The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass

The purpose of this study is to determine how often heart surgery patients who receive heparin develop an immune response (heparin-induced thrombocytopenia) that leads to clots forming in different parts of the body. These clots usually occur in the legs (deep venous thrombosis or DVT) or lungs (pulmonary embolism or PE) or cause heart attacks (myocardial infarction or MI) and strokes.

• Study Weblinks:
  • ClinicalTrials.gov
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Longitudinal
  • Prospective
  • Population
  • Sequencing
• Total number of consented subjects: 1051
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• MeSH

Inclusion Criteria:

• Patient scheduled to undergo cardiopulmonary bypass

Exclusion Criteria:

• Definite plan for warfarin to be administered during the post-operative hospital stay
• Definite plan for low molecular weight heparin (LMWH) to be administered in full anticoagulant doses during the post-operative hospital stay (for example, enoxaparin 1.0 mg/kg q12hr or 1.5 mg/kg q24 hours)
• Definite plan for heparin to be administered in full anticoagulant doses during the post-operative hospital stay (goal: partial thromboplastin time (PTT) ≥1.5 times the control)

Please note that the following do not constitute exclusion criteria:

1. Warfarin, heparin or LMWH administered during a readmission to the hospital for a reason apart from an outcome event. For example, a patient who develops atrial fibrillation five weeks after surgery and is treated with LMWH followed by warfarin would not be excluded, but the use, indication for and timing of these drugs would be captured in the data collection forms.
2. Incompetence, difficulty hearing or impairment to communication will not constitute exclusion criteria. In this situation, the patient's next-of-kin or healthcare power-of-attorney (HCPOA, where one exists) will be approached for consent.
3. The pediatric age group will not be excluded because there is emerging evidence that the rate of heparin-induced thrombocytopenia and thrombotic complications after cardiac surgery in this age group is comparable to the rates established in studies of adults (Alsoufi 2004).

Although several studies have shown that up to 61% of patients develop elevated antibodies to heparin-PF4 after cardiac bypass surgery (Visentin 1996, Bauer 1997, Trossaërt 1998, Pouplard 1999, Warkentin 2000, Francis 2003), the incidence of clinically important heparin-induced thrombocytopenia (HIT) with thrombotic complications is reportedly rare (~0.75% of all patients undergoing bypass) (Singer 1993). However, one study found that 3.2% of 1033 consecutive bypass patients were diagnosed with clinically important PE within two weeks following bypass (Josa 1993). There are also reports of delayed-onset HIT, which presents later than the classic 5 to 14 day window after heparin exposure (Warkentin Ann Int Med 2001, Rice 2002). Bypass patients who suffered delayed-onset HIT were unlikely to have been captured in previous studies, which generally followed patients over a much shorter time period or were underpowered (Bauer 1997, Trossaërt 1998, Pouplard 1999, Warkentin 2000, Francis 2003). Therefore, the true incidence of HIT among bypass patients remains unknown. Moreover, among patients treated with heparin for acute coronary syndromes, development of antibodies to heparin-PF4 in the absence of thrombocytopenia predicted an increased incidence of death or MI (30.4 vs. 11.3%, p=0.011) at 30 days compared with similar patients who did not develop these antibodies (Williams 2003). It is unknown whether these antibodies portend a worse long-term prognosis among bypass patients as well. However, since the antibody persists for a median of 85 days (Warkentin NEJM 2001), we postulate that late-occurring thrombotic manifestations might arise among seropositive bypass patients too.

• Primary Phenotype: Cardiovascular Diseases
• Venous Thrombosis
• Pulmonary Embolism
• Myocardial Infarction

• Principal Investigator
  • Dr. Thomas Ortel, MD, PhD. Duke University Health System Durham, NC, USA.
• Funding Source
  • National Institutes of Health, Bethesda, MD, USA.