Antistreptokinase platelet-activating antibodies are common and heterogeneous.

BACKGROUND: Platelet activation by antistreptokinase (SK) antibodies could impair the clinical effect of SK administration. OBJECTIVE: To better describe anti-SK antibodies with particular emphasis on procoagulant activities as a result of platelet activation. PATIENTS AND METHODS: Sera were collected from 146 patients with coronary artery disease: non-SK-treated, 95 from mainland France, 31 from French Polynesia; 20 patients from mainland in year 2 after SK treatment. Serum-induced SK-dependent platelet activation resulting in procoagulant activities was assessed with washed platelets from five donors representative of the known patterns of reactivities to IgG. RESULTS: Concentrations (2-5252 microg mL(-1)) and fibrinolytic neutralization titres (< 10 to > 1280) were found in the expected wide range and correlated (rho = 0.66, P < 0.0001). Platelet activation was detected with 145 samples, but varied in intensity and pattern (depending on the donors), although there was no systematic hierarchy; it was presumably due to IgG (inhibited by an IgG Fc receptor-blocking antibody and recovered in the IgG fraction) and only partially affected by aspirin. Marked platelet activation could be detected in samples with concentration as low as 2 microg mL(-1), and/or no detectable neutralizing titers. The way of immunization to SK was not found to influence the functional profile of antibodies. CONCLUSION: Anti-SK platelet-activating antibodies are widespread, heterogeneous, poorly predictable on the basis of their antifibrinolytic effect and strong enough to trigger procoagulant activities. Their clinical relevance should be formally assessed, using patients' own platelets for detection owing to the variation of platelet reactivity.

Lack of agreement between left ventricular volumes and ejection fraction determined by two-dimensional echocardiography and contrast cineangiography in postinfarction patients.

OBJECTIVE: To assess the agreement between left ventricular (LV) volumes and ejection fraction (EF) determined by two-dimensional echocardiography (2-D echo) and by cineangiography in postinfarction patients. DESIGN: LV end-diastolic and end-systolic volumes indexed (EDVI and ESVI) to body surface area as well as EF were determined by both methods in all patients. SETTING: Multicenter trial conducted in five university hospitals. PATIENTS: 63 patients, 61 male, two female, mean age 55.5 +/- 10.4 years, suffering from a recent myocardial infarction. Eighty-one pairs of measurements were available. METHODS: The results of biplane 2-D echo measures, using apical four-chamber (4C) and two-chamber (2C) views were compared to those of a 30 degrees right anterior oblique cineangiography projection, using either the apical method of discs or the area-length 2-D echo method. Moreover, eyeball EF was estimated at 2-D echo and cineangiography, and was compared to the conventional methods. The agreement between results was assessed by the Bland and Altman method. RESULTS: The agreement between 2-D echo and cineangiography results was poor. Mean differences (MD) were -21.8 (EDVI, ml/m(2)), -9.5 (ESVI, ml/m(2)), and -0.9 (EF, %), respectively for 2-D echo method of discs versus cineangiography, and -23.2, -9.3, and -5.7 for area-length 2-D echo versus cineangiography. For EF (%), MD was -3.6 for eyeball cineangiography versus cineangiography, -1.3 for eyeball 2-D echo versus method of discs, and +0.30 for eyeball 2-D echo versus area-length 2-D echo, respectively. Two-dimensional echo is likely to underestimate LV volumes compared to cineangiography, especially for largest volumes. Even for EF, discrepancies are large, with a lack of agreement of 21%-25% between conventional methods, but agreement is better between eyeball EF and usual methods. CONCLUSIONS: Even with modern echocardiographic devices, agreement between 2-D echo and cineangiography-derived LV volumes and EF remains moderate, and both methods must not be considered interchangeable in clinical practice.

Effects of increasing balloon pressure on mechanism and results of balloon angioplasty for treatment of restenosis after Palmaz-Schatz stent implantation: an angiographic and intravascular ultrasound study.

Repeat balloon angioplasty is a widely used therapeutic option for in-stent restenosis, but the optimal balloon inflation pressure has not yet been determined. We used angiography and intravascular ultrasound imaging to assess the mechanism and results of lumen enlargement at various inflation pressures. Thirteen consecutive patients with restenosis post-Palmaz-Schatz stent implantation were submitted to a four-step balloon angioplasty using increasing balloon pressure of 2, 4, 8, and >12 atm. As a global result, the lumen size was only 80% of that observed at stent implantation. Significant changes in angiographic minimal lumen diameter, minimal lumen cross-sectional area, and lumen volume were observed after each step except after the highest-pressure inflation. At low inflation pressure (<8 atm), the decrease in neointimal tissue and the stent over expansion explained the lumen enlargement, whereas after further high inflation pressure (>8 atm), only additional stent over expansion was observed. These results suggest that only moderate balloon inflation pressure (up to 12 atm) is needed for angioplasty of post-Palmaz-Schatz stent restenotic lesions.

Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent--a pilot study in the setting of coronary angioplasty.

AIM OF THE STUDY: To assess the antithrombotic properties of SR90107/ORG31540. a sulfated pentasaccharide, which enhances specifically antithrombin III mediated inactivation of factor-Xa, in a clinical setting known to promote arterial thrombosis, i.e. coronary angioplasty. METHODS AND RESULTS: Percutaneous transluminal coronary angioplasty (PTCA) was carried out with conventional balloons with a single 5 min intravenous infusion of 12 mg pentasaccharide, and 500 mg intravenous aspirin. Heparin was not allowed before, during PTCA, and within 24 h after PTCA. The primary end point was the rate of abrupt vessel closure during and within 24 h after the procedure. The sample size was set at 60 evaluable patients, in order to be able to conclude with a good level of confidence (>95%) that the abrupt vessel closure rate was less than 10%, if less than 3 abrupt vessel closures were observed. Seventy-one patients were included in the study, of whom 10 needed elective stenting, and were not considered as evaluable for efficacy. Two out of the 61 remaining evaluable patients experienced acute vessel closure during the study period [3.28%, 95% confidence interval (0.4%; 11.4%)]. No major bleeding occurred. The drug plasma concentrations reached 1.91+/-0.39 mg/], 10 min after pentasaccharide injection, and decreased on average to 1. 18+/-0.27 mg/l at 2 h, and to 0.36+/-0.11 mg/l at 23 h after administration of pentasaccharide. Activated clotting time (ACT) and activated partial thromboplastin (aPTT) time remained within normal range. Thrombin-antithrombin complex levels fell from 22+/-17.1 to 4.5+/-3.4 microg/ml, prothrombin fragment 1+2 levels decreased from 2.15+/-1.01 to 1.73+/-0.87, and activated factor VII levels decreased from 43.4+/-16.8 mU/ml to 18.9+/-7.3 mU/ml respectively from baseline to 2 h following injection of the tested drug. CONCLUSIONS: Administration of pentasaccharide led to the inhibition of thrombin generation without modification of aPTT and ACT. The rate of abrupt vessel closure was within range of rates reported in historical series. Thus we conclude that the anti-thrombotic activity of pentasaccharide, as shown in this pilot trial in the setting of coronary angioplasty, deserves further investigation.

Coronary stent for variant angina: atypical presentation.

Pharmacological therapy remains the treatment of choice for Prinzmetal angina. We report an unconventional approach of coronary artery stenting to treat coronary artery spasm in variant angina refractory to triple drug therapy. Favorable clinical and angiographic results and a negative Ergonovine test, under less aggressive medical therapy, are valuable arguments for stenting. Four-month angiographic follow-up showed absence of intrastent restenosis with a negative Ergonovine test. However, long-term follow-up is necessary before advocating this as a systematic approach.

"Rescue" abciximab for complicated percutaneous transluminal coronary angioplasty.

We studied the in-hospital outcome of 138 consecutive patients who received abciximab as a "rescue" intervention for complicated coronary angioplasty in a high-risk clinical setting. "Rescue" treatment with abciximab was associated with clinical and angiographic success rates of 83% and 84%, respectively, whereas the risk of bleeding was higher in patients of low body weight.

Impact of intravascular ultrasound guidance in stent deployment on 6-month restenosis rate: a multicenter, randomized study comparing two strategies--with and without intravascular ultrasound guidance. RESIST Study Group. REStenosis after Ivus guided STenting.

OBJECTIVES: We aimed to investigate the impact of intravascular ultrasound (IVUS)-guided stent implantation on the 6-month restenosis rate, which has not yet been fully established in randomized trials. BACKGROUND: The 6-month angiographic restenosis rate was compared in patients with symptomatic ischemic heart disease who were randomly allocated to angioplasty and stent deployment, with versus without IVUS guidance. METHODS: After successful stent implantation, patients were randomized into two groups: Group A had no further dilation, and Group B had additional balloon dilation until achievement of IVUS criterion for stent expansion. The study group consisted of 164 patients, assuming a 50% reduction of the restenosis rate in Group B (15% vs. 30%) (alpha = 10%, beta = 20%). RESULTS: We enrolled 155 patients. Overdilation was carried out in 31 (39%) of 79 Group B patients, with the IVUS criterion being achieved in 63 (80%) of 79. No significant difference was observed in the minimal luminal diameter (MLD), but the stent lumen cross-sectional area (CSA) was significantly larger in Group B (mean +/- SD) (7.16 +/- 2.48 vs. 7.95 +/- 2.21 mm2, p = 0.04). At 6 months, there was no significant difference in the restenosis rate, (28.8% [21 of 73] in Group A vs. 22.5% [16 of 71] in Group B, p = 0.25), but according to the observed difference in the restenosis rate, the power of the study was only 40%. The difference in MLD was also nonsignificant (1.60 +/- 0.65 mm in Group A vs. 1.70 +/- 0.64 mm in Group B, p = 0.20), whereas the lumen CSA was 20% larger in the IVUS-guided group (4.47 +/- 2.59 vs. 5.36 +/- 2.81 mm2, p = 0.03). Lumen CSA was the only predictor of restenosis by multivariate logistic regression analysis. CONCLUSIONS: A nonsignificant 6.3% absolute reduction in the restenosis rate and a nonsignificant difference in MLD were observed in this study. Nonetheless, we still cannot rule out a beneficial effect of IVUS guidance, although this may have gone undetected owing to a lack of statistical power. A significant increase was observed in immediate and 6-month lumen size, as detected by IVUS, indicating that ultrasound guidance in stent deployment may be beneficial.

Treatment of in-stent restenosis with high speed rotational atherectomy and IVUS guidance in small <3.0 mm vessels.

The management of in-stent restenosis remains a subject for debate because no one revascularization option is considered the most appropriate. Since a high restenosis rate still occurs after repeat balloon angioplasty, new techniques are attempted in order to reduce this rate. A combination of high speed rotational atherectomy (HSRA) and adjunctive balloon angioplasty is likely to achieve good results. In small (<3.0 mm diameter) vessels, the risk of interaction between the burr and the stent increases. We thus used intravascular ultrasound (IVUS) guidance in the treatment of in-stent restenosis with HSRA in small <3.0 mm small diameter vessels. Nine patients with in-stent restenosis in small vessels were referred for repeat angioplasty. Initial IVUS examination was used to assess the minimal stent struts diameter and to guide the burr size selection. A combination of HSRA and additional balloon angioplasty was performed under IVUS and angiographic guidance. Mean angiographic reference diameter was 2.25 +/- 0.35 mm and mean stent struts diameter was 2.38 +/- 0.20 mm. Burr size was selected approximately 0.5 mm smaller than stent struts diameter and ranged from 1.75 to 2.5 mm, with a 0.88 +/- 0.12 mean burr/artery ratio (range 0.71, 1.08). In two patients, a second larger burr was used. In 4/9 patients, the burr size chosen under IVUS guidance was close to angiographic MLD at stent implantation and thus larger than what would be used without IVUS guidance. Additional balloon angioplasty was decided in all cases, using a 1.1 +/- 0.15 balloon/artery ratio. No complication occurred. Mean relative gain in minimal lumen diameter (MLD) was 94 +/- 90% after HSRA and 54 +/- 34% after balloon angioplasty (total relative gain 180 +/- 100%). IVUS guidance allowed safe management of in-stent restenosis in small vessels using combination of HSRA and balloon angioplasty. Long-term follow-up and comparison with other techniques are necessary to assess whether this technique should be used routinely.

Comparative efficacy of a two-hour regimen of streptokinase versus alteplase in acute massive pulmonary embolism: immediate clinical and hemodynamic outcome and one-year follow-up.

OBJECTIVES: This study sought to compare the efficacy of 2-h regimens of alteplase and streptokinase in acute massive pulmonary embolism. The primary end point was immediate hemodynamic improvement, and secondary end points included early clinical efficacy and safety, as well as 1-year clinical outcome. BACKGROUND: Several thrombolytic regimens have been compared for the past 10 years in randomized studies, showing that 2-h infusion regimens of alteplase or urokinase lead to faster hemodynamic improvement than former 12- to 24-h administration protocols in acute massive pulmonary embolism. Many trials have focused on immediate hemodynamic and angiographic outcomes, but none has addressed long-term follow-up after thrombolysis. METHODS: Sixty-six patients with acute massive pulmonary embolism (Miller score > 17 and mean pulmonary artery pressure >20 mm Hg) were randomly assigned to receive either a 100-mg 2-h infusion of alteplase (n = 23) or 1.5 million IU of streptokinase over 2 h (n = 43). In both groups, heparin infusion was started at the end of thrombolytic infusion and adapted thereafter. Total pulmonary resistance was monitored over a 12-h period. Pulmonary vascular obstruction was assessed 36 to 48 h after thrombolytic therapy. One-year follow-up information included death, cause of death, recurrent pulmonary embolism, chronic thromboembolic pulmonary hypertension, stroke and bleeding. RESULTS: Both groups had similar baseline angiographic and hemodynamic characteristics of severity, with maintained cardiac output in 64 (97%) of 66 patients. The results (mean +/- SD) demonstrated that despite a faster total pulmonary resistance improvement observed at 1 h in the alteplase group compared with the streptokinase group (33+/-16% vs. 19 16%, p = 0.006), a similar hemodynamic efficacy was obtained at 2 h when both thrombolytic regimens were completed (38+/-18% vs. 31+/-19%). There was no significant difference in either pulmonary vascular obstruction at 36 to 48 h or bleeding complication rates. One-year event-free survival was similar in both groups, as most events were related to concomitant diseases. CONCLUSIONS: These results suggest that a 2-h regimen of streptokinase can be routinely used in patients with massive pulmonary embolism and maintained cardiac output without obviously compromising efficacy or safety.

Streptokinase vs alteplase in massive pulmonary embolism. A randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction.

OBJECTIVE: The aim of the study was to test the efficacy of recombinant tissue plasminogen activator and streptokinase in massive pulmonary embolism, the primary endpoints being haemodynamic improvement and thrombus lysis, and the secondary endpoints efficacy and safety. DESIGN: Fifty patients with massive pulmonary embolism were randomly allocated either to a 100 mg 2 h infusion of recombinant tissue plasminogen activator followed by a 20 IU.kg-1.h-1 infusion of heparin, or to a 100,000 IU.h-1 12 h infusion of streptokinase after a initial bolus of 250,000 IU over 15 min, followed by heparin infusion of 10 IU.kg-1.h-1. Total pulmonary resistance and right ventricular ejection fraction were monitored over a 12 h period. Pulmonary vascular obstruction was assessed at 24 to 48 h and 10 days after thrombolytic therapy. RESULTS: Thrombolysis occurred more rapidly with recombinant tissue plasminogen activator than with streptokinase, but without any significant difference in terms of right heart haemodynamics at 12 h or in improvement of pulmonary vascular obstruction at 24-48 h or at 10 days. There was no significant difference in bleeding complication rates and no patients suffered intracranial haemorrhage. CONCLUSION: These results proved that, when the full dose of streptokinase has been given over 12 h, its efficacy is as good as that of 2 h of recombinant tissue plasminogen. A further trial aimed at comparing recombinant tissue plasminogen activator and streptokinase infused over a 2 h period is needed to determine whether a similar efficacy can be obtained.

Planimetry of aortic valve area using multiplane transoesophageal echocardiography is not a reliable method for assessing severity of aortic stenosis.

OBJECTIVE: To assess the reliability of aortic valve area planimetry by multiplane transoesophageal echocardiography (TOE) in aortic stenosis. DESIGN: Study of the diagnostic value of aortic valve area planimetry using multiplane TOE, compared with catheterisation and the continuity equation, both being considered as criterion standards. SETTING: University hospital. PATIENTS: 49 consecutive patients (29 male, 20 female, aged 44 to 82 years, average 66.6 (SD 8.5)), referred for haemodynamic evaluation of an aortic stenosis, were enrolled in a prospective study. From this sample, 37 patients were eligible for the final analysis. METHODS: Transthoracic and multiplane transoesophageal echocardiograms were performed within 24 hours before catheterisation. At transthoracic echo, aortic valve area was calculated by the continuity equation. At TOE, the image of the aortic valve opening was obtained with a 30-65 degrees rotation of the transducer. Numerical dynamic images were stored on optical discs for off-line analysis and were reviewed by two blinded observers. Catheterisation was performed in all cases and aortic valve area was calculated by the Gorlin formula. RESULTS: Feasibility of the method was 92% (48/52). The agreement between aortic valve area measured at TOE (mean 0.88 (SD 0.35) cm2) and at catheterisation (0.79 (0.24) cm2) was very poor. The same discrepancies were found between TOE and the continuity equation (0.72 (0.26) cm2). TOE planimetry overestimated aortic valve area determined by the two other methods. Predictive positive and negative values of planimetry to detect aortic valve area < 0.75 cm2 were 62% (10/16) and 43% (9/21) respectively. CONCLUSIONS: Planimetry of aortic valve area by TOE is difficult and less accurate than the continuity equation for assessing the severity of aortic stenosis.

[Long-term outcome of subvalvular aortic stenoses. A comparative study in adults and children]. / Evolution à long terme des sténoses sous-valvulaires aortiques. Etude comparative chez les adultes et les enfants.

The aim of the study was to determine the medium and long-term outcome of discrete subaortic stenosis after surgery: the data of two groups of patients classified according to age (children versus adults) at the time of diagnosis were compared retrospectively. Sixteen patients, with subaortic stenosis, were followed up clinically and by annual echocardiography for an average period of 5.7 +/- 3.6 years (range 1 day to 16 years) and patients in group II were aged 43.6 +/- 6 years (range: 3 to 17 years). Patients in group I were aged 5.4 +/- 4.2 years (range: 37 to 53 years). Four patients from group II had significant aortic incompetence. All but one patient had a membranous stenosis. Seven patients from group I and all in group II underwent surgery during the follow-up period. Four of the 5 adults in Group II were asymptomatic compared with only 1 in group I. Three patients of group II developed left ventricular dysfunction during the preoperative period compared with none in group I. Four patients in group II underwent aortic valve replacement compared with none in group I. Four of the 7 operated patients in group I had recurrence of subaortic stenosis, one of which was a tunnel form. Two reoperations were necessary in group I. There were no recurrences in group II. In conclusion, the poor outcome of adult subaortic stenosis has led to early surgical referral. This attitude should be nuanced in view of the risk of recurrence and of reoperation in childhood.

[Anticoagulant therapy with recombinant hirudin in patients with thrombopenia induced by heparin]. / Traitement anti-thrombique par hirudine recombinante chez des patients ayant une thrombopénie induite par l'héparine.

OBJECTIVES: Heparin-induced thrombocytopenia is an uncommon and severe complication of heparin therapy. Both venous and arterial thromboembolic events can occur, requiring withdrawal of the heparin therapy. When anticoagulant therapy is mandatory, recombinant hirudin can be used. METHODS: We used recombinant hirudin (HBW 023) in 6 patients with heparin induced thrombocytopenia. In case of venous thromboembolism, an initial intravenous bolus (0.07 mg/kg) was followed by continuous infusion (0.05 mg/kg/h); for arterial thromboembolism the initial bolus was 0.7 mg/kg and infusion rate 0.15 mg/kg/h. When possible oral anticoagulants were started and hirudin withdrawn when the INR ratio reached 3. RESULTS: The clinical course was uneventful in all 6 patients. There was no recurrent thromboembolism. Cephalin-activated coagulation time (patient/control) varied between 1.8 and 3.5 (median 2.4) during hirudin administration. Platelet count rose to the nadir (median 70 x 10(9)/l, range 15-90) reaching over 100 x 10(9)/l in all patients between the third and sixth day (median 5 days) after stopping heparin. CONCLUSION: Intravenous administration of hirudin provides effective immediate anticoagulation in patients with heparin-induced thrombocytopenia, thus allowing conversion to oral anticoagulants without risking recurrent thromboembolism.

[Coronary recanalization in the acute phase of myocardial infarction]. / Reperméabilisation coronaire à la phase aiguë de l'infarctus du myocarde.

Early reopening of the infarct-related artery limits infarct size, preserves left ventricular function and reduces short and long term mortality rate. The earlier the reopening, the higher the benefit, the best results being obtained within the first 3 hours, but remaining significant up to 12 hours after onset of symptoms. In addition, complete reperfusion of the infarct-related artery without delay of distal filling enhances the results. Early reopening can be obtained with use of intravenous thrombolysis. The indication of rescue angioplasty in case of failed thrombolysis or of immediate, deferred or elective adjunctive angioplasty after successful thrombolysis remain debated. Contraindications to thrombolysis exist in about 13% of patients, in whom the only solution is direct angioplasty without thrombolysis.

[Severe pulmonary embolism: value of clinical findings and complementary investigations]. / Embolie pulmonaire grave: apports de la clinique et des examens complémentaires.

Pulmonary embolism is severe when pulmonary arterial obstruction affects right heart haemodynamics and gas exchanges. The clinical signs are not very discriminating in the assessment of the severity of pulmonary embolism: shock, neurological signs and cyanosis are the most suggestive signs of severe embolism. Of the routine complementary investigations, normal blood gases does not exclude the diagnosis of even severe pulmonary embolism but when the pO2 is less than 50 mmHg the vascular obstruction is severe. The risk of haemorrhage due to thrombolysis, commonly used in severe pulmonary embolism, is greater after invasive investigations. This makes it preferable to resort to non-invasive investigation initially, echocardiography, spiral computed tomography or pulmonary scintigraphy, depending on which technique is available in an emergency. In a suggestive clinical setting, echocardiographic signs of right ventricular overload and visualisation of a thrombus in the right heart chambers or pulmonary artery on echocardiography or spiral computed tomography practically confirms the diagnosis of severe pulmonary embolism. Transoesophageal echocardiography is more sensitive than transthoracic echocardiography for the visualization of a thrombus in the pulmonary outflow tract, but is not always inoffensive in those patients in an unstable condition. Lung scintigraphy, when interpretable, provides the diagnosis of pulmonary embolism, shows the anatomic extension and allows follow-up of the outcome. However, the specificity of this investigation is problematic. Pulmonary angiography, coupled with catheterisation of the right heart, remains the reference investigation in the diagnosis of pulmonary embolism and its anatomical diffusion. It is reserved to situations in which echocardiography is difficult and scintigraphy is uninterpretable, notably in patients with previous cardiopulmonary disease.

[Complications of thrombolytic therapy in pulmonary embolism]. / Accidents du traitement thrombolytique dans l'embolie pulmonaire.

Thrombolysis in massive embolism is associated with a number of complications, mainly haemorrhagic, justifying an evaluation of the individual risk/benefit ratio before prescription. Major bleeding episodes, the most serious complication, are observed in 8 to 15% of cases and result from mechanisms involving the coagulation factors, platelet function and the vessel wall. In over 70% of cases, they are directly related to sites of vascular puncture, especially for the carrying out of pulmonary angiography which triples the haemorrhagic risk. Uncontrolled hypertension, the prescription of active oral anticoagulants at the time of thrombolysis, low body weight, diabetes, female gender, and ages over 70 have also been identified as factors predictive of bleeding. The prevention of haemorrhage is based on strict observance of the contraindications of thrombolysis and the limitation of early vascular puncture sites, especially femoral, for pulmonary angiography. In cases of haemorrhage, treatment requires interruption of thrombolysis and heparin, the neutralisation of circulating plasmin, inactivation of plasminogen and correction of fibrinogen-induced deficits. Allergic reaction may also occur during thrombolysis, especially with the use of streptokinase. They are usually mild and be prevented by prior routine administration of steroids. The same applies to hypotensive episodes, also more common with streptokinase and rapidly reversible by transient interruption of thrombolysis.

Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant hirudin is potentially effective as an antithrombotic treatment in the management of heparin-induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous recombinant hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin-induced thrombocytopenia. Six patients suffering from heparin-induced thrombocytopenia were submitted to intravenous recombinant hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as recombinant hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of recombinant hirudin. Heparins responsible for heparin-induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of recombinant hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of recombinant hirudin. Platelet count rose from nadir (median value 60 x 10(9), 15 to 90) to above 100 x 10(9)/L in every patient within 3-6 days (median 5), after discontinuation of heparin. Intravenous administration of recombinant hirudin ensured safe anticoagulation in patients with heparin-induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.

[Subcutaneous recombinant hirudin in the treatment of deep venous thrombosis. A pharmacokinetic study]. / Hirudine recombinée par voie sous-cutanée dans le traitement de la thrombose veineuse profonde constituée. Etude pharmacocinétique.

Recombinant hirudin (HBW 023) has a pure and specific antithrombotic activity. It could be more effective than heparin in the treatment of deep venous thrombosis. Its half life is about three hours when administered intravenously which requires continuous infusion whereas subcutaneous administration can ensure stable plasma concentrations and antithrombotic activity over a period of approximatively 12 hours. The aim of the study was to check the safety and clinical and radiographic efficacy of recombinant hirudin administered subcutaneously to patients with recent deep venous thrombosis and to analyse the pharmacokinetics of the product and its effects on tests of coagulation. Ten patients were treated with 0.75 mg/kg of subcutaneous recombinant hirudin twice a day for 5 days. Anticoagulation was performed with standard heparin and acenocoumarol. Bilateral phlebography, pulmonary angiography or ventilation and perfusion scintigraphy were carried out before and on the 5th day of recombinant hirudin treatment. The activated cephalin time and standard anticoagulant tests and the plasma kinetics of recombinant hirudin were assayed between the 1st and 12th hour on the first and fifth days of treatment. The clinical course was simple in all but one patient who had a recurrence of pulmonary embolism on the 4th day justifying thrombolytic treatment. No haemorrhagic complications or secondary biological effects were observed. On the 5th day, control phlebography was unchanged or improved in all patients. The peak plasma concentration of recombinant hirudin was observed between the 3rd and the 4th hour following subcutaneous injection. The activated cephalin time was increased in parallel with increased concentrations of recombinant hirudin.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial neutrophil sequestration and activation related to the reperfusion of human heart during coronary artery surgery.

OBJECTIVE: The aim was to determine if neutrophils are activated and sequestered as they pass through postischaemic human myocardium. METHODS: The occurrence of neutrophil activation during the reperfusion of the ischaemic myocardium was investigated in 16 selected patients undergoing coronary artery bypass surgery. Neutrophils were counted and elastase and lactoferrin released into the plasma were measured simultaneously in myocardial venous blood and in peripheral venous blood, before aortic cross clamping (T0), and two (T1), 10 (T2), and 20 (T3) min after unclamping. RESULTS: At T0, no statistically significant difference was noted between peripheral and myocardial blood with respect to the three variables studied. Reperfusion was associated with a significantly lower neutrophil count in myocardial blood compared to peripheral blood (p < 0.001), suggesting that neutrophils were trapped within the myocardium during reperfusion. In addition, levels of elastase (T1, T2, and T3), and lactoferrin (T1) were significantly higher in myocardial blood as compared to peripheral blood (p < 0.001), suggesting that activated neutrophils released their granular content into the plasma milieu. CONCLUSION: We provide evidence consistent with local neutrophil activation during myocardial reperfusion in patients undergoing coronary artery bypass surgery, in addition to the well described systemic activation related to cardiopulmonary bypass.