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Percutaneous Coronary Intervention in a Patient with von Willebrand’s Disease Presenting with an Acute Coronary Syndrome
April 2006
Case Example. A 56-year-old man was admitted to the hospital complaining of dull, retrosternal chest pain that had lasted for 2 hours at rest. Over the previous 2 months, he had experienced exertional chest pain episodes that were increasing in frequency and duration. Although his serum troponin I concentration was not elevated, his 12-lead electrocardiogram during pain showed deep T-wave inversion in the anterolateral chest leads. Echocardiography demonstrated mild apical hypokinesia. He had no history of ischemic heart disease. His cardiac risk factors included hyperlipidemia, prior cigarette smoking and a positive family history (his mother had developed angina in her sixties). He was not diabetic or hypertensive. Physical examination was unremarkable. A diagnosis of crescendo-type unstable angina was made.
The patient had previously been diagnosed with Type I von Willebrand’s disease (vWD) after difficulty in achieving hemostasis following open fixation of a right Colle’s fracture. He had also suffered from recurrent epistaxis, but this had ceased following nasal cautery. Interestingly, his sister had menorrhagia and had been diagnosed with Type I vWD as well. In view of his bleeding disorder, he was not initially administered low-molecular weight heparin or clopidogrel. However, aspirin was prescribed along with anti-anginal agents and a statin.
Despite medical treatment, the patient continued to complain of episodes of dull, retrosternal chest pain associated with dynamic electrocardiographic changes. In view of these high-risk features, he was scheduled to undergo diagnostic coronary angiography followed by revascularization if appropriate. In view of his history of bleeding problems, hematological advice on minimizing periprocedural bleeding problems was sought. It was recommended that he receive Factor VIII von Willebrand’s factor (vWF) concentrate (hemate P) for 48 hours preprocedure. A loading dose of 3,500 Units followed by 1,500 Units twice daily was administered.
The patient was taken to the cardiac catheterization laboratory where the right radial approach was favored over femoral access because of the potential for hemostatic difficulties. Diagnostic angiography using 6 Fr Judkins catheters revealed a tight proximal left anterior descending artery (LAD) bifurcation stenosis involving the first diagonal (D1) branch (culprit lesion) and a 60–70% mid-right coronary artery (RCA) plaque (Figure 2).
After detailed discussion with the patient, an informed decision was made to proceed to angioplasty and stenting. Loading doses of clopidogrel and unfractionated heparin were given. However, abciximab was not administered. An activated clotting time of 250–350 seconds was maintained during the procedure. Balanced middle-weight (BMW) guidewires were positioned in the LAD and D1. A 2.5 x 12 mm balloon was used to dilate the D1 stenosis. The LAD lesion was predilated with a 2.5 x 12 mm balloon and stented with a 3.5 x 16 mm Taxus® (Boston Scientific Corp., Natick, Massachusetts) paclitaxel-eluting stent. The D1 ostial stenosis required further dilatation with a 2.5 x 12 mm balloon following deployment of the LAD stent. A good final angiographic result was obtained (Figure 3). The RCA lesion was dealt with by primary stenting with a 3.5 x 24 mm Taxus stent. A passive hemostatic device (RadiStop®, Radi Medical Systems, Inc., Wilmington, Massachusetts) was positioned over the radial artery to facilitate hemostasis after sheath removal. As a precaution, this was left in position overnight rather than the usual few hours. There were no major cardiac or vascular periprocedural complications. However, the following day, he developed epistaxis that required cauterization. There was no decrease in the patient’s hemoglobin concentration.
Discussion
von Willebrand factor and von Willebrand disease. vWF is a large glycoprotein encoded on chromosome 12 produced by vascular endothelial cells and megakaryocytes.1 It is also contained in alpha granules within platelets and plays a crucial role in the formation of a platelet plug at sites of endothelial damage. It binds to exposed collagen-containing subendothelium and forms a bridge between the subendothelium and platelets, allowing platelet adhesion (Figure 1). Platelet aggregation is also partly mediated by vWF, as it binds to platelets via the Ib/IX/V and IIb-IIIa glycoprotein complexes. vWF stabilizes the circulating procoagulant factor VIII by forming a noncovalent complex with it. Factor VIII is an essential cofactor in the activation of factor X, leading ultimately to the formation of thrombin and fibrin.
vWD affects approximately 1% of the population and is the most common congenital bleeding disorder.1 It is subdivided into three types. The majority of cases are Type I (75%), which is inherited in an autosomal-dominant fashion. A mutation at the vWF gene on chromosome 12 impairs the export of vWF out of storage organelles, thus resulting in a reduction in circulating levels of vWF. This slows platelet plug formation and reduces circulating levels of Factor VIII (which rapidly degrades in the absence of vWF). Typical clinical manifestations include epistaxis, menorrhagia and difficult hemostasis following surgery. Type II vWD is caused by the production of flawed vWF due to point, insertion or missenses mutations. A moderate bleeding risk results and there are several subtypes. A major gene deletion causing a complete lack of vWF results in a severe bleeding tendency (Type III). Fortunately, this subtype is rare.
von Willebrand factor and coronary disease. The initiating event of an acute coronary syndrome is usually rupture of a vulnerable atherosclerotic plaque that exposes the subendothelium. Platelet adhesion, activation and aggregation occur, followed by initiation of the clotting cascade. Intraluminal thrombus forms, and if obstruction to coronary flow occurs, an acute coronary syndrome results. Because vWF-mediated platelet adhesion to exposed collagen following injury to the vascular endothelium is the first step in thrombus formation, interest was stimulated as to whether vWF levels affected cardiovascular risk. That is, are low levels of vWF protective against coronary events and are higher levels associated with an increased risk of coronary events?
Basic science studies. Atherosclerosis develops in hypercholesterolemic vWD swine to the same extent as hypercholesterolemic normal animals.2,3 However, vWF is required to induce occlusive thrombus in balloon-injured coronary arteries in the same animal model.4,5 These findings suggest that vWF is key in mediating thrombosis after endothelial injury, but is less important in the development of atherosclerosis, at least in the short term. In essence, the risk of a plaque rupture is unchanged, but in the event of plaque rupture, occlusive thrombus is less likely to occur in the absence of vWF. It is therefore possible that individuals with low levels of vWF are less prone to acute coronary syndromes than those with higher levels.
Atherosclerosis can occur in humans with severe vWD.6,7 However, two small cross-sectional ultrasound studies in humans have demonstrated a modest reduction in atherosclerotic burden in large arteries of individuals with vWD or hemophilia A compared to controls.8,9 This may appear at odds with the animal data, but the variant results are possibly due to the differing periods of time that the circulation was exposed to high or low levels of vWF before the atherosclerotic load was assessed. The human studies were cross-sectional investigations of controls versus individuals who had lived for many years with low levels of vWF or Factor VIII, whereas the animal studies were necessarily short-term prospective experiments. It is therefore possible that sustained, low levels of vWF over time may retard the progression of atherosclerosis.
Prospective clinical studies. A recent meta-analysis of six long-term, prospective studies of members of the general population suggested an association between higher levels of vWF and the incidence of myocardial infarction.10 The population examined included 1,524 patients who developed coronary artery disease and 19,830 who did not. Individuals with vWF levels in the highest tertile (> 126 IU/dL) had a combined odds ratio of myocardial infarction of 1.5 (95% CI 1.1–2.0) compared to those in the lowest tertile (11 Overall, this evidence suggests that vWF is a moderate, independent predictor of coronary artery disease, comparable to CRP (odds ratio = 1.45; 95% CI 1.25–1.68). Stronger associations, such as current smoking and total cholesterol, have higher values (Table 1).
In persons with risk factors for coronary artery disease, a recent meta-analysis involving 6,423 patients demonstrated a combined odds ratio of 1.6 (1.0–2.5) for myocardial infarction in those in the highest tertile of vWF levels compared to those in the lowest third.
It is unclear whether the association of a high level of vWF with an increased risk of coronary disease is causal, or whether it is only a marker of increased risk. Possible causal mechanisms include the promotion of platelet adhesion and aggregation by vWF itself, and increased fibrinogenesis by stable factor VIII–vWF complex. Otherwise, vWF is known to be a nonspecific marker of endothelial damage and local or systemic inflammation.12,13 At best, it is a moderately good predictor of coronary events, but it is nonspecific and less important than classic coronary risk factors. Furthermore, high levels are not amenable to treatment in the same way as cholesterol, blood pressure and smoking.
Case reports of coronary disease management in patients with vWD. The optimal management strategy for acute coronary syndromes in individuals with vWD is unknown. Case reports and anecdotes are the only sources of information. The major issue is the bleeding risk associated with antiplatelet agents, heparin and thrombolytic drugs. Aspirin therapy results in a minor decrease in vWF levels and only significantly lengthens bleeding time in severe vWD.15–17 It is therefore safe to administer in most cases. Heparin does not affect vWF levels.17 Furthermore, the effect of unfractionated heparin on antithrombin can be rapidly reversed with protamine in the event of bleeding complications.18 The safety of other agents and the role of angioplasty are unclear. Various approaches have been adopted in patients with Type I vWD.
Thrombolysis and aspirin, followed by intravenous heparin, have been successfully used to open an occluded coronary in acute ST-elevation myocardial infarction (STEMI).19 Unfortunately, major extracerebral bleeding occurred, necessitating blood transfusion. Thrombolytics, however, have been administered without clinically significant bleeding.20 This is perhaps not surprising when one considers that the prevalence of Type I vWD in the general population is approximately 1%. Given the very high incidence of STEMI, and despite their lower relative risk, many patients with Type I vWD (perhaps undiagnosed) must receive thrombolytics. Most of these patients, presumably have not suffered major bleeding complications. This is possibly because vWF levels increase in acute STEMI, perhaps as a result of elevated catecholamine levels.21,22
Coronary angioplasty and stenting with the hemate P hemostatic cover has also successfully been employed in acute STEMI at the expense of a small groin hematoma.20 Other authors have used primary angioplasty without stenting to open the culprit vessel.23 They argue that this avoids the bleeding risks associated with thrombolysis or the intensive antiplatelet therapy that is necessary during and following stenting.
Furthermore, hemate P was not administered due to a concern over the increase in thrombotic tendency. However, outcomes following stent placement are superior to angioplasty alone, and glycoprotein (GP) IIb-IIIa antagonists further improve results.24,25 This is especially true in more complex interventions or when an extensive intracoronary clot is present. Another important consideration is the possible use of drug-eluting stents (DES) in these patients. As these devices take longer to endothelialize than bare metal stents (BMS), a longer period of thienopyridine therapy in addition to aspirin is needed to minimize the risk of late thrombosis.26–28 Therefore, it may be preferable to use BMS in vWD to reduce the duration of dual antiplatelet treatment.
Our patient had sustained a non-ST elevation myocardial infarction (NSTEMI), rather than a STEMI. However, the concerns regarding bleeding risk were similar to the other cases. Hemate P was administered prior to and after the procedure. Theoretically, this may have increased thrombotic risk (multimer vWF levels are elevated for 22–26 hours following administration) and in retrospect, perhaps its use was unnecessary. Furthermore, there is a paucity of data regarding the prophylactic, periprocedural use of Hemate P in vWD, and it is not recommended for this purpose. We used the radial artery access in preference to the femoral route as one virtually eliminates local vascular complications employing this technique.29 This is due to its superficial site, underlying bone and the use of mechanical hemostatic devices. It is easy to apply firm, well-localized pressure by squeezing the artery between bone and device. Any bleeding from the artery is easily identified, especially with transparent, inflatable pressure devices. The device is then simply tightened. Furthermore, the risk of major intra-abdominal hemorrhage is completely removed.
We administered aspirin, clopidogrel and heparin. There was no major bleeding with this approach. The goal of this therapy is to impair platelet function and fibrinogenesis, which are already impaired to a degree in vWD, and thus it is possible that further impairment of function may lead to bleeding. In fact, our patient developed epistaxis the day after his procedure. Having said this, the risk of stent thrombosis with its possible sequelae of angina, repeat procedures and even sudden cardiac death, is not to be ignored and we would favor the use of these antithrombotic agents in this situation.
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