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Background —The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. Methods and Results —After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 μg/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5±0.8 mm 3 /mm vessel (range 0.6 to 13.7 mm 3 /mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside ( P P r =−0.61, P =0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31±23 IU/min; ex-smokers, 50±33 IU/min; nonsmokers 202±73 IU/min; P Conclusions —We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Angiotensin II and bradykinin are potent endogenous vasoactive peptides which may play a role in the regulation of endogenous fibrinolysis and, thereby, contribute to the beneficial actions of ACE inhibitors. The aims of the study were to determine the acute effect of angiotensin II and bradykinin on the local vascular release of tissue plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), and the endothelium-derived haemostatic factor, von Willebrand factor (vWf) from the forearm.Blood flow, and plasma haemostatic and fibrinolytic factors, were measured in both forearms of sixteen healthy men: eight subjects received intra-arterial angiotensin II (5, 50 and 500 pmol/min) which was coinfused with sodium nitroprusside (SNP; 0.3, 1.5 and 7.5 microg/min, respectively), and eight received intra-arterial bradykinin at 10-3000 pmol/min.Despite substantial rises in plasma angiotensin II concentrations (P0.001) which caused pressor effects (P0.003) at the highest dose, angiotensin II infusion did not affect local plasma t-PA, PAI-1 or vWf concentrations. In contrast, bradykinin caused substantial dose-dependent increases in blood flow and t-PA release (100 ng/100 ml of tissue/min) in the infused forearm (P0. 001 for both) without affecting plasma PAI-1 or vWf concentrations.Despite high local concentrations with breakthrough of significant systemic effects, angiotensin II did not affect acute endothelial cell t-PA, PAI-1 or vWf release in healthy men. In contrast, bradykinin is a potent vasodilator and selective stimulus for acute local t-PA release. This may, at least in part, explain the fibrinolytic actions of ACE inhibitors in heart failure and ischaemic heart disease.

Purpose : Hemorrhage and thrombosis predisposing to myocardial infarction, multiple organ failure, and thromboembolism account for the majority of the morbidity and mortality associated with repair of ruptured and nonruptured abdominal aortic aneurysms (AAAs). The aim of this study was to examine coagulation and fibrinolysis in patients operated on for ruptured and nonruptured infrarenal AAAs. Methods : Ten patients operated on for ruptured and 9 patients operated on for nonruptured AAAs were studied. Tissue plasminogen activator (t-PA) antigen, thrombin-antithrombin (TAT), and D-dimer were measured before induction of anesthesia. Plasminogen activator inhibitor (PAI) activity, t-PA activity, and prothrombin fragment (PF) 1+2 were measured before induction of anesthesia, immediately before aortic clamp release, and 5 minutes and 24 hours after aortic clamp release. Results : Preoperatively, ruptured AAA was associated with significantly elevated t-PA antigen (median 15.7 ng/mL, range 9.0 to 22.1 ng/mL versus nonrupture: median 6.6 ng/mL, range 4.7 to 16.4 ng/mL; P < .01, Mann-Whitney test), increased PAI activity (median 36.5 arbitrary units/mL, range 20.6 to 38.8 arbitrary units/mL versus nonrupture: median 8.2 arbitrary units/mL, range 3.2 to 21.7 arbitrary units/mL; P < .001), reduced t-PA activity (median 0.12 IU/mL, range 0.06 to 0.4 IU/mL versus nonrupture: median 0.49 IU/mL, range 0.14 to 3.2 IU/mL; P < .01), elevated TAT (median 135.5 μg/L, range 61.2 to 209.4 μg/L versus nonrupture: median 21.6 μg/L, range 6.6 to 180.4 μg/L; P < .02) and elevated PF 1+2 (median 9.0 nmol/L, range 5.4 to 11.6 nmol/L versus nonrupture: median 2.2 nmol/L, range 0.7 to 7.1 nmol/L, P < .001). There was no significant difference in preoperative D-dimer levels (median 3460 ng/mL, range 1236 to 7860 ng/mL versus nonrupture: median 1642 ng/mL, range 728 to 5334 ng/mL; P = .07). The differences in PAI activity, t-PA activity, and PF 1+2 persisted throughout the course of surgery, but there was no significant difference between the groups at 24 hours. Conclusion: These novel data demonstrate that ruptured AAA repair is associated with inhibition of systemic fibrinolysis and intense thrombin generation. Similar changes are seen in nonruptured AAA but are of a lesser magnitude. This procoagulant state may contribute to the microvascular and macrovascular thrombosis that leads to myocardial infarction, multiple organ failure, and thromboembolism. (J Vasc Surg 1999;30:641-50.)

Background —Angiotensin converting enzyme (ACE) inhibition after myocardial infarction is associated with an improvement in plasma fibrinolytic parameters. The aim of the present study was to determine whether acute ACE inhibition and angiotensin II type 1 (AT 1 ) receptor antagonism have similar effects in patients with heart failure. Methods and Results —Twenty patients with moderately severe chronic heart failure received enalapril 10 mg and losartan 50 mg on 2 separate occasions in a single-blind, randomized, crossover design. Plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) antigen and activity were measured at baseline and 6 hours after the dose. Acute administration of losartan but not of enalapril reduced plasma t-PA (11%; P =0.003) and PAI-1 (38%; P P =0.03) and decreases in PAI-1 (48%; P =0.01) activity. Changes in plasma fibrinolytic parameters were more marked during losartan treatment ( P P Conclusions —Acute AT 1 antagonism in patients with heart failure is associated with a significant improvement in plasma fibrinolytic parameters that is greater than during ACE inhibition. These beneficial effects of AT 1 antagonism and ACE inhibition would therefore appear to be mediated principally through suppression of angiotensin II.

Background —Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P–induced tPA release in vivo in humans. Methods and Results —Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity ( P P =0.03) and release of tPA antigen ( P =0.04) and activity ( P Conclusions —Cigarette smoking causes marked inhibition of substance P–induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.

The CD4 count has been reported to decline less rapidly in HIV-infected haemophiliacs treated with monoclonally purified factor VIII concentrates than in those using intermediate-purity concentrates. No survival advantage has been demonstrated for this effect, and it is unclear whether this effect occurs with all high-purity concentrates. Two cohorts of patients with severe haemophilia A and HIV treated with either ion-exchange-purified or monoclonally-purified concentrates were compared. The CD4 count, survival, AIDS-defining illnesses, CDC category and anti-retroviral therapy were recorded at 6-monthly intervals for 3 years following the change from intermediate to high-purity factor VIII. 116 patients were recruited, 37 of whom were treated with an ion-exchange purified factor VIII concentrate at three centres, mean (SD) age 31.1 (12.2) years, and 79 were treated with monoclonally purified factor VIII concentrate at two centres, mean (SD) age 29.8 (11.2) years. At the start of the study the median CD4 count was (monoclonal v ion-exchange) 0.30 v 0.16 x 10(9)/l. The CD4 count declined in both arms to a median of (monoclonal v ion-exchange) 0.16 v 0.08 x 10(9)/l at the final visit. Analysis of the (CD4 count)(1/2) over time, using a random coefficients model, found that the mean (SE) rates of decline were not statistically significantly different in the two treatment groups (monoclonal v ion exchange: -0.050 (0.008) v -0.034 (0.011) (CD4 count)(1/2) per year, P = 0.24). No statistically significant difference in survival (log-rank test: P = 0.33) was found. There was no difference in the proportion of individuals experiencing one or more AIDS-defining illnesses (P = 0.32) or in the proportion progressing to CDC category IV (P = 0.28) during the study. The CD4 count declined during the study at a rate similar to that previously reported in patients treated with intermediate-purity factor VIII concentrate, and there was no evidence of any difference between the two treatment groups.

Editor—Recently the United Kingdom Haemophilia Centre Directors Organisation issued evidence based guidelines on therapeutic products for treating haemophilia. Before finalisation the draft guidelines were circulated to professional societies, royal colleges, and departments of health and modified accordingly. The final guidelines were unanimously approved at the organisation's annual geneal meeting and published.1 One recommendation was that the treatment of choice for haemophilia A was recombinant factor VIII concentrate (rFVIII). This is because plasma derived factor VIII concentrates (pdFVIII) still transmit viral infections—for example, those caused by non-lipid coated viruses such as hepatitis A and parvovirus—despite the incorporation of viral inactivation steps in the manufacturing process.2 3 At present the licenced rFVIIIs contain human …

Objective— Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue plasminogen activator (t-PA) to limit acute in situ thrombus formation. Approach and Results— Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200, and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions ( P P P P P =0.03) and a trend toward a reduction in the high shear chamber (13±7%; P =0.07). Conclusions— Using a well-characterized clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential are warranted.

Summary Background Hepatitis G virus (HGV or GBV-C) is a newly discovered human flavivirus distantly related to hepatitis C virus (HCV). Little information is available on its natural history or routes of transmission, although it can be transmitted parenterally. We investigated the prevalence of persistent infection of HGV and HCV in patients exposed to non-virus-inactivated pooled blood products associated with transmission of HCV. Methods RNA was extracted from the plasma of 112 patients with haemophilia and 57 with hypogamma-globulinaemia, as well as from 64 different batches of archived coagulation-factor concentrates and immuno-globulins. RNA was reverse transcribed and amplified with primers from the 5' non-coding region of HCV and HGV by a nested polymerase chain reaction (PCR). Viral RNA was quantified by titration of complementary DNA before amplification. Findings Among non-remunerated UK blood donors HGV infection (detected by PCR) was more common than HCV infection (four [32%] of 125 compared with 137 [0076%] of 180 658 in southeast Scotland). Testing of batches of factor VIII and factor IX concentrates prepared without viral inactivation procedures showed high frequencies of contamination with HGV (16 of 17 factor VIII batches positive; six of six factor IX batches positive), with no difference between remunerated and non-renumerated donors. However, among 95 haemophiliacs who had received non-virus-inactivated concentrates, 13 (14%) were positive for HGV compared with 79 (83%) who were positive for HCV. Two of 37 recipients of long-term immunoglobulin replacement therapy were positive for HGV. Virus inactivation of blood products substantially reduced or eliminated contamination by HGV RNA sequences. Interpretation Despite the extremely high level of HGV contamination of non-virus-inactivated blood products, their use was not associated with high rates of persistent infection in recipients. The infectivity of HGV in blood products may be lower than that of HCV, or the virus may be less able to establish persistent infection in humans. Whatever the case, the high prevalence of active HGV infection in the general population remains difficult to explain.

The development of anti-interferon antibodies may lead to treatment failure during interferon therapy. We have studied the development of such antibodies in a group of 39 haemophiliacs receiving interferon-alpha 2a for chronic hepatitis C virus (HCV) infection. Anti-interferon antibodies developed in five (13%) patients and were associated with "breakthrough hepatitis' in three cases. There was an association between the development of anti-interferon antibodies and infection with HCV genotype 3a (P = 0.01). This study suggests that the development of anti-interferon antibodies may lead to treatment failure in a proportion of haemophiliacs with HCV infection. The association with genotype 3a has not previously been reported. Monitoring for the development of breakthrough hepatitis due to anti-interferon antibodies may provide the opportunity to develop strategies to overcome their effects.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease in individuals with haemophilia. A wide spectrum of disease severity is found in this group, ranging from mild hepatitis to cirrhosis. We have studied a cohort of 87 anti-HCV positive haemophiliacs who have been infected with HCV for 10-25 years and assessed the relative value of invasive and non-invasive methods of evaluating liver disease. The severity of liver disease was assessed using ultrasound scan (n = 77), upper GI endoscopy (n = 50), laparoscopic liver inspection (n = 33) and liver biopsy (n = 22). Invasive investigations were performed without any significant bleeding complications. Evidence of severe liver disease was found in approximately 25% of patients. There was agreement between the severity of liver histology and the information derived from the laparoscopic liver inspection, endoscopy and ultrasound in 86%. Co-infection with HIV was significantly associated with more severe liver disease (P = 0.006). This study provides further evidence that liver disease is emerging as a major complication in haemophiliacs and severe liver disease is more common in those co-infected with HIV. We have shown the potential value of laparoscopic liver inspection, in combination with endoscopy and ultrasound, in staging the extent of liver disease, and suggest that most patients may be managed without resorting to liver biopsy.

Summary. Recent reports of hepatitis A virus (HAV) infection in haemophiliacs receiving high-purity solvent detergent (HP.SD) treated factor VIII concentrates have brought into question the efficacy of this virucidal method for inactivating HAV. To assess whether HAV may have been transmitted by HP.SD concentrates, we compared seroprevalence in haemophiliacs with different disease severity, sought evidence of seroconversion to HAV since introduction of HP.SD products, and directly examined concentrates for HAV RNA by PCR. Our data suggest that Scottish haemophiliacs are not being infected with HAV by HP.SD concentrates produced initially by CRTS Lille and presently by PFC Edinburgh and supplied by the Scottish National Blood Transfusion Service (SNBTS).

BACKGROUND--Among patients with independent evidence of coronary disease and recent onset unstable angina or non-Q wave myocardial infarction the incidence of subsequent cardiovascular events is high. Markers predictive of adverse cardiac outcome in unstable angina and non-Q wave myocardial infarction need to be defined more accurately. Endothelin-1 is a potent endothelium derived vasoconstrictor peptide that may play a part in the pathophysiology of acute myocardial ischaemia. AIM AND STUDY DESIGN--In a study that specifically identified high risk patients a group of 16 consecutive patients with either unstable angina at rest or non-Q wave myocardial infarction were prospectively investigated to establish whether these conditions are associated with high plasma immunoreactive endothelin and whether endothelin concentration at presentation is related to cardiovascular events within the next 12 weeks. Controls consisted of a group of 40 healthy subjects. RESULTS--Patients had significantly higher mean (SD) plasma endothelin at presentation than did healthy controls (7.4 (1.1) v 5.0 (1.2) pg/ml, P < 0.0001). At nine weeks plasma endothelin was still significantly higher in those patients who had subsequent cardiovascular events, (n = 9, acute myocardial infarction or refractory angina with electrocardiographic changes and revascularisation procedures, 8.5 (2.6) pg/ml, P < 0.005 v controls) whereas its concentration returned to normal in those patients who had a favourable outcome (n = 7, 5.9 (0.7) pg/ml). Compared with those patients who had an uneventful course, patients with subsequent events had significantly higher plasma endothelin, both at presentation and at nine weeks (P < 0.05 on both occasions). IMPLICATIONS--Endothelin may contribute to the pathophysiology of acute coronary syndromes and may relate to subsequent cardiovascular outcome.

The frequency and dynamics of infection with different genotypes of hepatitis C virus were investigated in a cohort of hemophiliacs repeatedly exposed to non-virus-inactivated clotting factor. Among 63 infected hemophiliacs, genotype 1 (n = 38, subtypes 1a [27] and 1b [11]) was predominant; genotypes 2a (n = 1), 2b (n = 3), 3a (n = 20), and 5a (n = 1) accounted for the remainder. This distribution was similar to that found in Scottish blood donors from whom the infected blood products were manufactured. Hemophiliacs with severe disease were more likely to be polymerase chain reaction-positive than those with moderate or mild disease. Over 10 years, changes in the circulating major genotype and serotype were observed in 9 of 29 hemophiliacs and from one subtype to another in 3, although there was no clear trend toward replacement with any particular variant. Replacement occurred after the introduction of inactivated clotting factor in 4 subjects, implicating reactivation rather than reinfection. Those coinfected with human immunodeficiency virus were more likely to show a change in genotype.

Among patients with recent-onset unstable angina and evidence of ischemia or coronary artery disease, the incidence of subsequent cardiovascular events is high. The aim of this study was to investigate, in this high-risk population, whether unstable angina was associated with abnormalities of tissue-type plasminogen activator (t-PA) or plasminogen activator inhibitor (PAI) activities and whether, in a prospective study, any of these parameters would identify patients with an adverse cardiovascular prognosis. A group of 22 high-risk patients with unstable angina (64% event rate at 3 months) was studied prospectively for 12 weeks, and the fibrinolytic parameters measured at presentation were related to subsequent cardiovascular progress. A group of 20 age- and sex-matched healthy subjects acted as control subjects. Patients who had subsequent cardiovascular events (acute myocardial infarction or severe recurrent angina +/- intervention) had significantly elevated PAI activity at presentation compared with both those who remained event-free (p0.05) or with control subjects (p0.02). In addition, basal activation of fibrinolysis was demonstrated in unstable angina at presentation; this persisted at 9 weeks in patients with a favorable outcome (p0.02 vs control subjects), whereas it was no longer evident in those who developed cardiac events. These findings suggest that measurements of t-PA/PAI activity may reflect the underlying pathophysiologic state and relate to subsequent cardiovascular events in unstable angina.

In an investigation of the evolution of the third hypervariable loop of gp120 (V3), the principal neutralization determinant of human immunodeficiency virus type 1, we have analyzed 89 V3 sequences of plasma viral RNA purified from peripheral blood samples donated over 7 years by an infected hemophiliac. Considerable sequence diversity in the V3 region was found at all time points after seroconversion. Phylogenetic analysis revealed that an important diversification had occurred by 3 years postinfection and that, subsequently, most sequences could be allocated to either one of two major lineages that persisted throughout the remainder of the infection. Rapid changes in frequency of the most common sequences and the observation that the same hexapeptide motif (GPGSAV) at the crown of the V3 loop has evolved convergently provide strong evidence that selective processes determine the evolutionary fate of sequence variants in this region.

To investigate the prevalence of hepatitis C virus infection in two risk groups, stored serum samples from treated haemophiliacs and intravenous drug users were tested for anti-HCV by both anti-C-100 based and second generation ELISAs (Abbott and Ortho) followed by testing in two confirmatory immunoblot assays that incorporate core as well as other non-structural antigens (Innogenetics LIA and Chiron RIBA-HCV test). Clear evidence of HCV infection was found in all but one of 78 haemophiliacs treated with non-virus inactivated clotting factor concentrates, but in none exposed only to super dry heat-treated concentrates. Only four samples gave rise to conflicting serological results between the four tests, two of these occurred in patients with advanced HIV related disease and almost certainly reflected loss of humoral immunity associated with disease progression, and the others occurred in the only two patients tested who were chronic carriers of hepatitis B infection and may reflect an interaction between the two viruses. Comparison of anti-C-100 versus second generation tests in immunocompetent drug users revealed a false negative rate of 20% using C-100 alone, indicating the advantage of using second generation assays for detection of past or current HCV infection. Of all of the antigens used in the confirmatory assay, positive sera showed strongest and most frequent reactivity with the C22 and C33c proteins (Ortho RIBA).

Sequence change in different hypervariable regions of the external membrane glycoprotein (gp120) of human immunodeficiency virus type 1 (HIV-1) was studied. Viral RNA associated with cell-free virus particles circulating in plasma and proviral DNA present in HIV-infected peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of two currently asymptomatic hemophiliac patients over a 5-year period. HIV sequences were amplified by polymerase chain reaction to allow analysis in the V3, V4, and V5 hypervariable regions of gp120. Rapid sequence change, consisting of regular replacements by a succession of distinct viral populations, was found in both plasma virus and PBMC provirus populations. Significant differences between the frequencies of sequence variants in DNA and RNA populations within the same sample were observed, indicating that at any one time point, the predominant plasma virus variants were antigenically distinct from viruses encoded by HIV DNA sequences in PBMCs. How these findings contribute to current models of HIV pathogenesis is discussed.

The polymerase chain reaction (PCR) detected specific hepatitis C viral (HCV) RNA sequences in plasma from 15 of 21 haemophiliacs (12 HCV-antibody positive) and 7 of 27 intravenous drug users (13 HCV-antibody positive). Quantification of RNA-positive samples showed high levels of HCV (10(5) to 10(6) copies of RNA/ml) in infected patients. HCV was more frequently found in haemophiliacs infected with human immunodeficiency virus (11/11 HIV-positive and 4/10 HIV-negative patients). HCV-RNA was detected in all batches of commercially available factor VIII tested and in low concentrations in some pools of plasma donations from volunteers. Factor VIII, manufactured from volunteer donations, was uniformly negative by PCR. Phylogenetic analysis of viral sequences showed two distinct groups: one was associated with intravenous drug users and the other with haemophiliacs infected with Scottish factor VIII preparations. Both were distinct from sequences found in commercially available factor VIII.

Patients with myeloproliferative disorders (MPD) have an excess of thrombotic complications which is not fully corrected by normalisation of their elevated haematocrit or thrombocytosis. The mechanisms responsible for this are not completely understood but platelets, leucocytes and endothelial cells have all been implicated. Plasma microparticles are observed to be elevated in other diseases associated with thrombotic complications. We measured platelet (PMP), endothelial (EMP), red cell (RMP) and leucocyte (LMP) microparticles in patients with MPD compared to healthy controls. Microparticles, of less than 1μm were measured by flow cytometry on platelet poor plasma obtained from citrated peripheral blood samples. Subtypes were identified using fluorescent conjugated monoclonal antibodies; EMP CD31+CD42-, PMP CD31+42+, RMP Glycophorin A + and LMP CD45+ events. Absolute concentrations of microparticles per μl plasma were calculated using Trucount beads. Results are currently available for 27 MPD patients, 9 polycythaemia vera (PV), and 18 primary thrombocythaemia and 14 healthy controls. All patients except 1 PV were on current treatment with hydroxycarbamide and all but 3 were receiving aspirin. PMP and LMP were elevated in MPD patients compared to healthy controls, PMP 12432 (1653) v 2371 (278) per μl, mean (SEM) p

Introduction: In patients with hemophilia, the development of inhibitors against exogenous factor VIII (FVIII) or factor IX (FIX) is one of the most serious complications of repeated exposure to replacement therapy and has major clinical and economic consequences. The multicenter, non-interventional, cross-sectional, case-control ESOS study aimed to evaluate the relationship between inhibitor status of patients with hemophilia and their quality of life (QoL) and degree of arthropathy, as well as to compare the orthopedic status of patients with inhibitors with that of patients without inhibitors. Methods: Overall, 128 patients were enrolled: group A (n=38), males aged 14–35 years, with severe congenital hemophilia A or B (basal FVIII/FIX level 5 BU) and who have had the inhibitors >5 years; group B (n=41), as group A, but aged 36–65 years; and group C (n=49), as group A, but without inhibitors. Key assessments included: socio-demographics; data on replacement therapy, inhibitor characteristics, immune tolerance testing, genotype, and prophylaxis; care management; QoL (EuroQoL questionnaire); and Gilbert’s and Pettersson’s classifications. Results: A maximum inhibitor titer >50 BU was observed in 71% of patients in group A and 63% in group B. There were significant differences in genotype for patients in groups A and B compared with those in group C (e.g. inversions, large deletions, missense mutations). Prior to enrolling in the study, orthopedic procedures had been performed in 66% of patients in group A compared with 34% in group B and 37% in group C; arthroplasty had been performed only in patients with inhibitors (groups A and B, n=2 in each). During the 12-month study period, patients with inhibitors had more absence from work or school due to orthopedic complications than patients without inhibitors. In groups A and B, 16% and 27% of patients were hospitalized for orthopedic procedures compared with only 4% in group C. Patient mobility was severely reduced in groups A and B, with 24% and 23% of patients using wheelchairs compared with only 4% in group C, and 50% and 51% of patients needing a walking aid compared with only 29% in group C. In terms of orthopedic status, significantly more joint pain was reported by patients in group A compared with those in group C; clinical/radiological orthopedic scores were also worse in group A compared with group C. In terms of bleeding, there was no difference in the incidence of muscle hematomas between the groups; the incidences of hemarthroses were higher in younger patients (groups A and C) than in older ones (group B). For the QoL analysis, patients in group A reported significantly more joint abnormality than those in group C. Conclusion: Our study confirms that the burden of orthopedic complications and the impact on QoL is more severe in patients with hemophilia who have developed inhibitors compared with those patients without inhibitors.

The management of haemorrhage or risk of haemorrhage in anticoagulated patients increasingly involves those providing services for haemophilia. This is particularly so in the use of prothrombin complex concentrates where experience of the use of these products exists almost entirely within haemophilia centres. As the majority of bleeding anticoagulated patients present to hospitals that do not have haemophila centres, and where there is little experience in the use of PCCs, there is clearly a need for practical guidelines to guide use of these products. Clinicians must be made aware of the potential benefits and risks of using concentrated coagulation factors prepared from large plasma pools. A key aspects of the safe use of PCCs is the careful selection of the clinical indications for their use. Only those patients with or at risk from life-threatening haemorrhage should be treated. And where a licensed product is available, this should be used in preference to those that are not. Data are lacking on the comparative efficacy of products containing factors II, VII, IX (FIX) and X against those lacking factor VII. There is evidence to show that factor VII levels may be extremely low in patients with high INRs, suggesting that overanticoagulated patients may benefit more from PCCs containing all four vitamin K-dependent factors. The optimal dose of PCC required to reverse anticoagulation is not fully established but does depend on the degree of the coagulation defect. The experience of this group suggests that doses between 25 IU FIX/kg and 50 IU FIX/kg are effective. We present a practical protocol for the use of PCC in reversal of coumarin-induced anticoagulation.

Background: Thrombophilia is increasingly recognized as a risk factor for deep venous thrombosis (DVT), which in turn is a major risk factor for chronic venous ulceration (CVU). However, the relationship between thrombophilia and CVU remains unknown. The aim of this study was to define the prevalence of thrombophilia in patients with CVU and to determine whether this is associated with a history or duplex scan evidence of DVT. Methods: Eighty-eight patients with CVU were prospectively studied. The patients underwent clinical assessment and duplex ultrasound scanning. Blood was drawn for antithrombin, proteins C and S, activated protein C resistance, factor V Leiden, prothrombin 20210A, lupus anticoagulant, and anticardiolipin antibodies. Results: The study included 35 men with a median age of 61 years (interquartile range, 45 to 72 years) and 53 women with a median age of 76 years (interquartile range, 69 to 82 years). Thirty-six percent of the patients had either a history or duplex scan evidence suggestive of previous DVT. The following abnormalities were detected: four, five, and six cases of antithrombin, protein C, and protein S deficiencies, respectively; 14 cases of activated protein C resistance; 11 cases of factor V Leiden mutation; three cases of prothrombin 20210A mutation; eight cases of lupus anticoagulant; and 12 cases of anticardiolipin antibodies. Thrombophilia was not significantly related to previous DVT, deep reflux, or disease severity. Conclusion: Patients with CVU have a 41% prevalence rate of thrombophilia. This rate is two to 30 times higher than the rate of the general population but is similar to that reported for patients with previous DVT. However, in patients with CVU, thrombophilia does not appear to be related to a history of DVT, a pattern of reflux, or severity of disease. Many patients with CVU may have unsuspected postthrombotic disease. (J Vasc Surg 2002;35:718-22.)