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Stroke. 2000;31:3067-3078

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(Stroke. 2000;31:3067.)
© 2000 American Heart Association, Inc.

Progress Review

Diagnostic Testing for Coagulopathies in Patients With Ischemic Stroke

Cheryl D. Bushnell, MD Larry B. Goldstein, MD

From the Department of Medicine (Neurology), Duke Center for Cerebrovascular Disease, Center for Clinical Health Policy Research, Duke University, and Durham VA Medical Center, Durham, NC.

Correspondence to Larry B. Goldstein, MD, Duke Center for Cerebrovascular Disease, Department of Medicine (Neurology), PO Box 3651, Durham, NC 27710. E-mail Golds004{at}mc.duke.edu


*    Abstract
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 *Abstract
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Background—Hypercoagulable states are a recognized, albeit uncommon, etiology of ischemic stroke. It is unclear how often the results of specialized coagulation tests affect management. Using data compiled from a systematic review of available studies, we employed quantitative methodology to assess the diagnostic yield of coagulation tests for identification of coagulopathies in ischemic stroke patients.

Summary of Review—We performed a MEDLINE search to identify controlled studies published during 1966–1999 that reported the prevalence of deficiencies of protein C, protein S, antithrombin III, plasminogen, activated protein C resistance (APCR)/factor V Leiden mutation (FVL), anticardiolipin antibodies (ACL), or lupus anticoagulant (LA) in patients with ischemic stroke. The cumulative prevalence rates (pretest probabilities) and positive likelihood ratios for all studies and for those including only patients aged <=50 years were used to calculate posttest probabilities for each coagulopathy, reflecting diagnostic yield. The cumulative pretest probabilities of coagulation defects in ischemic stroke patients are as follows: LA, 3% (8% for those aged <=50 years); ACL, 17% (21% for those aged <=50 years); APCR/FVL, 7% (11% for those aged <=50 years); and prothrombin mutation, 4.5% (5.7% for those aged <=50 years). The posttest probabilities of ACL, LA, and APCR increased with increasing pretest probability, the specificity of the tests, and features of the patients’ history and clinical presentation.

Conclusions—–The pretest probabilities of coagulation defects in ischemic stroke patients are low. The diagnostic yield of coagulation tests may be increased by using tests with the highest specificities and by targeting patients with clinical or historical features that increase pretest probability. Consideration of these data might lead to more rational ordering of tests and an associated cost savings.


Key Words: cerebral infarction • coagulation • decision analysis • diagnosis


*    Introduction
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The etiology of ischemic stroke remains undetermined in nearly 40% of patients despite extensive evaluations.1 The recognition that hypercoagulable states are sometimes found in ischemic stroke patients has led to testing for these rare conditions. Coagulopathies related to protein C (PC), protein S (PS), antithrombin III (ATIII), or plasminogen deficiencies, activated protein C resistance (APCR), prothrombin gene mutation, anticardiolipin antibodies (ACL), or lupus anticoagulant (LA) can be evaluated with various coagulation testing strategies. Rational use and interpretation of this array of tests can be daunting for noncoagulation specialists.

Before ordering any diagnostic test, the physician should first consider its diagnostic yield (ie, the physician should consider whether the results add to the evaluation, potentially altering therapy and improving patient outcome). The diagnostic yield is a direct reflection of the positive predictive value or posttest probability of the test.2 This is defined as the proportion of patients with positive tests that have the diagnosis (in this case, a coagulopathy). To calculate this estimate, the pretest probability (prevalence of the disease in the target population) and the positive likelihood ratio (LR), which is based on the sensitivity and specificity of the test, must be determined.2 Although topic reviews have been published previously,3 4 5 6 7 this type of diagnostic yield assessment has not been systematically applied to coagulation testing in ischemic stroke patients.

The aim of this review is to compile the available data necessary to estimate posttest probabilities for coagulation tests in general ischemic stroke patients and to indicate where these data are lacking. Separate probabilities are estimated for younger patients who have been traditionally considered at higher risk for coagulopathies.4 5 To accomplish these aims, the currently available diagnostic tests as well as the physiological or pharmacological factors that may interfere with their interpretation are critically reviewed. Next, the reported prevalence rates and odds ratios (ORs) from controlled studies of inherited and acquired coagulopathies in these populations are summarized. Positive LRs are then calculated with the use of assessments of the sensitivities and specificities of the tests. The prevalence rates and LRs are subsequently used for estimation of the posttest probabilities for different subpopulations of patients. On the basis of these data, we suggest a scheme for coagulation testing that should prove useful to physicians evaluating ischemic stroke patients.


*    Methods
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 *Methods
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Publications reporting the prevalence of coagulopathies in patients with ischemic stroke (case-control, cross-sectional, or prospective cohort studies) and the use of specific diagnostic tests for coagulopathies, including sensitivity and specificity measurements, were systematically identified. Sources included MEDLINE (limited to English language and human studies), cited references from publications, letters to the editor, and abstracts published between January 1966 and December 1999. Studies of coronary heart disease, case series, case reports, and other studies lacking controls were excluded. If the numbers of ischemic stroke cases and controls were included but ORs and 95% CIs were not stated, the latter were calculated with the use of a standard formula.8 The cumulative prevalence for APCR, prothrombin mutation, ACL, and LA was calculated by dividing the total number of ischemic stroke cases with the coagulation defect by the total number of ischemic stroke cases. Cumulative prevalence rates were calculated for patients aged <=50 years and for all age ranges. These prevalence rates, in addition to the LRs, provided data for calculation of the posttest probability estimates described below.

Whenever possible, the sensitivity and specificity for an individual diagnostic test were used to calculate the positive likelihood ratio [LR+=Sensitivity/(1-Specificity), expressed as a percentage]. This result was then used to calculate the posttest probability for the corresponding diagnostic test [Pretest Odds=Probability/(1-Probability), where probability is equal to the prevalence of the disease in the target population; Posttest Odds=Pretest OddsxLR for Desired Result; Posttest Probability=Posttest Odds/(Odds+1)].2


*    Results
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 *Results
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Coagulation Tests: Factors Affecting Interpretation
Table 1Down lists the coagulation tests and the influence of various physiological, pharmacological, and hematologic factors on these tests. Although 2 different tests may be influenced by the same factor, the relative degree of influence is not indicated in this table.


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  		Table 1. Physiological, Pharmacological, and Hematologic Factors Altering Coagulation Test Results

Protein C, Protein S, ATIII, and Plasminogen Deficiencies
Hereditary coagulation defects are evaluated in a similar fashion by screening functional assays, followed by quantitative assays.3 However, accurate diagnosis of these defects is quite complex, since the functional assays are influenced by acute thrombosis or acute phase reactants. As a result, if the tests are to be performed, patients should be tested at least 3 months after an acute thrombotic event and have no ongoing active illness that may artificially affect the studies. In addition, many other medical conditions and medications can potentially influence the test results (Table 1Up).9 10 11 12 13 14 15 Abnormal tests must be repeated and confirmed with the appropriate functional or quantitative assays. If a patient’s family history is suspicious for venous thrombosis, then family members should be considered for testing, because PC, PS, and ATIII deficiencies have autosomal dominant patterns of inheritance.3 16

Activated Protein C Resistance
In approximately 95% of patients with APCR, the condition is due to the factor V Leiden (FVL) mutation.17 This is diagnosed with a screening assay for APCR followed by polymerase chain reaction (PCR) for the FVL mutation or by PCR alone. Screening for APCR can be accomplished with the original or modified activated partial thromboplastin time ratio (predilution of patient plasma with factor V–depleted plasma).18 The most commonly reported APCR ratio cutoff is 2.1,19 but the ratio is determined by the individual laboratory performing the test. The original APCR screening test can be influenced by multiple physiological, pharmacological, and hematologic factors (Table 1Up). If the APCR is abnormal and a hereditary diagnosis is suspected, ethnic variations in the prevalence of FVL mutation should be considered.20

Prothrombin Gene Mutation
The only test available for detection of the prothrombin gene mutation is the PCR test for the guanine-to-arginine mutation at position 20210 of the 3'-untranslated region of this gene.21 The mechanism of hypercoagulability due to the mutation is still not known but is thought to be related to increased amounts of thrombin formation once thrombin generation is triggered.22 Plasma prothrombin levels have been correlated with the mutation in homozygous and heterozygous individuals, but to our knowledge, prothrombin levels have not been evaluated for sensitivity or specificity in comparison to the genetic test.23 24

Lupus Anticoagulant
The laboratory criteria for establishing a diagnosis of LA have recently been revised.25 Laboratory diagnosis of LA is complex because multiple LA tests measuring different types of phospholipids are available.26 The heterogeneity of these tests was demonstrated in a study reporting sensitivities of 62% to 100%, depending on the cutoff value chosen.27 Therefore, at least 2 different screening assays should be negative before the diagnosis is excluded (eg, activated partial thromboplastin time and direct Russell viper venom time).25 The results are also dependent on the reagents used,28 with both the tests and the reagents varying among laboratories.27 Table 1Up also lists factors that may influence LA screening test results. Of note, LA test results can still be interpreted in warfarin-treated patients, provided that mixing studies are performed (Thomas Ortel, MD, oral communication, March 2000).

Anticardiolipin Antibodies
The standard screening assay for measuring ACL is based on an enzyme-linked immunosorbent assay (ELISA). The ACL ELISA can be false-positive in the setting of infection, hypergammaglobulinemia, rheumatoid factor, and heat treatment of serum samples (Table 1Up).29 In addition, titers increase with increasing age and multiparity (Table 1Up).29 Unlike LA, which is based on a functional assay, the ACL ELISA is not influenced by concurrent anticoagulation with heparin. In the diagnostic evaluation of antiphospholipid (APL) syndrome, both LA and ACL should be obtained, because patients may have either one or both tests positive at the same time.30

Prevalence Rates of Coagulopathies in Ischemic Stroke Patients
Given this background of limitations in test interpretation, a total of 107 studies of coagulopathies in ischemic stroke patients were identified. Fourteen case reports and 38 case series were excluded on the basis of the listed criteria; therefore, 55 controlled studies were included in the analysis of prevalence rates, ORs, and pretest and posttest probabilities. Five studies providing sensitivities and specificities of ACL, LA, and APCR were used to calculate positive LRs and posttest probabilities.

Hereditary Coagulation Defects
Only 4 case-control studies of the prevalence of hereditary deficiencies of PC, PS, and ATIII in ischemic stroke were identified, ranging from 0% to 21% (Table 2Down).31 32 33 34 Case-series studies reported prevalence rates of 0% to 23%.32 35 36 37 38 39 40 Hereditary fibrinolytic defects such as plasminogen deficiency have a reported prevalence of 0% to 2.7% in case-control and case-series studies of ischemic stroke patients aged <45 years.32 35 37 39 These data do not permit calculation of cumulative prevalence rates.


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  		Table 2. Prevalence of PC, PS, ATIII, and Plasminogen Deficiencies in Ischemic Stroke

Activated Protein C Resistance/Factor V Leiden Mutation
Data related to APCR prevalence range from 0% to 38% in studies of ischemic stroke (Appendix 1).24 31 32 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 However, of the 31 studies measuring APCR and/or FVL mutation, 5 studies (2 studies of APCR49 68 and 3 studies of FVL43 51 61 ) found significantly increased odds in ischemic stroke patients compared with controls (Appendix 1).

The 5 studies that showed a significant association between ischemic stroke and APCR/FVL all had features that limit generalization to unselected ischemic stroke populations.43 51 59 61 68 These limitations include cases identified with obsolete APCR assays that have been modified since elucidation of the genetic mutation,68 highly selected patients with transient ischemic attack only,61 patients aged 0 to 10 years,51 young adults with stroke referred for thrombophilic workup,43 and use of the modified APCR assay without confirmation with PCR for FVL.49

Evidence against an association between FVL and ischemic stroke comes from 2 well-designed prospective studies. The Physicians’ Health Study followed subjects over many years recording the incidence of venous thrombosis, ischemic stroke, and myocardial infarction. A nested case-control study of this cohort, matched for age, smoking habits, and time since randomization, showed a similar prevalence of FVL for those with strokes (4.3%) and controls without cardiovascular disease (6%).64 The Cardiovascular Health Study also failed to find an association between FVL and ischemic stroke in elderly patients.44 Therefore, although some studies have suggested a trend toward an association between APCR/FVL and ischemic stroke,41 58 62 the majority of the identified studies did not report a significant association and had significant methodological limitations (Appendix 1).

Given these limitations, a cumulative prevalence rate (pretest probability) of 7% for APCR/FVL was calculated (Table 4Down). It should be noted that this cumulative prevalence rate was derived from a large, heterogeneous population of patients with a lower than expected prevalence rate in controls (4.4%). Several studies excluded patients with traditional stroke risk factors32 45 49 56 or a history of thromboembolism.61 Others included patients with only minor stroke or transient ischemic attack41 or transient ischemic attack alone.61 Although the OR appears to be increased in patients aged <50 years (OR, 3.1; Table 3Down), patients within this younger group were also highly selected.32 45 49 61


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  		Table 4. Pretest and Posttest Probabilities for ACL, LA, and APCR


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  		Table 3. Cumulative ORs for APCR, Prothrombin Mutation, ACL, and LA

Prothrombin Gene Mutation
The prevalence of prothrombin gene mutation in ischemic stroke patients varied from 1% to 12.5% (Appendix 1).* Of the 13 relevant studies, 2 found a significant association with ischemic stroke (Appendix 1)45 69 ; however, the patients were highly selected. One of the studies included patients with first stroke before age 50 years, with no history of hypertension, diabetes, hypercholesterolemia, or hypertriglyceridemia, and no age-matched controls.45 The other study included a selected population of patients with prior myocardial infarction who subsequently had venous or arterial events. The controls were consecutive newborns and not age matched.69 In contrast to these studies with highly selected patients, the majority of the case-control studies identified (Appendix 1) showed no association between the prothrombin mutation and ischemic stroke. The cumulative prevalence of this mutation was 5.7% in studies of those aged <=50 years and 4.5% in studies including all age ranges, with a slightly increased odds of ischemic stroke (1.4; 95% CI, 1.03 to 1.9; Table 3Up).

Anticardiolipin Antibodies/Lupus Anticoagulant
Studies of the prevalence of APL antibodies in ischemic stroke patients were often reported for either ACL or LA alone. Appendix 2 shows the wide variability in the reported prevalence of these antibodies in ischemic stroke patients aged <=50 years74 75 76 77 and in studies including patients of all ages.74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 Eight of 15 controlled studies of ACL or LA (Appendix 2) found a significant association with ischemic stroke.77 78 80 81 83 86 87 88 The association between ACL/LA and ischemic stroke has been well established in patients with primary APL syndrome and with systemic lupus erythematosus (SLE)–associated secondary APL syndrome, but a growing body of evidence supports an association in unselected patients as well.89 A large multiethnic case-control study recently showed that prevalence rates of ACL in ischemic stroke were similarly increased in whites (OR, 4.7; 95% CI, 2.3 to 8.2), blacks (OR, 4.0; 95% CI, 2.4 to 6.6), and Hispanics (OR, 4.0; 95% CI, 1.8 to 8.8).78 In contrast, the Physicians’ Health Study reported no significant association between ACL and ischemic stroke in men.84 However, the ACL ELISA assay was performed on plasma frozen for >=8 years, and therefore the reliability of the test is uncertain.78

Despite the relationship between detection of ACL and ischemic stroke, the specificity of these antibodies is unclear. D’Olhaberriague et al80 reported a significantly increased odds of ACL positivity in ischemic stroke patients compared with patients with other neurological diseases, suggesting that the antibodies are specific to stroke. However, a more recent study by the same group showed that ACL IgG titers may be a general marker of cardiovascular disease.90 Tanne et al91 reported that ACL IgG titers are associated with the presence of multiple stroke risk factors such as age >65 years, atrial fibrillation, valvular heart disease, and congestive heart failure. The increase in ACL prevalence with age is documented in healthy subjects as well.92 93 These results suggest that the ACL IgG titer may represent a risk marker for atherosclerosis but may not be a specific causal factor.

Comparisons among ACL prevalence studies are fraught with difficulty for at least 3 reasons. First, neither the ACL ELISA test94 nor the selection of a cutoff value for a positive test has been standardized among laboratories.95 The significance of IgM titers is also unclear because they may be elevated in diseases other than stroke.80 Second, the diagnosis of ACL or LA positivity must be confirmed with repeated testing3 94 since another important feature of ACL and LA is that the titers can fluctuate over time.96 97 Only 2 studies87 88 mentioned confirmation of abnormal titers. Third, in addition to the widely recognized groups of patients with either SLE-associated or primary APL syndrome, there appears to be a third category of patients with ACL in the setting of multiple atherosclerotic risk factors.78 Prospective studies are needed to ascertain the significance of fluctuations of antibodies over time and the prognosis of further arterial events in this latter group.78

The cumulative prevalence rates of ACL and LA in patients of all ages and in those aged <=50 years are listed in Table 4Up. These rates for ACL in ischemic stroke patients were relatively high (all ages, 17%; aged <=50 years, 21%), with an increased odds of ischemic stroke with ACL (Tables 3Up and 4Up).77 78 80 81 83 86

Estimation of Posttest Probabilities
With allowances for the limitations reviewed in the previous sections, Table 4Up lists the calculated posttest probabilities for specific coagulopathies and available coagulation tests based on the indicated pretest probabilities, sensitivities, specificities, and positive LRs.18 19 98 Of note, for the combined LA screening and confirmatory tests, the sensitivity was 67% and the specificity was 100%, resulting in a LR+ approaching infinity.99 Therefore, an arbitrary value of 1000 was used for this calculation. Table 4Up also shows that the pretest probabilities for ACL and APCR, but not LA, increased by 4% in patients aged <=50 years and that the highest posttest probabilities resulted from tests with the highest specificities. Because of the paucity of data on the prevalence of deficiencies of PC, PS, ATIII, and plasminogen in ischemic stroke, combined with a lack of sensitivity and specificity data for these coagulation tests, pretest and posttest probabilities could not be calculated.

Coagulation Tests and Clinical Decision Making in Patients With Ischemic Stroke
Using data from controlled studies, we calculated cumulative prevalence rates (pretest probabilities) that ranged from 3% to 21% (Table 4Up). A diagnostic test is typically most helpful with a pretest probability in the range of 40% to 60%.2 This represents a situation in which the clinician is undecided about the diagnosis, and the diagnostic test will aid in decisions concerning further testing or lead to a change in treatment.2 However, the posttest probability decreases as the pretest probability decreases. Because none of the coagulopathies had a cumulative pretest probability greater than approximately 20%, unselected use of coagulation tests is unlikely to lead to a change in diagnostic or treatment strategies.

Given this limitation, a proposed scheme based on the calculated pretest and posttest probabilities in conjunction with patient-related factors for each coagulopathy is given in the FigureDown. Because data are lacking for estimating pretest (and therefore posttest) probabilities for the hereditary coagulation defects in ischemic stroke patients, the left column lists the general features of these disorders.95 3 The testing strategy for these potential coagulopathies is based on evidence not from controlled trials but from the practical issues related to coagulation testing as recommended by coagulation experts.3 95 The middle and right columns include the cumulative pretest probabilities and associated common features for ACL/LA (primary or SLE-associated APL syndrome)89 and APCR/FVL/prothrombin (FII) mutations, respectively.100 101



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  		Figure 1. Scheme for testing ischemic stroke patients for coagulation (Coag.) defects. FII indicates prothrombin gene mutation; def., deficiency; ß2GPI, ß2 glycoprotein; AphL, antiphospholipid syndrome; PNP, platelet neutralization procedure; HPP, hexphase phospholipid; PTT, partial thromboplastin time; and NR, normalized ratio.

The strategy of when to test patients after ischemic stroke applies to the screening tests that are uninterpretable in the setting of acute phase reactants or infections, such as the functional tests for hereditary deficiencies, ACL ELISA, LA screening tests, and APCR screening tests (Table 1Up). Therefore, these tests should generally be performed when the patient is not in an active thrombotic state and the coagulation and fibrinolytic factors have stabilized, usually 6 to 8 weeks after the thrombotic event.3 4 15 16 Genetic tests such as the PCR for FVL and prothrombin gene mutation are not influenced by acute thrombosis.


*    Discussion
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 up arrowResults
 *Discussion
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 down arrowAppendix 2
 down arrowReferences
 
This systematic review of the literature shows that the prevalence of inherited deficiencies of PC, PS, ATIII, or plasminogen is low in unselected ischemic stroke patients. The prevalence of mutations of FVL or prothrombin genes in ischemic stroke patients is also low, but there may be an association between these deficiencies and ischemic stroke in younger patients. Before one reaches definitive conclusions of any association between these 2 mutations and ischemic stroke, additional well-designed prospective studies are required. The prevalence ranges reported for APL antibodies in ischemic stroke patients were quite variable, with more than half of the controlled studies showing a significant association with ischemic stroke. However, concurrent atherosclerotic risk factors make the significance of this association difficult to interpret, and further prospective clinical trials are needed to assess the risk of recurrent stroke in these patients. The posttest probabilities for ACL, LA, and APCR detection are related to the corresponding pretest probabilities and the specificities of the screening tests (Table 4Up).

Despite the systematic nature of this review, combining heterogeneous studies, ie, those with varying patient populations, leads to limitations in interpretation of the results. Including only studies of unselected ischemic stroke patients would have provided conclusions that are more generalizable. However, combining available prevalence studies of both selected and unselected patients provides larger numbers for calculating the estimates, and many clinicians select patients in a similar manner when justifying further testing.

Another limitation is that the sensitivity and specificity measurements, crucial for the calculation of posttest probabilities, were available for only a few diagnostic studies.18 19 98 99 102 103 Most of these studies did not meet the methodological standards considered necessary for diagnostic test research.104 Documentation of the spectrum of patients tested is an important methodological consideration,104 and the studies of ACL and LA diagnostic tests were limited to patients with secondary APL syndrome in the setting of SLE or to patients with primary APL syndrome.102 103 To our knowledge, these measurements have not been performed in unselected populations of seropositive patients with other atherosclerotic risk factors for ischemic stroke. Adequate sample size is another methodological standard, and 2 studies of ACL/LA tests made assessments using only a small number of patients.99 102 The results of studies with <=30 patients will often produce sensitivity and specificity measurements with wide CIs and poorer test accuracy.104 Test reproducibility is a very important methodological consideration, and this is a significant problem in the diagnostic testing for ACL. Although the cited studies used an average of multiple test results from the same laboratory,102 103 the potential for interlaboratory variability was not addressed.94 On the basis of these methodological issues, the posttest probabilities calculated in this study should be viewed as rough estimates.

Information that could potentially increase the pretest probability includes clinical or historical factors, physical examination findings, and other diagnostic test results. Because of the low prevalence of coagulopathies in the general population of stroke patients, these factors formed the basis for development of the scheme for coagulation testing shown in the FigureUp. For example, the pretest probability of a positive LA and/or ACL may be 40% to 60% in a 30-year-old woman admitted with an ischemic stroke who has a history of miscarriages and marantic endocarditis (3 features of the APL syndrome; FigureUp ). In contrast, the pretest probability of LA and/or ACL may be only 20% in a 65-year-old woman with an ischemic stroke who has 1 or 2 traditional stroke risk factors.78 80 The screening ELISA produces a better yield for the 30-year-old woman with 3 features of APL syndrome because these historical features increase her pretest probability, thereby resulting in a in a posttest probability of 60% (Table 4Up).

Deciding on a pretest probability estimate for an individual patient is difficult, but studies have shown that this skill can be improved with clinical experience in the target disorder105 or with the use of nomograms or computerized algorithms.106 Another useful method is to choose a range of pretest probabilities and calculate a posttest probability for the middle, upper, and lower ranges.2 This type of sensitivity analysis can help the clinician to appreciate the spectrum in which the coagulation test might be useful. Once the decision is made to pursue the diagnosis, selecting a test with a high specificity will result in a high posttest probability. The diagnostic yield in this situation is optimized by the use of the quantitative approach of pretest and posttest probabilities.

Conclusion
Because of the lack of strong evidence supporting an association between most coagulopathies and ischemic stroke in general populations of patients, the difficulty with interpretation of these tests in the setting of an acute ischemic stroke, and the methodological problems with the reviewed prevalence studies, our conclusion is that coagulation tests are often of little value in the evaluation of general patients with ischemic stroke. On the basis of the current data, the low diagnostic yield necessitates careful consideration before these tests are obtained. Additional prospective, controlled studies of unselected ischemic stroke patients are needed to better assess the roles of hereditary coagulation defects, APCR/FVL, prothrombin gene mutation, and ACL/LA in the etiology of ischemic stroke. The suggested scheme developed on the basis of the results of this comprehensive literature review should be further validated in prospective studies.


*    Appendix 1
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Down


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  		Table 5. Prevalence of APCR and Prothrombin Mutation in Ischemic Stroke


*    Appendix 2
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 *Appendix 2
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  		Table 6. Prevalence of APL Antibodies in Ischemic Stroke


*    Acknowledgments
 
This study was supported by a training grant from the Agency for Health Care Research and Quality.


*    Footnotes
 
1 References 24, 42, 43, 45, 47, 48, 51, 54, 69–73. Back

Received March 9, 2000; revision received August 10, 2000; accepted August 10, 2000.


*    References
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 *References
 

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