitors, has included the use of both high and low doses of clotting factor, with and without immune modulation. Overall success rates for ITT in haemophilia A have been similar (63-83%), while median time to IT has been variable (1.2-24 months). The role of type and purity of clotting factor used remains unclear. Three immune tolerance registries have suggested the potential importance of treatment parameters such as pre-induction inhibitor titer and daily factor dose in the prediction of successful outcome. Ultimately, prospective randomized studies of ITT are required to definitively compare therapeutic regimens with respect to efficacy, safety, and cost effectiveness.

Summary. Based on information accumulated to date, it is still difficult to assess the risk of Creutzfeldt-Jakob disease (CJD) and blood transfusion with any degree of confidence. However, it is reasonable to conclude that CJD is produced by a transmittable agent which is probably contained in low titer in the blood of infected people and animals. From the present clinical and epidemiological studies, transmission by blood or blood products appears to be a rare or non-existent cause of current and past cases of CJD in humans. Since blood products are necessary to prevent the immediate risk of death or significant morbidity in many clinical conditions, therapeutic decisions should be made after consideration of the known risk in these situations vs the theoretical long-term risk of the rare occurrence of CJD.

Summary. In this report we describe an in vitro model of blood coagulation reactions that mimics as closely as possible the in vivo condition. Our model indicates that the tissue factor—factor VIIa complex initiates coagulation by activating small amounts of both factor IX and factor X in the environment of the tissue factor bearing cell. Factor Xa and factor IXa formed in the initial reaction then play very distinct roles in the subsequent interactions of the clotting mechanism leading to a burst of thrombin generation on the platelet surface. Our results also indicate that factor XI can be activated by thrombin in the absence of factor XII and that the function of factor XI is simply to enhance conversion of factor IX to factor IXa resulting in enhanced thrombin generation on the platelet surface.

Resistance to the HIV-1 protease inhibitor indinavir involves the accumulation of multiple amino acid substitutions in the viral protease. A minimum of 11 amino acid positions have been identified as potential contributors to phenotypic resistance. Three or more amino acid substitutions in the protease are required before resistance becomes measurable (> or = four-fold). Further losses in susceptibility follow the stepwise accumulation of additional amino acid substitutions, indicating that antiviral activity (selective pressure) is maintained despite the appearance of multiple amino acid substitutions in the viral protease. Importantly, the sequential nature of these changes indicates that the effects of these substitutions are additive, and that the evolution of resistance is driven by viral replication. This result has significant implications for therapy. It predicts that viral variants resistant to indinavir are unlikely to pre-exist in protease inhibitor-naive patients, and further, that high-level resistance can only develop if the virus is allowed to replicate in the presence of the drug. The use of indinavir in combination with other antiretroviral agents has been demonstrated to dramatically reduce the incidence of resistance mutations, suggesting that with maximal suppression of viral replication, long-term control of HIV-1 infection may be achievable. Thus, the goal of therapy must be to never to allow the virus to replicate. This can be best accomplished by initiating therapy with a maximally suppressive regimen, to reduce viral replication as much as possible, and by imposing a high genetic barrier to resistance. Previous use of other protease inhibitors or inadequate adherence to therapy may compromise the long-term benefit of indinavir by allowing the virus to gain a foothold through the development of resistance. An understanding of these issues will be critical in realizing the full potential of this potent new drug for the control of HIV-1 infection.

The risk of bleeding among thrombocytopenic patients was evaluated using our new cone and platelet analyser (CPA) test. Using this test, adherence of platelets was quantitated on extracellular matrix and expressed as percent of surface coverage (SC) and the average size (AS) of aggregates. 42 thrombocytopenic patients with ITP (n=23), post chemotherapy (n= 12) and others (n= 7) were tested over a total of 82 visits. On each visit, complete blood count and CPA tests were performed and patients were evaluated for evidence of bleeding (found in 40 visits). Bleeding patients had significantly lower platelet counts (27.4 +/- 22.0 v 47.1 +/- 21.0 x 10(9)/l), lower haematocrit values (30.2 +/- 8.1 v 35.2 +/- 6.6%), lower MPV (6.83 +/-1.89 v 8.98 +/- 1.13 fl), and lower SC (4.87 +/- 3.95 v 10.33 +/-5.48%) and AS (33.99 +/- 14.94 v 52.9 +/- 24.34 microm2). Univariate analysis yielded platelet count < or =20.0 x 10(9)/l, MPV < or =8 fl, haematocrit

Continuous infusions of factor VIII have proved feasible in patients with hemophilia A, and the hemostatic efficacy has sometimes been superior to that of repeated bolus injections of factor VIII. Avoiding dangerously low trough levels by maintaining a constant therapeutic level not only promotes hemostasis but requires substantially less factor concentrate, which represents a considerable saving. Only limited data on continuous infusion of factor IX are available, but these data suggest similar benefits. An investigation of the stability of four prothrombin complex concentrates and three highly purified factor IX concentrates is described, as is the successful treatment of four hemophilia B patients with continuous infusions of Mononine.

The application of coagulation factor therapy by continuous infusion (CI) was first suggested by Brinkhous in the early 1950s. The recent introduction of this mode of therapy to everyday practice was made possible after the demonstration of a good stability of most factor concentrates which were also found safe regarding potential bacterial contamination. Other developments included a better understanding of the pharmacokinetics of factors concentrates as well as the availability of a new delivery system. Continuous infusion was shown to be superior to bolus injection (BI) in achieving a stabile haemostatic effect, in the prevention of post-operative bleeding and was found to save between 20-50% in the required factor. This mode of therapy was found effective in haemophilia A and B as well as among patients with inhibitors to FVIII and with von Willebrand disease (vWD).

Factor XI deficiency is a rare bleeding diathesis found predominantly in Ashkenazi Jewish kindreds. A recent study of six Jewish patients identified three distinct mutations (Types I, II, and III) in the factor XI gene that were sufficient to fully define the genotypes of the patients. We have investigated 63 patients with factor XI deficiency and find overall allele frequencies of 44% for the type II mutation, 31% for the type III mutation, and 0% for the type I mutation. Therefore, 25% of the mutant factor XI alleles in our sample remain undefined. However, the distribution of mutant alleles is significantly different between Jewish and non-Jewish populations with hitherto undefined mutations accounting for 84% of the disease alleles in non-Jewish patients. Plasma factor XI:C levels were found to differ significantly between different homozygous and compound heterozygous genotypes and the inheritance of the II/III genotype was found to carry an increased risk of the most severe bleeding tendency.

Factor VIII inhibitor bypass activity (FEIBA) and recombinant factor VIIa (rFVIIa) are the common bypassing agents for treating haemophilia A or haemophilia B patients who developed an inhibitor to factor VIII or IX, respectively. As these preparations differ in their composition and mode of action, combined therapy, either sequential or simultaneous has recently been used for achieving haemostasis during bleeding episodes in patients who became refractory to FEIBA or rFVIIa when each was given alone. In this in vitro study, we show by a sensitive assay of thrombin generation that phospholipids present in FEIBA and other procoagulants contribute to FEIBA's activity and that exogenous phospholipids are essential for the activity of rFVIIa. We also demonstrate that the combination of FEIBA and rFVIIa has a marked synergistic effect on thrombin generation in plasma of a haemophilia A patient with a high titre of an inhibitor. It is conceivable that simultaneous administration of small doses of FEIBA and rFVIIa may be beneficial in treating haemophilia A patients, with an inhibitor to FVIII, who are resistant to conventional therapy.

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.

Port-A-Caths have been used increasingly in children with severe haemophilia. In non-inhibitor patients where Port-a-Caths were used to facilitate long-term prophylaxis, the infection rate is rather low and ranges in the various studies from 0 to 29%, with a median follow-up time of about 27 months. Patients that received the Port-A-Cath for the induction of immune tolerance (inhibitor patients) have a high infection rate of 50% to 83%. Although this percentage is high, good venous access is extremely important, especially in this group. The number of both inhibitor and non-inhibitor patients in the studies are very small, and a prospective survey is important to obtain more adequate data.

Adequate factor substitution is a prerequisite for successful conservative or operative treatment of haemophilic synovitis. Subsequent prophylactic factor substitution can prevent further joint problems in the future. Orthopaedic treatment regimes are dependent on the classification of the synovitis and the stage of the arthropathy. Synovitis can be classified into acute and chronic forms. The arthropathy is classified according to Arnold and Hilgartner. When the synovitis has already become chronic, early arthroscopic synovectomy is recommended in order to prevent the otherwise inexorable progress of the arthropathy. Failure to treat in the early phase of the pathology causes problems in the correction of further stages. The progression of the joint disease can be shown both clinically and radiologically as the arthropathy develops, and influences the treatment.

Summary. Over the last 2 years, advances in many areas of HIV clinical research and data on the effectiveness of potent combination therapy have substantially influenced the overall perspective of long-term management of HIV disease. However, the progress against HIV also came as a result of the better understanding of HIV pathogenesis. Research work in basic science has contributed considerably to obtain a clearer picture of the mechanisms of HIV infection, mainly through the understanding of key steps in the dynamics and kinetics of viral replication in vivo. Molecular biology also revealed much about the mechanisms of HIV virulence and the emergence of drug resistance. This article will give a short overview of the most recent advances in the field.

The development of inhibitor antibodies is a serious complication of haemophilia in young children. Occurrence of anaphylaxis at the time of inhibitor development is a recently described complication unique to haemophilia B. Management of these inhibitor patients with allergy is complicated due to the absence of any readily available products for treatment of acute bleeding episodes. Clinical experience suggests that recombinant activated factor VII is the most appropriate and logical treatment for acute bleeding episodes in these patients. From the limited information available regarding immune tolerance induction (ITI) in these patients, it appears that ITI regimens have been only minimally successful and are associated with a high rate of complication (nephrotic syndrome).

Summary. Background: Recombinant factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII- and FIX-dependent amplification of FX activation. Tissue factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity. Objective: To evaluate the relative effects of TF and phospholipids on rFVIIa-induced TG in FVIII-, FIX- and FXI-deficient plasmas. Methods: Phospholipids had an independent effect that was augmented by TF. The contribution of blood-borne TF in FVIII-, FIX- and FXI-deficient plasma to rFVIIa-induced TG was demonstrated by removing microparticles and use of anti-TF antibodies. Results: At increasing concentrations of rFVIIa, the dependence of rFVIIa-induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa-induced TG was dramatically augmented in FVIII- or FIX-deficient plasma in which the level of FVIII or FIX was increased to 1 or 2 U dL−1. Conclusions: The data indicate that rFVIIa-induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX.

The pathophysiology of coagulopathy in the trauma patient is complex and multifactorial. The term ‘DIC’ is incorrectly used to define trauma-related coagulopathy. Although the routine laboratory results resemble those of DIC because they detect activation of coagulation and fibrinolysis and consumption of platelets and coagulation factors, the pathophysiology of the coagulopathy is quite different. While DIC reflects a hypercoagulable state with loss of localization of the coagulation process, leading to diffuse deposition of fibrin, trauma-related coagulopathy is a hypocoagulable state with fibrin deposition limited to the site of injury. The use of the right terms is not only a semantic issue but has major implications for treatment. In fact this was the main reason for the delay in introduction of rFVIIa to trauma patients a few years after its introduction to hemophilia and bleeding disorders: The use of agents markedly enhancing hemostasis, such as rFVIIa, in patients already suffering from a hypercoagulable state seemed to be risky. Much of the early data in the literature are not applicable due to the change of blood components and transfusion policy in the modern area of trauma patient resuscitation. A multidisciplinary approach involving anesthesiologists, transfusion specialists, hematologists, laboratory specialists and surgeons is required for the diagnosis and treatment of traumatic bleeding.

Recombinant activated factor VII (rFVIIa, NovoSeven) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa 'megadose' (300 micro g kg(-1) bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 micro g kg(-1) every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 micro g kg(-1)) was higher than with standard boluses (180-270 micro g kg(-1)), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL(-1); range: 19.8-54 U mL(-1)). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.

A case of an HIV-positive hemophilic girl with an ependymoblastoma is presented. The unusual association between the HIV-related condition and her brain tumor is discussed, speculating a viral mechanism involved in the induction of neoplasia. © 1994 Wiley-Liss, Inc.

Recombinant activated factor VII (rFVIIa, NovoSeven) was used in three patients with massive obstetric hemorrhage due to placenta previa accreta, rupture of the uterus and pre-eclampsia with HELLP. Administration of the drug markedly decreased the bleeding and enabled control of the hemorrhage. rFVIIa seems to be an adjunctive hemostatic measure for the treatment of severe obstetric hemorrhage.

Radioactive Yttrium-90 (90Y) was injected into 163 joints. Of these patients 115 were persons with haemophilia and they suffered from recurrent haemarthroses. The median age at the time of the initial exposure to 90Y was between 11 and 15 years and the median follow-up period 11 years. Over 80% of the patients with haemophilia reported a decrease in the number of haemarthroses and 15% stopped bleeding altogether in the treated articulation. The safety of this modality of management has been reported and hence the patients age should not be regarded as a criteria.

Most authors agree upon the causal association between antiphosholipid antibodies [lupus anticoagulant (LAC) and/or anticardiolipin antibodies] and adverse pregnancy outcome. Placental insufficiency, caused by thrombosis, infarction and maldevelopment, is thought to be the main cause of fetal loss in patients with LAC. Therapy given thus far to prevent fetal loss can be divided into (1) immunosuppression by corticosteroids, azathioprine, or intravenous gamma globulin (IVGG), (2) anti-aggregants to overcome imbalance of thromboxane/prostacycline production in patients with LAC, and (3) anticoagulants to neutralize the possible impairment of clotting inhibitor systems. Different therapeutic success rates have been reported by various authors who used the same combination of therapy. We report the results of different therapy regimens in 154 pregnancies in 31 women with LAC. These patients suffered from SLE with LAC or from APLA syndrome and experienced either recurrent miscarriages or thromboembolic phenomena in the past. With no therapy there were seven (6.8%) live births and 95 (93.2%) failures. Various combinations of corticosteroids, anti-aggregants and anticoagulants were used for treatment. Of 52 treated pregnancies, 27 (51.9%) were successful. Sixteen (69.1%) of 23 pregnancies treated by all three modalities ended in live births. Four of these successful pregnancies occurred after failure of treatment by prednisone and anti-aggregants only. In order to minimize osteoporosis caused by the combination of steroids and heparin, we have used warfarin in the second trimester and have lately substituted low molecular weight heparin for heparin. In the absence of a therapeutic schedule predicated on a large prospective study, therapy during pregnancy in patients having LAC should be individualized according to their obstetric and medical history. Anticoagulants are indicated in patients who have suffered from thromboembolic phenomena and could be tried after failure of steroids and anti-aggregants.

Summary. von Willebrand disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of treatment is to correct the dual defects of haemostasis, i.e., abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 80% of cases. This pharmacological compound raises endogenous factor VIII and von Willebrand factors and thereby corrects the intrinsic coagulation defect and the prolonged bleeding time in most type 1 patients. In type 3 and in the majority of type 2 patients desmopressin is not effective, and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time after concentrates is associated with continued bleeding.