Keywords
INTRODUCTION
The role of glycoprotein IIb/IIIa receptor blockers in the treatment of the acute coronary syndrome is becoming increasingly important. Abciximab, tirofiban, and eptifibatide have all shown good clinical results.1 Abciximab, the Fab fragment of the chimeric monoclonal antibody 7E3, inhibits platelet aggregation, preventing binding of the Von Willebrand factor, fibrinogen and other adhesive molecules to the glycoprotein IIb/IIIa receptor of activated platelets. Abciximab also blocks the generation of thrombin which follows platelet activation.2
The main indication for abciximab is prevention of the acute coronary syndrome, especially in patients scheduled to undergo interventional coronary procedures.3 The most important adverse side effects of abciximab are hemorrhage and thrombocytopenia,4 which Berkowitz et al5 classified into four progressive groups depending on the reduction in the platelet count. Severe acute thrombocytopenia shows a platelet count below 20 000/μL and its incidence ranges from 2.4% to 4%, according to the series.6 The origin of severe acute thrombocytopenia is unknown, although a possible mechanism involves the appearance of specific monoclonal glycoprotein IIb/IIIa antibodies or IgG antibodies against the murine sequences of activated platelets after a second administration of the drug.7,8 The aim of this study was to determine and analyze the incidence of complications of severe acute thrombocytopenia secondary to the administration of abciximab in our hospital.
PATIENTS AND METHODS
A prospective study was undertaken from January 1997 to January 2002 of 375 consecutive patients who underwent percutaneous coronary intervention (PCI) for 436 lesions and who were treated with abciximab according to the hospital protocol. Measurements were made of demographic, clinical, and angiographic variables, as well as of the platelet count 4 hours after and 12 hours after starting treatment with abciximab. The qualitative variables were expressed as percentages and the quantitative variables as the mean ± standard deviation or the median. The Kruskal-Wallis test was used to analyze the difference between groups in hematocrit count. The data were processed statistically with SPSS, version 9.0.
A patient was considered to have severe acute thrombocytopenia when the platelet count was below 20 000 /μL. For the diagnosis of thrombocytopenia, additional platelet counts were made using 2 separator tubes which contained ethylenediaminetetraacetic acid (EDTA) and citrate, respectively. A manual count was also done to rule out the possibility of pseudothrombocytopenia.
The indications for the use of abciximab were established according to the hospital protocol:
- Percutaneous coronary intervention in the clear presence of a thrombus or unstable plaque, or closure of the artery during angioplasty.
- Diabetic patients undergoing angioplasty in the context of stable or unstable angina.9,10
- Short-term reduction of the risk for acute myocardial infarction in patients with unstable angina who fail to respond to conventional medical therapy and who are due for early PCI.
The abciximab dose was 0.25 mg/kg given in an intravenous bolus 10-60 min before the operation, followed by continuous intravenous infusion of 0.125 μg/kg/min for 12 hours (up to a maximum of 10 μg/kg/min).
Besides abciximab, all the patients were treated with 300 mg of acetyl salicylic acid (ASA) 2 hours before the intervention and daily thereafter. Clopidogrel was also used in 99% of the patients (300 mg loading dose, followed by 75 mg daily after the intervention for 1 month) or ticlopidine (500 mg loading dose, followed by 250 mg/12 h) in the unusual case of intolerance to clopidogrel. Heparin was given to all patients, and the dose adjusted according to body weight, with an initial bolus of 70 U/kg, to maintain an activated coagulation time of 200-300 seconds.
RESULTS
The mean age of the 375 patients, 74% of whom were men, was 60.5±8.2 years (median, 64 years). A stent was implanted in 97% of the patients (mean, 1.25 stents per patient). Table 1 shows the demographic variables, the history and the angiographic data of the patients. The mean ejection fraction was 56.3±6.8%.
The mean platelet count after the administration of abciximab was 231 466±47 000/μL. The mean overall hematocrit was 35.7% (42% in the patients without thrombocytopenia). The accumulated overall incidence of thrombocytopenia was 11.5%. Table 2 shows the accumulated incidences in the different thrombocytopenia groups, as well as the mean hematocrit value in each group. No significant differences were detected between the groups in hematocrit values.
In the whole series there were just 4 cases of severe acute thrombocytopenia, which represented an incidence of 1.1%. All 4 cases were in men with a platelet count prior to administration of abciximab within the normal range. The course, concentrated platelet needs and recovery times from the thrombocytopenia are shown in Table 3. Hemorrhagic complications were not important: 2 patients had a mild inguinal hematoma, 1 of whom also had occasional epistaxis. Only 1 patient required a blood transfusion, of 2 units of concentrated red cells. No patient presented hemodynamic instability or needed vasoactive drugs.
DISCUSSION
Thrombocytopenia secondary to treatment with abciximab is an uncommon side-effect and related with the risk of hemorrhage. A recent meta-analysis showed the incidence of severe thrombocytopenia to be 1%.11 The incidence of severe acute thrombocytopenia in the different series ranges around 0.7%,4,5,12-14 which approximates to the 1.1% found in our study. Risk factors for thrombocytopenia secondary to abciximab include age >65 years, weight <90 kg, and a platelet count before intervention of <200 000/μL.11 The only one of these factors in our study was weight, which is of little importance.
Several studies show that important hemorrhagic complications are unusual in this type of severe acute thrombocytopenia.11,15 In our patients only 2 had mild inguinal hernias, one of these accompanied by epistaxis. Thus, hemorrhagic complications were mild and with no clinical consequences, except for the requirement for closer follow-up for signs of bleeding and a longer stay in our unit than the mean stay for scheduled PCI. Special care was taken to prevent increasing the risk of hemorrhage, with avoidance of intramuscular injections and venous lines. Arterial introducers were withdrawn accompanied by manual compression and weights.
Other studies have shown increased requirements for transfusion of platelets and other blood-derived products according to the bleeding, the period of resolution and the degree of thrombocytopenia.5,11,14,16 Following these indications, 3 of our patients needed an important supply of concentrated platelets (Table 3). The remaining patient presented no obvious bleeding or fall in hematocrit, and therefore received no platelet transfusion despite the degree of thrombocytopenia. A case of massive cerebral hemorrhage in association with severe acute thrombocytopenia (4000/μl), 90 minutes after starting treatment with abciximab, has recently been reported in a patient who underwent angioplasty because of acute myocardial infarction.13
The management of thrombocytopenia secondary to abciximab is controversial. Platelet transfusion and immediate cessation of treatment appear to be the most effective measures15; whether other antiplatelet therapies should also be suspended is unclear. Studies are under way of the administration of corticoids17 together with the platelet transfusion, which would enable either abciximab to be restarted or another glycoprotein IIb/IIIa receptor blocker to be used.
Our experience suggests that platelet transfusion and cessation of abciximab, as well as of other drugs with the potential to cause bleeding (heparin, ASA, ticlopidine, and clopidogrel), have reduced and lessened the hemorrhagic complications, and the resolution phase was no greater than previously reported, from 3 days to 1 week.12,15 Accordingly, we closely monitor the platelet count and the hematocrit until the resolution phase.
Pseudothrombocytopenia, which is responsible for more than one third (36%) of the reduction in platelet count in patients who undergo PCI,18 differed from true thrombocytopenia, as mentioned in the section on Patients and Methods.
Types I and II thrombocytopenia induced by heparin should be borne in mind when giving this drug concomitantly with abciximab. However, these types of thrombocytopenia rarely occur until at least 24 hours after exposure, they favor the onset of thrombosis, specific anti-heparin antibodies appear and the resolution of the symptoms takes longer.19,20
The incidence of thrombocytopenia following the combined administration of abciximab, ticlopidine, and clopidogrel has not yet been sufficiently examined. Whereas ticlopidine does not increase the incidence of thrombocytopenia, clopidogrel appears to do so.21
Replacement of abciximab by eptifibatide22 or tirofiban23 seems to be safe in patients who have thrombocytopenia secondary to abciximab and who still require glycoprotein IIb/IIIa receptor blockers.22,23
The 4 patients were reported to the hospital pharmacovigilance committee in order to obtain a truer reflection of the incidence of thrombocytopenia in daily clinical practice. Our protocol now includes a blood test 2 hours after starting abciximab therapy in order to enable the early detection of thrombocytopenia.
Correspondence: Dra. R. Aragonés Manzanares.
Hospital Universitario Carlos Haya. Unidad de Cuidados Intensivos.
Avda. Carlos Haya, s/n. 29010 Málaga. España.
E-mail: kreusa@terra.es