Fibrinogen Geneva, a new case of A alpha 16 Arg----Cys dysfibrinogenaemia.

A new congenital variant of fibrinogen, from which only half the normal amount of fibrinopeptide A can be released by thrombin, was found in three members of a family having no major bleeding or thrombotic tendency. Following carboxamidomethylation of the reduced fibrinogen chains, an abnormal peptide was cleaved by thrombin from the amino terminus of the A alpha-chain (A* alpha 1-19) and isolated by reversed phase high-performance liquid chromatography. Amino acid analysis indicated the presence of carboxymethyl cysteine in this A alpha-chain fragment which in normal fibrinogen is devoid of cysteine. We conclude that fibrinogen Geneva is another fibrinogen variant with the substitution A alpha 16 Arg----Cys.

Anticoagulation by ancrod for carbon dioxide removal by extracorporeal membrane lung in the dog.

Ten dogs were subjected to defibrinogenation with an intravenous perfusion of ancrod (1 unit/kg) (Arvin, Knoll AG, Ludwigshafen, Federal Republic of Germany) over a 2 1/2 hour period. Six of them were subjected to extracorporeal elimination of carbon dioxide with a polypropylene membrane lung by means of veno-venous bypass. The remaining four dogs did not undergo extracorporeal circulation and served as control subjects. In both groups, ancrod administration itself resulted in a marked drop in alpha 2-antiplasmin (33% and 67%, respectively, of the baseline values) and in slight but significant decreases in factor II and plasminogen activities of 25% and 20%, respectively (p less than 0.05), in the group subjected to carbon dioxide removal. There were no significant changes in platelet number or factor V and antithrombin III activities. During the 6-hour bypass period, platelet count and antithrombin III and factor II and V levels decreased significantly. No bleeding was observed. Histologic examination of lung biopsy tissue showed no pathologic features. Analysis of the membrane of the artificial lungs revealed no fibrin deposits. In the control group, except for a drop in alpha 2-antiplasmin levels (54%), no significant changes in hemostatic parameters occurred during the corresponding 6 hours. We conclude that, despite the drop in coagulation factors and in alpha 2-antiplasmin activity during bypass, ancrod can be considered as a valuable alternative anticoagulant for extracorporeal carbon dioxide removal.

[Prolonged anticoagulation following chlorophacinone poisoning]. / Anticoagulation prolongée lors d'une intoxication à la chlorphacinone.

In 1985 and 1986 the Swiss Toxicologic Information Center registered 152 cases of rodenticide poisoning. Among those substances chlorophacinone, an indanedione derivative, has a prolonged antivitamin K effect. We report here the case of an eighteen-year-old female hospitalized 3 days after deliberately ingesting some 100 mg chlorophacinone. Her Quick time at admission was less than 10% (Prothrombin time 79 sec., normal control 12 sec.). Under high dose vitamin K therapy the Quick was rapidly corrected but fell again on each vitamin K withdrawal. In a search for a relation between the variations of prothrombin time and chlorophacinone plasma levels, these were assessed by HPLC. Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion. Clinical condition remained satisfactory throughout and other biological parameters unaffected. This case emphasizes the need for prolonged clinical and laboratory follow-up for rodenticide intoxications and for vitamin K administration for several weeks.

[Acquired hemophilia. Apropos of a case report with a fatal course]. / Hémophilie acquise. A propos d'une observation avec évolution fatale.

We report the case of an 86-year-old female with an unremarkable past history who suddenly developed severe and generalized bleeding. Laboratory work-up revealed prolonged aPTT, a factor VIII level of 7% and the presence of a factor VIII inhibitor. In spite of whole blood, factor VIII concentrates and immunoglobulin administration, the patient died of multiple hemorrhages on the third day after admission. At autopsy no causal or associated pathology could be found. Chromatographic separation of plasma immunoglobulins showed that the anti-factor VIII activity was associated with the patient's IgG. This inhibition was partially corrected in vitro by injectable immunoglobulin preparation. The case report stresses the discrepancy between the measured levels of inhibitor and the severity of the bleeding; our in vitro results may shed light on the mode of action of intravenous immunoglobulins.

Comparison between a low molecular weight and standard heparin for anticoagulation during extracorporeal CO2 removal in the dog.

Anticoagulant properties towards an artificial surface of a chemically depolymerized low molecular weight heparin (LMWH) have been compared to those of a standard heparin (SH). The experimental model consisted in a seven hours extracorporeal veno-venous bypass for CO2 removal (EC-CO2R) using a membrane lung. Four animals received 150 anti-FXa U/kg followed by 40 anti-FXa U/kg/h of LMWH or 300 IU/kg followed by 100 IU/kg/h of SH. Mean Factor Xa inhibition was 49% in LMWH group and 28.5% in SH group. Mean Factor IIa inhibition was 31% and 49% respectively. After three hours of bypass fibrin deposition occurred in the reservoir in three out of four dogs receiving LMWH while none was observed under SH. No statistically significant difference between the two groups was found for any of the coagulation parameters tested (fibrinogen, factor V, antithrombin III, plasminogen, alpha 2-antiplasmin, platelet counts). At the end of bypass 5000 U protamine abolished both anti-FXa and anti-FIIa activities in the SH group but failed to neutralize more than half of the anti-FXa activity in the LMWH group. These results suggest that high anti-FIIa activities are required to prevent fibrin formation induced by artificial surfaces and that equivalent amounts of anti-FXa activities are ineffective for this purpose. In addition the use of LMWH may raise problems when emergency neutralization procedures are required.

[Bernard-Soulier syndrome in a Swiss family]. / Syndrome de Bernard-Soulier dans une famille suisse.

We report the case of a 38-year-old woman with hemorrhagic diathesis. Since early childhood she has suffered from epistaxis, gingival bleeding, ecchymoses and, since puberty, very frequent menorrhagia. Prolongation of bleeding time and thrombocytopenia (100,000 platelets/microliter) with giant platelets were observed. Since idiopathic thrombopenic purpura was suspected, splenectomy was performed. Neither this nor steroid treatment caused any improvement. The patient was able to give birth to an unaffected child, but delivery was followed by a major hemorrhage. In 1986, hysterectomy was considered because of frequent menorrhagia and, therefore, the patient's hemostasis was reinvestigated. The aforementioned abnormalities were confirmed and complementary examinations by electron microscope revealed giant platelets without granular abnormalities. While von Willebrand factor was normal, ristocetin agglutination was defective and analysis of platelet membrane glycoproteins showed absence of glycoprotein Ib. - These observations prompted the diagnosis of Bernard-Soulier syndrome. The study of the family demonstrated that 6 family members were heterozygote. This is believed to be the first large Bernard-Soulier family reported in Switzerland.

Antithrombin III Geneva: a hereditary abnormal AT III with defective heparin cofactor activity.

A 43-year-old man presented a pulmonary embolism. The unusual circumstances of apparition, the age and the increased heparin requirements suggested an antithrombin III (AT III) deficiency. AT III activity was low in the propositus and seven other members of his family (mean 55%), but immunologic levels were normal (mean 110%). Crossed immunoelectrophoresis in absence of heparin showed a normal pattern, but in presence of heparin showed an abnormal peak as compared with controls. Kinetics experiments showed a normal inhibition of thrombin and Xa in absence of heparin, but abnormal in presence of heparin. Affinity chromatography on heparin-Sepharose revealed two populations of AT III, one of which was devoid of heparin cofactor activity. The toponym AT III Geneva is proposed for this new familial abnormal AT III with defective heparin cofactor activity.

[Femoral artery thrombosis associated with heparin-induced thrombopenia]. / Thrombose artérielle fémorale associée à une thrombopénie induite par l'héparine.

We report a case of acute thrombosis of the common femoral artery which occurred on the tenth day of postoperative prophylactic heparin therapy. Platelet count was 14,000/mm3 at the time of the acute event. Cessation of heparin administration resulted in progressive normalization of the platelet count. Iliofemoral thrombectomy, followed by popliteal thromboembolectomy, allowed successful recanalization of the occluded arteries, after failure of local thrombolysis with low-dose streptokinase. The pathogenesis, diagnosis and treatment of heparin-induced thrombocytopenia associated with thromboembolic complications are discussed.

[Hypercoagulability syndrome associated with cerebral lesions. Prospective study of coagulation during surgery of primary brain tumors (17 cases)]. / Syndrome d'hypercoagulabilité lors de lésions cérébrales. Etude prospective de la coagulation lors d'opérations pour tumeurs primitives du cerveau (17 cas).

Variations in hemostatic factors have been studied in 17 patients undergoing neurosurgical operations for intracerebral primary tumors. Clotting time (plastic and glass), recalcification time (Howell), plasma fibrinogen level, fibrin split products, partial thromboplastin time, Quick and platelet count were measured before and after the surgical procedure and several times during the following 24 hours. Hemostasis was significantly disturbed, with maximal hypercoagulability 2 hours after operation. In 3 patients, fundus examination showed occlusion of retinal vessels. In all cases the surgical trauma was relatively minor compared with severe cerebral contusion, but was nevertheless enough to disturb the measured parameters, which appear to be sensitive indicators for assessing the severity of cerebral lesions, especially in cases of contusion. A systematic fundus examination is also of diagnostic interest. The state of blood hypercoagulability may lead to disseminated intravascular clotting (DIC) and therefore prophylactic heparin therapy should be administered.

[Endogenous prostacycline and coronaropathy. Plasma levels of 6-keto-PGF1 alpha]. / Prostacycline endogène et coronaropathie. Dosage de la 6-kéto-PGF1 alpha plasmatique.

Prostacycline may play a preventive role in the development of ischaemic complications of coronary atherosclerosis through its vasodilatory and platelet antiaggregant properties. Its biological instability makes it difficult to measure in the plasma; however, it is possible to determine plasma concentrations by radioimmune assay of one of its stable derivatives, 6-Keto-prostaglandin F1 alpha (6KPGF1 alpha). Systemic plasma concentrations at rest of 30 patients with severe atherosclerosis were not significantly different from those of healthy control subjects (7.5 +/- 6.5 vs 10 +/- 5 pg/ml). In addition ischaemia during exercise is not associated with significant variations; at rest 7.1 +/- 6 pg/ml in the "ischaemic" group (n = 20) compared to 7.6 +/- 6.4 pg/ml in the "non-ischaemic" group (n = 10); on effort: 9 +/- 10 pg/ml compared to 13.3 +/- 14 pg/ml. These results show that measuring the plasma 6KPGF1 alpha by peripheral vein blood sampling is of no use in the diagnosis of coronary atherosclerosis or of myocardial ischaemia on effort.

[Platelet function and coronary disease: demonstration of a so-called unstable platelet syndrome]. / Fonction plaquettaire et maladie coronarienne: mise en évidence d'un "syndrome d'instabilité plaquettaire".

Radio-immunological assay of specific platelet substances in the serum allows assessment of in vivo platelet function at a given moment. Plasma levels of beta thromboglobulin (beta TG) platelet factor 4 (PF4) and thromboxane B2 (TXB2) were measured at rest and during exercise stress testing in 39 patients with known coronary artery disease with stable effort angina. The patients were divided into two groups according to the results of exercise ECG and thallium 201 myocardial scintigraphy: ischaemic (n = 28) and non-ischaemic (n = 11). Resting and exercise levels of the three platelet substances were compared with a group of normal controls (n = 14). The average control values at rest and on exercise were, respectively: PF4: 8.5 +/- 5 and 22 +/- 14 ng/ml; beta TG: 36 +/- 17 and 68 +/- 36 ng/ml and TXB2: 112 +/- 41 and 201 +/- 81 pg/ml. The average values of the non-ischaemic patients did not differ significantly, either at rest or during exercise. The variation of pathological values was higher in the ischaemic group. This seems to reflect the absence of univocal platelet behaviour and does not allow statistical comparison of mean values. Our results suggest the existence of an "unstable platelet syndrome", which seems to be associated with poor effort tolerance especially when present under resting conditions. There would seem to be a causal relationship between platelet instability and myocardial ischaemia, which would justify anti-platelet aggregation therapy in primary and secondary prophylaxis of myocardial infarction.

Anticoagulant properties of three mucopolysaccharides used in rheumatology.

Three mucopolysaccharides (MPS) used in the treatment of degenerative joint disease were compared to heparin to establish their relative potencies on 3 coagulation tests, the aPTT, the antifactor Xa activity and the dilute thrombin time. One of the compounds, Arteparon, was one fourth as potent as heparin on the aPTT, but had little or no influence on the 2 other tests. Further in vitro studies suggested that Arteparon acted at a higher level than factor Xa generation in the intrinsic amplification system and that its effect was independent of antithrombin III. In vivo administration of Arteparon confirmed its anticoagulant properties, which raises the question of the clinical use of this MPS.

Haemostatic changes during open heart surgery with extracorporeal circulation and deep hypothermia in children.

The haemostatic status of twenty children with cyanotic and acyanotic cardiopathies was studied before, during and after cardiopulmonary bypass (CPB) under deep hypothermia and haemodilution. Eleven patients had various haemostatic troubles before surgery. Haemodilution with a crystalloid solution to an haematocrit of 21,8 vol. +/- 1,3% resulted in a severe lowering of all coagulation factors. Forced diuresis after CPB induced partial normalization. The observed alterations included moderate thrombocytopenia, prolongation of the prothrombin time, transient decrease of factors V and plasminogen, elevation of fibrin degradation products (FDP), significant lowering of factor VII-X, marked elevation of factor VIII and mild increase of fibrinogen. No correlation was found between coagulation abnormalities and postoperative bleeding, duration of CPB or type of cardiopathies. It is concluded that CPB with haemodilution proves as safe as more conventional approaches in respect to coagulant activities.

Skeletal changes in congenital fibrinogen abnormalities.

We report an anatomico-radiologic study of humerus, femur, and tibia from a case of total congenital afibrinogenemia. Juxtatrabecular hemorrhages occur mainly in metaphyses and seem to be related to normal lines of stress. They may lead to the formation of intraosseous cysts and to a remodelling of bone trabeculae. The radiologic lesions in a second case, diagnosed as congenital dysfibrinogenemia, are similar to those found in Case 1 (femoral trabeculae remodelling) but also resemble some alterations described in hemophilia (pseudotumor of the right iliac bone). Anatomic study of the lesions in Case 2 was not possible. The significance of these observations could be better defined by a more extended skeletal study (radiologic and when feasible anatomic) of patients with congenital clotting defects and especially with inherited disorders of the fibrinogen molecule. It would also be worthwhile investigating manifest or latent hemostatic disorders (particularly at the fibrinogen level) in patients with solitary or aneurysmal bone cysts, and even with bone infarct or unexplained trabecular remodelling.

[Heparin treatment. Comparison between intravenous and subcutaneous administration]. / Traitement héparinique. comparaison entre les voies d'administration intraveineuse et sous-cutanée.

48 patients with acute deep venous thrombosis of the lower limbs were treated with sodium heparin. In 23 patients heparin was injected subcutaneously (s.c.) twice a day and in 25 patients heparin was given by continuous intravenous perfusion (i.v.). Pain and edema disappeared after 8.7 days (s.c.) and 11.7 days (i.v.) respectively. One non fatal pulmonary embolism occurred in each group. A second venography was performed in 24 patients after 7 days of treatment and revealed no difference between the two groups. As judged by repeated thrombin time determination, anticoagulation was ineffective on at least one day in 39% of patients treated subcutaneously and in 60% of patients treated intravenously. The two pulmonary embolisms occurred in patients with ineffective anticoagulation. It is concluded that heparin may be used either intravenously or subcutaneously in the treatment of acute deep venous thrombosis. Thromboembolic complications occurred with both methods of treatment when anticoagulation was ineffective.

Evidence for an HLA-linked resistance gene in Buerger's disease.

The incidence of Thromboangiitis Obliterans in brothers and the high prevalence in some ethnic groups have led us to investigate the histocompatibility HLA-A, B and DR antigens of 46 Buerger's disease patients. The main result indicates a marked decreased freqeuncy of the B12 antigen: 2.2% vs 28% in controls. Our study suggests that Buerger's disease is, on the basis of HLA antigens, a distinct immunogenetic entity and not a particular form of arteriosclerosis. Moreover, this disorder may represent a clue to the existence of resistance genes linked to HLA.