Journal of Thrombosis and Thrombolysis

, Volume 35, Issue 2, pp 271–278

Percutaneous coronary intervention in patients with haemophilia presenting with acute coronary syndrome: an interventional dilemma: case series, review of the literature, and tips for management

Authors

    • Leviev Heart CenterSheba Medical Center and Tel Aviv University
  • Sharon Gannot
    • Leviev Heart CenterSheba Medical Center and Tel Aviv University
  • Aaron Lubetsky
    • The National Hemophilia CenterSheba Medical Center and Tel Aviv University
  • Uri Martinowitz
    • The National Hemophilia CenterSheba Medical Center and Tel Aviv University
  • Shlomi Matetzky
    • Leviev Heart CenterSheba Medical Center and Tel Aviv University
  • Victor Guetta
    • Leviev Heart CenterSheba Medical Center and Tel Aviv University
  • Amit Segev
    • Leviev Heart CenterSheba Medical Center and Tel Aviv University
Article

DOI: 10.1007/s11239-012-0802-y

Cite this article as:
Fefer, P., Gannot, S., Lubetsky, A. et al. J Thromb Thrombolysis (2013) 35: 271. doi:10.1007/s11239-012-0802-y

Abstract

Since the introduction of clotting factor concentrates over 50 years ago the life expectancy of patients with hemophilia (PWH) has increased to over 70 years. Consequently, diseases of the ageing population, including coronary artery disease, are increasingly being encountered. These patients present a unique therapeutic problem due to their greatly increased bleeding risk. Randomized controlled studies specific to PWH are lacking, emphasizing the need for case series. We present three cases of acute coronary syndrome in PWH who underwent urgent percutaneous coronary intervention at our institution, and summarize the available literature on the topic. We describe their management and outcome and provide points to consider when treating these complex patients.

Keywords

HaemophiliaAcute coronary syndromePercutaneous coronary angioplastyCoagulation factorsAnticoagulationAnti-platelets

Introduction

Haemophilia is a sex-linked genetic deficiency of coagulation factor VIII or IX, resulting in provoked or spontaneous bleeding episodes. In the past, most patients with severe haemophilia had a markedly reduced life expectancy. However, since the introduction of clotting factor concentrates over 50 years ago the life expectancy of patients with haemophilia (PWH) has increased to over 70 years [13], and consequently, diseases of the ageing population, including coronary artery disease, are increasingly being encountered in these patients [4]. Furthermore, reports in the literature have also associated acute coronary syndromes (ACS) with the infusion of factor concentrates in PWH [5, 6]. Current clinical guidelines for treating patients with high-risk ACS advocate an early invasive approach [7, 8]. Implementation of such an approach has been associated with improved short- and long-term mortality [9]. However, periprocedural anticoagulation is needed to support percutaneous coronary intervention (PCI) and furthermore, prolonged antiplatelet therapy is indicated for patients who undergo stent implantation, both of which may be potentially hazardous in patients with a predisposing bleeding diathesis such as haemophilia.

We present three cases of ACS in patients with haemophilia A who underwent urgent PCI at our institution. We describe their management and outcome and propose a scheme for treating these complex patients.

Case #1

A 63 years old male patient suffers from severe haemophilia A (factor VIII levels < 1 U/dL) and is treated with 2,000 U factor VIII twice-weekly. He previously had bilateral total knee replacements due to haemophilia related arthropathy. The patient had known hypertension and a recent past history of smoking, and was treated 3 years earlier for hepatitis C with ribavirin and interferon. He was admitted with an acute inferior ST-elevation myocardial infarction (STEMI) occurring 4 h after injecting his regular dose of factor VIII. No major abnormalities were noted on his blood count and chemistry (platelet count of 202,000/mL, and hemoglobin level was 15.4 g/dL). Upon admission, he was given 2,000 U factor VIII along with loading doses of aspirin (300 mg) and clopidogrel (600 mg) and was referred for urgent coronary angiography which demonstrated an occluded right coronary artery (RCA). Arterial access was obtained by the radial route and anticoagulation was achieved with the use of standard weight adjusted bolus and continuous infusion of bivalirudin during PCI. Primary PCI was performed by standard procedure, namely, manual thrombus aspiration was performed followed by balloon dilation and bare metal stent (BMS) implantation of the infarct related lesion. Haemostasis at the radial puncture site was successfully attained by the use of a radial arm band. Creatine phosphokinase peaked at 1,400 U/dL and echocardiography demonstrated normal left-ventricular function. Subsequent hospital course was uneventful. He was treated with 1,000 IU factor VIII twice daily for the duration of his hospital stay, after which he resumed regular maintenance doses of factor VIII and was discharged on aspirin 100 mg/day and clopidogrel 75 mg/day for 9 months without significant bleeding episodes on follow-up.

Case #2

A 60 years old male patient suffers from mild haemophilia A diagnosed at age 18 after a bleeding episode following an operation on his ear. Factor VIII levels measured at around 10 U/dL. Over the years, infrequent bleeding episodes were treated with factor VIII. Occasional joint bleeding led to the development of arthropathy in his left hip and knee joints. He was admitted due to recurrent episodes of precordial pain at rest with new T wave inversion in the anterior chest leads on the admission ECG. His biomarker levels were normal. He was referred for coronary angiography due to unstable angina pectoris. Immediately before angiography he was treated with 2,000 IU of factor VIII. Arterial access was attained by the radial route. Anticoagulation was achieved by weight adjusted unfractionated heparin (UFH). A critical stenosis of the proximal left anterior descending artery was found, and balloon dilatation was performed with subsequent implantation of a BMS. Treatment with 1,000 IU factor VIII twice daily was continued for 4 days after angioplasty. Subsequent hospital course was uneventful. Factor VIII levels were around 10 U/dL and thus further treatment with factor VIII was discontinued. Aspirin was continued indefinitely and clopidogrel therapy was continued for 3 months. The patient noted increased frequency of minor bleeding episodes while on dual anti-platelet therapy but did not need subsequent support with factor VIII. He has had no recurrent ischemic episodes or major bleeding episodes on follow-up and was free of angina at 15 months after PCI.

Case #3

A 52 years old male patient suffers from severe haemophilia A (factor VIII levels < 1 U/dL) and is treated on demand with an average dosing interval of factor VIII infusions once every week with occasional need for more frequent dosing. Previous bilateral total knee replacements were complicated by infection and he has since been wheelchair ridden. Other medical history included type-2 diabetes mellitus, dyslipidemia and non-hodgkin lymphoma treated with chemotherapy 14 years previously. He initially presented with unstable angina pectoris. The patient was loaded with aspirin and clopidogrel and anticoagulated with weight adjusted UFH. After treatment with 2,000 U factor VIII coronary angiography was performed through the radial route. Angiography revealed a diseased but small RCA and a significant stenosis of the LAD which underwent PTCA and BMS implantation. Due to proximal dissection an additional BMS was implanted. Patient was given intravenous glycoprotein IIb/IIIa antagonist as a bailout due to angiographic distal embolization. Treatment with 1,000 IU factor VIII twice daily was continued for 4 days after PCI. The patient was discharged on clopidogrel 75 mg/day for 3 months and aspirin indefinitely. He continued to receive standard factor VIII replacement without major bleeding episodes during the first year after PCI, at which time he was admitted with recurrent severe unstable angina. After administration of 2,000 IU factor VIII, repeat coronary angiography was performed. It revealed severe in-stent-restenosis in the LAD stent and since the implantation of a drug-eluting stent was aimed to be avoided; he was treated with cutting balloon dilatation alone. Clopidogrel was continued for 1 month without adverse events. Over 6 months follow-up there were minor bleeding episodes and no recurrent angina. At 1 year post his second procedure, a thallium scan showed no anterior wall ischemia.

Discussion

We describe herein three cases of patients with haemophilia A presenting with ACS and undergoing PCI. When treated correctly both pharmacologically and invasively, these patients may have a favorable outcome without significant bleeding or recurrent ischemic events.

Haemophilia A and B are sex-linked genetic deficiencies of coagulation factors VIII or IX, respectively. After activation of factor IX to factor IXa, this enzyme interacts with the active cofactor form of factor VIII, factor VIIIa, to form a complex on membrane surfaces. This complex converts factor X to Xa [10]. Thus, both factor IX and factor VIII are critical components of blood coagulation pathways [11]. The clinical manifestations include spontaneous or provoked bleeding episodes. Disease severity is defined by the plasma factor levels, and often correlates with clinical severity [12]. Severe disease is defined by a factor level of less than 1 U/dL (<1 % of normal), and is usually associated with spontaneous unprovoked bleeding episodes. Patients with moderate (2–5 U/dL) or mild disease (>5–40 U/dL) commonly present with bleeding mainly after trauma or surgery.

The contemporary medical treatment of ACS includes an aggressive antithrombotic regimen including heparin and dual anti-platelet therapy. Furthermore, current guidelines for the treatment of ACS advocate an early invasive strategy (coronary angiography followed by PCI if indicated) for moderate to high risk ACS patients. Even patients initially treated conservatively may require invasive treatment based on presence of ischemia or persistent symptoms, and any patient undergoing PCI with coronary stenting will require prolonged dual anti-platelet therapy. Indeed, as shown in a recent meta-analysis [13], an invasive strategy was associated with reduced rates of refractory angina, rehospitalization, and myocardial infarction, especially in patients at high risk for recurrent events, but was also associated with an increased risk of bleeding. Periprocedural bleeding in patients undergoing PCI for ACS is not merely a nuisance but increasingly has been recognized as an independent predictor of increased long-term mortality [1416]. While haemophilia is a rare disease, especially in the field of ACS, patients present a unique therapeutic problem due to their greatly increased bleeding risk. Randomized controlled studies specific to PWH are lacking and unlikely to be available in the foreseeable future, emphasizing the need for case series. In an attempt to identify all cases reported in the literature, we scanned the literature by a formal search of the MEDLINE electronic database using the keywords: hemophilia AND [angioplasty OR acute coronary syndrome OR myocardial infarction OR coronary stent]. In addition we searched the reference lists of identified publications for further published case reports. All reports in the English language were included regardless of completeness of data. We identified an additional 17 cases in the literature, which are presented along with our three cases in Table 1. Patients ranged from 31 to 73 years old, with an average age of 54. Five patients presented with STEMI, and most of the remaining patients presented with unstable angina or NSTEMI. Eleven patients had severe haemophilia, three had moderate haemophilia, and six had mild haemophilia. The majority of the patients underwent BMS implantation, while three patients underwent balloon angioplasty alone, and one underwent drug eluting stent (DES) implantation. Procedural characteristics were not available for all procedures. However, use of the radial technique, which has been shown to reduce bleeding complications [17] in patients undergoing PCI was utilized in only four cases, three of which were performed by us. However, only one major access site complication requiring transfusion was reported. No other major bleeding events were reported for the other patients within the available follow up period. Bivalirudin has been shown to reduce bleeding complications in ACS patients undergoing PCI [18], however, bivalirudin was used in only four cases, while most cases utilized unfractionated heparin (UFH). Although this is a very small cohort, the only major periprocedural bleeding complication occurred in a patient treated with UFH. Glycoprotein IIa/IIIb inhibitors were used in a minority of cases without mention of complication. Antiplatelet use and duration varied widely between patients. Among patients treated with BMS, most received long term aspirin and a variable course of thienopyridine ranging from 10 days to over 9 months. Among patients with severe haemophilia, only two (cases #1 and #3) patients received clopidogrel for over 1 month without mention of increased bleeding events up to 9 months. No information regarding antiplatelet duration was available for the only patient treated with a DES. Reported outcomes were on the whole very favorable. No deaths or stent thromboses were reported. On long term follow-up only mild bleeding complications were reported for four patients requiring clopidogrel cessation at 4 months in one case. While the sample collected herein is very small, the outcomes described are comparable to those observed in large registries and studies of patients with ACS undergoing PCI [19].
Table 1

Summary of published cases of patients with haemophilia undergoing percutaneous coronary interventions

References

Age

Indication

Condition

Baseline factor concentration (%)

Procedure

Access

Anticoag during PCI

GP IIb, IIIa during PCI

Antiplatelet (duration)

Follow-up (duration)

Forman et al. [35]

45

Non ACS

Haemophilia A

1–5

PTCA

Femoral

UFH

NA

None

NA

Helft et al. [36]

58

UAP

Haemophilia B

5–40

BMS

NA

UFH

NA

None

No angina recurrence (3 months)

Peerlinck and Vermylen [37]

72

MI

Haemophilia A

<1

BMS

Femoral

UFH

None

ASA, 6 days

Groin hematoma requiring transfusion, (≥5 days)

Alsolaiman et al. [6]

44

STEMI

Haemophilia A

6

PTCA

NA

NA

None

ASA 3 years at least

No bleeding or chest pain (3 years)

MacKinlay et al. [38]

52

NA

Haemophilia A

<25

PTCA

Femoral

NA

NA

ASA, NA

No bleeding complications (NA)

Au et al. [39]

31

UAP

Haemophilia B

1

BMS

NA

Heparin unspec

None

ASA + ticlop, 1 month

No angina (6 months)

Bovenzi et al. [40]

73

UAP

Haemophilia B

<1

BMS

NA

UFH

Abciximab

ASA + clopid, 1 month

No angina or bleeding (6 months)

Virtanen et al. [22]

59

STEMI

Haemophilia A

>5

BMS

Radial

None

Eptifibatide

Clopid, 2 months

No stent thrombosis (2 years)

Arora et al. [41]

64

NSTEMI

Haemophilia A

<1

BMS

Femoral

Bivalirudin

None

NA

NA

Kerkhoffs et al. [42]

62

STEMI

Haemophilia A

16

Stent unspec

NA

None

Abciximab

Clopid 1 month then ASA indefinitely

NA

Krolick [27]

54

Prior stent thrombosis

Haemophilia A

<1

DES

Femoral

Bivalirudin

None

NA

NA

Ferrario et al. [43]

57

UAP

Haemophilia A

<1

BMS

NA

UFH

None

Clopid 1 month, then ASA indefinitely

No increase in bleeding (NA)

Smolka et al. [44]

62

UAP

Haemophilia A

2–3

BMS

Femoral

UFH

None

Clopid + ASA 1 month, then ASA indefinitely

1 episode angina, subcutaneous bleeding with clopid (5 months)

Quintero et al. [45]

44

STEMI

Haemophilia A

1–5

BMS

NA

Bivalirudin

None

ASA + clopid 4 months, then ASA indefinitely

Increased bleeding clopidogrel stopped at 4 months (2 years)

Pesaro et al. [46]

37

UAP

Haemophilia B

<1

BMS

NA

NA

NA

ASA + clopid 1 month, then ASA indefinitely

No angina or bleeding (6 months)

Kim et al. [47]

52

UAP

Haemophilia A

<1

BMS

Femoral

UFH

None

ASA + clopid 1 month, then ASA indefinitely

Asymptomatic, stent restenosis on angiography (10 months)

Petrillo et al. [26]

38

NSTEMI

Haemophilia A

<1

Other: genous

Femoral

None

None

ASA + clopid 10 days, then ASA indefinitely

Minor bleeding on clopidogrel, stopped day 19 (1 month)

Case report 1

63

STEMI

Haemophilia A

<0.001

BMS

Radial

Bivalirudin

None

ASA + clopid, indefinitely

No major bleeding (9 months)

Case report 2

60

UAP

Haemophilia A

10

BMS

Radial

UFH

None

ASA + clopid 3 months, then ASA indefinitely

Minor bleeding, no ischemia (15 months)

Case report 3

52

UAP

Haemophilia A

<0.001

BMS

Radial

UFH

Tirofiban

ASA + clopid 3 months, then ASA indefinitely

Minor bleeding, severe UAP, balloon dilatation for in stent restenosis at 12 months, no angina or bleeding (24 months)

PCI percutaneous coronary intervention, ACS acute coronary syndrome, PTCA percutaneous transluminal coronary angioplasty, UFH unfractionated heparin, NA information not available, UAP unstable angina pectoris, BMS bare metal stent, ASA aspirin, Clopid clopidogrel, MI myocardial infarction, STEMI ST-elevation myocardial infarction, NSTEMI non-ST-elevation myocardial infarction, Ticlop ticlopidine

A number of different treatment regimens were used in these patients, emphasizing the lack of a universally accepted protocol. A number of treatment protocols have been proposed, most recently by a group in the Netherlands [20]. The cases presented in this paper exemplify the complexity of caring for these patients, and stress the need for a multidisciplinary approach involving a concerted decision making process involving cardiologists and hematologists. In an effort to optimize treatment of ACS while minimizing bleeding complications in these patients, the following points should be considered:
  1. 1.

    Careful triage: The indications for intervention, which are similar in American and in European evidence based guidelines [7, 8] should be the same in PWH as in the general population. In general the urgency of intervention should be weighed against the individual bleeding risk and decisions should be made by a team including an interventional cardiologist and a hematologist experienced in treating PWH. Urgent PCI should be performed in patients presenting either with STEMI presenting within 12 h of pain onset or NSTE-ACS accompanied by persistent symptoms and/or dynamic ECG changes. In relatively low-risk ACS patients (e.g. patients without ongoing pain, hemodynamic instability, dynamic ECG changes, biomarker elevation, and who have normal left-ventricular function), an initial conservative approach can be considered, with an invasive approach reserved for patients with recurring symptoms or significant ischaemia on non-invasive testing as suggested by the guidelines [7]. Bleeding diatheses are considered an absolute contraindication to thrombolytic therapy [7]. Furthermore, we did not find any published reports of thrombolytic use in PWH presenting with STEMI. Therefore, PWH presenting with STEMI should be transported preferentially to a center offering around the clock primary PCI-capabilities.

     
  2. 2.

    Vascular access: In patients referred for coronary angiography we suggest preferential use of the radial approach. Recent evidence has suggested that radial access reduces vascular complications and bleeding when compared to femoral access especially in the setting of ACS [21]. Therefore, it makes sense to use this approach in patients with increased bleeding propensity. In all three of our cases, the radial technique was used without any major bleeding or vascular complications. Interestingly, only one other case in the literature utilized this approach [22].

     
  3. 3.

    Selection of stent: Bare-metal stents have an advantage over DES in that only one month of dual anti-platelet therapy may be sufficient after stent implantation [7]. If available, the use of BMS with supposedly reduced thrombogenic risk such as titanium-NO coated stents [23], carbofilm coated stents [24], or endothelial progenitor cell capture stents [25] may be preferred in these patients. Use of an endothelial progenitor cell capturing stent has been reported in one case in the literature [26] with favorable outcome. The issue of restenosis is especially pertinent in this regard. As DES use was reported in only one case in the literature [27], no long-term follow-up data exists on this treatment option. The advantages of DES over BMS are reduced target lesion revascularization and reduced major adverse cardiac events. Notably, DES use has not been associated with reduced mortality or recurrent MI in stable or unstable coronary patients and thus the use of DES should be reserved for patients with symptomatic restenosis or patients at very high risk of developing restenosis (e.g. diabetic patients with long lesions in small coronary arteries). The major problem with DES use is the need for prolonged dual antiplatelet therapy to prevent stent thrombosis. While current guidelines advocate at least 12 months of dual antiplatelet therapy [7], a recent trial found no benefit of 24 months of dual antiplatelet therapy over a shorter period of 6 months [28]. Drug eluting balloons have shown favorable results in treating BMS restenosis [29]. While it is not clear how long anti-platelet therapy should be continued in these cases, it is tempting to use this technology in lieu of DES with the hope that avoiding the placement of an additional stent layer may be associated with lower risk of stent thrombosis. Given our favorable, albeit limited experience with prolonged dual antiplatelet therapy, selective use of DES can be considered in patients at high risk of developing restenosis, such as diabetics patients with small coronary arteries or patients with restenosis in a previously implanted stent.

     
  4. 4.

    Choice of anticoagulant to support PCI: Since PWH are prone to bleeding, the duration of action and reversibility are the most important considerations in choosing an anticoagulant. Unfractionated heparin was the most commonly utilized agent used in patients with haemophilia (Table 1), likely due to its short duration of action and reversibility. Low molecular weight heparin has the advantage of lower incidence of bleeding complication [30] and heparin-induced thrombocytopenia [31] when compared to UFH, but its effect is harder to control and reverse, making UFH a safer choice. Bivalirudin, a direct thrombin inhibitor, also has a short half life and its use has been associated with a significant reduction in major bleeding complications compared with UFH [18]. Bivalirudin to support PCI has been used successfully in a few cases (Table 1). Of our three cases, two patients received UFH, and one received bivalirudin in the setting of ACS undergoing primary PCI. No major bleeding complications related to these agents occurred.

     
  5. 5.

    Use of purified coagulation factors: Appropriate support with purified factors during the vulnerable period is essential to prevent life-threatening bleeding. There are no specific guidelines for patients undergoing angiography or PCI. However, since patients undergoing PCI receive a combination of antiplatelet and anticoagulant therapy, they are at increased risk of both access and non-access site major hemorrhage. In non-haemophiliac populations, the risk of major haemorrhage in patients undergoing PCI is around 2–2.5 % [32, 33]. Thus we recommend that patients undergoing diagnostic angiography and/or PCI receive factor replacement therapy prior to the procedure to achieve 40–60 % of factor VIII activity, which is slightly less than that recommended for major surgery in PWH [34]. This recommendation is slightly less stringent than that proposed by Schutgens et al. [20]. At our institution, a bolus of 2,000 IU of factor VIII was administered just prior to the procedure, and boluses of 1,000 IU were administered twice daily for the first few days after the procedure to achieve a factor level of 40–60 %. The need for subsequent maintenance factor replacement in patients on (dual) antiplatelet therapy should be made on an individual basis and should balance the need for continued antiplatelet therapy and severity of bleeding associated with such therapy. In patients with moderate and severe haemophilia, we recommend following factor levels more closely while patients are on concomitant dual antiplatelet therapy. The frequency and factor target levels should be tailored individually. In urgent situations, such as acute STEMI, factor levels should be measured after the PCI and subsequent replacement treatment made accordingly. Infusion of factor concentrates has been associated with precipitation of acute MI, as exemplified by our case #1 and others in the literature [5, 6]. Since coronary thrombosis is usually associated with coronary atherosclerosis and plaque rupture, the induction of coronary thrombosis by clotting factors is only one aspect of the atherothrombotic process. Treating the atherothrombotic plaque by coronary stenting and antiplatelet agents will resolve the acute atherothrombotic process, however peri-procedural bleeding secondary to arterial puncture and combined anticoagulant and anti-platelet therapy will still predispose the patient to major bleeding risk. The delicate balance between the pro-thrombotic properties of factor concentrates and the need to offset increased bleeding in these patients is a fine art but we believe that a factor level approaching 40–60 % achieves a reasonable balance between the two.

     

In conclusion, based on the limited data available, PWH presenting with ACS can be treated safely and effectively by invasive procedures, provided that a multidisciplinary team works to provide extra care in the form of factor replacement and close observation.

Copyright information

© Springer Science+Business Media, LLC 2012