By Craig Kessler, MD
2008-07-01
Dr. Kessler is Professor of Medicine and Director of the Coagulation Laboratory at Georgetown University.
I recently received the following question from an ASH member through the Society's Consult-a-Colleague program. He asked:
I have a patient with mild hemophilia and a factor VIII level of 21
percent. He is 61 years old. He has recent-onset atrial fibrillation. I
have recommended acetylsalicylic acid (ASA) since he has basically lone
atrial fibrillation and no evidence of any cardiac disease. I also
recommended the possibility of doing a transesophageal echocardiogram
and, if negative, cardioverting him without anticoagulation. He has
bled with surgery in the past but never otherwise. Do you agree with
these recommendations?
The Response
I agree with this approach in this patient in the context of mild
hemophilia A (factor VIII level of 21 percent of normal); however, my
recommendations are empirical and are derived from my own experience,
since these clinical situations are too unusual to develop
evidence-based guidelines. In addition, the approach to mild hemophilia
A is going to be somewhat less challenging than what would be required
with severe hemophilia A. In any case, a factor VIII level of 21
percent should be adequate to sustain the anti-platelet aggregation
effects of ASA (81 mg daily).
The fundamental question here is whether aspirin is an effective
single agent to prevent the cardioembolic complications of atrial
fibrillation. Recent large clinical trials and meta-analyses provide
some insights. Warfarin appears to be superior to anti-platelet agents
in preventing embolic stroke in patients over the age of 75 and in
those with hypertension, prosthetic heart valves, mitral stenosis, or
congestive heart failure. Others with atrial fibrillation seem to do
equally well with aspirin alone.1 The 2007 Cochrane Report
on this topic analyzed data from eight trials including more than 9,500
non-coagulopathic individuals (mean age = 69 years) with non-valvular
atrial fibrillation.2 There were mixed statistical messages
delivered in this publication in that while warfarin reduced the risk
of all strokes by 32 percent compared with aspirin (P=0.0007) and
decreased the incidence of disabling or fatal stroke by 31 percent
(P=0.06), the mortality rate in both groups was similar. Of note,
warfarin increased the risk of intracranial hemorrhage by 98 percent
compared with aspirin. This latter risk issue has particular relevance
for an individual with hemophilia, since it is very likely that any
intracranial bleed (warfarin- or aspirin-induced) would result in
exaggerated morbidity and mortality.
For the patient at hand with mild hemophilia A, I would place him on
aspirin (81 mg daily) and would avoid warfarin until or unless an
embolic event occurs or unless it is determined that there is a
mitigating circumstance contributing to the onset of atrial
fibrillation (e.g., valvular disease, cardiac disease, etc.). I would
not expect any significant aspirin-induced hemorrhagic events to occur
at this level of factor VIII activity. If the patient has severe or
moderate-severity hemophilia A (FVIII <5 percent), I would recommend
the same aspirin dose, initiate a secondary prophylaxis regimen of
FVIII replacement therapy with a recombinant factor VIII concentrate
(25-30 IU/Kg three times weekly), maintain the trough FVIII level
greater than 5 to 10 percent, and subsequently titrate the dose of
FVIII concentrate to achieve a FVIII activity adequate to minimize the
development of spontaneous bleeding complications. If warfarin is
needed in the context of hemophilia, I would aim for a target INR of 2
to 2.5 and administer once or twice daily FVIII concentrate to maintain
FVIII levels of >50 percent, titrated upward based on the propensity
of the patient to experience bleeding complications.
As for cardioversion, I would replace this patient's factor VIII
activity level to at least 50 percent of normal with recombinant factor
VIII concentrate prior to the procedure and then proceed with
cardioversion without concurrent anticoagulation. Lastly, I think that
this patient should be screened for the von Willebrand disease (VWD)
variant 2 Normandy, since a number of patients with mild
cases of hemophilia have been shown to be phenotypically similar to and
genotypically confirmed to actually have this VWD variant.3
- Fuster V, Rydén LE, Cannom DS, et al. J Am Coll Cardiol. 2006;48:854-906.
- Aquilar MI, Hart R, Pearce LA. Cochrane Database Syst Rev. 2007; Cochrane Database Syst Rev. 2007; 3:CD006186.
- Tuley EA, Gaucher C, Jorieux S, et al. Proc Natl Acad Sci USA. 1991;88:6377-81.
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