Lilian Tengborn

Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.

Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized

The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3–5 and 15 at the age of 6–9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient.

Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors

Abstract. Insulin resistance and hyperinsulinaemia may play an important role in both the development of hypertension and its accompanying metabolic aberrations. In order to investigate this possibility, nine non‐obese, non‐diabetic, non‐smoking, middle‐aged men with untreated hypertension were treated with metformin 850 mg b.i.d. for 6 weeks as a pilot study and within‐patient comparison. Metformin decreased total and LDL‐cholesterol (P< 0.01), triglyceride (P< 0.01), fasting plasma insulin (P< 0.01) and C‐peptide levels (P< 0.02). Glucose disposal, an indicator of insulin action measured by means of the euglycaemic clamp technique, increased (P< 0.001). Tissue plasminogen activator (t‐PA) activity increased (P< 0.02), and t‐PA antigen decreased (P< 0.01), whereas plasminogen activator inhibitor (PAI‐1) and fibrinogen were unaffected by metformin treatment. Body weight remained unchanged. Withdrawal of metformin was associated with the return of both blood pressure and metabolism towards the initial levels. In conclusion, metformin treatment increased insulin action, lowered blood pressure, improved the metabolic risk factor profile and tended to increase the fibrinolytic activity in these mildly hypertensive subjects. These results support the view that insulin resistance plays a role in hypertension, and may open up a new field for the alleviation of abnormalities associated with cardiovascular disease.

Deep vein thrombosis of the axillary-subclavian veins: Epidemiologic data, effects of different types of treatment and late sequele

Upper extremity deep venous thrombosis (DVT) is uncommon. In the city of Malmo, Sweden (240 000 inhabitants), 296 cases undergoing phlebography due to a suspicion of upper extremity DVT, during 1971–1986 were analysed. 165 arm phlebograms did not reveal any thrombi (56%). In 11 cases (4%) external compression of the vein was found. Thrombi in the axillary or subclavian vein were found in 120 cases (40%) and were classified as primary in 73 cases and secondary in 47 cases. Only seven cases of effort thrombosis were found. Four cases had neurovascular symptoms mimicking thoracic outlet syndrome and underwent elective first rib resection. None of the patients with primary DVT had a fatal pulmonary embolism (FPE). One patient had clinical signs suspicious of pulmonary embolism (PE), however, scintigraphy of the lungs was negative. Of the cases with secondary thrombi three cases had fatal, and one case had contributory PE at autopsy. Additionally, one patient had a nonfatal PE verified scintigraphically. Post-thrombotic sequelae from the arm were in no case so severe that the patient had to change occupation. Patients with primary DVT had moderate complaints in three and mild in fifteen cases. Those with secondary arm thrombi experienced only moderate symptoms in two cases and mild sequelae in fourteen. There was no correlation between the type of treatment and late post-thrombotic symptoms. From this study it can be concluded that phlebography must be undertaken before treatment can be started in patients with a suspected arm DVT. Primary DVT seems to be a “benign” disease, and in general treatment with anticoagulants is sufficient. Only in selected cases may more aggressive treatment be needed. In patients with secondary DVT there is a risk of PE and more prolonged anticoagulation may be indicated.

Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Recurrent thromboembolism in pregnancy and puerperium. Is there a need for thromboprophylaxis

By sending a questionnaire (response rate 93%) to 321 women with a history of venous thromboembolism and previous coagulation tests, 72 patients were identified who had a total of 87 pregnancies after the thromboembolic episode. The main aim of the study was to analyze the influence of prophylaxis during pregnancy and delivery on the development of further thromboembolic complications. During pregnancy there was no difference in frequency of thromboses between the group given prophylaxis (n = 20) and the group not receiving it (n = 67). At delivery the frequency of thrombosis was 5.3% among the 57 women given prophylaxis and 11.1% among the 30 without prophylaxis, a difference that is not significant. The implication of these findings is discussed both concerning the indications for giving prophylaxis and concerning the problem of designing relevant prophylactic trials.

Demographic and clinical data in acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2)

Summary.  Background:  Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA.

Immunosuppression for acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2)

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

On‐demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome

Summary.  Using an 11‐year panel of 156 Norwegian and Swedish patients with severe haemophilia, and including retrospective case‐book data from birth, we compared the differences in the haemophilia‐related resource use between on‐demand and prophylactic treatment. Patients treated on‐demand had more surgery (arthrodeses, prostheses implantations and synovectomies) and more days lost from work. Median annual factor‐concentrate consumption among adults (18+) was 211 000 IU [interquartile range (IQR) 154 000–268 000] or 3 024 IU kg−1 year−1 for patients on prophylactic treatment and 55 000 IU (IQR 28 000–91 000) for on‐demand patients (780 IU kg−1 year−1). This was partly explained by the fact that the median dose per kg body weight was twice as great 28, (IQR 24–32) for prophylaxis compared with 14 (IQR 12–16) for on‐demand. Prescribed dose per kg body weight was found to be an important factor explaining the variation in total annual factor‐concentrate consumption per patient for both types of treatment. Other variables included in the panel‐data regression analysis were the number of weeks on secondary prophylaxis for on‐demand patients and age, body weight and type of haemophilia for children (0–17 years) on prophylaxis. Differences were consistently substantial and will affect both costs and benefits of the two treatment strategies.

Normal vaginal delivery is to be recommended for haemophilia carrier gravidae

Ljung R, Lindgren A‐C, Petrini P, Tengborn L. Normal vaginal delivery is to be recommended for haemophilia carrier gravidae. Acta Pædiatr 1994;83:609–11. Stockholm. ISSN 0803–5253