Acute Myocardial Infarction in a Patient with von Willebrand Disease: Pathogenetic Dilemmas and Therapeutic Challenges

Heidar Arjomand, MD, *Patrick Aquilina, MD, Daniel McCormick, DO
Heidar Arjomand, MD, *Patrick Aquilina, MD, Daniel McCormick, DO
Von Willebrand disease (vWD) results from deficiency of von Willebrand factor (vWf), an essential element needed for initial platelet adhesion and subsequent thrombosis.1 The presence of atherosclerotic coronary lesions without occlusive arterial thrombi has been demonstrated in patients with vWD at autopsy as well as in experimental animal models.2,3 The occurrence of arterial thrombotic events including acute myocardial infarction (MI) is exceedingly rare in patients with vWD. In this report, we present a case of acute anterior MI in a patient with vWD and describe the therapeutic challenges of adjuvant antiplatelet and antithrombotic therapy posed by the patient’s inherent increased risk of bleeding. Case Report. A 45-year-old Caucasian female with a history of hypertension, previous cigarette smoking, scleroderma (CREST variant) and vWD disease presented to our hospital emergency department after an out-of-hospital cardiac arrest. While attending a meeting, she developed mid-substernal chest pressure and diaphoresis, followed by loss of consciousness. Eventual downloading of the automatic external defibrillator demonstrated ventricular fibrillation as the initial rhythm. On initial examination, the patient’s blood pressure was 138/76 mmHg and her heart rate was 96 beats/minute. Cardiac examination revealed a regular rhythm with a prominent S4 gallop. Lungs were clear to auscultation and peripheral pulses were palpable. Electrocardiogram revealed sinus rhythm and prominent ST-segment elevations in leads V2-V3 with more subtle elevations laterally and ST-segment depressions inferiorly (Figure 1). The patient was treated with metoprolol, aspirin and nitroglycerin. The patient’s past medical history included a diagnosis of vWD, initially diagnosed following her first pregnancy after prolonged post partum vaginal bleeding. The patient also had a history of gastrointestinal bleed at age 22 and easy bruising throughout her life. The last evaluation of her vWD was approximately ten years prior, which included a Factor VIII activity of 36% (normal, 50–150%) and a vWF antigen of 73% (normal, > 50%). Cardiac catheterization revealed a normal left main, 100% occlusion of the mid left anterior descending (LAD) coronary artery (Figure 2), a 60–70% lesion in the proximal left circumflex artery and luminal irregularities of the right coronary artery. Balloon angioplasty of the mid-LAD occlusion led to reestablishment of flow in the distal LAD. A 3.0 x 12 mm NIROYAL stent (Boston Scientific/Scimed, Inc., Maple Grove, Minnesota) was deployed at the mid-LAD site. Follow-up angiography revealed a narrowing beyond the stent, which did not respond to intracoronary nitroglycerin. A second 3.0 x 12 mm NIROYAL stent was advanced and placed distally, overlapping the first stent. Final coronary angiography revealed TIMI 3 flow in the LAD without any evidence of dissection or residual stenosis (Figure 3). Anticoagulation for the angioplasty was achieved with heparin bolus to maintain an activated clotting time of > 300 seconds. Adjuvant therapy with tirofiban was started as a bolus during the procedure and continued as a drip for 24 hours. Femoral arterial and venous sheaths were removed several hours later without significant bleeding at the vascular access site. The patient’s post-catheterization electrocardiogram demonstrated resolution of the ST-segment elevations and depressions without the appearance of Q-waves (Figure 4). Peak creatine kinase was 1,187 U/L (normal, 200 U/L) with a peak troponin I of 160.8 ng/ml (normal, 1.9 ng/ml) following percutaneous coronary intervention. Tirofiban and heparin were continued for 24 hours, and the patient was maintained on aspirin, clopidogrel, metoprolol, captopril and pravastatin. Echocardiogram demonstrated an ejection fraction of 45% and mild to moderate septal and anterior hypokinesis. During hospitalization, hematological work-up indicated a factor VIII activity of 82% (normal, 50–150%) and vWf antigen of 74% (normal, > 50%). On the fifth hospital day, the patient was ambulating without any chest pain; she was discharged home with instructions for regular follow-up. At 3-week follow-up exam, she was free of symptoms and attending a cardiac rehabilitation program. Discussion. In this report, we describe a case of acute anterior MI in a patient with vWD. Our patient underwent successful percutaneous coronary intervention of her LAD, followed by adjuvant therapy with tirofiban, aspirin, clopidogrel and heparin. The occurrence of acute MI in patients with vWD is very rare.4–6 There are no reports of acute MI in patients with vWD documenting the use of glycoprotein (GP) IIb/IIIa inhibitors, which could potentially lead to significant hemorrhage in the presence of a bleeding diathesis. Von Willebrand disease results from qualitative as well as quantitative defects in the vWf molecule. Von Willebrand factor is a large adhesive GP, found in plasma, platelet granules and endothelial cells.1 In the circulation, vWf binds to and stabilizes coagulation factor VIII but does not bind to platelets. However, following platelet injury, as occurs with rupture of atherosclerotic plaques in patients with acute MI, vWf binds to exposed subendothelial collagen. This binding results in a change in protein conformation that enables vWf to interact with platelet surface GP Ib-IX, mediating initial platelet adhesion. Following platelet adhesion, vWf will also bind to GP IIb/IIIa, but this interaction is not involved in the initial binding to subendothelium.1 Once activated, platelets release adenosine diphosphate and thromboxane A2, resulting in platelet recruitment, further platelet stimulation, and finally platelet aggregation via surface GP IIb/IIIa receptors.1 The prevalence of vWD in the general population is about 1%. Based on the pathophysiologic defect as well as the mode of inheritance, there are 6 types of vWD, with the more severe forms being considerably less common.1 Clinical manifestations of vWD include epistaxis, easy bruising, mucosal bleeding, gastrointestinal hemorrhage and menorrhagia.1 Based on findings in von Willebrand factor-deficient pigs, it has been suggested that subjects with deficiency of vWf are protected from spontaneous and diet-induced atherosclerosis.7,8 However, patients with vWD are found to have atherosclerotic coronary lesions at autopsy.2 Furthermore, it has been shown that vWf function is not essential to the development of atherosclerotic lesions after balloon catheter injury in pigs homozygous and heterozygous for vWD.3 Given the crucial role of vWf in platelet thrombus formation, it is important to note that there was no evidence of occlusive arterial thrombi at autopsy in patients with vWD.2 It is, therefore, intriguing to encounter acute arterial thrombotic events such as acute MI in patients with vWD. Von Willebrand factor is an acute-phase reactant and its circulating levels increase with age, pregnancy and acute inflammation. Though not directly applicable to patients with vWD, it is important to note that higher levels of vWf in patients with stable angina, unstable angina and MI are associated with poor short- and long-term outcomes.9–11 In the presence of a bleeding diathesis such as vWD, treatment modalities utilized in patients with acute MI, including antiplatelet therapy with GP IIb/IIIa inhibitors, aspirin, clopidogrel and antithrombotic therapy with heparin, can pose a significant therapeutic dilemma. There are no data measuring the vWf levels in patients with vWD who present with acute coronary syndromes. However, given the time needed to measure the vWf levels and the fact that prompt initiation of antiplatelet and antithrombotic therapy is associated with improved outcome in patients with acute coronary syndromes, it is probably reasonable to proceed carefully with initiation of such therapies and monitor the patient closely for any sign of bleeding. In patients with acute MI, early administration of the GP IIb/IIIa inhibitor abciximab combined with primary stenting improves coronary patency before stenting12 and is associated with improved left ventricular function and clinical outcomes.12,13 There are no data on the effectiveness of tirofiban in the setting of ST-segment elevation MI, while tirofiban and abciximab have comparable efficacy when administered to acute MI patients during elective or urgent coronary stenting.14 Considering the patient’s bleeding diathesis, we opted to administer tirofiban for 24 hours. Our decision was based on the fact that tirofiban has a shorter half-life, and in case of bleeding its discontinuation would minimize the risk of further bleeding.15 Whether adjuvant antiplatelet therapy with GP IIb/IIIa inhibitors has similar efficacy in patients with vWD is not known. However, since our patient presented with an acute arterial thrombotic event despite the inherent protection given by low vWf levels, we decided to carefully proceed with adjuvant antiplatelet and antithrombotic therapy. As stated previously, there were no bleeding complications. In summary, acute MI occurs very rarely in patients with vWD. In this report, we have described a young patient with vWD and acute anterior MI and explained the therapeutic challenges of treating her with adjuvant antiplatelet and antithrombotic therapy after coronary intervention. This case, although isolated, illustrates that a diagnosis of von Willebrand disease does not mean that antiplatelet and antithrombotic agents are contraindicated.
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