SKMINAKS I N NEUKOI.OGY-VOLUME
11, N O . 4
DECEMBER 1991
Antiphospholipid Antibodies and Ischemic Cerebrovascular Disease
A logarithmic increase in published medical literature dealing with antiphospholipid antibodies (aPL) has occurred over the past 8 years. This explosion has been attributed to a diverse multidisciplinary interest in the clinical manifestations and associated conditions putatively related to antibodies that bind phospholipids.' A major clinical association with these antibodies has attracted the attention of many neurologists, namely, that to ischeniic cerebrovascular disease. This article will discuss aPL and stroke, specifically addressing aspects related to the historical background, characterization and clinical testing of aPL-associated stroke syndromes-clinical, radiologic, and pathologic features, epitiemiologic aspects, possible mechanisms of aPL action, and management.
BACKGROUND AND PERSPECTIVE In 85 years, from the first report in 1906, of ~ ~ l i o ~ h o l i p i d - b i n d iantibodies ng in patients with syphilis' lo 199 1, when many investigators in seemingly unrelated disciplines are trying to establish a definitive, causative link between aPI, and clinical phenomena including stroke, there has been a series of key insights that warrant mention. Following Wassermann's detection of' aPL,V35 years passed befbre the specific serologically active phospholipid, cardiolipin, was isolated from beef heart hy Pangborn.:' Antibodies to cardiolipin (aCL) bind to cause a positive o r false-positive VDKI, test for syphilis, because cardiolipin is one of' the antigens in the VDKL, assay. Eleven years after Pangborn's report, two notable reports appeared. Moore and Mohr' found that patients with a longstanding false-positive VDKL had a high prevalence of au-
toimmune diseases, including systemic lupus erythematosus (SLE) and hemoilytic anemia. Conley arid HartmannQeported two people with SLE, a false-positive VDKL, and abnormal coagulation studies that suggested these patients should have a bleeding dyscrasia. These authors determined that the coagulopathy was due to a circulating serum "anticoagulant" and this in vitro phenomenon was subsequently ascribed to a "lupus anticoagulant" (LA). T h e possibility of a relationship between the LA and the presence of a false-positive VDRI, arose. In retrospect, Aggeler et al" were probably the first group to document a thrombotic complication in a patient with thrombocytopenic purpura and a "circulating anticoagulant." Eleven years after Conley and Hartmann's report, Bowie et a17 insightfully recognized that in patients with SLE, stroke and other thrombotic events were associated with the LA. Several groups confirmed this association in SLE patientsx-"' and drew attention to other seemingly unrelated features such as thrornbocytopenia, miscarriages, and a false-positive VDKL. Since the coagulation studies to determine the presence of LA are functional, there has been a general lack of universally accepted diagnostic criteria for the LA.'' T h e current assays are based on the ability of the LA to prolong phospholipid-dependent coagulation pathways in a nonspecific rather than specific manner (that is, against a specific coagulation factor, such as Factor VIII-see Table I)."-" Because of the need for better standardization, combined with the growing interest in the clinical multidisciplinary phenomena associated with the LA, Harris et all8 initiated development of a more specific assay for phospholipid binding antibodies. T h e antigen cardiolipin,
Centet- lot- Stroke Research, Dcparttnetlt of' Neurology, Ileriry Ford Hospital a r ~ dIlcaltli Scietices Cetltcr. Detroit, Michigan, and the 1)epartmcnt of Medicine (h'eul-ology), LJniversity 01' Tcxaa, Health Sciences Center-, San Antonio, Texas K r p r i t ~ trequests: Dr. Levir~e,Center for Stroke Research, Department of' Neurology, K-1 I . Henry Ford Hospital 8c Health Sciences Center, 2799 W. (;rand Boulevard, Detroit, MI 48202-2689 Copyright O 1091 by l'hieme Medical Publishers, Inc., 381 Park .4venue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
Steven K . Levine, M.D. and Robin L. Brey, M.D.
Table 1. Laboratory Diagnosis of Lupus Anticoagulant
PREVALENCE
Several studies have described aP1. in 2 to 5%' of healthy people under 60 years ol'agcb,'" increasing in some but riot in all studies to 12 to 50% in those over 60 years of age.'"," 'l'hese mitibodies have also been described in a variety ol'disease settings, including syphilis," human inirnunodef'iciency vit-us,"' and other viral infections,:"' 1.yriie clisease,:" malignancies, arid inflammatory anti bacterial disort1e1-s, as well as in association with certain clr-ugs, most frequently pheriothiuines such as chlorprornazine, hydralazine, pr-ocainaniide, c]ui~iitli~ie, plicnytoin, and valpr-oic acitl.'"'The clinical syndrome associated with aPI, is rai-ely seen in found in the VDKL assay, was chosen. A radio- these ptielits. immunoassaylx was initially used and an enzymeAntibodies directed against phospliolipids are linked imrriurlosorbent assay (ELISA) was later commonly descr-ibed in patients with other autodeveloped and standardized.'"-"" I n the standard- immune diseases such as S I X and other collage11 ization study irivolving many laboratories,"' it was vascular diseases. In studies evaluating urisclectetl Ibund that there was generally very good agree- patients with SLE, aPI, prevalcrice estimates I-arige ment between laboratories ti)r sera that were either from 7 to 58%8.2"rn Love a n d Santoro's critical reriegative o r highly positive for aCI,, whereas the in- view of' the aP1, literatureY"a f'requencv of' aCL 01' terlaboratory differences in results were greatest 44%' of' H I5 patients \ d l S1.F. fl-on] 12 series and for sera that were nlininlally to moderately positive 42% of 479 SLE patients from a series of consecfor aCL. This assay is sensitive and quantitative utive patients was founcl. I n this setting, aPL-assoand can be measured in patients receiving heparitl c:iatetl clinical symptomatology does occur. T h e o r warfarin. However, variability iri the assay re- presence of aPL in these patients is associated with mains problematic and the relationship between an approxin~ately fivetold greater f't-eque~icyof' aCL and other antiphospholipid diagnostic studies thrombotic: events than in patients without them." has not been established." Patients with aI'L and thrombosis, thromboT h e aCl, E1,ISA assay still has limitations."' I t cytopenia, o r lttal loss, but who do not have a n is probably most accurate in the negative o r uncle- other ticfi~lableautoimrnunc disease, are said to tectable range anti in the very high positive range. have the "primary" aPL. syndrome.":' Other paT h e 95% confidence interval for a specific aPI>ti- tients falling into this category include those with a ter may be as high as ?40%, of the actual optical variety of' cardiac abnormalities, and those with a density value (Johrl Carey, M.D., Imn~uriopathol- rlu~nl,er of neurologic syntlro~ries.~' T h e majority ogy Laboratory, Henry Ford Hospital, personal of' nonc:erel)t-althromboernbolic events in these pacommunication, March 27, 1991). However, iri the tients is venous, whereas the ~najorityof cerel)txl Second International Ariticartliolipin Standardiza- throinboem t~olicevents is arterial. Thus, stroke is tion Workshop,"' interlaboratory agreement was an important feature of the primary al'L sy~iacceptable for negative and high-, mediurn-, and drorne. '['he prevalence of'al'L in unselected scrics low-positive results. Semiquantitative reporting of' of stroke patients is 6 to 46% ,:".:'" and such patiults aCL results has been adopted hy rrlany laboratories are likely to be young anti have incre:~sed risk for and is reported as negative, indeterminate, posi- stroke recurrence. T h e role of' aPI, iri the general tive, and high-positive, based o n irn~~lunoglobulin stroke populatio~iis unclear. (; (IgC;) aP1, and IgM aPL units, desigrlated G1'1. and mPL. Although the aPI. were initially described in THROMBOTIC COMPLICATIONS patierits with SLE, it has become apparent that ASSOCIATED WITH many patients with aP1, d o not fulfill the American ANTIPHOSPHOLIPID ANTIBODIES Kheumatisrri Association (AKA) criteria f i ~ rSLE. s o m e have a "lupus-like" illness," whereas others Many of the large studies investigating the have what has been called the "primary aPL syn- clinical associations of'aPI, have been pel-formed in drome" (aPS).':' Still others appear other-wise to- patients with SLE.'-"'.'A recent thol-ough rekiew and tncta-analysis of 29 published scrics invol\-irig tally healthy, without specific di~ease.":"~
330
Downloaded by: Universite Laval. Copyrighted material.
1. Prolonged phospholipid-dependent coagulation screening test 2. Failure to correct with mixing studies 3. Demonstration of phospholipid specificity Studies Prothombin time Activated partial thromboplastin time (APTT) Tissue thromboplastin inhibition Platelet neutralization procedure Dilute phospholipid APTT Kaolin clotting time Russell viper venom time Dilute Russell viper venom time
19841X.l!?,.':{ tlocu~nented,in relatively small riumhers of patients, the association of stroke with aP1.. Most were women, generally younger than patients with stroke associated with atherothrornbosis. Most had S I X and other concomitant stroke risk factors. As interest in this association grew, larger number-s of patients were reported, including a large retrospective data hank of 128 selected patients with cerebrovascular disease and aPL comwho clearly seem to f i t the clinical syndrome asso- bined from an efl'ort involving 11 centers.:'" 'l'he ciated with aP1, (Table 2)."".'" T h e presumption is average age of the patients, who were nearly that the aPL is either causative o r a marker for an equally divided between men arid women, was just r years. Over 75%) of' the patientspreimmune-nie~li~ited coagulopathy ancl throrrit)ot~c ~ ~ r i t l e43 sented with ccret)ral infarction, almost 157% pretendency. '' Although it appears that the most commonly sented with transient ischemic attacks (TIAs), and recog~iized thrombotic comp1ic:ation associated two patients presented with cerebral venous w i h al'l, is deep vein thrombosis (IIVT), probably thrombosis. About 30%)had clinical evidence o f a the most common site of' arterial occlusion associ- prior cerebral i n f rction, multiple in almost 10%'. ated with either the 1.A or aC1, is the cerebral and Fifteen percent had a prior history of TIA. S I X precerebral vasculature.'."." 'Therefor-e this asso- was present in 16%. Other vascular risk factors ciation has gained the interest of' neurologists and known to be present included hypertension in stroke physic:ians. 'I'hel-e have bee11 several re- 26';1', hype'-(:holeste~.olemiain l9%#,arid diabetes \.iews ancl cliliic:al tlescriptivc series detailing the mellitus in 6%).T h e activated partial thromboplasclinical, r-adiologic, and pathologic features of isch- tin time (A1"I"I') was prolongecl in only half of the emic cerebl-ovascular disease associated with the patierits and the IgG aC1, isotope was present in almost '70%).Appl-oximately 55% of the patients tested positive for antiriuclear antibodies (ANA). O n e in five patients had a false-positive VDKL. Investigations into the cause of the stroke revealed Table 2. Features Associated with aPL and the that one third had abnormal echocardiography Antiphospholipid Antibody Syndrome and about one fifth had abnormalities of'the rnitral Clinical Laboratory valve, including myxornatous thickening, mitral Arterial thrombosis Prolonged APTT* valve prolapse, and mitral insufficiency. ?I'en perCerebral false-positive VDRL cent had cardiac wall abnormalities (akinetic segOcular thrombocytopenia ment o r cal-diomyopatliy) anti 4%)had iritracardiac Peripheral hemolytic anemia Myocardial positive ANA* thrornt~usseen o n echocardiography. Others have Dermalldigital Reduced C4 reported an association of verrucous (LibmanPulmonary Increased Sacks) erlcloca~-clitiswith aPL-f'i111-in-plateletdeposMesenteric complement fragment SC5b-9 its primarily on the left-sided cardiac valves.".'" About one third of' the cerebral angiograrns in the Venous thrombosis Deep leg 11lultic:enter retrospective data bank project were Hepatic (Budd-Chiari syndrome) r~orrrialand two thirds were abnormal, with intraRetinal cranial ahnorrnalities occurring twice as conlrnonly Cerebral Adrenal as cxtr-acranial lesions."" T h e most common single Miscarriages cerebr-al angiographic abnormality was a middle Livedo reticularis cerebral artery (MCA) branch occlusion. Ischemic strokes associated with aPL are genPulmonary hypertension erally small to moderate sized, in the territory of Left-sided cardiac valvular lesions Verrucous endocarditis the large ant1 small branches of. the MCA trunk. (Libman-Sacks endocarditis) Small, deep infhrcts ("lacunar syndromes") have Myxomatous mitral valve also been (1esc1-ibed."' I n more recent prospective degeneration lntracardiac thrombi screening of consecutive, unselected first ischemic Chorea stroke patients with aCI., the average age of' the patients is approximately 65 years, not sigriificantly 'ANA: antinuclear antibody; APTT: activated partial thrombodifterent I'rorri nonstroke controls (Antiphospholi- 33 1 plastin time.
Downloaded by: Universite Laval. Copyrighted material.
over 1000 S1.E patients" f i ) ~ ~ na dstatistically signil'icant associatiori txtweeri the presence of either the L A o r aCL and a histol-y of' thrornbosis, neurologic disorders, o r thrombocytopenia. There is ;dso ;I possible i~ssociationof miscar-riage arid aPI, in women with SIX. In patie~itswithout SIX, these associations have not I~cenconclusively proven, fi)r most of these studies are retl-ospective arid involve selected rather- than ~~nselected consecutive pats,:~i.:37 ,I'here are, however, individual patients
pid Antibodies in Stroke S t ~ ~ dayprevalence , s t ~ ~ d y with , n o evidence for a systeriiic disease such as interim analysis, unpublished data). SI,F., in a I-elatively young person. A more perplexKrey et al:'4 prospectively evaluated 46 consec- ing pl-ol~lernis the patient who presents with a n utive patients with stroke o r 'I'IA, who were less ischemic stroke in tlie typical age range for cerethan 50 years of' age, for the presence of' aPI, and br-ovascula~-disease, has one o r rnore well-estabcompa~-edthese patients to age- and sex-matched lished risk fActors fim vascular tliscase. does not patients with other neurologic diseases. Of' the 46 have the other clinical o r laboratory f'eatr~resof the patients with cerebl-ovascular disease, 2 1 (46%) aPI. syndrome, and has a 1,A o r positive aCL. 'l'his had aP1,. Comparing the aPL and aP1. - stroke1 111-oblem is made even more difficult because the T I A patients, there were no diff'erences between aP1, could be coincidental, related to medication o r the two groups with respect to age and frequency a viral illness, o r pathogenetically r-elated to tlie of' normal cerebral angiography. Only 2 of' I5 stroke. I t remains possible that al'L are merely epiaPl,+ patients undergoing echocardiog~-aphyhad phcnoniena and are not ~)athophysiologicaIlyrean abnormal stutly-110th with rnitral valve pro- lated to the ischemic cerelx-ovascular disease o r to lapse. No other stroke risk factors were hunt1 in 8 other clinical thrombotic events. 'l'he al'L rnay also of' 2 1 (38%,)of' the aPL stroke/'IIA patients antl reflect :I nonspecific immune activation, plyclonal there were n o riiajor dif'ferences in the risk f'actor I3 cell I-esponse.:"' Given the current x t i v e and profiles between the aPL a n d aPL - patients, al- widespl-eat1 interest in aPI,, important answers though the numbers were small. 'l'his was the first should be forthcoming soon. Some authorities have suggested that the isocontrolled study of' aPL, and the study showed a highly significant association with al'L and cere- type o f t h e aCI, response may be helpf'ul in sorting brovascular disease compared with other rieuro- out the 111-oblen-that is, the IgG aCX, has more logic disorders, s ~ ~ casl ivascular headache and epi- often k e n associated with thr-ombotic cornplicalepsy. In patients with a first stroke and IgG aC:l>, tion-and there are sorne data to suggest that the the elevations detected within 7 days of the event higher the a(:L titer, the more likely and more sewere unlikely t o be a result of'the stroke, I~ecausc vere the thrombotic complications.' FLII-therniore, IgG antibodies require u p to 2 weeks t o reach cle- it still rerimins unknown whether the presence of tectable levels." Brey et alY'also found that aPL+ the al'l, ill a stroke patient should altel- treatnwnt stroke patients more commonly had multiple that would other-wise he given. I" stroke1TIA episodes (28%) compared with the A 1.A was lbund in one third of' 100 consecw aPL- stroke patients (8%). Others have also tive patients evaluated for a prolonged aP'1"1'.'!' fbund, predominantly in uncontl-olled studies, that Ahout one third of those with a I,A had an undet-aPL+ stroke patients appear to have fl-equent re- lying disorder, 15% had drug-induceti SLE, a n d current thromtmtic events; the finding highlights sliglitly over half' had n o evidence fbr- an autoimthe need fix- effective treatment. Nearly half of a mune disease. When heparin is excluded f'rorri the referral-based, selected patient population of' al- plasliia s;iniple, the most comnloli cause of' a promost 50 patients who had cerebrovascular or- other longed aP'l''1' is 1.A.' ' In patients with SLE, 23 series yielded 338 1x1neurologic involvement associated with aPI, went o n to have a subsequent transient o r permanent tients without LA, of whom 12% had thrombosis, thromboembolic event after the index event in just compared to 340 with LA, of' whom 42%' had over 1 year of' prospective fbllow-up.:" I'rospective throni1)osis (11 1:640. An electroencephalogran~showed moderate to severe, diffuse encephalopathy. Brainsteni auditory evoked potentials were normal. 'l'he patient died sutltlenly of a cardiopulmonary arrest. Autopsy, limited to the liver, revealed multiple hepatic inl'arcts. CUSP 3. A 48-year-old man developed intermittent tliplopia, dizziness, and bilateral lid ptosis, which would totally clear and return. Bilateral cerebellar dysfunction and transient confusion were present. Prior history included 111ild hypertension, thl-ombophlebitis, pulmonary embolus. complex partial seizures, two myocardial infarctions, atrial fibrillation, aortic valve disease, and false-positive VDKI,. Head C ' I and cerebral angiography were normal. T ~ v odays later, (;SF revealed eight WBC (78% polynlorpl~onu(:Iear neutropl~ils) but was otherwise normal. Platelet count was 83,000. LA was documented, WESK was 104 rnm/hr. ANA was negative. Kheuniatoid f'actor was 1 : 160. CA complement was reduced. T ~ v oweeks later-, a renal Iliopsy revealed orlcocytorna. ~l'11epatient developed DV'I' and died 72 hours later of pulmonary embolism. Autopsy (not including the central nervous system) revci~ledmultiple clots in heart, lung, a ~ l d adrenal glands, without evidcnce of vasculitis. (;clso 4. A 28-year-old man in excellent health experienced three transient episodes of' painlcss right eye visual loss. He smoked 20 cigar-etlc-s daily. Ophthalmologic and neurologic examiirations were normal except f0r a questionable lcfr Babinski sig~i.Heat C I ' was ~iormal.Extensive I d oratory studies revealed rnild hyperlipidemia and LA, but n o aCL. Cerebral angiography revealed a 60 to 70% stenotic lesion of' the right ii1tracrani;il inter-~ialcarotid artery (Pig. 2) before the origin of' the ophthalmic artery. He has I)cen asynlptomatic on aspirin (325 rnglday) fbr over 1 year. Figures 3 a n d 4 are examples of imaging studies in aP1,-positive stroke patients.
PUTATIVE MECHANISMS
334
Figure 1. Cerebral angiogram demonstrating a relatively long stenotic segment at the origin of the left vertebral artery.
'l'he pathogenic signifitarlte of aPI, is still 1111certain and even controversial,' despite a reason-
Downloaded by: Universite Laval. Copyrighted material.
SEMINARS IN NEUROLOGY
Downloaded by: Universite Laval. Copyrighted material.
single-strantled DNA, double-str-anded DNA a n d cartliolipin. With the change of' one amino acid in this niolccule, the cross-reactivity is lost a n d only cartliolipin is I-ecognizetl. T h e immunoglobulin heavy chain gene fi~rnilyused by this hybr-idoma is ,1558. It is ol'interest that several other groups have ~ q ~ o r t ethe t l use of' this same firiiily hy other aPLproducing cells (hybridomas a n d spontaneous spleen cells)."'." This consistent use of'a single imnnunoglo1)ulin heavy chain gene flimily implies that the aP1, produced are the result oS a specific antigenic stimulation (fi~reigno r self) arid riot the result of' polyclonal activation. 'I'he antigen I-esponsi1)le for the autoimmune al'l, response is uncertain. 'l'he phosphodiester linkage coninlorn to phospholipitls anti DNA has heen suggested,"' explaining the cross-reactivity oftell seen. Phospholipid fatty acid chain length nnay be important as well."" O n e major problem
Figure 2. Cerebral angiogram of the right internal carotid artery demonstrating an atypically shaped stenotic lesion of the artery, proximal to the takeoff of the ophthalmic artery.
ably good association of' aP1, with throm1)osis in the SLE population. aPI, comprise a hetcroger~eous . .. . . group with ;i variety of s p e c ~ f ~ c ~ t icl-oss-reactivies, ties, a n d isotope patterns. Some aPL are considered part of the irnniune response to a foreign antigen (for example, those associated with syphilis o r Lyrne ~lisease).'~.." 'I'hose associated with SLE o r primary LIPSare considel-ed autoantibotlie~.'"~ Antibody characteristics that are most closely associated with clinical synnptoms appear to be penistently high titer, 1gG isotype, and cross-reactivity with multiple negatively charged phospholipids (and occasionally with DNA)."' S u p ~ x ) r tf01- the idea that stroke associated with al'I. has an i ~ n ~ n i ~ n o l obasis g i c comes from the 2 0 % 01- so of' patients with ~11'1,-associated stroke who have no other known risk f'ictors tol- stroke but who LISLI;III~ have a hlse-positive VDKI,, lowpositive ANA, thr-oml)ocytoperii;i, low fbur-th coniponenl of' the cornplernent cascade (titers, cornpar-ed with age-matched tiortnal mice without aPI,. Gharavi and colleagues':' also found thrombocytopenia as well as a signif'icantly decreased litter size in animals with high titers of'aPI. conipared with norrnal control animals. Using a different approach, Branch a n d colleag~~es'"dernonstrated irnmune-
tive VDRL, and positive antinuclear antibody in the absence of SLE, Her cardiac evaluation was normal,
mediated thrombosis of' placental vessels leading to universal l'etal loss in norril;~l mice with passivc tr-msfer of'al'l. IgG. 'l'hese exciting aninial ~noclels appear- to have great 111-ornisc for tlef'initig the mechatlistns of' most clinical relevance.
TREATMENT In the absence of' a clear cat-diac soul-cc of' cnl1,olism in patients with al'L-associated ischemic cvI-cht-ovascular-disease, we I-ecomrnend an e x t e n s i ~ e hematologic evaluatiort to try to ascertain a specific. coagulation o r platelet deficit or- 110th that may suggest a specific mode of therapy. Currently, there is n o good eviclencc to supper-t one niode of therapy (that is, aspirin, war-fat-in, o r cor-ticoster-oids) ovtrr another and, therefore, iritliviclual patient management remains erripiric. I n the absence of' a docu-
Downloaded by: Universite Laval. Copyrighted material.
with 110th of' these hypotlieses is that although pliospholipids are ubiquitous in cell membranes, they are genet-ally i t 1 a nonimm~~ttogenic, bilayer corll'iguration. Mernhrane phospholipicls can exist in an immunogenic, hexagonal t i m n during the cou I-seol' ret~iotleling.K a ~ ~ calni d colleag~~es"' have suggested that phospholipids so exposed tilay well be the self-antigen against which pathogenic at'L are directed. A plasma col'xtor having the ability to cause further 111-olotigationof'the lupus anticoagulant ell'ect has been recognized since 1959."' ~I'hiscofiictor (beta-2-1il)ol)rotein I , apolipoprotein H ) ~vhich has been indepclltictitly isolated 1)): three g r o ~ ~ p s , appears to erillarice al'L t)inding in the ELISA systent in a way similar to the potentiating effccts described in coagulation assa).s.""-"' Apolipopt.oteir1 H l ~ ~ o l > a bplays l y a t.egul;ito~-).role in the coi1g111ation systern as a n inhibitor o l ' t h e intrinsic pathway and by altering prothr-01111)itiaseactivity ill platelets."" It~ltibitionoS apolipoprotein H by aPl. could lead to hypercoagulability a n d the clinical features of' the aPI, syndt-onte. Several other al'l, effects on both etidothelial cells a l ~ dplatelets have been pr-oposctl lvhich c o ~ d d lead to thl-onil)osis. A decrease in pr-ostacyclin production by set-uni containing al'L has been denionstrated in some I ~ u tnot all studies."'~"' aPL tnav also interfere with the l'unctioriing of'othcr ~ l a t u r a l Figure 4. Magnetic resonance image (coronal, T, anticoagulants such as proteins
11, N O . 4
DECEMBER 1991
Antiphospholipid Antibodies and Ischemic Cerebrovascular Disease
A logarithmic increase in published medical literature dealing with antiphospholipid antibodies (aPL) has occurred over the past 8 years. This explosion has been attributed to a diverse multidisciplinary interest in the clinical manifestations and associated conditions putatively related to antibodies that bind phospholipids.' A major clinical association with these antibodies has attracted the attention of many neurologists, namely, that to ischeniic cerebrovascular disease. This article will discuss aPL and stroke, specifically addressing aspects related to the historical background, characterization and clinical testing of aPL-associated stroke syndromes-clinical, radiologic, and pathologic features, epitiemiologic aspects, possible mechanisms of aPL action, and management.
BACKGROUND AND PERSPECTIVE In 85 years, from the first report in 1906, of ~ ~ l i o ~ h o l i p i d - b i n d iantibodies ng in patients with syphilis' lo 199 1, when many investigators in seemingly unrelated disciplines are trying to establish a definitive, causative link between aPI, and clinical phenomena including stroke, there has been a series of key insights that warrant mention. Following Wassermann's detection of' aPL,V35 years passed befbre the specific serologically active phospholipid, cardiolipin, was isolated from beef heart hy Pangborn.:' Antibodies to cardiolipin (aCL) bind to cause a positive o r false-positive VDKI, test for syphilis, because cardiolipin is one of' the antigens in the VDKL, assay. Eleven years after Pangborn's report, two notable reports appeared. Moore and Mohr' found that patients with a longstanding false-positive VDKL had a high prevalence of au-
toimmune diseases, including systemic lupus erythematosus (SLE) and hemoilytic anemia. Conley arid HartmannQeported two people with SLE, a false-positive VDKL, and abnormal coagulation studies that suggested these patients should have a bleeding dyscrasia. These authors determined that the coagulopathy was due to a circulating serum "anticoagulant" and this in vitro phenomenon was subsequently ascribed to a "lupus anticoagulant" (LA). T h e possibility of a relationship between the LA and the presence of a false-positive VDRI, arose. In retrospect, Aggeler et al" were probably the first group to document a thrombotic complication in a patient with thrombocytopenic purpura and a "circulating anticoagulant." Eleven years after Conley and Hartmann's report, Bowie et a17 insightfully recognized that in patients with SLE, stroke and other thrombotic events were associated with the LA. Several groups confirmed this association in SLE patientsx-"' and drew attention to other seemingly unrelated features such as thrornbocytopenia, miscarriages, and a false-positive VDKL. Since the coagulation studies to determine the presence of LA are functional, there has been a general lack of universally accepted diagnostic criteria for the LA.'' T h e current assays are based on the ability of the LA to prolong phospholipid-dependent coagulation pathways in a nonspecific rather than specific manner (that is, against a specific coagulation factor, such as Factor VIII-see Table I)."-" Because of the need for better standardization, combined with the growing interest in the clinical multidisciplinary phenomena associated with the LA, Harris et all8 initiated development of a more specific assay for phospholipid binding antibodies. T h e antigen cardiolipin,
Centet- lot- Stroke Research, Dcparttnetlt of' Neurology, Ileriry Ford Hospital a r ~ dIlcaltli Scietices Cetltcr. Detroit, Michigan, and the 1)epartmcnt of Medicine (h'eul-ology), LJniversity 01' Tcxaa, Health Sciences Center-, San Antonio, Texas K r p r i t ~ trequests: Dr. Levir~e,Center for Stroke Research, Department of' Neurology, K-1 I . Henry Ford Hospital 8c Health Sciences Center, 2799 W. (;rand Boulevard, Detroit, MI 48202-2689 Copyright O 1091 by l'hieme Medical Publishers, Inc., 381 Park .4venue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
Steven K . Levine, M.D. and Robin L. Brey, M.D.
Table 1. Laboratory Diagnosis of Lupus Anticoagulant
PREVALENCE
Several studies have described aP1. in 2 to 5%' of healthy people under 60 years ol'agcb,'" increasing in some but riot in all studies to 12 to 50% in those over 60 years of age.'"," 'l'hese mitibodies have also been described in a variety ol'disease settings, including syphilis," human inirnunodef'iciency vit-us,"' and other viral infections,:"' 1.yriie clisease,:" malignancies, arid inflammatory anti bacterial disort1e1-s, as well as in association with certain clr-ugs, most frequently pheriothiuines such as chlorprornazine, hydralazine, pr-ocainaniide, c]ui~iitli~ie, plicnytoin, and valpr-oic acitl.'"'The clinical syndrome associated with aPI, is rai-ely seen in found in the VDKL assay, was chosen. A radio- these ptielits. immunoassaylx was initially used and an enzymeAntibodies directed against phospliolipids are linked imrriurlosorbent assay (ELISA) was later commonly descr-ibed in patients with other autodeveloped and standardized.'"-"" I n the standard- immune diseases such as S I X and other collage11 ization study irivolving many laboratories,"' it was vascular diseases. In studies evaluating urisclectetl Ibund that there was generally very good agree- patients with SLE, aPI, prevalcrice estimates I-arige ment between laboratories ti)r sera that were either from 7 to 58%8.2"rn Love a n d Santoro's critical reriegative o r highly positive for aCI,, whereas the in- view of' the aP1, literatureY"a f'requencv of' aCL 01' terlaboratory differences in results were greatest 44%' of' H I5 patients \ d l S1.F. fl-on] 12 series and for sera that were nlininlally to moderately positive 42% of 479 SLE patients from a series of consecfor aCL. This assay is sensitive and quantitative utive patients was founcl. I n this setting, aPL-assoand can be measured in patients receiving heparitl c:iatetl clinical symptomatology does occur. T h e o r warfarin. However, variability iri the assay re- presence of aPL in these patients is associated with mains problematic and the relationship between an approxin~ately fivetold greater f't-eque~icyof' aCL and other antiphospholipid diagnostic studies thrombotic: events than in patients without them." has not been established." Patients with aI'L and thrombosis, thromboT h e aCl, E1,ISA assay still has limitations."' I t cytopenia, o r lttal loss, but who do not have a n is probably most accurate in the negative o r uncle- other ticfi~lableautoimrnunc disease, are said to tectable range anti in the very high positive range. have the "primary" aPL. syndrome.":' Other paT h e 95% confidence interval for a specific aPI>ti- tients falling into this category include those with a ter may be as high as ?40%, of the actual optical variety of' cardiac abnormalities, and those with a density value (Johrl Carey, M.D., Imn~uriopathol- rlu~nl,er of neurologic syntlro~ries.~' T h e majority ogy Laboratory, Henry Ford Hospital, personal of' nonc:erel)t-althromboernbolic events in these pacommunication, March 27, 1991). However, iri the tients is venous, whereas the ~najorityof cerel)txl Second International Ariticartliolipin Standardiza- throinboem t~olicevents is arterial. Thus, stroke is tion Workshop,"' interlaboratory agreement was an important feature of the primary al'L sy~iacceptable for negative and high-, mediurn-, and drorne. '['he prevalence of'al'L in unselected scrics low-positive results. Semiquantitative reporting of' of stroke patients is 6 to 46% ,:".:'" and such patiults aCL results has been adopted hy rrlany laboratories are likely to be young anti have incre:~sed risk for and is reported as negative, indeterminate, posi- stroke recurrence. T h e role of' aPI, iri the general tive, and high-positive, based o n irn~~lunoglobulin stroke populatio~iis unclear. (; (IgC;) aP1, and IgM aPL units, desigrlated G1'1. and mPL. Although the aPI. were initially described in THROMBOTIC COMPLICATIONS patierits with SLE, it has become apparent that ASSOCIATED WITH many patients with aP1, d o not fulfill the American ANTIPHOSPHOLIPID ANTIBODIES Kheumatisrri Association (AKA) criteria f i ~ rSLE. s o m e have a "lupus-like" illness," whereas others Many of the large studies investigating the have what has been called the "primary aPL syn- clinical associations of'aPI, have been pel-formed in drome" (aPS).':' Still others appear other-wise to- patients with SLE.'-"'.'A recent thol-ough rekiew and tncta-analysis of 29 published scrics invol\-irig tally healthy, without specific di~ease.":"~
330
Downloaded by: Universite Laval. Copyrighted material.
1. Prolonged phospholipid-dependent coagulation screening test 2. Failure to correct with mixing studies 3. Demonstration of phospholipid specificity Studies Prothombin time Activated partial thromboplastin time (APTT) Tissue thromboplastin inhibition Platelet neutralization procedure Dilute phospholipid APTT Kaolin clotting time Russell viper venom time Dilute Russell viper venom time
19841X.l!?,.':{ tlocu~nented,in relatively small riumhers of patients, the association of stroke with aP1.. Most were women, generally younger than patients with stroke associated with atherothrornbosis. Most had S I X and other concomitant stroke risk factors. As interest in this association grew, larger number-s of patients were reported, including a large retrospective data hank of 128 selected patients with cerebrovascular disease and aPL comwho clearly seem to f i t the clinical syndrome asso- bined from an efl'ort involving 11 centers.:'" 'l'he ciated with aP1, (Table 2)."".'" T h e presumption is average age of the patients, who were nearly that the aPL is either causative o r a marker for an equally divided between men arid women, was just r years. Over 75%) of' the patientspreimmune-nie~li~ited coagulopathy ancl throrrit)ot~c ~ ~ r i t l e43 sented with ccret)ral infarction, almost 157% pretendency. '' Although it appears that the most commonly sented with transient ischemic attacks (TIAs), and recog~iized thrombotic comp1ic:ation associated two patients presented with cerebral venous w i h al'l, is deep vein thrombosis (IIVT), probably thrombosis. About 30%)had clinical evidence o f a the most common site of' arterial occlusion associ- prior cerebral i n f rction, multiple in almost 10%'. ated with either the 1.A or aC1, is the cerebral and Fifteen percent had a prior history of TIA. S I X precerebral vasculature.'."." 'Therefor-e this asso- was present in 16%. Other vascular risk factors ciation has gained the interest of' neurologists and known to be present included hypertension in stroke physic:ians. 'I'hel-e have bee11 several re- 26';1', hype'-(:holeste~.olemiain l9%#,arid diabetes \.iews ancl cliliic:al tlescriptivc series detailing the mellitus in 6%).T h e activated partial thromboplasclinical, r-adiologic, and pathologic features of isch- tin time (A1"I"I') was prolongecl in only half of the emic cerebl-ovascular disease associated with the patierits and the IgG aC1, isotope was present in almost '70%).Appl-oximately 55% of the patients tested positive for antiriuclear antibodies (ANA). O n e in five patients had a false-positive VDKL. Investigations into the cause of the stroke revealed Table 2. Features Associated with aPL and the that one third had abnormal echocardiography Antiphospholipid Antibody Syndrome and about one fifth had abnormalities of'the rnitral Clinical Laboratory valve, including myxornatous thickening, mitral Arterial thrombosis Prolonged APTT* valve prolapse, and mitral insufficiency. ?I'en perCerebral false-positive VDRL cent had cardiac wall abnormalities (akinetic segOcular thrombocytopenia ment o r cal-diomyopatliy) anti 4%)had iritracardiac Peripheral hemolytic anemia Myocardial positive ANA* thrornt~usseen o n echocardiography. Others have Dermalldigital Reduced C4 reported an association of verrucous (LibmanPulmonary Increased Sacks) erlcloca~-clitiswith aPL-f'i111-in-plateletdeposMesenteric complement fragment SC5b-9 its primarily on the left-sided cardiac valves.".'" About one third of' the cerebral angiograrns in the Venous thrombosis Deep leg 11lultic:enter retrospective data bank project were Hepatic (Budd-Chiari syndrome) r~orrrialand two thirds were abnormal, with intraRetinal cranial ahnorrnalities occurring twice as conlrnonly Cerebral Adrenal as cxtr-acranial lesions."" T h e most common single Miscarriages cerebr-al angiographic abnormality was a middle Livedo reticularis cerebral artery (MCA) branch occlusion. Ischemic strokes associated with aPL are genPulmonary hypertension erally small to moderate sized, in the territory of Left-sided cardiac valvular lesions Verrucous endocarditis the large ant1 small branches of. the MCA trunk. (Libman-Sacks endocarditis) Small, deep infhrcts ("lacunar syndromes") have Myxomatous mitral valve also been (1esc1-ibed."' I n more recent prospective degeneration lntracardiac thrombi screening of consecutive, unselected first ischemic Chorea stroke patients with aCI., the average age of' the patients is approximately 65 years, not sigriificantly 'ANA: antinuclear antibody; APTT: activated partial thrombodifterent I'rorri nonstroke controls (Antiphospholi- 33 1 plastin time.
Downloaded by: Universite Laval. Copyrighted material.
over 1000 S1.E patients" f i ) ~ ~ na dstatistically signil'icant associatiori txtweeri the presence of either the L A o r aCL and a histol-y of' thrornbosis, neurologic disorders, o r thrombocytopenia. There is ;dso ;I possible i~ssociationof miscar-riage arid aPI, in women with SIX. In patie~itswithout SIX, these associations have not I~cenconclusively proven, fi)r most of these studies are retl-ospective arid involve selected rather- than ~~nselected consecutive pats,:~i.:37 ,I'here are, however, individual patients
pid Antibodies in Stroke S t ~ ~ dayprevalence , s t ~ ~ d y with , n o evidence for a systeriiic disease such as interim analysis, unpublished data). SI,F., in a I-elatively young person. A more perplexKrey et al:'4 prospectively evaluated 46 consec- ing pl-ol~lernis the patient who presents with a n utive patients with stroke o r 'I'IA, who were less ischemic stroke in tlie typical age range for cerethan 50 years of' age, for the presence of' aPI, and br-ovascula~-disease, has one o r rnore well-estabcompa~-edthese patients to age- and sex-matched lished risk fActors fim vascular tliscase. does not patients with other neurologic diseases. Of' the 46 have the other clinical o r laboratory f'eatr~resof the patients with cerebl-ovascular disease, 2 1 (46%) aPI. syndrome, and has a 1,A o r positive aCL. 'l'his had aP1,. Comparing the aPL and aP1. - stroke1 111-oblem is made even more difficult because the T I A patients, there were no diff'erences between aP1, could be coincidental, related to medication o r the two groups with respect to age and frequency a viral illness, o r pathogenetically r-elated to tlie of' normal cerebral angiography. Only 2 of' I5 stroke. I t remains possible that al'L are merely epiaPl,+ patients undergoing echocardiog~-aphyhad phcnoniena and are not ~)athophysiologicaIlyrean abnormal stutly-110th with rnitral valve pro- lated to the ischemic cerelx-ovascular disease o r to lapse. No other stroke risk factors were hunt1 in 8 other clinical thrombotic events. 'l'he al'L rnay also of' 2 1 (38%,)of' the aPL stroke/'IIA patients antl reflect :I nonspecific immune activation, plyclonal there were n o riiajor dif'ferences in the risk f'actor I3 cell I-esponse.:"' Given the current x t i v e and profiles between the aPL a n d aPL - patients, al- widespl-eat1 interest in aPI,, important answers though the numbers were small. 'l'his was the first should be forthcoming soon. Some authorities have suggested that the isocontrolled study of' aPL, and the study showed a highly significant association with al'L and cere- type o f t h e aCI, response may be helpf'ul in sorting brovascular disease compared with other rieuro- out the 111-oblen-that is, the IgG aCX, has more logic disorders, s ~ ~ casl ivascular headache and epi- often k e n associated with thr-ombotic cornplicalepsy. In patients with a first stroke and IgG aC:l>, tion-and there are sorne data to suggest that the the elevations detected within 7 days of the event higher the a(:L titer, the more likely and more sewere unlikely t o be a result of'the stroke, I~ecausc vere the thrombotic complications.' FLII-therniore, IgG antibodies require u p to 2 weeks t o reach cle- it still rerimins unknown whether the presence of tectable levels." Brey et alY'also found that aPL+ the al'l, ill a stroke patient should altel- treatnwnt stroke patients more commonly had multiple that would other-wise he given. I" stroke1TIA episodes (28%) compared with the A 1.A was lbund in one third of' 100 consecw aPL- stroke patients (8%). Others have also tive patients evaluated for a prolonged aP'1"1'.'!' fbund, predominantly in uncontl-olled studies, that Ahout one third of those with a I,A had an undet-aPL+ stroke patients appear to have fl-equent re- lying disorder, 15% had drug-induceti SLE, a n d current thromtmtic events; the finding highlights sliglitly over half' had n o evidence fbr- an autoimthe need fix- effective treatment. Nearly half of a mune disease. When heparin is excluded f'rorri the referral-based, selected patient population of' al- plasliia s;iniple, the most comnloli cause of' a promost 50 patients who had cerebrovascular or- other longed aP'l''1' is 1.A.' ' In patients with SLE, 23 series yielded 338 1x1neurologic involvement associated with aPI, went o n to have a subsequent transient o r permanent tients without LA, of whom 12% had thrombosis, thromboembolic event after the index event in just compared to 340 with LA, of' whom 42%' had over 1 year of' prospective fbllow-up.:" I'rospective throni1)osis (11 1:640. An electroencephalogran~showed moderate to severe, diffuse encephalopathy. Brainsteni auditory evoked potentials were normal. 'l'he patient died sutltlenly of a cardiopulmonary arrest. Autopsy, limited to the liver, revealed multiple hepatic inl'arcts. CUSP 3. A 48-year-old man developed intermittent tliplopia, dizziness, and bilateral lid ptosis, which would totally clear and return. Bilateral cerebellar dysfunction and transient confusion were present. Prior history included 111ild hypertension, thl-ombophlebitis, pulmonary embolus. complex partial seizures, two myocardial infarctions, atrial fibrillation, aortic valve disease, and false-positive VDKI,. Head C ' I and cerebral angiography were normal. T ~ v odays later, (;SF revealed eight WBC (78% polynlorpl~onu(:Iear neutropl~ils) but was otherwise normal. Platelet count was 83,000. LA was documented, WESK was 104 rnm/hr. ANA was negative. Kheuniatoid f'actor was 1 : 160. CA complement was reduced. T ~ v oweeks later-, a renal Iliopsy revealed orlcocytorna. ~l'11epatient developed DV'I' and died 72 hours later of pulmonary embolism. Autopsy (not including the central nervous system) revci~ledmultiple clots in heart, lung, a ~ l d adrenal glands, without evidcnce of vasculitis. (;clso 4. A 28-year-old man in excellent health experienced three transient episodes of' painlcss right eye visual loss. He smoked 20 cigar-etlc-s daily. Ophthalmologic and neurologic examiirations were normal except f0r a questionable lcfr Babinski sig~i.Heat C I ' was ~iormal.Extensive I d oratory studies revealed rnild hyperlipidemia and LA, but n o aCL. Cerebral angiography revealed a 60 to 70% stenotic lesion of' the right ii1tracrani;il inter-~ialcarotid artery (Pig. 2) before the origin of' the ophthalmic artery. He has I)cen asynlptomatic on aspirin (325 rnglday) fbr over 1 year. Figures 3 a n d 4 are examples of imaging studies in aP1,-positive stroke patients.
PUTATIVE MECHANISMS
334
Figure 1. Cerebral angiogram demonstrating a relatively long stenotic segment at the origin of the left vertebral artery.
'l'he pathogenic signifitarlte of aPI, is still 1111certain and even controversial,' despite a reason-
Downloaded by: Universite Laval. Copyrighted material.
SEMINARS IN NEUROLOGY
Downloaded by: Universite Laval. Copyrighted material.
single-strantled DNA, double-str-anded DNA a n d cartliolipin. With the change of' one amino acid in this niolccule, the cross-reactivity is lost a n d only cartliolipin is I-ecognizetl. T h e immunoglobulin heavy chain gene fi~rnilyused by this hybr-idoma is ,1558. It is ol'interest that several other groups have ~ q ~ o r t ethe t l use of' this same firiiily hy other aPLproducing cells (hybridomas a n d spontaneous spleen cells)."'." This consistent use of'a single imnnunoglo1)ulin heavy chain gene flimily implies that the aP1, produced are the result oS a specific antigenic stimulation (fi~reigno r self) arid riot the result of' polyclonal activation. 'I'he antigen I-esponsi1)le for the autoimmune al'l, response is uncertain. 'l'he phosphodiester linkage coninlorn to phospholipitls anti DNA has heen suggested,"' explaining the cross-reactivity oftell seen. Phospholipid fatty acid chain length nnay be important as well."" O n e major problem
Figure 2. Cerebral angiogram of the right internal carotid artery demonstrating an atypically shaped stenotic lesion of the artery, proximal to the takeoff of the ophthalmic artery.
ably good association of' aP1, with throm1)osis in the SLE population. aPI, comprise a hetcroger~eous . .. . . group with ;i variety of s p e c ~ f ~ c ~ t icl-oss-reactivies, ties, a n d isotope patterns. Some aPL are considered part of the irnniune response to a foreign antigen (for example, those associated with syphilis o r Lyrne ~lisease).'~.." 'I'hose associated with SLE o r primary LIPSare considel-ed autoantibotlie~.'"~ Antibody characteristics that are most closely associated with clinical synnptoms appear to be penistently high titer, 1gG isotype, and cross-reactivity with multiple negatively charged phospholipids (and occasionally with DNA)."' S u p ~ x ) r tf01- the idea that stroke associated with al'I. has an i ~ n ~ n i ~ n o l obasis g i c comes from the 2 0 % 01- so of' patients with ~11'1,-associated stroke who have no other known risk f'ictors tol- stroke but who LISLI;III~ have a hlse-positive VDKI,, lowpositive ANA, thr-oml)ocytoperii;i, low fbur-th coniponenl of' the cornplernent cascade (titers, cornpar-ed with age-matched tiortnal mice without aPI,. Gharavi and colleagues':' also found thrombocytopenia as well as a signif'icantly decreased litter size in animals with high titers of'aPI. conipared with norrnal control animals. Using a different approach, Branch a n d colleag~~es'"dernonstrated irnmune-
tive VDRL, and positive antinuclear antibody in the absence of SLE, Her cardiac evaluation was normal,
mediated thrombosis of' placental vessels leading to universal l'etal loss in norril;~l mice with passivc tr-msfer of'al'l. IgG. 'l'hese exciting aninial ~noclels appear- to have great 111-ornisc for tlef'initig the mechatlistns of' most clinical relevance.
TREATMENT In the absence of' a clear cat-diac soul-cc of' cnl1,olism in patients with al'L-associated ischemic cvI-cht-ovascular-disease, we I-ecomrnend an e x t e n s i ~ e hematologic evaluatiort to try to ascertain a specific. coagulation o r platelet deficit or- 110th that may suggest a specific mode of therapy. Currently, there is n o good eviclencc to supper-t one niode of therapy (that is, aspirin, war-fat-in, o r cor-ticoster-oids) ovtrr another and, therefore, iritliviclual patient management remains erripiric. I n the absence of' a docu-
Downloaded by: Universite Laval. Copyrighted material.
with 110th of' these hypotlieses is that although pliospholipids are ubiquitous in cell membranes, they are genet-ally i t 1 a nonimm~~ttogenic, bilayer corll'iguration. Mernhrane phospholipicls can exist in an immunogenic, hexagonal t i m n during the cou I-seol' ret~iotleling.K a ~ ~ calni d colleag~~es"' have suggested that phospholipids so exposed tilay well be the self-antigen against which pathogenic at'L are directed. A plasma col'xtor having the ability to cause further 111-olotigationof'the lupus anticoagulant ell'ect has been recognized since 1959."' ~I'hiscofiictor (beta-2-1il)ol)rotein I , apolipoprotein H ) ~vhich has been indepclltictitly isolated 1)): three g r o ~ ~ p s , appears to erillarice al'L t)inding in the ELISA systent in a way similar to the potentiating effccts described in coagulation assa).s.""-"' Apolipopt.oteir1 H l ~ ~ o l > a bplays l y a t.egul;ito~-).role in the coi1g111ation systern as a n inhibitor o l ' t h e intrinsic pathway and by altering prothr-01111)itiaseactivity ill platelets."" It~ltibitionoS apolipoprotein H by aPl. could lead to hypercoagulability a n d the clinical features of' the aPI, syndt-onte. Several other al'l, effects on both etidothelial cells a l ~ dplatelets have been pr-oposctl lvhich c o ~ d d lead to thl-onil)osis. A decrease in pr-ostacyclin production by set-uni containing al'L has been denionstrated in some I ~ u tnot all studies."'~"' aPL tnav also interfere with the l'unctioriing of'othcr ~ l a t u r a l Figure 4. Magnetic resonance image (coronal, T, anticoagulants such as proteins
