Catherine Durrieu-Jaïs

Platelet Glycoprotein IIb/IIIa Inhibitors Basic and Clinical Aspects

Glycoprotein IIb/IIIa (GPIIb-IIIa) complexes (integrin αIIbβ3) mediate platelet aggregation by binding fibrinogen or von Willebrand factor (vWF), protein cofactors that form bridges between adjacent platelets. The cross-linked adhesive proteins assemble platelets into the aggregate. Agents that block the function of the GPIIb-IIIa complex of platelets constitute a powerful new generation of antithrombotic drugs.1 Among the short- and long-term aims of such drugs are (1) to provide immediate relief in the case of ongoing arterial thrombosis and (2) to eliminate excessive platelet reactivity in diseased vessels so that occlusive thrombi and restenosis do not occur, while allowing sufficient hemostasis to prevent spontaneous bleeding. It should be emphasized that stenosis and partial occlusion are both prothrombotic, with increased shear stress promoting platelet activation. Under these conditions, vWF plays a major role in the mediation of thrombus formation, interacting with GPIIb-IIIa and the adhesion receptor GPIb.2 Otherwise, fibrinogen is the major cofactor of platelet aggregation, essentially binding through a dodecapeptide sequence (aa400 to aa411) present at the carboxy terminus of each γ chain. Binding of vWF and other adhesive proteins, such as fibronectin, to GPIIb-IIIa is mediated by the Arg-Gly-Asp (RGD) sequence, a universal mediator of cellular interactions with the extracellular matrix.1 2 3 Anti–GPIIb-IIIa drugs block this final step of the platelet aggregation process. They also block the “outside-in” signaling that follows the binding of adhesive proteins to activated GPIIb-IIIa and the onset of platelet aggregation.3 This signaling may promote events such as secretion, clot retraction, and the expression of procoagulant activity; therefore, its inhibition extends the influence of anti–GPIIb-IIIa drugs beyond the blocking of platelet-to-platelet cohesion. The present review will mostly be illustrated by results obtained with abciximab (c7E3 Fab, ReoPro), a chimeric antibody fragment that is the most widely used of the new …

Management of prosthetic heart valve obstruction: fibrinolysis versus surgery. Early results and long-term follow-up in a single-centre study of 263 cases.

Optimal management of prosthetic heart valve obstruction (PHVO) remains controversial even though surgery is usually recommended. To better define the efficacy and safety of fibrinolysis versus surgery in the pre- and post-transoesophageal echocardiography (TEE) eras. We analysed initial results and follow-up data from a large, retrospective, single-centre series, comparing fibrinolysis and surgery in patients with PHVO treated over 20 years. Two hundred and sixty-three consecutive episodes of PHVO in 210 patients, mainly left sided, were managed in our institution by either fibrinolysis (n=127) or surgery (n=136). Early clinical evolution was assessed in terms of haemodynamic success and complications. Concerning early results, there were no significant differences between the two groups in terms of mortality (10%). However, haemodynamic success was significantly more frequent in the surgical group (89% versus 70.9% p<0.001), embolic episodes were significantly more frequent in the fibrinolysis group (15% versus 0.7%, p<0.001), as were total complications (25.2% versus 11.1%, p=0.005). Long-term follow-up, with a mean duration of 6 years (range: 0-20), was obtained and showed significantly better results in the surgical group in terms of recurrence (p=0.021) and mortality (p=0.002). In univariate and multivariable analyses, NYHA functional class at presentation was a strong predictor of late death (p<0.01). Management of patients during the pre- and post-TEE eras was significantly different, since introduction of TEE surgery has become the preferred therapeutic strategy. Results of this extensive single-centre experience indicate that since the introduction of TEE, surgery is more frequently performed than fibrinolysis due to the improvement of thromboembolic risk assessment. Furthermore, prompt surgical treatment is associated with a better early success rate and a significantly lower incidence of complications than fibrinolysis in left-sided PHVO. However, fibrinolysis may be justified in selected cases. Long-term follow-up showed significantly better results in the surgical group in terms of recurrence and mortality.

Comparative Analysis of Cardiac Magnetic Resonance Viability Indexes to Predict Functional Recovery After Successful Percutaneous Coronary Intervention in Acute Myocardial Infarction

The aim of this study was to examine the relative value and the influence of the association of 4 cardiac magnetic resonance (CMR) viability indexes for predicting segmental functional recovery after optimal pharmacologic therapies and early percutaneous coronary intervention in acute myocardial infarction (AMI). CMR has been shown to predict functional recovery after AMI. The relative predictive value of CMR viability indexes remains disputed and has not been described in AMI reperfused within the first 12 hours. Sixty-nine patients with a first reperfused (<12 hours) Thrombolysis In Myocardial Infarction grade 3 AMI (61 men, 57.6 +/- 12.6 years) were studied on day 5 +/- 2. Low-dose (10 microg/kg/min) dobutamine response (DOB), microvascular obstruction (MVO), relative delayed enhancement extent (DE), and transmural DE pattern (TMDE) were assessed in each of the 17 left ventricular segments. Segmental functional outcome was assessed by CMR at 3 months. Logistic regression and Bayesian probabilities evaluated the association between viability indexes and functional segmental outcome. At rest, 27% of segments (314 of 1,173) were dysfunctional of which 53% (165 of 314) recovered at follow-up. Odd ratios for dobutamine response, MVO, DE, and TMDE were 15.8, 5.9, 2.6, and 2.5 respectively. The probability of segmental recovery was 0.84 when dobutamine response was positive and increased successively to 0.91 when adding MVO absence, 0.94 when adding TMDE absence, and 0.97 when adding DE absence. In conclusion, contractile response to low-dose dobutamine is the best predictive factor of segmental recovery after Thrombolysis In Myocardial Infarction grade 3 early reperfused AMI. Its value is further increased by other CMR viability indexes.

Accessibility of abciximab to megakaryocytes and endothelial cells in the bone marrow compartment: studies on a patient receiving antithrombotic therapy

Abciximab, chimaeric Fab fragments of the monoclonal antibody 7E3 (c7E3 Fab), has achieved widespread use as an anti‐platelet agent for blocking GP IIb–IIIa (αIIbβ3) function and preventing ischaemic complications after coronary artery angioplasty. However, its accessibility to the bone marrow compartment during therapy is unknown, as is its ability to bind αvβ3in vivo. Using electron microscopy and immunogold labelling, we have looked for abciximab in the bone marrow of a patient who became thrombocytopenic during treatment. The presence of abciximab was assessed on ultrathin frozen sections of a marrow aspirate, the drug being revealed by a rabbit antibody to c7E3 Fab. Labelling was maximal on fragmenting megakaryocytes (MK) and proplatelets in the vascular sinus and in direct access to the blood compartment. Not only the plasma membrane but also the demarcation membrane system (DMS) and the membranes of α‐granules were labelled. Abciximab was also revealed on the luminal surface of endothelial cells lining the marrow sinuses, thereby confirming for the first time its ability to bind to αvβ3in vivo. The study revealed no signs that abciximab had accumulated in the marrow.