The role of individual risk factors in anticoagulant-associated hemorrhages.

Hemorrhagic complications during therapy with anticoagulant drugs have long been considered as simply and directly related to overdosage. Yet, such adverse events have also been observed in patients correctly anticoagulated, i.e., within the therapeutic range, thus demonstrating that the predictive value of laboratory monitoring is, at best, unclear. There are, indeed, individual risk factors leading to bleeding, despite optimal anticoagulant therapy. They may be totally asymptomatic, but screening for such parameters may also be more or less neglected. It is possible to prevent a good number of these complications provided that individual risk factors are carefully sought. Individual risk factors characterize each patient's destiny; to strive to detect them is the physician's responsibility.

[Monitoring of heparin in the treatment of deep venous thrombosis. An obsolete question?]. / Le "monitoring" de l'héparine dans le traitement des thromboses veineuses profondes. Une question dépassée?

For over 25 years, it has been the rule to monitor heparin in this indication, mostly using the TCA (or APTT) test. The goal to be reached (APTT ratio), not yet definitely defined, results from multiplying an uncertain baseline value (control APTT) by a variable factor (> or = 1.5 control value), these values being, in turn, determined using different reagents not providing uniform responses. With time, it has become clear that it was difficult to maintain the successive APTTs' within the therapeutic range and moreover, that a biologically satisfying monitoring could not, by itself, prevents from complications or clinical failures. Other classical methods experienced the same shortcomings. Low molecular weight heparin fractions have been proved to be easier to administer, since there is no need for biological monitoring. Although persisting a still unresolved problem, heparin monitoring in this indication appears to be, to date, an obsolete situation and in the process of being circumvented.

[Difficulties of assessing postoperative pulmonary embolisms. Risks of meta-analysis from clinical trials]. / Difficultés d'appréciation des embolies pulmonaires postopératoires. Risques d'une méta-analyse des essais cliniques.

During the 1970's, several large clinical trials have shown low dose subcutaneous heparin to be effective in the prevention of post-operative lethal pulmonary embolism. These claims have been widely accepted mainly because the selected main criterion was effectively pulmonary embolism. To-date, this criterion appears to be poorly reliable clinically and ethically unacceptable due to lethal risk. In practically all recent trials with low molecular weight heparin fractions in this indication, the main criterion has been prevention of deep vein thrombosis and not of pulmonary embolism. This is why, among other reasons exposed in this study, it would be hazardous to perform any meta-analysis related to pulmonary embolism from trials which have not been designed for this purpose.

Effects of aprotinin on heparin activities and heparin neutralization with protamine.

In order to investigate the new situation in which aprotinin is proposed as a novel approach to reducing post operative bleeding, specially in cardiopulmonary bypass (CPB) surgery during which heparin and protamine are commonly used, preliminary in vitro and in vivo studies have been performed. Aprotinin increases the anticoagulant heparin effects in vitro, and the hemorrhage time in vivo. But in addition to protamine, there are no statistically significant differences with heparin-protamine situation, indicating aprotinin does not disturb the neutralizing activities of protamine on heparin.

[Prevention of deep venous thrombosis of the leg by a very low molecular weight heparin fraction (CY 222) in patients with hemiplegia following cerebral infarction: a randomized pilot study (30 patients)]. / Prévention des thromboses veineuses profondes des membres inférieurs par une fraction d'héparine de très bas poids moléculaire (CY 222) chez des patients porteurs d'une hémiplégie secondaire à un infarctus cérébral: étude pilote randomisée (30 patients).

The effectiveness and safety of a very low molecular weight heparin fraction were evaluated in the prevention of deep-vein thrombosis in patients confined to bed due to hemiplegia consecutive to a recent cerebral infarction. CY 222 was administered within 48 hours of the stroke by one single daily subcutaneous injection of 0.6 ml (= 15,000 U AXa IC) during 14 days. This randomized pilot study involved 30 patients. The effects of CY 222 were assessed in a group of 15 patients compared with a control group of 15 untreated patients. No deep-vein thrombosis was detected by the labelled fibrinogen test in the treated group, as against 12 patients in the control group. Six patients (3 in each group) died during the study. One case of lethal pulmonary embolism was observed and confirmed at autopsy in the control group. In the remaining 5 patients, no systematic autopsy which would have asserted the absence of pulmonary embolism or drug-induced haemorrhage was performed. Numerous standard laboratory tests confirmed that CY 222 was well tolerated.

Strategy for the development of the low molecular weight heparin fraction CY 216 in the prevention of postoperative deep vein thromboses in general surgery.

The polymorphism in the composition and actions of heparin and the parallel complexity of the thrombotic process have led to the design of a cautious, methodical, and pragmatic program of development of the first low molecular heparin fraction presently available in France (CY 216). The main idea was always to present the objective observation of facts and to reject any theoretical construction. After many stages, the value of this fraction in this indication, which appears as safe as possible but more effective than unfractionated heparin, has become obvious.

[Treatment of acute pulmonary embolism with a low molecular weight heparin by the intravenous route. Study of the optimal dosage]. / Traitement des embolies pulmonaires aiguës par une héparine de bas poids moléculaire par voie intraveineuse. Recherche de la posologie optimale.

Experimental studies on rabbits have shown that CY 222, a low molecular weight heparin (mean: 2.500 daltons), has the anti-thrombosis properties of heparin but reduces the risk of haemorrhage in optimal doses of 1.000 AXa IC (Institut Choay) units/kg/day. The safety and effectiveness of CY 222 were tested in 47 patients presenting with a less than 5 days' old pulmonary embolism. The patients were divided into three groups according to dosage: group I (n = 16) received 500 AXa ICu/kg/day; group II (n = 17), 750 AX ICu/kg/day, and group III (n = 14), 1.000 AXa ICu/kg/day. The drug was administered by continuous intravenous infusion during 10 days. Its effectiveness was assessed from the Miller index calculated on conventional pulmonary angiograms on days 0, 5 and 10. On the 10th day of treatment, the percentage of revascularization was similar in all three groups (group I 65.9 +/- 9.9 p. 100; group II 71 +/- 6.8 p. 100; group III 68 +/- 8.5 p. 100), but the improvement was significantly more rapid in group III patients. Embolism recurred in 5 cases (2 in group I, 1 in group II, 2 in group III) and was fatal in 1 case (group I). Haemorrhagic complications were noted in 3 cases (group III patients). Except for thromboelastography, all coagulation tests were unmodified by CY 222. The anti Xa and the (very low) anti IIa activities of the drug were directly related to the doses administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in plasma fibrin degradation products as a marker of thrombus evolution in patients with deep vein thrombosis.

The level of fibrin degradation products (fdp) as a marker of fibrin clot dissolution was studied prospectively in 51 patients with phlebographically identified deep vein thrombosis (DVT). For this purpose a highly sensitive fdp assay using an anti D neo monoclonal antibody (McAb) was used. At the onset of the hospitalization, in 47 (92%) of the 51 patients tested, the plasma fdp level performed was high, but does not reflect the size of the thrombus, demonstrating that spontaneous thrombus lysis varies from one patient to another. During 10 days of standard heparin or low molecular weight heparin treatment, two different patterns of fdp evolution could be identified in these patients, independent of the type of heparin used. The first was characterized by a gradual decrease in fdp level and a corresponding reduction in the thrombus size. The second pattern showed a persistence of high levels of fdp after 10 days of therapy although the phlebographic score reveals a poor or partial response indicating that fibrinolysis or the balance of thrombus formation/fibrinolysis did not insure total thrombus dissolution. The 4 patients whose initial plasma fdp levels were only slightly increased during the 10 days, seem to have poor thrombolysis, as was shown by the unmodified phlebographic score after 10 days of treatment. Consequently, we conclude that the investigation of plasma fdp levels with a highly sensitive assay should contribute to the evaluation of thrombus evolution in DVT.