346 Case report

Antithrombotic therapy in a patient with mild haemophilia A and atrial fibrillation: case report and brief review of the literature Carlos Aguilar The remarkable advances made in recent decades in the treatment of haemophilia have resulted in a longer life expectancy for haemophilia patients. The care of diseases related to ageing in these patients is becoming of great interest. We briefly discuss the current possibilities for antithrombotic therapy in patients with haemophilia describing the case of a 67-year-old patient with mild haemophilia A and atrial fibrillation requiring antithrombotic therapy. Blood Coagul Fibrinolysis 26:346–349 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

Blood Coagulation and Fibrinolysis 2015, 26:346–349

The remarkable advances made in recent decades in developed countries for the treatment of haemophilia have resulted in a shift in the relative importance of diverse disorders when providing care to these patients. Thus, concerns regarding musculoskeletal complications or the transmission of blood-borne infectious agents have been reduced, thanks to the widespread use of prophylactic treatment regimens and the increasing use of recombinant products, respectively. However, the increase in life expectancy of haemophiliacs has also resulted in increased interest in an emerging health problem in this group: age-related diseases, particularly the development of malignancies and cardiovascular disease. These conditions have created new challenges related to the high risk of haemorrhage involved in many of the necessary diagnostic tests and treatments and chemotherapeutic and antithrombotic drugs that frequently induce thrombocytopenia. Data from the British Haemophilia Registry indicate that in 2007 patients with mild-moderate haemophilia without HIV infection or hepatitis C virus (HCV)-related chronic liver disease had a median life expectancy of 77 years (66 years for those with severe haemophilia), compared with the life expectancy of 78 years in the healthy male population [1]. This means that, fortunately, an increasing number of older haemophiliacs will need our care, and we have to adapt to new therapeutic strategies, greater use of replacement therapy, higher costs and a greater need for multidisciplinary collaboration.

strategy should be tailored. This challenge is enormous in the context of haemophiliacs who have developed an inhibitor, although very few patients with these characteristics also develop any of the disorders mentioned. Two aspects are involved, namely that the efficacy of bypassing agents in these special haemostatic circumstances is uncertain, and these drugs are potentially thrombogenic, and possibly complex to administer in situations of haemostatic activation, such as acute coronary syndromes or malignancies.

Haemophiliacs, especially those with milder forms, do present with thrombotic risk [2]. For this reason, antithrombotic treatment cannot be excluded in these patients, especially in the case of heart disease, but the benefits and risks should be assessed individually, and both the antithrombotic therapy and the factor replacement 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

Keywords: antithrombotic therapy, atrial fibrillation, cardioversion, haemophilia Hematology Department, Santa Ba´rbara General Hospital, Soria, Spain Correspondence to Carlos Aguilar, Hospital General Santa Ba´rbara, Servicio de Hematologı´a, P Santa Ba´rbara s/n., 42005 Soria, Spain Tel: +34 975214156; fax: +34 975214156; e-mail: [email protected] Received 4 April 2013 Revised 29 August 2013 Accepted 1 September 2013

In order to illustrate the clinical relevance of the problem, we describe the case of a patient with mild haemophilia A diagnosed with atrial fibrillation, who had criteria indicating antithrombotic treatment. The decision was taken to start treatment with low-dose aspirin.

Case presentation The patient was a 67-year-old man with mild haemophilia A (Factor VIII level 17 IU/dl at diagnosis in 1983), HIV-negative, with a history of past HCV infection (antiHCV positive; negative PCR), hypertension and diabetes mellitus. He presented with a symptomatic episode of paroxysmal atrial fibrillation, later confirmed with a 24-h electrocardiogram at the Cardiology Service as recurrent. Echocardiography showed left atrial enlargement (diameter 5.1 cm) without atrial thrombi, left ventricular hypertrophy and mild mitral regurgitation. The left ventricular ejection fraction was normal. The patient had a CHADS2 score of 2 (CHA2DS2-VASc ¼ 3), making him a candidate for anticoagulant treatment [3]. The haematological evaluation determined a FVIII level of 24 IU/dl. The therapeutic alternatives were discussed with the patient, and treatment with aspirin at a dose of 100 mg daily was initiated. After 6 months with this DOI:10.1097/MBC.0000000000000282

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Antithrombotic therapy for atrial fibrillation in haemophilia Aguilar 347

treatment, no increase in haemorrhagic symptoms has been reported. The antiarrhythmic treatment was dronedarone.

Discussion Epidemiological data have led to haemophilia being traditionally considered as a protection factor against thrombus formation [4], a key mechanism in the pathogenesis of atherothrombotic coronary disease and the frequent formation of atrial thrombi in patients with atrial fibrillation. However, this concept should be refined, because most published data are from patients with severe haemophilia and this protection should be, at least hypothetically, inversely proportional to the level of coagulation factor deficiency. Notwithstanding, objective reports prove that haemophilia is not protective against arteriosclerosis at any level of severity [5], and haemophilia patients should follow a risk-factor control for this disease similar to that recommended for the general population. However, no data are available on the risk of embolic stroke in haemophiliacs with nonvalvular atrial fibrillation compared with nonhaemophiliac patients with similar characteristics, so the assumed protective role of haemophilia against thrombosis cannot be currently extended to this group. Because of the rarity of these situations in current clinical practice, there are no evidence-based guidelines for their treatment, and future randomized clinical trials in this population in particular are not expected. The most cited recommendations at present are the guidelines prepared jointly by two expert panels: the Utrecht University Hospital (Van Creveld Klinik) and the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan [6–8]. These guidelines assess the risk of embolism using the same criteria employed for nonhaemophilic patients. Briefly, oral anticoagulant therapy is recommended for patients with valvular atrial fibrillation, or in cases of nonvalvular atrial fibrillation, if CHADS2 score is at least 2. In cases with a high risk of bleeding, dual antiplatelet therapy with aspirin and clopidogrel is suggested as an alternative. When CHADS2 score is 1, antiplatelet therapy with aspirin (doses of 100–300 mg) is preferable to oral anticoagulation, although both alternatives are considered. Finally, no antithrombotic treatment is needed if CHADS2 score is 0. The aspirin-related bleeding risk in nonhaemophilic patients with atrial fibrillation over 75 years of age has been described to be similar to that produced by antivitamin K [9]. However, the above-mentioned guidelines establish differences with respect to the minimum concentrations of FVIII or IX considered optimal to reduce the risk of bleeding when various antithrombotic drugs are used in this context. Thus, when antivitamin K or combined antiplatelet therapy

with aspirin and clopidogrel are used, stable minimum levels of 30 IU/dl are suggested, whereas the factor concentration is set at 10 IU/dl when using antiplatelet therapy with aspirin or clopidogrel. Maintenance of these minimum concentrations of FVIII or IX would need very intensive prophylaxis or even continuous factor infusion in severe haemophiliacs, which are both very demanding for the patient and practically unfeasible due to costs. For this reason, antiplatelet therapy is most frequently prescribed in these circumstances, even considering the scientific reasoning outlined above, perhaps with the exception of mild haemophilia with basal factor levels at least 30 IU/dl, the management of which would be similar to that of nonhaemophiliac patients with atrial fibrillation. Figure 1 shows the algorithm of antithrombotic treatment for patients with nonvalvular atrial fibrillation proposed in the above-mentioned guidelines [6]. Another aspect to consider, at least from a theoretical point of view, is the significant increase in the intensive use of factor concentrates in elderly haemophiliacs, which might result in an increase in the frequency of inhibitor occurrence (especially in patients with mild to moderate disease) at these ages, which are unusual in current practice. Regarding arrhythmia control, two treatment options are available: heart rate control or the attempt to restore sinus rhythm. No differences have been found in cardiovascular mortality or stroke rate between these two strategies, although quality of life is better with the latter [10]. Thromboprophylaxis is required in patients considered at a high risk of embolism by the cardiologist, even after successful cardioversion. Figure 2 shows a cardioversion strategy for haemophiliacs. Transoesophageal echocardiography should be performed to rule out atrial thrombi in patients with atrial fibrillation longer than 48 h who are candidates for cardioversion. This avoids the 4-week delay caused by preventive anticoagulation therapy. In this case, low-molecular-weight heparin at therapeutic doses over 5 days, while maintaining minimum levels of FVIII/IX of 80 IU/dl, is enough. Otherwise, oral anticoagulation with antivitamin K for an international normalized ratio (INR) range 2–3 for 4 weeks before cardioversion should be maintained, regardless of the type of intervention chosen. All these strategies require appropriate prophylaxis with minimum levels of coagulation factor of 30 IU/dl after cardioversion. The longterm antithrombotic therapy should follow the guidelines summarized in Fig. 1. Two distinct groups of patients should be mentioned in the context of antithrombotic treatment: B haemophiliacs and those who develop an inhibitor. Treatment with vitamin K antagonists entails particular problems in the first group, because these drugs reduce levels of factor IX (one of the vitamin K-dependent clotting factors), increasing the severity of haemophilia B and lengthening

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348 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3

Fig. 1

Atrial fibrillation + haemophilia

Anti-thrombotic treatment according to baseline FVIII/FIX and risk for stroke

Baseline FVIII/FIX ≥30 IU/dl

Baseline FVIII/FIX 10–30 IU/dl

Baseline FVIII/FIX 1-10 IU/dl

CHADS2

CHADS2

Antithrombotic therapy in a patient with mild haemophilia A and atrial fibrillation: case report and brief review of the literature.

The remarkable advances made in recent decades in the treatment of haemophilia have resulted in a longer life expectancy for haemophilia patients. The...
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