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Discusses the management of disseminated intravascular coagulation (DIC), a clinical syndrome in which the delicate balance between the various components of the hemostatic mechanism is disturbed. Features which are likely to be common to all forms of DIC; Antithrombotic agents; Antifibrinolytic agents; Hemostatic support.

As the management of haemophilia is complex, it is essential that those with the disorder should have ready access to a range of services provided by a multidisciplinary team of specialists. This document sets out the principles of comprehensive haemophilia care in Europe. Within each country there should be a national organization which oversees the provision of specialist Comprehensive Care Centres that provide the entire spectrum of clinical and laboratory services. Depending upon the size and geographical distribution of the population, a network of smaller haemophilia centres may also be necessary. There should be arrangements for the supply of safe clotting factor concentrates which can also be used in home treatment and prophylaxis programmes. A national register of patients is recommended along with collection of treatment statistics. As comprehensive haemophilia care is multidisciplinary by nature, the need for education and research programmes for all staff members is emphasized: Members of the Interdisciplinary Working Group not represented in the list of authors are mentioned in Section 4 of this document.

Context: Medical students experience significant stress and stress-related problems. The benefits of support during training are described in this paper. Recently, student support systems have become increasingly stretched as medical schools merge, courses become modular and staff face increasing clinical and research pressures. The pastoral support system at St Bartholomew's and the Royal London School of Medicine has been changed in response to an evaluation of the old system of personal tutors. Pastoral care is now provided by a group of willing staff members known to have an interest in student welfare. The group is known as the 'Pastoral Pool' (PP)., Methods: Students and staff PP members completed similar questionnaires addressing their expectations of the PP and identifying the need for support systems in general. Pastoral Pool activity was investigated using confidential record sheets stating the frequency, duration and content of each PP encounter., Results: Students were aware of the PP and many would consider using it. Staff and students agreed over the functions of the PP. Students frequently expressed concerns over confidentiality within the system. Uptake was low, with only 3% of students approaching the PP and the majority of PP work performed by only two staff members. The content of meetings was often multifactorial and usually on a subject within the PP remit., Conclusions: The PP is beneficial because pastoral care is provided only by dedicated staff members with an interest in student welfare. Membership is small enough to enable staff training and development. However, the system relies on self-referral by students. Rather than preventing problems arising, it therefore provides secondary support to those students insightful enough to identify their problems and motivated enough to seek help.

Congenital afibrinogenaemia and hypofibrinogenaemia are rare disorders of haemostasis. In this case report the problems posed in the management of two patients with fibrinogen levels less than 0.1g L(-1) and who developed intracranial bleeding are considered. The value of fibrinogen concentrate and the role of prophylaxis is also discussed.

The birth of a very premature infant with haemophilia A is a rare event. In this case report the problems posed in the management of a child with a factor VIII level of 0.03 IU mL-1 born at 28 weeks of gestation and weighing 1590 g are considered. The value of recombinant factor VIII, the pharmacokinetics of factor VIII in this situation and the importance of close cooperation between paediatricians and haematologists are discussed.

Twenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths. The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage. Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.

Although the nature of haemophilia has been understood for thousands of years, knowledge of its molecular genetics is recent. These X-linked bleeding disorders have diverse underlying DNA defects and, in 1992, DNA inversion within the X chromosome was found to explain half of the most serious cases of haemophilia A. The life-span and quality-of-life for patients with haemophilia had improved steadily throughout the early 1980s but the principal cause of death remained intracranial haemorrhage until the epidemic of HIV infection due to contaminated factor concentrates. Infection with hepatitis C virus is almost universal for patients treated with clotting factors before 1985. No curative treatment is available for hepatitis C at present. Knowledge of the transmission of viruses in concentrates has led to important developments in processing techniques to eliminate them. Recombinant technology has produced factor VIII and, more recently, factor IX concentrate which is likely to be very safe. Development of inhibitors to factor concentrates (especially factor VIII) remains one of the most serious complications of haemophilia. The variety of treatments available testifies to the lack of a single universally efficacious one. The use of prophylactic treatment has been conclusively demonstrated to result in a preservation of joint function in severely affected patients who might otherwise develop significant joint problems. The many facets of the care of patients with severe haemophilia, ranging from dental care to genetic counselling, can be advantageously co-ordinated in a haemophilia comprehensive care centre.

The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (> 10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion. HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies form 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA-DRB*1501, DQB1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7, 1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB1*01, DQB1*0501, DQA1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.

Haematologists are long standing proponents of evidence based practice-well exemplified among professionals who care for patients with haemophilia. The rapidly expanding range of therapeutic products and the numerous accompanying clinical trials are swiftly interpreted and translated into clinical practice. This translation is formalised by frequently updated quidelines issued by the United Kingdom Haemophilia Centre Directors' Organisation (UKHCDO) and relevant to all doctors involved in the care of patients with haemophilia. In the last five years eight sets of guidelines have been issued in the UK alone relating to the treatment of haemophilia and its complications [1-8]. Against this background we aim to review current practice in the treatment of haemophilia.

A strategy is described for the initial detection, management and elimination of factor VIII inhibitors arising in patients with congenital and acquired haemophilia A. It is suggested that children with severe haemophilia A should be screened every 3 months up to the age of 10 years for inhibitors using the Bethesda method. Factor VIII inhibitors arising in these patients should be abolished using immune-tolerance induction wherever possible. Such regimes should be started as early as possible, preferably when the inhibitor titre is < 10 Bethesda Units (BU)/ml, and should not be interrupted. High-intensity regimes are recommended for patients whose inhibitors exceed 10 BU. Autoantibodies to factor VIII giving rise to acquired haemophilia should be abolished using high-dose immunoglobulin or conventional immunosuppression. The choice of haemostatic agent for the treatment of severe bleeding should be based upon the clinical circumstances and the current inhibitor value, measured using both human and porcine factor VIII in the Bethesda assay. The past anamnestic response should also be considered when choosing treatment for minor bleeding episodes.

Although there are numerous risk factors for venous thromboembolic disease, the term 'thrombophilia' refers only to those familial or acquired disorders of the haemostatic system that result in an increased risk of thrombosis. The inherited thrombophilias include antithrombin III deficiency, resistance to activated protein C (factor V Leiden), protein C and protein S deficiencies as well as some rare forms of dysfibrinogenaemia. It is possible that other inherited conditions might also predispose to thrombosis. In contrast, when using the above definition, the antiphospholipid syndrome is the only genuine acquired thrombophilic state. Patients who have thromboembolic disease at a young age with no provoking event or who have a positive family history or whose thrombosis involves an unusual site should be investigated for thrombophilia. The management of a patient identified as having a laboratory abnormality associated with thrombophilia will depend on a variety of factors such as the patient's individual and family thrombotic history, the site of the thrombosis and the presence of other prothrombotic risk factors. The use of prophylactic anticoagulation during pregnancy and the puerperium requires particularly careful consideration in thrombophilic women. As more becomes known about the thrombophilias it will become possible to formulate more exact guidelines as to the management of these conditions.

The molecular basis for a family with Type I antithrombin deficiency has been established. Amplification and sequencing of the antithrombin gene identified two mutations: Met20Thr (2523T-->C) within exon 2 and Tyr166Cys (5493A-->G) within exon 3a. Further analysis indicated that the propositus was a compound heterozygote but in addition provided evidence for phase disruption during the amplification and/or cloning procedure. The Met20Thr mutation appears to be a neutral mutation with no functional consequences. In contrast, the Tyr166Cys mutation is associated with a Type I phenotype.

The evolution of comprehensive care centres for haemophilia has altered the work of those involved in the care of haemophilia patients. The role of the haemophilia sister has expanded and the concept of the haemophilia nurse specialist has emerged. We describe the implementation of a local policy which has enabled haemophilia nurse specialists to requisition and administer clotting factor concentrates, DDAVP, tranexamic acid and hepatitis vaccines independently, in hospital and community settings. Since the introduction of this policy on 2 August 1994, prescribing practice has not changed in the haemophilia centre, nor has the involvement of medical staff in the care of haemophilia patients. This approach is widely applicable in other centres and should be a logical progression of the haemophilia nurse specialist's role.

Reports of all the factor VIII inhibitors arising in the United Kingdom in patients with haemophilia A during the years 1990-93 have been collated by the United Kingdom Haemophilia Centre Directors Organization. 32 new inhibitors were reported during this period, giving an average incidence of new inhibitors of 1.5 per 1000 patients registered per year. Although most occurred in patients with severe haemophilia under the age of 10, 29% occurred in patients whose VIIIC was > 3 iu/dl, and 38% in patients over the age of 10 years. The incidence of inhibitors rose during the study period, but this change was not statistically significant.

The affinity of anti-gag antibody was studied for up to 9 years (1984-1993) in sera from 15 HIV-1+ patients with haemophilia. On the basis of their 1993 clinical status patients were divided into two groups: (i) patients who remained asymptomatic (n = 9); and (ii) those who progressed to AIDS between late 1987 and 1993. The affinity constants of antibody for p24 and p17 were determined by a double isotope fluid-phase radioimmunoassay; and the relationships between antibody affinity and titre, patient clinical course, CD4 cell counts and p24 antigenaemia were analysed. The affinity of p24- and p17-specific antibody was up to 100 times greater in asymptomatic patients than in patients who progressed to AIDS. Patients who developed AIDS either lost or failed to develop high-affinity antibodies early in the infection. Asymptomatic patients maintained high-affinity antibodies for several years; however, in some of these patients the affinity of anti-p24 and p17 antibodies subsequently fell later in the study period. The presence of low-affinity antibody and progressive reduction in the titre of specific antibody were earlier predictors of disease onset than CD4 cell counts. The failure to either develop or maintain high affinity gag-specific antibody suggests an early impairment of T helper function in individuals who progressed to AIDS. The presence of antibody of high affinity could be essential in controlling virus replication and the onset of AIDS.

The haemostatic efficacy of a new highly purified factor IX concentrate, prepared by metal chelate affinity chromatography, was assessed in 13 patients with haemophilia B undergoing a variety of surgical operations. Four of the patients had developed post-operative thromboembolic complications following previous operations, when treated with a prothrombin complex concentrate. None of the patients in the present series developed any evidence of post-operative thrombotic complications. Effective haemostasis was achieved in all patients, with the exception of a surgical bleed in one case, and late post-operative bleeding in a second patient when the factor IX activity fell below 20iu/dl. The product is treated with a solvent-detergent process that destroys lipid-enveloped viruses, while the affinity chromatography process during manufacture removes in excess of 4 log10 of a non-lipid-enveloped virus. In follow-up studies, none of the patients has shown evidence of fresh infection from the concentrate, when assessed by virological markers. It is concluded that this high-purity concentrate (tradenane 'Replenine') is effective for the treatment of patients with haemophilia B who undergo surgical operations.

Haemorrhagic diatheses due to platelet function defects are a heterogenous and poorly understood group of conditions. We report the investigation of a female with a lifelong history of epistaxes, haemarthroses, menorrhagia and persistent iron-deficiency anaemia. Although platelet numbers and morphology were normal, platelet function was abnormal both in vivo and in vitro. Skin bleeding time was prolonged and aggregation thresholds in platelet-rich plasma to a variety of weak and strong agonists were increased. Platelet granule contents were normal and membrane glycoproteins GpIb and GpIIIa were present in normal amounts. Polyphosphoinositide metabolism and phosphatidic acid generation were diminished in thrombin-stimulated platelets, as was phosphorylation of the 47 kD substrate for protein kinase C and the 20 kD protein myosin light chain kinase, indicating impaired generation of the intracellular second messengers diacylglycerol and inositol trisphosphate due to diminished stimulated phospholipase C activity. Although intracellular free calcium, calmodulin activity and basal cAMP concentrations were normal, washed platelets showed increased cAMP accumulation following stimulation with prostaglandin E1 and forskolin. Platelet membrane lipid analysis revealed a reduction in plasmalogen phosphatidylethanolamine content. It is suggested that the membrane phospholipid abnormalities cause the abnormal platelet reactivity by interfering with signal transduction from platelet receptor, via intermediary G proteins, to phospholipase C and adenylate cylase. The bleeding tendency is likely to be a consequence of the altered stimulus-response coupling.

Both the development of factor VIII inhibitors and infection by hepatitis C virus are serious complications of haemophilia A. We describe the first reported case of the subsequent development of a factor VIII inhibitor in a patient with haemophilia A after treatment with interferon-alpha for chronic active hepatitis C.

Objective: To study the humoral immune response to HIV-1 p17 and p24 Gag proteins longitudinally and assess any prognostic value., Design and Methods: Fifteen HIV-1 infected patients with haemophilia were asymptomatic at entry to the study in 1986. Each patient was monitored at 6- to 12-month intervals for up to 7 years for p17 and p24 immunoglobulin (Ig)G titres, p17 IgG avidity, total IgG, p24 antigenaemia and CD4 cell counts. Results were correlated with the clinical course., Results: Between 1986 and 1993, six of the patients developed CD4 cell counts below 200 x 10(6)/l (AIDS patients) while nine retained counts above this level (asymptomatic patients). All AIDS patients were characterized by declining IgG titres to p17 and p24 from 1986-1987 onwards. A reduction in specific p17 and p24 IgG preceded, by at least 3-4 years, the onset of CD4 cell depletion (< 200 x 10(6)/l). These six patients also had significantly lower p17 IgG avidity than the asymptomatic patients throughout the study., Conclusion: Titres of p17 and p24 IgG appeared to alter in the same manner. A progressive reduction in IgG titres and a low p17 IgG avidity were earlier predictors of disease progression than CD4 cell counts or p24 antigenaemia.

The IgG response to HIV-1 p17 gag protein was studied for up to 6 years in 12 HIV-1-infected patients with haemophilia, who had seroconverted between 1982 and 1985. To assess any prognostic value, p17 IgG titres were compared with p24 IgG titres, CD4 cell counts and p24 antigenaemia. p17 IgG avidity index was also examined. A strong similarity was found between the IgG titre to HIV-1 p17 and that to p24. In patients who developed AIDS the decline in p17 IgG titres could precede by several years the drop in CD4 cells to under 200 cells/microliters; whereas some long-term asymptomatic patients (CDCII) had increasing p17 IgG titres and stable CD4 cell counts. Declining p17 and p24 IgG titres were not always associated with an increase in p24 antigenaemia. IgG titres were found to be better predictors of disease progression than CD4 cell counts or p24 antigenaemia. Patients who developed AIDS during the study were also characterized by a lower p17 IgG avidity than patients who remained asymptomatic. This result suggests that IgG avidity could have prognostic relevance and be of importance for host resistance to AIDS onset.

CTL and antibody responses to HIV-1 p17 and p24 antigens were monitored from 1986-1991, in 4 hemophiliacs. The patients had been infected with HIV-1 between 1980 and 1984. Two patients have remained asymptomatic while two progressed to AIDS in 1990. CTL were boosted by culturing with peptides from p17 aa 86-115, or p24 aa 265-279; and aa 270-373 or PHA. Lysis was measured on autologous or allogeneic targets pulsed with peptides or infected with recombinant vaccinia virus carrying HIV-1 gag or influenza A matrix genes. Antibodies to p17 and p24 were tested by ELISA using peptides and by Western blotting. High levels of CTL activity to p17 and p24 antigens could be generated only with lymphocytes from the two asymptomatic patients between 1986 and 1989, but these responses were absent in 1990 and 1991. Antibodies to p17 peptides disappeared in parallel with CTL activity. Antibodies to some p24 peptides also declined but most patients retained activity to others. In all patients a > or = 3-fold increase in CD8+ cell numbers occurred over time and accompanied the decline of CTL and antibody responses. The loss of CTL and p17 antibodies occurred irrespective of whether patients remained asymptomatic or progressed to AIDS in the intervening two years.

We report on 2 patients with sideroblastic anaemia an secondary iron overload whose presenting symptom was an arthropathy of small an large joints. One patient had marked spinal symptoms which were severe enough to suggest ankylosing spondylitis, and the pattern of arthritis in the other resembled seronegative rheumatoid arthritis. We believe these to be the first cases described of an arthropathy associated with iron overload secondary to sideroblastic anaemia.

A strategy for the prevention and management of haemorrhage in patients with inhibitors to factor VIII by intensive plasma exchange and human factor VIII infusion is described. The advantages and disadvantages of this approach are discussed in the light of the authors' experience with the technique and the alternative methods of treatment described in the literature.

Thrombocytopenia is a common haematological abnormality in pregnancy which has important implications for both mother and fetus. It may occur as part of the pathophysiology of pregnancy itself, but in many cases pregnancy is superimposed on a background of haematological disease. Failure of platelet production remains a difficult and dangerous problem to manage while the outlook for non-immune platelet destruction has improved as a result of a clearer understanding of the haemostatic changes taking place in the pregnant woman. Immune-mediated thrombocytopenia is now also better understood because of recent advances in antibody detection and quantitation but it has been difficult to translate this new knowledge into the planning of well considered treatment strategies. The administration of high-dose ivIgG to either mother or fetus shows promise as a new and safer method of managing delivery and neonatal life in autoimmune and alloimmune thrombocytopenia but further evaluation is necessary before the indications for giving ivIgG are clear. Close cooperation between obstetricians, haematologists and scientific staff is essential if the best treatment for the thrombocytopenia of pregnancy is to be given.

Plasma-exchange is one of many treatments available for the prevention and management of hemorrhage in patients with factor VIII inhibitors. Details of exchange technique and the frequency of treatment are determined by the clinical situation, venous access and the availability of equipment, staff and blood products. In view of the many difficulties associated with plasma-exchange, other treatment options are likely to be preferred in most circumstances. The technique remains attractive as a means for reducing inhibitory activity before elective surgery and during life-threatening hemorrhage.

A 17 year old girl had a myocardial infarction. Three days later coronary angiography showed an occlusive thrombus in the circumflex and anterior descending arteries. The coronary arteries themselves appeared to be normal, and this was confirmed at repeat angiography three months later. Tests of haemostasis showed a deficiency of factor XII.

In a prospective study of cryoprecipitate administration to patients who had never received large pool concentrates, no evidence of hepatitis or HIV infection was detected in a follow up period of one year. Following the introduction of screening of blood donors for anti-HIV in the UK in October 1985 the use of cryoprecipitate in selected cases should be reconsidered.

Highly purified porcine factor VIII has been advocated for the treatment of bleeding episodes in patients with haemophilia who have inhibitors to factor VIII. This approach has been successful in a patient with an intermediate potency inhibitor showing little cross-reactivity to porcine material. As in some other reported cases, a severe allergic reaction occurred on one occasion but did not preclude the subsequent use of the porcine concentrate in carefully controlled conditions.

The North-east Thames Region has appointed a nursing sister to co-ordinate the organisation of care for haemophiliacs in the region. As a result of the appointment, facilities for home treatment have expanded rapidly. Several associate centres providing care to haemophiliacs have been set up around the region in addition to the four main haemophilia centres, which are all in the south-west corner of the region. As well as providing support and supervision of patients on home treatment, the co-ordinator helps to place haemophiliac children in suitable schools, maintains the regional register of haemophiliacs, and has a more general role in ensuring that services are available where they are needed throughout the region.

A case of maxillo-facial injuries in a patient with severe haemophilia is described. Problems of treatment and management are discussed from both surgical and haematological points of view.

In renal calculus surgery, human dried fibrinogen produces a coagulum with a much greater tensile strength, stickiness deformability and extractability than cryoprecipitate, which produces a relatively weak and friable clot. A useful coagulum may be prepared at room temperature at any convenient time prior to use if a mixture of 19 ml human dried fibrinogen solution and 1 ml thrombin solution is used. If mixed in a single syringe and injected within 35 s through a butterfly needle into the renal pelvis, complete mixing of the solutions is guaranteed. By using this simple method, the unpredictability of the coagulum can now be eliminated and a strong and elastic clot can be produced.