Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment.

OBJECTIVE: To evaluate the effects of a 14-day intensive insulin therapy and short-term improvement of glycemic control on serum levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in NIDDM patients with poor glycemic control. RESEARCH DESIGN AND METHODS: A total of 16 NIDDM patients were compared with 23 healthy subjects (control group) and investigated before and after intensive insulin treatment. RESULTS: On day 0, sE-selectin and sVCAM-1 levels were significantly higher in NIDDM patients than in nondiabetic control subjects (median 87, range 63-115; median 544, range 408-797 vs. 58, 43-80; 443, 395-573 ng/ml, respectively) (P < 0.008 in both cases). On day 15, the fall in sE-selectin levels was significant (P < 0.0001) and at a lesser extent in sVCAM-1 levels (64, 48-85; 506, 417-678 ng/ml, respectively); these levels reached values that no longer differed from those of control subjects (P = 0.23 and 0.15, respectively). Moreover, the fall in sE-selectin was positively associated with the change in LDL cholesterol and the improvement of glycemia. CONCLUSIONS: In poorly controlled NIDDM patients, sE-selectin levels are increased and significantly fall to normal after short-term improvement of glycemic control. This suggests that assaying sE-selectin makes it possible to detect endothelium activation and to follow its reversal with euglycemia.

High levels of circulating thrombomodulin in human foetuses and children.

Thrombomodulin (TM) is an endothelial cell surface proteoglycan with anticoagulant functions, also implicated in cell proliferation, cell-cell adhesion and differentiation. In this study we determined circulating plasma TM (pTM) levels in human foetuses at different stages of pregnancy, at birth and in childhood. TM levels increased with gestational age, the median level reaching a peak of approximately 165 ng/ml between the 23rd and 26th week, thereafter decreasing gradually, reaching a value of 108 ng/ml at birth. pTM continues to decrease progressively during childhood, reaching in the 5-15 years group a median of 56 ng/ml which approaches the adult value. The pTM peak was statistically significant and represents a specific foetal phenomenon as it was independent of the corresponding maternal values. As a whole, the pTM pattern during foetal maturation appears totally different from that of protein C, prothrombin and other coagulation activators and inhibitors and thus, TM may play in the foetus another role in addition to its well-known anticoagulant function.

Hyperinsulinemia and hypofibrinolysis: effects of short-term optimized glycemic control with continuous insulin infusion in type II diabetic patients.

A defect in the fibrinolytic system results from an increase in type 1 plasminogen activator inhibitor (PAI-1) in diabetes. It can be considered an independent risk factor for the development of cardiovascular disease. In obese and type II diabetic patients, plasma PAI-1 level correlates with fasting insulinemia. However, during the euglycemic clamp, acute hyperinsulinemia does not increase PAI-1 production. The present study was undertaken to investigate the effect of optimized glycemic control by continuous subcutaneous insulin infusion (CSII) on the hypofibrinolytic state for 14 days in 16 type II diabetic patients with poor metabolic control despite maximal oral antidiabetic treatment. Plasma PAI-1 activity levels decreased from 13.38 +/- 2.85 IU/mL to 6.77 +/- 1.81 IU/mL (P = .002) during CSII, along with a concurrent improvement in insulin sensitivity (index obtained by basal glycemia-nadir glycemia/basal glycemia) during the insulin sensitivity test (0.121 +/- 0.03 v 0.057 +/- 0.02, P = .02). These results suggest that insulin resistance rather than hyperinsulinism may be involved in the hypofibrinolytic state in type II diabetic patients. The positive correlation between the changes in triglycerides and in PAI-1 activity (r = .589, P = .026) strongly suggests a role for triglycerides in the impairment of fibrinolysis, which could be a link between insulin resistance and hypofibrinolysis.

Fibrinogen Bondy: a new case of dysfibrinogenemia. Isolation of the abnormal fibrinogen molecules.

In a 81 year old health woman, gross abnormalities of fibrin formation led to the discovery of an abnormal fibrinogen named fibrinogen Bondy. Clottability of purified fibrinogen Bondy was only 53% compared to 95-98% for normal fibrinogen. Functional studies revealed (i) delayed coagulation by thrombin and batroxobin (Reptilase), (ii) incomplete release of fibrino-peptides A and B, (iii) poor fibrin monomer aggregation, (iv) delayed fibrin proteolysis by plasmin. Electrophoretic mobility of fibrinogen Bondy, its three chains and the products of fibrin cross-linking, was normal. Fibrinogen NH2-terminal residues of fibrinogen Bondy were found to be normal. The presence of Ala, in addition to Gly and Tyr in the fibrin clot and its supernatant, showed that a part of fibrinogen molecules was not clotted, i.e. either copolymerised with fibrin or remaining in solutions. Gel filtration of the supernatant allowed the separation of both soluble complexes and fibrinogen. This fibrinogen population was shown to be unclottable by thrombin and to inhibit clotting of normal fibrinogen.

Comparison between the effect of pentosan polysulphate heparin and antithrombin III injections in antithrombin III deficient patients.

Pentosan polysulphate is an heparin analogue which acts via an antithrombin III (AT III) independent pathway. We compared the effect of this drug to that of heparin and AT III infusions in AT III deficient patients. Four patients with AT III congenital deficiency received on three different occasions: (i) an infusion of human AT III concentrate (20 U/kg or 40 U/kg), (ii) an intramuscular injection of pentosan polysulphate (2 mg/kg), (iii) a subcutaneous calcium heparin injection (100 U/kg). AT III infusion inhibits the excessive thrombin generation (46% of inhibition) observed in the plasma of AT III deficient patients during at least 12 hours, but does not modify the factor Xa formation. On the contrary, pentosan polysulphate has a marked effect on both thrombin (62% of inhibition) and factor Xa generation (57% of inhibition) still present 8 hours after injection. Heparin injection has the same effect, more prolonged, as pentosan polysulphate on thrombin generation but is not so effective on impairing factor Xa generation (27% of inhibition). The marked effect of pentosan polysulphate on thrombin and factor Xa generation in these patients is due to its AT III independent mechanism of action.

[Portal vein thrombosis: a rare complication of Crohn disease]. / La thrombose porte: une complication exceptionnelle de la maladie de Crohn.

Among usual extra digestive manifestations of inflammatory bowel diseases, vascular injuries are rare, but often of excessive gravity. The emergence of a portal thrombosis, often accelerated by infection or traumatism, particularly surgical, remains exceptional. We report the case of a young patient who is followed for a severe crohn's disease and affected with a brutal portal vein thrombosis. Although initial prognosis was bad, the patient now lead a normal life ten months after this episode. It's the third described case of portal thrombosis in crohn's disease. We discuss the predisposing role of an acquired protein S deficiency during a estroprogestative treatment.

[Transient dysfibrinogenemia and thrombocytopenia associated with recurrent acute pancreatitis in the course of isotretinoin therapy]. / Dysfibrinogénémie et thrombocytopénie transitoires associées à une pancréatite aiguë récidivante lors d'un traitement par l'siotrétinoïne.

A 17 year-old young man developed two episodes of acute pancreatitis, separated by a 2 year interval and associated with isotretinoin therapy. In 1989, vesicular sludge without lithiasis was evidenced and in 1991, gall bladder stones were found by cholecystectomy. Concomitantly, transient dysfibrinogenemia and thrombopenia were present. It is interesting to note that far away from the use of isotretinoin, the patient suffered from another episode of acute pancreatitis without any coagulation disorder. The involvement of Roaccutane in cellular differentiation is discussed as well as its causal association with acquired dysfibrinogenemia and transient thrombocytopenia.

[Ovarian vein thrombophlebitis and post-partum fever]. / Thrombophlébite de la veine ovarienne et fièvre du post-partum.

INTRODUCTION: Ovarian vein thrombophlebitis (OVT) is a rare but potentially threatening complication of the postpartum period. Diagnosing it may be of some difficulty especially in case of symptoms mimicking appendicitis or pyelonephritis. EXEGESIS: We report 2 patients with postpartum right OVT. The clinical presentation included high grade fever, and pain, lumbar in one case, of the right flank in the other. Pulmonary embolism complicated both cases. CONCLUSION: Diagnostic and therapeutic management of OVT was transformed by progresses in medical imaging during the 1980's. However, optimal duration of anticoagulant treatment and secondary prevention indications have to be determined.

[Circulating anticoagulants excluding hemophilia. Multicenter survey undertaken under the aegis of the French National Society of Internal Medicine apropos of 207 cases]. / Anticoagulants circulants en dehors de l'hémophilie. Enquête multicentrique conduite par le secrétariat à la recherche de la SNFMI à propos de 207 observations.

A retrospective multicentre study, undertaken under the aegis of the French National Society of Internal Medicine, involved 200 subjects with acquired circulating anticoagulants; 130 were female and 77 were male; mean age was 45 +/- 23 years (range: 10 months to 80 years). Mean duration of follow-up was 23 months. In 130 subjects the anticoagulants were detected as a result of a systematic screening examination. The main overt clinical manifestations were haemorrhages, venous or arterial thrombosis and spontaneous abortion. Typing of the anticoagulant, performed in 166 cases, showed the presence of an antiprothrombinase in 141; this enzyme is not responsible for severe bleeding unless it is associated with other disorders of coagulation; less frequent were an anti-factor VIIIc (n = 16) and an anti-factor V (n = 2) anticoagulants. An underlying pathology was found in 172 subjects, including systemic lupus erythematosus (n = 60), induced lupus (n = 11), discoid lupus (n = 3), infection (n = 23), blood disease (n = 19), cancer (n = 15) and vasculitis (n = 15); other factors were pregnancy (n = 5) and medicines (n = 6). The anticoagulant disappeared spontaneously in 10 cases and in 33 of the 115 subjects treated. In subjects with lupus and in children under twelve years of age, an antiprothrombinase was regularly identified at typing.

[Neonatal cutaneous lupus. Necessary interdisciplinary collaboration]. / Lupus cutané néonatal. Nécessaire collaboration interdisciplinaire.

INTRODUCTION: Neonatal lupus erythematosus is a rare syndrome (affecting 5% of the children born of mothers with lupus), characterized essentially by cutaneous lesions and/or congenital auricular-ventricular heart block. It is due to the transplacental passage of maternal antibodies (anti-SSA or anti-SSB, or occasionally anti-U1RNP antibodies) into the fetal circulation. OBSERVATION: We report a case of neonatal lupus erythematosus, having appeared 4 weeks after birth. The 26 years old mother exhibited systemic lupus erythematosus concomitant to Gougerot-Sjögren's syndrome, with positive antinuclear factors (1/2560), native anti-DNA, anti-SSA and anti-SSB antibodies and anticardiolipin antibodies. During pregnancy, the mother had been treated with aspirin at the dose of 100 mg/day, followed by subcutaneous enoxaparin 0.4 ml/day, and combined with prednisone 10 mg/d and hydroxychloroquine 400 mg/day. Early and regular cardiac monitoring of the foetus was performed. The clinical examination and the electrocardiogram at birth were normal. Four weeks later, the infant presented with erythematous cutaneous lesions with atrophic center. No systemic treatment was initiated and the lesions partially regressed. CONCLUSION: Cutaneous lesions can also appear after the 4th week of life. It is important that the pediatricians clinically monitor all the children born to mothers exhibiting anti-SSA or anti-SSB antibodies, at least during the first 7 months of life.

European registry of infants born to mothers with antiphospholipid syndrome: preliminary results.

The registry is an European, multicentre, prospective and longitudinal study which follows a cohort of children born to mothers with antiphospholipid syndrome (APS). In this article we report preliminary results obtained from 138 mothers and 141 babies (three twin pregnancies). At birth, 16.3% of neonates were less than 37 weeks of gestation and 17% were low birth weight; in addition, 11.3% of neonates were small for gestational age. No cases of neonatal thrombosis were observed. During follow-up period five children showed behavioral abnormalities. A long term clinical follow-up will be necessary to evaluate the neuropsychological development of these children.

European registry of babies born to mothers with antiphospholipid syndrome: a result update.

The registry is a prospective, European, multicentric, longitudinal study, which follows a cohort of children born to mothers with antiphospholipid syndrome (APS). It was started in 2003. In this report, we update the results obtained from the study of 110 mothers and 112 children (two twin births). Eighty per cent of the mothers (n = 86) had primary APS. Purely obstetrical, thrombotic and mixed (obstetrical and thrombotic) APS represent 65.5 %, 21.8 % and 12.7 % of the whole cohort respectively. Isolated antiphospholipid antibodies and isolated anticardiolipin antibodies positivity were present in 50 of 109 (46%) and in 34 of 109 (31%) of the pregnant women, respectively. In the babies, in spite of a high rate of prematurity (14.3%) with four (3.6%) of the premature babies born before 33 weeks of gestation and an increased number of newborns small for gestational age (17%), the large majority of the neonates were healthy. Thirty-one infants are now older than 24 months. Among them, three displayed behavioural abnormalities before 3 years of age. After completing data, there will be the possibility to evaluate the newborn status in relation to the mothers' diseases, treatments and antibodies and to follow the neuropsychological development and immunological evolution of the babies during the next 5 years.

Antithrombin III versus prothrombin in liver cirrhosis.

In patients with liver cirrhosis, a close relationship was observed between the respective levels of antithrombin III and prothrombin, both below 50% in 20 our 27 patients. The absence of any thrombotic complication, despite low plasma antithrombin III, suggests that the preserved balance between the inhibitor and the zymogens of the inhibited enzymes could have a protective effect against thrombotic tendency.

Activated partial thromboplastin time performed on capillary blood.

Activated partial thromboplastin time is one of the most frequently used assay in haemostasis investigation, but sampling of venous blood is often difficult in newborns (as well as some adult patients). We analysed a method described by Zondag et al [9] performed on capillary blood samples. We studied normal adults and newborns, patients with liver diseases, and those receiving therapy with vitamin K antagonists and heparin. Capillary assay was correlated with venous blood in normal subjects, in patients with liver diseases and during therapy by vitamin K antagonists. However results both in newborns and adults during heparin therapy were not accurate.

Risk of thromboembolism in relation to an in-vitro fertilization programme: three case reports.

Severe thrombotic events following ovarian stimulation for in-vitro fertilization (IVF) procedures in three women are reported. None of these patients presented any concomitant clinical sign of ovarian hyperstimulation syndrome. Coagulation inhibitors were in the normal range but cardiovascular risk factors were present. It is postulated that early thrombosis could be favoured by high endogenous plasma oestrogen concentrations subsequent to ovarian stimulation when associated with another risk factor. Our data are discussed in relation to previous publications. It is suggested that risk factors must be considered individually before each IVF attempt. In patients at high risk, clinical management of the post-transfer period is recommended.

[Familial thromboembolic disease associated with antithrombin III deficiency (author's transl)]. / Maladie thrombo-embolique familiale et déficit en antithrombine III.

The authors report the observation of a new kindred with hereditary antithrombin III deficiency. In the last three generations, the family comprised 10 subjects, 7 of whom were affected: the grandmother had recurrent thrombophlebitis; her three sons died from pulmonary embolism at 22, 26 and 28 respectively and her daughter had repeated bouts of thrombophlebitis. In patients with hereditary antithrombin III deficiency, venous thrombosis occurs under similar conditions as, and is clinically similar to, thrombosis in patients without this defect. Usual tests of hemostasis are normal. The diagnosis is however suspected through an history of recurrent episodes and of similar cases in relatives. The diagnosis is confirmed by demonstration of low levels of antithrombin III in suspected patient and family. The disease is transmitted as autosomic dominant trait. Heparin is ineffective but oral anticoagulants may prevent occurence or recurrence of thrombosis in patients with this genetic defect.

[Mitral valve prolapse and Willebrand disease. Study of 16 cases of Willebrand disease]. / Prolapsus valvulaire mitral et maladie de Willebrand. Etude sur seize cas de maladie de Willebrand.

We studied mitral valve morphology and kinetics in 16 children aged 3 to 15 years with documented von Willebrand disease. Mitral valve prolapse was demonstrated in four cases (25%); this result is consistent with findings of similar studies in adults. This non-random association between mitral valve prolapse and von Willebrand disease, as well as embryologic evidence and reports of other conditions found in patients with von Willebrand disease, suggest that mesenchymal dysplasia is the underlying anomaly. Patients with von Willebrand disease and mitral valve prolapse may be at increased risk for cerebrovascular events.