Percutaneous Coronary Intervention and the Management of Acute Coronary Syndromes in Patients With von Willebrand Disease

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Abstract: Background. Von Willebrand disease (vWD) results from quantitative or qualitative deficiency of von Willebrand factor (vWF). The occurrence of myocardial infarction is very rare in patients with vWD. A few case reports of acute coronary syndrome (ACS) in vWD patients are present in the literature, but no definite management recommendations are available for such patients. Case report. We report a case of successful percutaneous coronary intervention (PCI) with bare-metal stent (BMS) implantation in a 46-year-old woman with type 1 vWD and history of coronary artery disease (CAD). She received periprocedural dual-antiplatelet therapy for 2 weeks and then continued aspirin without any bleeding complications. Management proposal. The optimal management of patients with vWD and ACS is complex and presents a therapeutic challenge. We propose that dual-antiplatelet therapy can be used safely in most vWD patients presenting with ACS as most of them are type 1 vWD. PCI with BMS can be done safely. Long-term management of these patients requires a systemic approach including hematological consultation, ascertaining vWF levels, as well as patient education and close outpatient follow-up.  

J INVASIVE CARDIOL 2013;25(4):E81-E86

Key words: vWD, DAPT, dual-antiplatelet therapy, bleeding

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Von Willebrand disease (vWD) results from quantitative or qualitative deficiency of von Willebrand factor (vWF). In developed countries, introduction of clotting factor concentrates has significantly increased life expectancy for patients with vWD. In this aging patient population, the occurrence of ischemic cardiovascular disease has been on the rise and the presence of coronary artery disease has been demonstrated in autopsies of vWD patients.¹ The occurrence of myocardial infarction is very rare in patients with vWD.  

To our knowledge, a few case reports are present in the literature, but no definite management recommendations are available for vWD patients presenting with acute coronary syndrome (ACS). In this article, we review the literature and report the case of a vWD patient undergoing percutaneous coronary intervention (PCI). Finally, we present a proposal for antiplatelet and antithrombotic therapy in vWD patients presenting with ACS.

Case Report

A 46-year-old woman with history of diabetes mellitus, hypertension, hypercholesterolemia, tobacco use, and type 1 vWD disease was referred to our hospital with chest pain and abnormal nuclear stress test. Her cardiac history included coronary artery disease (CAD) status post balloon angioplasty of the left circumflex artery in 2005. She was not on any antiplatelet therapy since then due to risk of bleeding. She was diagnosed with vWD in 1993 with factor VIII activity of 25% (normal, 50%-150%). Her surgical history was significant for cholecystectomy and total abdominal hysterectomy complicated by excessive bleeding that was controlled with factor VIII/vWF complex. Physical examination was unremarkable and cardiac catheterization with possible intervention was scheduled. After hematological consultation, two doses of desmopressin 12 hours apart were given. She was given aspirin 325 mg and clopidogrel 600 mg precatheterization. The patient was taken to the cardiac catheterization laboratory, where the right radial approach was favored over femoral because of bleeding risks. 

At the time of arterial cannulation, 3000 units of intravenous heparin were administered. After sheath placement, nitroglycerin 100 µg and verapamil 2.5 mg were administered. Her starting activated clotting time (ACT) was 121 seconds. Prior to advancing the extra back-up (EBU) guide catheter to the aortic root, bivalirduin was administered and her ACT was >300 s. Judkin’s left and right curved catheters were used for left and right coronary angiography and EBU 3.5 curved guide catheter was advanced for left main cannulation and intervention.

Coronary angiography showed widely patent left main and left anterior descending (LAD) arteries. Right coronary artery (RCA) was 100% occluded, which was consistent with her previous cardiac catheterization findings in 2005.  Left circumflex artery showed stenosis up to 95% at the site of prior angioplasty. It was decided to stent this lesion and a 3.5 x 18 mm bare-metal stent (BMS) was deployed without any complications. The final angiograms showed excellent angiographic results without any evidence of edge dissections or thrombus (Figure 1).

There were no periprocedural complications and she was discharged the next day on clopidogrel 75 mg daily for 1 month and aspirin 325 mg daily. She was followed at our office and completed clopidogrel 75 mg and aspirin 325 mg daily therapy for 4 weeks without any bleeding sequelae. Aspirin 325 mg daily was continued and on last check 9 months after her PCI, she was tolerating aspirin without any bleeding complications. 

Von Willebrand Disease Pathophysiology and Classification

Von Willebrand disease is the most common inherited bleeding disorder, with an estimated prevalence of 1% in general population by laboratory screening, although less than 5% of these individuals are symptomatic.² Most cases are transmitted as an autosomal dominant trait that affects males and females equally, but there are some acquired forms of vWD as well.³ vWD is classified in three main phenotypes. Mechanisms, diagnostic basis, and treatment options are different in every phenotype (Table 1). Diagnostic test levels for vWD include vWF ristocetin cofactor acitivity (vWF:RCo <30 IU/dL), vWF antigen (vWF:Ag <30 IU/dL), and factor VIII (decreased or normal).⁴ vWD type 1 is the most common type, accounting for approximately 75% of cases.⁵

Von Willebrand Factor

Von Willebrand factor plays an important role in platelet adhesion, aggregation, and thrombus formation.⁶ It has three important functions in thrombus formation: (1) binding to platelets; (2) binding to subendothelium; and (3) carrier function for factor VIII. This requires activation of vWF that can occur with exposure to subendothelial structures after vascular injury or high shear stress present in atherosclerotic arteries (shear rates >1000/second).⁷

Von Willebrand factor is synthesized mostly in endothelial cells, but it can be found in alpha-granules of platelets with no interchange between the two compartments.⁸ Although plasma and platelet vWF differ significantly from each other, both factors play an important role in securing primary hemostasis.⁸ There is evidence of significant heterogeneity of platelet vWF levels in vWD types with platelet-low and platelet-normal phenotypes identified.⁸

vWF in Coronary Artery Disease

Many studies have shown that high levels of plasma vWF are associated with risk of coronary heart disease and increased levels of vWF have been found in patients with acute myocardial infarction.^9,10 Probably, this elevation of vWF level is also seen in vWD patients presenting with ACS as evident by their baseline and ACS vWF levels in case reports (Table 2). vWF levels rise in ST-elevation myocardial infarction (STEMI) up to 1.5-2 fold in the first 24 hours and peak at 48 to 72 hours, with levels returning to baseline within 14 days.¹¹ 

Safety of Antiplatelet and Antithrombotic Therapy in vWD and ACS

Dual-antiplatelet therapy with aspirin and a thienopyridine (eg, clopidogrel) is currently the standard of care for the majority of patients undergoing PCI. Usually, antiplatelet medications are avoided in vWD patients due to risk of bleeding and the safety of such agents is not well studied in patients with vWD and ACS. However, there are a few case reports describing the use of antiplatelet and antithrombotic agents in patients with vWD undergoing PCI (Table 2) and cardiac surgery.¹² Increase in vWF levels with ACS, as a result of catecholamine surge,^11,13 may play a role in better tolerance of antiplatelet and antithrombotic medications during ACS in vWD patients.

There are studies on aspirin-vWF interactions and tolerance in vWD patients,^14,15 but data are lacking for thienopyridines. Aspirin therapy results in a minor decrease in vWF levels and significantly lengthens bleeding time only in less prevalent severe vWD type patients.¹⁴ 

Heparin does not decrease vWF levels in a normal population¹⁶ and multiple reports have described use of heparin in vWD patients undergoing PCI and cardiac surgery without siginificant bleeding complications (Table 2).¹² Direct thrombin inhibitor (eg, bivalirudin) use has been reported in hemophilia A patients undergoing PCI.¹⁷ 

Glycoprotein (GP) IIb/IIIa inhibitor (tirofiban) use  has been reported in patients with vWD and ACS during PCI with BMS in a patient with vWD without major bleeding complications.¹⁸ 

Thrombolytic therapy poses a greater risk of bleeding in vWD patients and ACS. These agents can degrade vWF, further reducing the levels and increasing bleeding risk.¹⁹ Fragasso et al reported use of rtPA in a vWD patient and STEMI associated with significant extracerebral bleeding.²⁰ 

There are two main therapies available for treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin (DDAVP) and factor VIII/vWF concentrates. Desmopressin raises endogenous factor VIII and vWF up to 3-5 times and corrects the defects. In severe diseases like type 3 and in most type 2 cases, DDAVP is ineffective and factor VIII/vWF concentrate is the best choice (Table 1).²¹

Proposal of Management of Acute Coronary Syndrome in vWD

The optimal management of patients with vWD and ACS is complex and requires detailed history and laboratory work-up including factor levels that may not be available quickly especially while treating STEMI. Patients with vWD can have a variable degree of vWF deficiency and therefore management should be individualized. If recent evaluation of vWD including typing, vWF activity, and factor VIII levels are available, these can help in making decisions. vWF activity levels above 30% in vWD patients are considered safe for minor surgeries.⁵

However, given the fact that prompt initiation of antiplatelet and antithrombotic therapy is associated with improved outcomes in patients with ACS, it is reasonable to proceed carefully with initiation of such therapies in ACS-vWD patients. We suggest that antiplatelet therapy can be given with aspirin and clopidogrel both in STEMI and unstable angina/non-ST elevation myocardial infarction (UA/NSTEMI) in vWD patients, as 75% of them are type 1 vWD (Figure 2).

As in the case of non-vWD patients with CAD, indications for cardiac intervention should be the same in vWD patients presenting with ACS. In STEMI and vWD, where the outcomes are time-dependent, primary PCI should be preferred. 

For UA and NSTEMI, where more time is available, heparin in addition to dual-antiplatelet therapy can be given. Hematological consultation and factor levels may be considered unless a decision for urgent PCI is made. In case of urgent PCI, follow the STEMI track (Figure 1).

Similarly, in patients with abnormal cardiac stress test and vWD, appropriate medical treatment including antiplatelets, factor levels, and hematological opinion may be considered before proceeding to PCI (Figure 1).

Bleeding is the most feared complication in the treatment of ACS in vWD patients and can be associated with poor immediate and long-term outcomes. We suggest the following to minimize bleeding risks in such patients undergoing PCI: (1) a radial approach should be preferred over femoral approach for cardiac catheterization for better hemostatic control; (2) direct thrombin inhibitors like bivalirudin alone or in combination with heparin can be used for angiography and PCI; (3) BMSs should be preferred to reduce the duration of dual-antiplatelet therapy; (4) use of GP IIb/IIIa inhibitors should be minimized; and  (5) for bleeding prophylaxis, desmopressin should be avoided preprocedure in acute events due to greater risk of hypertension and thrombosis with DDAVP.^22,23 However, DDAVP can be used preprocedure in elective procedures under suitable hemodynamic conditions. Desmopressin infusion at a dose of 0.3 µg/kg 30 minutes preprocedure increases plasma factor VIII and vWF levels by 3-5 times, suitable for minor surgeries.⁵ In case of severe vWD and periprocedural bleeding, cryoprecipitate (may require up to 8-12 bags and contains both factor VIII and vWF) can be used.²⁴ Factor VIII/vWF complex, a commercially available concentrate, can also be used in consultation with a hematologist.

It is probably safe to continue aspirin (ASA) 81 mg/day after PCI indefinitely or as tolerated, like a non-vWD disease patient.²⁵ Clopidogrel 75 mg/day after BMS implantation for 1 month or at least 2 weeks if increased risk of bleeding²⁵ as with severe vWD, can be given. Antiplatelet agents should be stopped if bleeding occurs. Also, factor VIII and vWF levels should be checked during the ACS if available in the hospital, as well as after 4-6 weeks to guide long-term antiplatelet therapy with hematological consultation. Close outpatient follow-up and patient education are necessary. 

Summary 

ACS occurs rarely in vWD patients, but presents a therapeutic challenge. The rare occurrence of vWD and ACS together makes it difficult to develop evidence-based guidelines based on clinical trials for such patients. In this article, we describe the case of a patient with vWD undergoing elective PCI and periprocedural management. There are a few case reports of myocardial infarction in vWD patients treated with antiplatelet and antithrombotic therapy without significant bleeding complications. Antiplatelet and antithrombotic therapy can be given in most vWD cases presenting with ACS. Long-term management of these patients requires a systematic approach, hematological consultation, vWF levels, platelet-vWF type, patient education, and close outpatient follow-up. There are currently no definite recommendations or guidelines for use of antiplatelet therapy for primary and secondary prevention of ischemic heart disease in patients with vWD.

References

1. Federici AB, Mannucci PM, Fogato E, Ghidoni P, Matturri L. Autopsy findings in three patients with von Willebrand disease type IIB and type III: presence of atherosclerotic lesions without occlusive arterial thrombi. Thromb Haemost. 1993;70(5):758-761.
2. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood. 1987;69(2):454-459.
3. Nilsson IM. von Willebrand’s disease — fifty years old. Acta Med Scand. 1977;201(6):497-508.
4. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) expert panel report (USA). Haemophilia. 2008;14(2):171-232.
5. Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med. 2004;351(7):683-694.
6. Ruggeri ZM, Ware J. von Willebrand factor. FASEB J. 1993;7(2):308-316.
7. Siedlecki CA, Lestini BJ, Kottke-Marchant KK, Eppell SJ, Wilson DL, Marchant RE. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood. 1996;88(8):2939-2950.
8. McGrath RT, McRae E, Smith OP, O’Donnell JS. Platelet von Willebrand factor — structure, function and biological importance. Br J Haematol. 2010;148(6):834-843.
9. Paulinska P, Spiel A, Jilma B. Role of von Willebrand factor in vascular disease. Hamostaseologie. 2009;29(1):32-38.
10. Whincup PH, Danesh J, Walker M, et al. von Willebrand factor and coronary heart disease: prospective study and meta-analysis. Eur Heart J. 2002;23(22):1764-1770.
11. Sakai H, Goto S, Kim JY, et al. Plasma concentration of von Willebrand factor in acute myocardial infarction. Thromb Haemost. 2000;84(2):204-209.
12. Gerling V, Lahpor JR, Buhre W. Peri-operative management of an adult patient with type 2N von Willebrand’s disease scheduled for coronary artery bypass graft. Anaesthesia. 2007;62(4):405-408.
13. Rickles FR, Hoyer LW, Rick ME, Ahr DJ. The effects of epinephrine infusion in patients with von Willebrand’s disease. J Clin Invest. 1976;57(6):1618-1625.
14. Barbui T, Rodeghiero F, Dini E. The aspirin tolerance test in von Willebrand’s disease. Thromb Haemost. 1977;38(2):510-513.
15. Praga C, Cortellaro M. Effect of aspirin on platelet aggregation and bleeding time in haemophilia and von Willebrand’s disease. Acta Med Scand Suppl. 1971;525:219-221.
16. Pernerstorfer T, Eichler HG, Stohlawetz P, Speiser W, Jilma B. Effects of heparin and aspirin on circulating P-selectin, E-selectin and von Willebrand factor levels in healthy men. Atherosclerosis. 2001;155(2):389-393.
17. Arora UK, Dhir M, Cintron G, Strom JA. Successful multi-vessel percutaneous coronary intervention with bivalirudin in a patient with severe hemophilia A: a case report and review of literature. J Invasive Cardiol. 2004;16(6):330-332.
18. Arjomand H, Aquilina P, McCormick D. Acute myocardial infarction in a patient with von Willebrand disease: pathogenetic dilemmas and therapeutic challenges. J Invasive Cardiol. 2002;14(10):615-618.
19. Goto S, Tamura N, Li M, et al. Different effects of various anti-GP IIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity. J Thromb Haemost. 2003;1(9):2022-2030.
20. Fragasso G, Camba L, Pizzetti G, Pagnotta P, Chierchia SL. Successful thrombolysis for acute myocardial infarction in Type I von Willebrand’s disease (vWD). Am J Hematol. 1998;57(2):180.
21. Mannucci PM. How I treat patients with von Willebrand disease. Blood. 2001;97(7):1915-1919.
22. Bond L, Bevan D. Myocardial infarction in a patient with hemophilia treated with DDAVP. N Engl J Med. 1988;318(2):121.
23. Byrnes JJ, Larcada A, Moake JL. Thrombosis following desmopressin for uremic bleeding. Am J Hematol. 1988;28(1):63-65.
24. Perkins HA. Correction of the hemostatic defects in von Willebrand’s disease. Blood. 1967;30(3):375-380.
25. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44-e122.
26. Wong CB, Schreiber TL. Acute myocardial infarction in a patient with von Willebrand disease. Cathet Cardiovasc Diagn. 1996;38(3):287-288.
27. James PR, de Belder AJ, Kenny MW. Successful percutaneous transluminal coronary angioplasty for acute myocardial infarction in von Willebrand’s disease. Haemophilia. 2002;8(6):826-827.
28. Macdonald J, Srinivasan M, More R. Percutaneous coronary intervention in a patient with von Willebrand’s disease presenting with an acute coronary syndrome. J Invasive Cardiol. 2006;18(4):174-177.

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From the ¹Cardiology Section, Virginia-Tech Carilion School of Medicine and Research Instituite, Roanoke, Virginia and ²Shifa College of Medicine, Pakistan.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 6, 2012, provisional acceptance given August 23, 2012, final version accepted October 15, 2012.

Address for correspondence: Sulaiman Rathore, MD, 1906 Belleview Avenue, Roanoke, VA 24012. Email: srathore@carilionclinic.org