von Willebrand Disease and Coronary Artery Disease: A Contemporary Review

von Willebrand disease (vWD) is one of the more common inherited bleeding disorders, with an incidence of up to 1% in the general population.^1–3 Along the clinical spectrum are patients without any bleeding manifestations who are incidentally discovered, patients with mild mucosal bleeding, and patients with moderate to severe soft tissue bleeding with muscle hematomas and hemarthroses.^3,4 Although it was once thought that a deficiency in von Willebrand factor (vWF) could be atheroprotective, these patients are still at risk for coronary artery disease (CAD) and acute coronary syndromes (ACS).⁵ Given the increased hemorrhagic risk associated with antithrombotic and antiplatelet therapy, there is no consensus on the optimal approach to management, but there have been numerous case reports including the report by Macdonald, et al.⁶ in this issue of the Journal documenting various clinical strategies. The overall goal is to institute clinically effective therapy while minimizing the risk of bleeding. This article provides a brief review of vWD and its treatment in patients with coronary artery disease and delineates the various options in ACS management including pharmacologic and non-pharmacologic approaches to decrease bleeding risk. Background vWD is an inherited bleeding disorder secondary to a quantitative or qualitative defect within the von Willebrand factor protein, a large multimeric glycoprotein.⁷ This 178 kb protein, located on chromosome 12, is synthesized by endothelial cells and megakaryocytes.^1,2,7 Found in plasma, platelets, endothelial cells and the basement membrane of blood vessels, the function of this protein is to promote the formation of a platelet plug to achieve hemostasis. VWF is also required to maintain normal levels of factor VIII, and vWD results in a secondary deficiency of this clotting factor. Classification vWD is classified into 3 major categories as shown in Table 1.^1,3,8,9 Type 1 is the most common and accounts for 70 to 80 percent of cases with a mild to moderate quantitative decrease in vWF with levels in the 20–50% percent range. Mucosal bleeding may be absent or mild, with marked individual variation. There are four Type 2 subtypes and, in general, these are all associated with a higher likelihood of excessive spontaneous or procedure related bleeding. 2A vWD is a qualitative defect in vWF multimers leading to the loss of large multimers, which are more hemostatic than small ones. This qualitative abnormality (10–15% of the cases) is secondary to either a defect in vWF intracellular processing or increased sensitivity to proteolysis. Type 2B is also secondary to a loss of large vWF multimers but via a “gain of function” mutation that leads to spontaneous binding of vWF to platelets and subsequent clearance leading to loss of vWF multimers and thrombocytopenia. Type 2M disease is associated with defective vWF-dependent platelet adhesion. The Type 2N variant results from a decreased affinity of vWF to Factor VIII, which is required for the latter’s survival in vivo. Factor VIII levels are usually decreased to less than 25 percent of normal. This syndrome resembles hemophilia A. Type 3 vWD is the rarest and the most severe form, associated with both excessive mucosal and soft tissue bleeding. It is secondary to a near complete lack of vWF. While vWF levels are nearly undetectable, Factor VIII levels are typically less than 10 percent.^1–3 Acquired vWF has also been described in association with autoimmune disease (e.g., SLE), lymphoproloferative disorders and cancer and certain drugs (valproic acid). Clinical Manifestations The clinical manifestations of vWD vary from features secondary to platelet dysfunction or factor VIII deficiency, according to the clinical subtype.^1–3 Typically, there is easy bruising and mucosal bleeding such as epistaxis and menorrhagia in milder forms of vWD. The latter may only occur associated with aspirin or nonsteroidal anti-inflammatory drug use or after minor surgery or dental extractions. In the most severe cases of vWD, such as in Types 3 and 2N there may be hemarthroses and hematomas secondary to the deficiency in factor VIII. Bleeding episodes in Type 3 are characterized by GI bleeding in 20%, hemarthroses in 37%, postoperative bleeding in 41%, muscle hematomas in 52%, menorrhagia in 69%, oral cavity bleeding in 70% and severe nosebleeds in 77% according to one study.²Laboratory Diagnosis A number of diagnostic laboratory tests are available. Initial screening tests typically include bleeding time, platelet count and the activated partial thromboplastin time (APTT).^1–3 The bleeding time is prolonged in severe forms of vWD but may be normal or minimally prolonged in the milder forms. The platelet count is decreased in Type 2B. The APTT is prolonged in patients with vWD when Factor VIII levels are decreased. Normal values of the aforementioned test do not exclude vWD, especially in milder forms of the disease. Therefore, in patients with a bleeding history, especially with aspirin associated bruising or when there is a family history of vWD, more specific tests that include vWF antigen (vWF:Ag), ristocetin cofactor activity, and Factor VIII coagulant activity tests may be required to make or exclude the diagnosis. Plasma vWF:Ag levels measure the immunoreactive protein and are decreased in Type 1. The binding activity between vWF and platelet glycoprotein 1b is assessed via the ristocetin activity assay. Levels are decreased in Types 2A and 2M. Factor VIII activity levels usually parallel vWF:Ag. There are also assays to assess the multimeric pattern of vWF protein but usually these are not necessary to make the diagnosis. vWD and CAD Patients affected by vWD have not been shown to have a decreased incidence of coronary artery disease, as evidenced by autopsy studies and animal models.^10,11 Pigs that were homozygous and heterozygous for vWD still developed similar degrees of atherosclerosis in coronary arteries as compared to normal swine after being fed an atherogenic diet.10 Autopsy studies of human patients with vWD revealed the presence of atherosclerotic lesions in all patients across all vascular areas with severity similar to the general population.¹¹ The tantalizing thought that ACS incidence and/or severity might be reduced in the presence of vWD because of the reduced ability to form a clot has never been systematically studied and remains unanswered at the present time. Approach to the patient with vWD and coronary artery disease. When a patient with vWD comes to the cardiac catheterization lab, there are two short term issues to address: the risk of bleeding associated with vascular access and the bleeding risk associated with administration of acute anti-thrombotic medication in ACS and one long term issue: the use of anti-platelet therapy after percutaneous revascularization. Approach to cardiac catheterization: femoral versus radial Access. In terms of cardiac catheterization approach, there may be a nonsignificant trend towards decreased risk of bleeding with radial compared to femoral access.^12–14 The TEMPURA trial, which compared these two types of access in ST-elevation MI, showed a trend towards less severe bleeding with radial access (0% versus 3%, p = 0.14).15 In the ACCESS study, 900 patients with stable and unstable angina were randomized to radial, brachial, or femoral approach.¹³ Successful coronary cannulation was achieved in only 93 percent in the radial group versus 99.7 percent in the femoral approach group. No major entry site bleeding complications occurred in the radial group compared to 6 patients (2%) in the femoral group. However, radial artery occlusion occurred in 5% of the patients at hospital discharge. In the RADIAL-AMI trial, 50 patients with myocardial infarction requiring primary or rescue PCI were randomized to radial or femoral access,¹⁴ One patient in the radial arm group required crossover to femoral access because of inability to cannulate the radial artery. Glycoprotein IIb/IIIa inhibitors were used in a majority of the cases (94%) and lytic therapy in 66%. The time to balloon inflation was longer in the radial group by 6 minutes. There were nonsignificant trends toward decreases in hemoglobin levels (p = 0.12) and investigator reported hematomas (28% vs 8%, p = 0.07) in the femoral group. In conclusion, the small hemostatic benefit of radial artery access may be offset by a reduced radial artery cannulation success and longer door to balloon times. Femoral access: closure device versus manual compression. The method to achieve hemostasis after sheath removal may also impact bleeding risk. A meta analysis of 30 studies examining closure devices versus the use of manual compression revealed that relative risk (RR) of hematoma was 1.14 (95% CI, 0.86–1.51, p = 0.35), bleeding was 1.48 (95% CI, 0.88–2.48), and receiving a blood transfusion was 1.21 (95% CI, 0.57–2.55) when an arterial closure device was used.16 Data from the Evaluate Enoxaparin Clotting Time (ELECT) study suggested that the use of glycoprotein IIb/IIIa agents in combination with closure devices led to an increased bleeding risk.¹⁷ To extrapolate these data to patients with vWD, manual compression may decrease the likelihood of local bleeding and its complications compared to closure devices. Replacement Therapy Pharmacologic therapy is an important option for both prophylaxis and treatment of bleeding. Desmopressin, a synthetic analogue of vasopressin without major vasopressor activity can be given parenterally or by inhalation. It has been associated with vasodilatation and tachycardia with both hypo- and hypertension reported. Because of these potential adverse hemodynamic effects and reported association with MI and stroke, this agent should not be used in patients with CAD.^1,3,4,18 Virus-inactivated concentrates of factor VIII-VWF are safe options for the prophylaxis and treatment of bleeding.^3,4,5,19 Humate-P, an intermediate purity concentrate, is currently licensed for use in the United States. Recommendations regarding administration, dosage and target Plasma VIII:c levels are summarized in Table 2. Typically 1 IU/kg will increase plasma VIII:c levels by 2 U/dL.^3,4 Very high plasma VIII:c levels (> 200%) have been associated with deep venous thromboses post surgery in some rare instances.¹⁸ Monitoring bleeding time is not necessary since no lab test accurately predicts hemostatic response. In general, there is agreement that the goal of therapy is to maintain ristocetin cofactor levels between 50–100% with replacement therapy for a period of 3–10 days following major surgery and less following percutaneous procedures. The length of time required post catheterization has not been studied and there are no evidence-based guidelines. Platelet transfusions may also be required to achieve hemostasis in cases where bleeding is not corrected by the preceding pharmacologic maneuvers and in severe cases of Type III vWD.^3–5,19Treatment of Acute Coronary Syndromes Pharmacologic Therapy. Aspirin is standard therapy in acute coronary syndromes. This has safely been administered and described in case reports documenting various approaches to management of ACS in patients with vWD.^5,20 Thrombolytic therapy has been administered in the case of vWD and an ST elevation MI, but was associated with a significant decrease in hemoglobin requiring transfusion.²¹ Fragasso et al. reported a 61-year old vWD Type 1 patient (ristocetin cofactor activity 20%) with a large anterior myocardial infarction who was treated with rtPA followed by intravenous heparin for 48 hours. The patient’s hemoglobin decreased from 14.7 to 8.9 g/dL 48 hours after admission and required transfusion. The patient eventually underwent surgical revascularization for known three-vessel disease and was pretreated with Factor VIII concentrate. In contrast, James et al. have reported successful percutaneous transluminal coronary angioplasty without the use of anticoagulation in a patient with Type 1 vWD.⁵ They described a 70- year-old female with a history of menorrhagia and recurrent epistaxis who presented with an acute inferior myocardial infarction. Aspirin was administered. Cardiac catheterization was performed via the left femoral approach and right coronary artery angioplasty, without stent placement, was performed without preprocedural heparin. In this patient, Factor VIII levels were 137 IU/dL (range 50–200 IU/dL), vFW: Ag was 40 IU/dL (50–200 IU/dL), and vWF activity was 51 IU/dL (range 50–200 IU/dL). There were no bleeding complications. Others have noted the safe use of full antithrombotic and antiplatelet therapy in a patient with vWD and an anterior infarct and ventricular fibrillation arrest.²⁰ Arjomand et al. reported their experience in performing primary PCI via the femoral approach with the deployment of a bare metal stent and the use of full anticoagulation with heparin to maintain an activated clotting time of greater than 300 seconds. Glycoprotein IIb/IIIa therapy with tirofiban was also administered during the procedure and continued for 24 hours after the procedure. Tirofiban was chosen secondary to its shorter half life as compared with other IIb/IIIa inhibitors. The patient was also treated with aspirin and clopidogrel. The patient’s Factor VIII activity level was 82 percent (normal 50–100 percent) and vWF antigen was 74 percent (normal greater than 50 percent). There were no bleeding complications. In terms of antithrombin therapy, there is little information specifically regarding the approach to patients with vWD. The literature suggests that there may be a trend towards decreased bleeding risk with unfractionated versus low molecular weight heparin. A meta-analysis of the TIMI 11B and ESSENCE trials demonstrates an increase in minor bleeding risk with enoxaparin, with a pooled odds ratio of 1.23 for major bleeding and 2.38 for minor bleeding, favoring unfractionated heparin.²² Similar conclusions stem from the A to Z (Aggrastat to Zocor) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trials.^23,24 However, in a meta analysis of the primary data sets from 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in the treatment of ACS, there was no statistically significant difference in major bleeding or transfusion up to 7 days after randomization.²⁵ There is also literature to support the use of the direct thrombin inhibitor, bivalirudin in patients with bleeding disorders. Two case reports have noted the successful use of this agent in patients with hemophilia with acute coronary syndromes requiring PCI.^26–27 Bivalirudin, in addition to a 300 mg load of clopidogrel and 325 mg of aspirin, was used successfully in a patient with two-vessel disease undergoing elective PCI. Recombinant Factor VIII was also administered prophylatically.²⁶ Arora et al. also reported the use of bivalirudin in a patient with a non-ST segment elevation myocardial infarction.²⁷ Here, Factor VIII was administered to achieve activity levels of 100% and a bare metal stent was placed via femoral access. There were no bleeding complications and aspirin and clopidogrel were given long term. Data from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) trial which enrolled 6,010 patients referred for urgent or elective PCI, but excluding those undergoing reperfusion therapy for acute MI, demonstrated a decreased bleeding risk with bivalirudin and provisional IIb/IIIa use over unfractionated heparin and planned IIb/IIIa inhibitor use.^28,29 Patients with a history of bleeding diathesis were also excluded. There was a 40% reduction in major bleeding in the bivalirudin group compared with the unfractionated heparin and IIb/IIIa arm (4.1 versus 2.4%, p 30,31 We again reiterate the potential benefit of using short- versus long-acting agents. Conclusion and Recommendations For elective procedures, most patients with vWD do not present a significant risk of bleeding and require no prophylactic pharmacologic replacement therapy, especially if they have Type 1 disease and their ristocetin cofactor levels are more than 50% of normal. If the ristocetin cofactor level is less than 50%, patients should receive weight-adjusted doses of Factor VIII-vWF prior to and after the procedure to maintain their cofactor levels more than 50% of normal. In institutions with training programs, access to the vascular system should be performed by an experienced interventionalist and not an early trainee in these patients. This overall approach should be modulated by any prior history of spontaneous mucosal bleeding or excessive bleeding with any prior procedure. All patients should probably have manual compression rather than closure devices to achieve local groin hemostasis. All patients who come to the cardiac catheterization laboratory have baseline coagulation studies performed. In addition, specific questions should be a routine part of the pre-procedure evaluation to assess a history of bleeding in all patients and their first degree relatives since vWD can be present even with normal aPTT and bleeding times. Although bleeding time is not generally a part of the routine screening process, it probably should be done in anyone with a “positive” or suggestive history. For patients who present with ACS there are a number of options to help decrease the risk of bleeding. The data suggest the use of aspirin, unfractionated heparin or bivalirudin with the adjunctive use of short-acting glycoprotein IIb/IIIa inhibitors at the interventionalist’s discretion based on the perceived risk for cardiac morbidity and mortality. In terms of catheterization approach, there may be some advantage to reduce the risk of bleeding that favors the radial compared to the femoral approach; although there may not be a clear advantage over femoral access with manual compression. Caution in sheath management with early sheath removal may also decrease bleeding complications. Finally, Factor VIII-vWF can be administered prophylactically in patients with an increased risk of significant clinical bleeding or in the treatment of peri- or postprocedural bleeding. For patients with Type 1 vWD, long-term management of the patient post percutaneous revascularization with aspirin and clopidogrel should continue with careful monitoring and clear instructions for immediate follow-up at the first sign of any mucosal bleeding. For patients with other subtypes, individual decisions in consultation with a hematologist is necessary to tailor the type of revascularizaton (balloon alone, bare metal stent, drug-eluting stent) for the patient. The case report by Macdonald in this issue of the Journal reminds us that the co-existence of ACS with vWD is a real occurrence and we applaud their successful management of a complicated clinical problem.

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