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Bleeding and Recurrent Thrombosis in Definite Antiphospholipid Syndrome
Analysis of a Series of 66 Patients Treated With Oral Anticoagulation to a Target International Normalized Ratio of 3.5
Guillermo Ruiz-Irastorza, MD, PhD;
Munther A. Khamashta, MD, MRCP, PhD;
Beverley J. Hunt, MD, FRCP, FRCPath;
Alejandro Escudero, MD;
Maria J. Cuadrado, MD, PhD;
Graham R. V. Hughes, MD, FRCP
Arch Intern Med. 2002;162:1164-1169.
ABSTRACT
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Background Prolonged anticoagulation is the treatment of choice for patients with
thrombosis and the antiphospholipid syndrome. However, there is still debate
about the optimum intensity of anticoagulation.
Methods The study included 66 patients with antiphospholipid syndrome (Sapporo
criteria) and previous thrombosis. All were receiving oral anticoagulation
to a target international normalized ratio of 3.5. Every patient was individually
interviewed to recall major bleeding and thrombotic episodes during the previous
12 months.
Results Patients were mainly women and white. The rate of major bleeding was
6 cases per 100 patient-years (95% confidence interval [CI] 1.6-15.0). The
rate of intracranial bleed was 1.5 per 100 patient-years (95% CI, 0.04-8.4).
None of the bleeding episodes was fatal. The rate of thrombotic recurrences
was 9.1 cases per 100 patient-years (95% CI, 3.3-19.6). Most recurrences took
place in the same vascular bed as the original thrombosis. Age, time receiving
anticoagulant therapy, primary vs secondary antiphospholipid syndrome, positivity
for anticardiolipin antibodies, positivity for lupus anticoagulant, previous
arterial thrombosis, previous stroke, previous venous thrombosis, and previous
thrombocytopenia were not predictive of bleeding events. However, the risk
of thrombotic recurrences was independently higher in patients who were receiving
anticoagulation for longer periods.
Conclusions The risk of intracranial and fatal bleeding in patients with definite
antiphospholipid syndrome and previous thrombosis treated with oral anticoagulation
to a target international normalized ratio of 3.5 is similar than in groups
of patients treated to lower target ratios. The risk of thrombotic recurrences,
even during anticoagulation, was high. Most recurrences took place in the
same territory as original thromboses.
INTRODUCTION
SOON AFTER the description of Hughes (antiphospholipid) syndrome, it
became clear that anticoagulant therapy was more effective than treatment
with antiaggregant drugs for prevention of recurrent thrombosis in patients
with antiphospholipid antibodies (aPLs).1-4
However, the optimum intensity of oral anticoagulation has since been a matter
of debate. Two retrospective series including 701
and 1472 patients with the antiphospholipid
syndrome (APS) and thrombosis showed a lower rate of recurrences when international
normalized ratios (INRs) were higher than 3.0. In contrast, 2 small observational
prospective studies of patients with histories of venous thromboembolism and
aPL5-6 reported no thrombotic
recurrences in patients at INRs between 2.0 and 3.0. As a result, definite
conclusions are difficult to draw, and even recent guidelines for the treatment
of patients with APS and previous thrombosis do not agree, recommending target
INRs of 3.57 or 2.5.8
The heterogeneity of the different cohorts could explain in part these
divergent results. For instance, patients included in the prospective studies5-6 had no history of arterial thromboses,
a high prevalence of low-titer anticardiolipin antibodies (aCLs), and a lower
risk of recurrences after warfarin sodium withdrawal compared with those of
retrospective series.1-2 An additional
major concern has been the increased risk of bleeding with high-intensity
(INR, 3.0-4.0) oral anticoagulation. This study was an attempt to clarify
the risks and benefits of oral anticoagulation to a target INR of 3.5 in patients
with definite APS and previous thrombosis.
PATIENTS AND METHODS
STUDY DESIGN
This was a retrospective cohort study in which every patient included
was individually interviewed by one of us (G.R.-I., A.E., or M.J.C.). The
interview included specific questions to recall bleeding episodes and thrombotic
recurrences as well as the audit of anticoagulant therapy, all within the
previous 12 months (see "Patients" subsection). Every major bleeding episode
or thrombosis was documented by checking the clinical notes of the patient
or by medical letters if they attended other centers. We limited the study
to the 12 months before the interview to reduce heterogeneity in treatments
and anticoagulation surveillance and also to ensure a good recall of clinical
episodes by the patients.
PATIENTS
Patients attending our antiphospholipid clinic were enrolled consecutively
from March 1 to August 31, 2000. To be included in the study, patients had
to fulfill all of the following criteria:
1. Definite APS according to Sapporo criteria.9
Thus, only patients who tested positive—twice at least 6 weeks apart—for
aCLs at medium or high titers and/or lupus anticoagulant (LA) entered the
study.
2. History of thrombosis. Deep vein thrombosis was documented by appropriate
imaging (ultrasonography and/or venography); pulmonary embolism, by high-probability
lung scan, spiral computed tomographic scanning, or pulmonary arteriography;
stroke, by computed tomographic scanning or magnetic resonance imaging; and
peripheral and visceral arterial thrombosis, by arteriography or surgery.
Cerebral transient ischemic attacks were diagnosed in the setting of acute
focal neurologic symptoms or signs lasting less than 24 hours. Myocardial
infarction was defined as typical chest pain with characteristic electrocardiographic
features and elevated creatine kinase (MB fraction) levels.
3. Treatment with oral anticoagulants to a target INR of 3.5 (INR range,
3.0-4.0) during the previous 12 months.
ANTIPHOSPHOLIPID ANTIBODY DETERMINATIONS
All the determinations were performed at the laboratories of the Lupus
Research Unit (aCL assays) and the coagulation laboratories (LA assays) of
St Thomas' Hospital, London, England.
The IgG and IgM aCLs were measured by  2-glycoprotein
I–dependent standardized enzyme-linked immunosorbent assay, as described
elsewhere.10 Results are expressed in a semiquantitative
fashion as follows: negative (IgG, <5 G phospholipid [GPL] units; IgM,
<3.2 M phospholipid [MPL] units); low positive (IgG, 5-15 GPL units; IgM,
3.2-6 MPL units); medium positive (IgG, 16-80 GPL units; IgM, 7-50 MPL units);
and high positive (IgG, >80 GPL units; IgM, >50 MPL units).
The LA was detected according to the guidelines of the International
Society on Thrombosis and Hemostasis, Scientific Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent
Antibodies,11 using activated partial thromboplastin
time and diluted Russell viper venom time as screening tests.
Determinations of IgA aCLs or antibodies directed against other phospholipids
or phospholipid-binding proteins (eg, 2-glycoprotein I–specific
enzyme-linked immunosorbent assay, antiprothrombin antibodies, antiphosphatidylserine,
and phosphatidylcholine) were not considered for the purposes of this study.
AUDIT OF ANTICOAGULANT THERAPY
Although the target INR for every individual patient is recommended
by our unit, anticoagulant monitoring is provided by their local anticoagulation
clinic or general practitioner. The periodicity of INR controls was determined
by the physicians responsible for anticoagulation monitoring according to
their own judgment.
During the interview, every patient's personal anticoagulation book
was checked, when available. The audit12 consisted
of counting the number of times during the previous 12 months that the INR
lay within predefined limits: less than 2.0, 2.0 to 2.9, 3.0 to 4.0, 4.1 to
4.9, 5.0 to 6.0, and more than 6.0. The proportion of measurements in each
range was then calculated for the entire population. Patients who did not
provide their anticoagulation book were included in the study for clinical
end points (see "Clinical End Points" subsection), although they could not
be included in the audit.
CLINICAL END POINTS
The clinical end points were documented major bleeding and recurrent
thrombosis. Only episodes of major bleeding, defined as intracranial, intraocular,
gastrointestinal, retroperitoneal, or requiring transfusion or admission to
a hospital, were considered for the purposes of this study. Minor bleeding
was not an end point because of its clinical irrelevance and patients' difficulty
in recalling such episodes. Recurrent thromboses were diagnosed by the same
criteria as for original thromboses. Patients having bleeding or thrombosis
were investigated for specific risk factors at the time of the event.
One of the potential problems of the study was that patients who missed
the scheduled clinic could have been admitted somewhere else—or even
died—because of bleeding or thrombosis, thus underestimating the rate
of severe complications. However, it is usual practice for local hospitals
or general practitioners looking after our patients to inform us of any complications
arising. Any patients who failed to attend clinic in the study period were
contacted by staff nurses to ensure they had not had any major bleeding or
thrombotic events. No patient missed a clinic appointment during the study
period because of major bleeding, thrombosis, or death from any cause.
STATISTICAL ANALYSIS
Data filing and processing and statistical calculations were performed
with StatView software (version 5.0.1 for Power Macintosh; SAS Institute Inc,
Cary, NC). The results were expressed as rates of events per 100 patient-years,
which were calculated as
.
In this case, the total person-years was equal to the total number of
patients, as the study period was 12 months in all cases. Confidence intervals
(CIs) were calculated assuming a Poisson distribution, since the results were
expressed as rates, the events were random and independent, and the number
of events was small, thus not allowing a normal approximation.13
Univariate comparison between continuous variables was performed by
2-tailed t test. To disclose clinical variables that
could be risk factors for the specific outcomes (bleeding or thrombosis),
we performed backward stepwise logistic regression, with bleeding (yes/no)
and thrombosis (yes/no) used as dependent variables.
RESULTS
The clinical profile of our cohort is summarized in Table 1. Our study population was predominantly white, and the female-male
ratio was 9:1. Half of the patients had primary APS, and most of those with
the secondary form had systemic lupus erythematosus according to the 1982
American College of Rheumatology classification criteria.14
The median age was 40 years, and the median time receiving anticoagulation
was 5 years. Twenty-three patients (35%) had been taking warfarin for less
than 5 years and 11 (17%) for less than 3 years. Most patients (51 [77%])
had a history of arterial thrombosis, and 38 patients (58%) had a history
of stroke. The prevalence of the different aPLs is shown in Table 2.
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Table 1. Demographic Characteristics and Previous Clinical Manifestations
(N = 66)*
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Table 2. Antiphospholipid Antibodies (N = 66)*
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AUDIT OF ANTICOAGULANT THERAPY
Data on anticoagulation surveillance were available for 59 patients
(89%). One thousand fifty INR determinations were performed in a total of
638 patient-months, thus resulting in 1.65 determinations per patient-month.
The range of determinations per patient during the study period was 5 to 43.
The cumulative number of INR determinations within each predefined range
is shown in Figure 1. Of the INRs,
391 (37%) were between 3.0 and 4.0, 323 (31%) between 2.0 and 2.9, and 137
(13%) between 4.0 and 4.9. At the extremes, 123 (12%) were lower than 2.0
and 77 (7%) were higher than 5.0.
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Cumulative number of visits with the international normalized ratio
(INR) within predefined ranges.
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BLEEDING
Bleeding rates are given in Table
3, and details regarding bleeding episodes are given in Table 4.
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Table 4. Bleeding and Thrombotic Complications*
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Major bleeding was observed in 4 patients (2 retroperitoneal, 1 intracranial,
and 1 rectal), resulting in a rate of 6 cases per 100 patient-years (95% CI,
1.6-15.0). The rate of intracranial bleeding was 1.5 per 100 patient-years
(95% CI, 0.04-8.4). None of the bleeding episodes was fatal. In a population
of 66 patients, this results in a 95% CI of 0 to 3.7 deaths due to bleeding
per 100 patient-years.
One patient had bilateral subdural hematomas in South America, when
she omitted anticoagulation monitoring for more than 1 month. At the time
of bleeding, she had experienced a recent head trauma and her INR was more
than 20. After surgical intervention, she had full recovery. Two patients
had retroperitoneal bleeding when they restarted warfarin treatment after
a transient withdrawal for a renal biopsy. The INRs at the time of the events
were 5.2 and 1.9. Finally, 1 patient suffered continuous rectal bleeding at
INRs below 3 until surgery for internal hemorrhoids was performed. Thus, all
patients who bled had a clear precipitating factor. In addition, 2 patients
were taking aspirin (Table 4).
THROMBOSIS
Details of thrombotic episodes are summarized in Table 4. Six patients had thrombotic recurrences during the follow-up,
a rate of 9.1 per 100 patient-years (95% CI, 3.3-19.6). Four episodes were
arterial and 2 were venous thromboses. Three patients with arterial events
had additional risk factors such as high blood pressure and cigarette smoking.
The woman who suffered subdural hematomas had a subsequent venous thrombosis
when deprived of thromboprophylaxis postoperatively. Two patients had no other
risk factors for thrombosis. The INRs at the time of thrombosis were between
2.1 and 2.6 (it was not determined in 1 case). No patient died of thrombosis
(95% CI, 0-3.7). Five of 6 patients experienced a recurrence in the same vascular
bed as the original thrombosis.
PREDICTORS OF EVENTS
The following clinical variables were included in 2 logistic regression
models to determine which could predict bleeding or thrombosis: age, time
receiving anticoagulant therapy, primary vs secondary APS, aCL positive, LA
positive, previous arterial thrombosis, previous stroke, previous venous thrombosis,
and previous thrombocytopenia. Sex and race were not included in the model,
since more than 90% of the cohort were women and white.
None of the studied variables predicted bleeding. However, each successive
year of anticoagulation treatment increased the odds of thrombotic recurrences
within the previous year by 1.25 (95% CI, 1.03-1.5). Consistently, patients
with recurrent thrombosis within the previous year had been taking anticoagulants
for a mean of 11 years, while those without recurrent events had taken warfarin
for a mean of 6 years (mean difference, 5.0 years; 95% CI, 1.4-8.7 years; P = .008, 2-tailed t test).
COMMENT
Since 1995, we have adopted oral anticoagulation to a target INR of
3.5 (range, 3.0-4.0) as the standard therapy for patients with aPLs and previous
thromboses. In this study, we found that this practice does not result in
a high incidence of intracranial or fatal bleeding in patients with definite
APS who are at a high risk of recurrent thrombosis.
The actual risk of thrombosis in patients with aPLs is not well established,
particularly for patients without previous events.15
We know that the presence of LA or aCLs at medium to high titers increases
that risk, especially in the setting of a history of thrombosis.16-17
In retrospective series1-3
the rates of thrombotic recurrences in untreated subjects were between 19
and 29 events per 100 patient-years.
The risk of bleeding during oral anticoagulant treatment is not well
defined in the general population. Table
5 summarizes the results of 5 relevant studies that cover this issue:
a meta-analysis on the efficacy of anticoagulation in atrial fibrillation18; a randomized controlled trial of anticoagulation
vs aspirin after a transient ischemic attack19;
a prospective cohort of anticoagulation in clinical practice20;
a prospective inception cohort to study bleeding complications of oral anticoagulant
therapy21; and a randomized controlled trial
of long vs short anticoagulation in venous thromboembolism.22
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Table 5. Summary of Studies Including Cohorts of Warfarin-Treated Patients*
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In the meta-analysis by Hart et al,18
the risk per year of major extracranial bleeding and intracranial hemorrhage
was 0.9% and 0.3%, respectively. These figures are in keeping with the results
of the Italian prospective inception cohort21
and the prospective series of Kalra et al.20
However, other authors have found higher rates of bleeding.19, 22
The results of the Stroke Prevention in Reversible Ischemia Trial (SPIRIT)
were particularly striking. In that study, patients with a recent transient
ischemic attack allocated to receive oral anticoagulants to an INR of between
3.0 and 4.5 suffered major and intracranial bleeding at very high rates of
7 and 3.7 per 100 patient-years, respectively.19
Factors that may increase the risk of hemorrhage during oral anticoagulant
therapy include age greater than 65 to 75 years,21, 23-26
receiving multiple medications,26 history of
gastrointestinal tract bleeding,23, 25
arterial thrombosis21 or stroke,25
and INRs higher than 4.5 to 5.0.12, 21
If one focuses specifically on intracerebral bleeding, the presence of leukoariosis
(diffuse white matter hypodensity on magnetic resonance imaging or computed
tomographic scanning) has been recognized as the most important risk factor
for bleeding in the SPIRIT cohort.26 In the
same study, the intensity of anticoagulation was not an independent predictor
of bleeding in the multivariate model.26
In our group, anticoagulation control was not as strict as we wished.
The INRs within the "therapeutic" range between 3.0 and 4.0 were accomplished
in only 37% of determinations. Although the sort of audit we used implied
a bias toward an increase in "out of range" determinations—patients
with good control were tested less often—our results may also reflect
the fears of many anticoagulation clinics of long-term high-intensity anticoagulation
in routine clinical practice. In the United Kingdom, the majority of patients
attending anticoagulant clinics are receiving warfarin because they have atrial
fibrillation and are aiming for a target INR of 2.0 to 3.0. Our policy did,
however, maintain INRs above 2.0 in almost 90% of the cases, while only 7%
of determinations were above 5.0. When a target INR of 2.5 (range, 2.0-3.0)
is used, subtherapeutic INRs below 2.0 are found much more frequently,12, 20 a fact that may have devastating
implications in patients at high risk for thrombotic recurrences.
In fact, our population was at a particularly high risk for recurrent
thrombosis: we found 9 thrombotic events per 100 patient-years during anticoagulant
therapy, higher than the risk observed in the studies not including patients
with APS (Table 5). This rate
was also higher than that in patients receiving anticoagulation at INRs higher
than 3.0 from retrospective series,1-2
thus highlighting the different risk of recurrences depending on aCL titers
and presence of LA.16-17 The tendency
of patients with APS to have recurrent thrombosis in the same vascular bed
(venous or arterial) was notable in our group, as in other series.17, 27 In this study all thrombotic events
happened at INRs between 2.1 and 2.6. Nevertheless, 66% of patients with thrombosis
during the previous year had associated risk factors (such as smoking or hypertension),
a fact that has been observed by other authors.3
We observed a risk of major bleeding that was intermediate between those
of the SPIRIT study and groups of patients with atrial fibrillation (Table 5). In particular, our frequency
of intracranial bleeding was within the 95% CI of the "clinical practice"
cohort of Kalra et al20 and was not substantially
higher than in other series (Table 5).
The increased risk of using a high target INR may have been compensated for
by the fact that patients with APS are generally young, since advanced age
is a consistent risk factor for cerebral bleeding in patients receiving anticoagulation.21, 23-26
Moreover, the differences seen in the frequency of intracerebral bleeding
between our series and that of Gorter26 may
also suggest that the nature of the presumed small vessel damage may not be
the same in patients with cerebral thrombosis caused by APS and that caused
by long-standing arterial hypertension and/or diabetes. Of note, in a recent
article from our unit that describes 15 cases of major bleeding in patients
with APS between 1989 and 1999, we did not find any episode of intracerebral
bleeding.28 Finally, concurrent risk factors,
including renal biopsies in 2 patients, were present in all patients who bled
in our series.
Probably in part because of sample size restrictions, we could not define
factors that predict bleeding or recurrent thromboses in patients with APS.
The only relevant finding in the multivariate analysis was that the risk of
thrombotic recurrences does not decrease—it actually increases—with
time. Therefore, this study supports the belief that indefinite anticoagulation
is indicated for this group.1-2,4, 22
Our study has obvious limitations. The main one is its retrospective
design. This was partially compensated for by personally interviewing every
patient, which allowed recognition of major bleeding and thrombotic episodes
even if treated at other hospitals. The audit of anticoagulant therapy did
not calculate the actual time at each range of INRs, the most accurate method
of monitoring.20 Our audit does, however, offer
an indication of the quality of anticoagulation in our patients in the United
Kingdom. Finally, the relatively small sample size widened CIs.
On the other hand, to our knowledge, this is the first study of anticoagulation
including patients who fulfilled Sapporo criteria. Thus, our population had
definite APS (ie, low-titer aCLs were not included) and was at high risk of
thrombotic recurrences, as our own results confirm. Arterial events, which
are more disabling than venous, were also prevalent. All this results in a
critical difference from other series labeled APS,5
which reported a much more benign course of the disease and whose conclusions
have been the support for recent guidelines recommending a target INR of 2.5
for all patients with APS treated with oral anticoagulants.8
When the indication for and intensity of anticoagulant therapy are determined
in an individual patient, bleeding risk is clearly not the only factor to
consider. It must be weighed against the possibility of recurrent serious
thrombosis.23, 29 On the basis
of a cautious analysis of our results and those of previous studies,1-2 we believe that most patients with
definite APS and previous thrombosis should be treated to a target INR of
3.5. The exception could be individuals with only venous events and those
at high risk of bleeding (aged or with previous life-threatening bleeding
episodes), who could be considered for lower intensities of anticoagulation.29 Every effort must be made to limit concomitant medications
and invasive procedures in this group. Furthermore, the adequate control of
additional risk factors for thrombosis, such as smoking, hypertension, and
hyperlipidemia, must be considered an integral part of therapy in patients
with definite APS.
AUTHOR INFORMATION
Accepted for publication September 25, 2001.
This study was supported by grant 99/5007 of Fondo de Investigacion
Sanitaria, Spain; the Department of Health of the Basque Government, Vitoria-Gasteiz,
the Basque Country, Spain; and Lupus UK, Essex, England.
Corresponding author and reprints: Munther A. Khamashta, MD, MRCP,
PhD, Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London
SE1 7EH, England (e-mail: 106404.2325{at}compuserve.com).
From the Lupus Research Unit, St Thomas' Hospital, London, England
(Drs Ruiz-Irastorza, Khamashta, Hunt, Escudero, Cuadrado, and Hughes), and
Service of Internal Medicine, Hospital de Cruces, Bizkaia, the Basque Country,
Spain (Dr Ruiz-Irastorza).
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ABSTRACT
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The Antiphospholipid Syndrome
Rand
ASH Education Book 2007;2007:136-142.
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Treatment of menorrhagia associated with oral anticoagulation: efficacy and safety of the levonorgestrel releasing intrauterine device (Mirena coil)
Pisoni et al.
Lupus 2006;15:877-880.
ABSTRACT
Laboratory diagnosis and management challenges in the antiphospholipid syndrome
Bertolaccini and Khamashta
Lupus 2006;15:172-178.
ABSTRACT
Stroke and antiphospholipid syndrome: the treatment debate
Ruiz-Irastorza and Khamashta
Rheumatology (Oxford) 2005;44:971-974.
ABSTRACT
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Letter to the Editor
Letang et al.
Lupus 2005;14:336-337.
Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand?
Ferreira et al.
Rheumatology (Oxford) 2005;44:434-442.
ABSTRACT
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Renal artery stenosis in hypertensive patients with antiphospholipid (Hughes) syndrome: outcome following anticoagulation
Sangle et al.
Rheumatology (Oxford) 2005;44:372-377.
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Homocysteine, antiphospholipid antibodies and risk of thrombosis in patients with systemic lupus erythematosus
Martinez-Berriotxoa et al.
Lupus 2004;13:927-933.
ABSTRACT
Antiphospholipid Antibodies and Risk for Recurrent Vascular Events--Reply
Levine et al.
JAMA 2004;291:2702-2703.
FULL TEXT
Antiphospholipid Antibodies and Risk for Recurrent Vascular Events
Ruiz-Irastorza et al.
JAMA 2004;291:2701-2701.
FULL TEXT
Antiphospholipid Antibodies and Subsequent Thrombo-occlusive Events in Patients With Ischemic Stroke
APASS Investigators
JAMA 2004;291:576-584.
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High Impact of Antiphospholipid Syndrome on Irreversible Organ Damage and Survival of Patients With Systemic Lupus Erythematosus
Ruiz-Irastorza et al.
Arch Intern Med 2004;164:77-82.
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Warfarin Prophylaxis in the Antiphospholipid Antibody Syndrome
Paul et al.
NEJM 2003;349:2568-2570.
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A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome
Crowther et al.
NEJM 2003;349:1133-1138.
ABSTRACT
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Treatment of the Antiphospholipid Syndrome
Lockshin and Erkan
NEJM 2003;349:1177-1179.
FULL TEXT
Venous thromboembolism in the antiphospholipid syndrome: management guidelines for secondary prophylaxis
Meroni et al.
Lupus 2003;12:504-507.
ABSTRACT
Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002
Brey et al.
Lupus 2003;12:508-513.
ABSTRACT
Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report
Lockshin et al.
Lupus 2003;12:518-523.
ABSTRACT
Central nervous system involvement in the antiphospholipid (Hughes) syndrome
Sanna et al.
Rheumatology (Oxford) 2003;42:200-213.
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Heparin and osteoporosis during pregnancy: 2002 update
Ruiz-Irastorza et al.
Lupus 2002;11:680-682.
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