Systemic lupus erythematosus complicated by thrombotic microangiopathy
Transcript of Systemic lupus erythematosus complicated by thrombotic microangiopathy
Systemic Lupus Erythematosus Complicated by Thrombotic Microangiopathy
Rita Jain, Elliot Chartash, Myron Susin, Richard Furie
Seven patients with systemic lupus erythematosus (SLE) or SLE-like disease developed thrombotic microangiopathy. Prominent features of their acute illnesses were microangiopathic hemolytic anemia (7), thrombocytopenia (7), fever (I), nervous system disease (4), and renal dysfunction (5). Laboratory data were significant for antinuclear antibody (ANA) (7), DNA (5), low C3 level (3). low C4 level (2), antiphospholipid antibody (6), schistocytes (7), and lactate dehydrogenase > 500 (7). All seven patients received treatment that initially included steroids but later included cyclophosphamide (4), plasma infusion (I), plasmapheresis (5), intravenous y-globulin (2), anti-platelet agents (2), or vincristine (3). Six patients improved, and one patient expired during treatment. Of the six patients who survived this complication, three expired within the year following their acute illnesses. Histology, available in two cases, showed vascular changes consistent with a microangiopathic process. We conclude that the spectrum of vascular diseases in SLE extends beyond vasculitis to include noninflammatory vascular processes that can cause equally devastating compli- cations. Copyright c 1994 by W.B. Saunders Company
INDEX WORDS: Systemic lupus erythematosus; thrombotic microangiopathy; thrombotic thrombocytopenic purpura; vasculitis.
S YSTEMIC LUPUS erythematosus (SLE) is associated with a variety of inflammatory
and noninflammatory vascular disorders includ-
ing vasculitis of the arterial and venous beds, Raynaud’s phenomenon, and localized thrombo- sis. A rare vascular complication of SLE consist-
ing of diffuse thrombosis of the microvascula- ture has been previously reported.‘-‘” The
affected patients were believed to have coexist- ent SLE and thrombotic thrombocytopenic pur- pura (TTP) because they not only showed many
features of SLE but also of TTP, including hemolytic anemia, thrombocytopenia, central
nervous system disease, or renal dysfunction. Occlusion of the microvasculature by thrombi
composed of both platelets and fibrin has been documented in some of these cases. However, as the experience with such patients has been largely anecdotal, issues relating to the etiology, spectrum of clinical manifestations, and treat- ment of this complication in SLE remain unre- solved.
To better understand the microangiopathy seen in SLE, we performed a retrospective review of seven patients with pre-existing SLE or SLE-like syndromes whose courses were
complicated by acute illnesses consisting of hemolytic anemia and thrombocytopenia as well as neurological or renal disease. Based on the presence of a microangiopathic hemolytic ane- mia, acute organ dysfunction, and histology available in two cases, we suspected that these clinical events were secondary to widespread thrombosis of the microvasculature. Although the complications resembled those seen in TTP, we prefer the more inclusive term thrombotic microangiopathy introduced by Symmers in 1952?” to describe clinical disorders related by
From the Divisron of’ Rheumatology and Aller~Chnical
Immunolo~, Depurtmentc of Medicine, Lahorutorws, und
Pathology Notth Shore Univrrsrty Hospitul und Cornell Utm~r-
sig Medical College. Manhasset, NY
Rita Jain, MD: FeNow in Rheumutology; Elliot Chartash.
MD: Assrstant Professor of Medicine; Myron Susin, MD:
Associate Professor of Clinical Pathology: and Richard Furie.
MD: A.ssociute Professor of Clinical Medicine
Address reprint requests to Richard Furie, MD. Diwsron of
Rheumatology and AllqyXlinical Immunology. North Show
llniversip HospitalXornell Univer.G? Medical Colkqe, ,700
Communiq Dr, Manhasset, NY 11030.
Copyright !<)I994 by WB. Saunders Cornpam
0049.0172194l2403-0003%5.0010
Semmars m Arthritjs and Rheumatism, Vol24, No 3 (December), 1994: pp 173-182 173
174
the presence of localized or diffuse microvascu- lar thrombosis.
This series comprises the largest group of SLE patients who were recognized antemortem as having thrombotic microangiopathy. We re- viewed the clinical courses, laboratory data, therapeutic regimens, and outcomes of our patients as well as those cases previously de- scribed in the literature. We also address whether thrombotic microangiopathy should be viewed as a complication, albeit rare, of SLE or a distinct process unrelated to the underlying rheumatic disease.
METHODS
Seven cases of SLE complicated by throm- botic microangiopathy were encountered be- tween 1986 and 1990. All patients had been seen by two members of the Division of Rheuma- tology and Allergy-Clinical Immunology of North Shore University Hospital-Cornell University Medical College. Charts were abstracted by a single reviewer (R. Jain). A diagnosis of SLE was made using the 1982 American Rheuma- tism Association (ARA) revised classification criteria for SLE.21 Laboratory studies, including complete blood count (CBC), peripheral smear, reticulocyte count, direct Coombs test, haptoglo- bin, coagulation studies, biochemical profiles, and urinalysis, were reviewed. The results of serological testing, including antinuclear anti- body (ANA), DNA, Smith (Sm), C3, C4, anticar- diolipin antibodies, rapid plasma reagin, and
JAIN ET AL
lupus anticoagulant, as determined by dilute Russell viper venom time and platelet neutral- ization procedure, were also noted. The thera- pies given to the seven patients were reviewed as were their outcomes.
RESULTS
Pre-existing manifestations
Table 1 lists those features of SLE that existed before the development of the acute events described herein. Six of the seven pa- tients were women. Their ages ranged from 28 to 71, with a mean age of 48 years. The durations of their rheumatic illnesses ranged from 1 month to 30 years. Six of the seven patients satisfied the 1982 ARA criteria for SLE.21 The one patient who did not meet criteria was considered, although initially asymp- tomatic, to have primary antiphospholipid syn- drome. As Table 1 illustrates, two patients had rash, two had oral ulcerations, five had arthritis, and four had histories of pericarditis or pleuri- tis. Of the four patients who had pre-existing renal dysfunction, patient no. 2 had mild mesan- gial proliferation on kidney biopsy. Patient no. 5 had chronic renal failure for the preceding 3 years. The kidney biopsy specimen showed scle- rotic glomeruli and epithelial crescents. Patient no. 6, known to have diffuse proliferative glo- merulonephritis, developed acute renal failure just before her presentation. Patient no. 4 was felt to have lupus nephritis on clinical grounds.
Table 1: Pre-existing Manifestations of SLE
Patient No.
1 2 3 4 5 6 7
Age (vr)/Sex 37/F 56/F 28/M 71/F 48/F 30/F 66/F
Malar Rash - _ _ _ _ - _
Discoid Rash - - + _ + _ _
Photosensitivity - _ - _ _ - _
Oral Ulcer - + _ _ + _ _
Arthritis + - + + + _ +
Serositis _ - _ + + + +
Renal Disease _ + _ + + + _
Neurological Disease _ _ _ _ - _ _
Hematologic Disease _ + _ _ + _ _
Immunologic Disease VDRL DNA DNA DNA DNA DNA Sm
ANA 1:160 I:80 1:320 I:320 I:320 1:320 I:320
Abbreviations: ANA, antinuclear antibody; Sm. antibodies to Smith; VDRL, Veneral Disease Research Laboratory; DNA, antibodies to
DNA.
SLE COMPLICATED BY THROMBOTIC MICROANGIOPATHY
Table 2: Anti-Phospholipid Antibodies
Patient IgG aCL Ab IgM aCL Ab
No. (GPLunits) (MPLunits) RPR LAC
1 >80 NA + +
2 >I00 10.6 _ _
3 23 19 _ _
4 2 0 NA -
5 16 3 _ _
6 7 1 + _
7 29 6 _ _
Abbreviations: IgG aCL Ab GPL, immunoglobulin G anticardio-
lipin antibodies (normal GPL <14); IgM aCL Ab MPL, IgM
Anticardiolipin antibodies (normal MPL <5); RPR, rapid plasma
reagin; LAC, lupus anticoagulant; NA, not available.
One patient had a prior history of thrombocy- topenia. All seven patients had positive ANA tests with titers ranging from 1:80 to 1:320 and patterns that were either homogeneous or speck- led. Five patients had antibodies to double- stranded DNA, and one had antibodies to Sm. As shown in Table 2, antiphospholipid antibod- ies were present in six patients.
Clinical Features
Clinical manifestations at the time of presen-
tation are outlined in Table 3. Although these patients all had multiple manifestations, the chief reasons for seeking medical attention (identified in Table 3 by asterisks) were altered nervous system function in four patients, renal dysfunction in two, and hematologic abnormali-
ties in one. During the courses of their illnesses,
175
just one patient had fever, five had renal dis- ease, five had cardiac disease. and four had profound nervous system disease. There was no
evidence of neoplasm, malignant hypertension,
acute tubular necrosis, or infection that might have contributed to these manifestations. Those
five patients with renal dysfunction, either as a new manifestation or as a superimposed worsen-
ing of renal function, had proteinuria and eleva- tion of their creatinines above baseline values. Proteinuria on urinalysis ranged from 1 + to 4+,
and quantitative urinary protein excretions, available in three patients, ranged from 269
mgi24 hr to 4.2 g/24 hr. The peak serum creatinines ranged from 2.6 mg/dL to 5.8 mg/ dL, representing a mean increase of 113% over
baseline creatinines. Neurological abnormalities occurred in four
patients and consisted of marked encephalopa-
thy in patients no. 4 and no. 7, coma. myelopa- thy, and peripheral neuropathy in patient no. 3, and acute hemiparesis and aphasia in patient
no. 1. In each of these cases there was no prior neurological disease, and the onset of neurologi- cal symptoms was sudden. Imaging with either
computed tomography (CT) or magnetic reso- nance imaging (MRI) failed to show acute ischemic or hemorrhagic infarcts. Angiography
was not performed in any of the patients. Typical features of active SLE, such as arthri-
tis, rash, oral ulcerations, and serositis were generally absent. Similarly, cutaneous evidence of ischemic vascular disease was lacking as was
Table 3: Features of Thrombotic Microangiopathy
Patient No. -__
1 2 3 4 5 6 7
_ _ _ +*
Fever _ _ +
Renal dysfunction _ +* + +
Neurological dysfunction +* _ +* +*
Nadir platelet count (103/mm3) 16 39 78 16
Nadir hemoglobin (g/dL) 6.4 8.9 8.3 6.3
Maximum LDH (IU/L) 738 1441 1808 744
Maximum reticulocyte count (%) 19.7 9.4 NA 2.7
Schistocytes + + + +
Haptoglobin (mg/dL) <IO.4 NA 13 < 10.4
Direct coombs test results _ _ NA _
-
13* 31
5.8 6.6
2001 597
13.6 3.0
+ +
< 10.4 6.3 _ +
+ +*
31
8.2
672
5.6
+
NA
NA
NOTE. Renal dysfunction: +, worsening from baseline; -, unchanged from baseline. Neurological dysfunction: t, new findings; , unchanged from baseline.
Abbreviations: LDH, lactate dehydrogenase; NA, not available,
*Presenting manifestation.
176 JAIN ET AL
0 1 2 J 4 5 6 0 10 20 JO 40 50
month ?.*w prersnla”on day after presentation ID-
pmdni*one (Ill&!, *_I “eurologic StatUs
cyclwhph;Phamlde ,I”) D I IO I, ,1.11, MP @I
arp,rln ,325 In&t, I cyclopholphsmids (I”, El Q Wm’l IO.4 w,
pl,smaphelesl* I l”GG (0.4 glkgld, q
Fig 1: Treatments and outcomes of seven patients with SLE complicated by thrombotic microangiopa-
thy . -, Platelets (thousands/mm3); -, LDH (W/L); ----, creatinine (mg/dL); MP, methylprednisolone;
IVGG, intravenous y-globulin. Numbers with boxes denote total days of continuous therapy.
purpura or livedo reticularis. Six patients had evidence of cardiac abnormalities consisting of pericarditis, mitral valve leaflet thickening, ar- rhythmias, hypertrophic ventricles, tricuspid re- gurgitation, or Libman-Sacks endocarditis.
Laboratory Features
During the courses of their acute illnesses, all seven patients were anemic and thrombocytope- nit (Table 3). Schistocytes, seen on peripheral blood smears of all patients, provided evidence of microangiopathic hemolytic anemia (MAHA) in each of the cases. These patients collectively had a mean nadir hemoglobin of 7.2 g/dL. Lactate dehydrogenase (LDH) was elevated with a mean maximum LDH of 1143 IU/L (normal < 200 W/L). Elevated reticulocyte
counts were noted in four patients, and low haptoglobin levels were detected in the five patients tested. Direct Coombs test results were negative in five patients and weakly positive in one. In addition to the presence of MAHA, all patients had significant thrombocytopenia with a collective mean nadir of 32,000 platelets/mm3.
The patients were evaluated for the presence of disseminated intravascular coagulation (DIC) as the cause of the MAHA. Six of the patients had normal prothrombin (PT) and activated partial thromboplastin times (APTT). One pa- tient had a normal PT and an elevated APTT; however, the presence of a lupus anticoagulant had previously been documented in this patient. Of the six patients tested, all had normal or elevated fibrinogen concentrations, but two had
SLE COMPLICATED BY THROMBOTIC MICROANGIOPATHY
Fig 1 (cont’d).
fibrin split products between 10 and 40 u,g/mL. D-dimer was not detectable in the two patients tested. Therefore, none of the patients was believed to have significant DIC. Anti-DNA antibodies were detected in several of these patients, although the titers were not signifi- cantly different than those obtained before the development of the microangiopathy. Of the six patients whose C3 and C4 levels were deter- mined, only two were hypocomplementemic during their acute illnesses.
Treatment and Outcomes
All seven patients were immediately treated at the time of presentation with corticosteroids. Figure 1 depicts the treatments and responses. Four patients received prednisone (30 to 60 mg/d), one patient received parenteral methyl- prednisolone (50 mg/d) and three patients re- ceived 1 g of parenteral methylprednisolone per day for between 1 and 3 days during the early
parts of their hospitalizations. Because of a resemblance of their syndromes to TTP, five patients underwent plasmapheresis with infu- sion of fresh frozen plasma, whereas one pa- tient received plasma infusions without ex- changes. The number of exchanges, which ranged between 3 and 9, was determined by improvement of clinical status. In addition, one patient received oral cyclophosphamide, and intravenous cyclophosphamide was adminis- tered to three others. Two patients received intravenous y-globulin infusions. Three pa- tients were given vincristine, and two patients received antiplatelet agents.
Overall, six of the seven patients improved. Patient no. 6 had a respiratory arrest secondary to a leukoagglutination reaction during plasma- pheresis and expired shortly thereafter. Three patients had full return of neurological func- tion, but patient no. 3 had residual leg weakness several months after discharge from the hospi-
178
tal. Of the five patients with renal dysfunction, three improved, one had progressive renal dis- ease, and one expired before an assessment of renal outcome could be made. Among those who improved, creatinines returned to their baseline values, but quantitative protein deter- minations were not performed. Thrombocytope- nia improved in all patients. Hemolytic anemia improved in six of seven patients but subse- quently recurred in patients no. 4 and 5.
Of the six patients who survived the acute illnesses, three expired within the year following the onset of thrombotic microangiopathy. Pa- tient no. 3 died of widespread occlusive disease and multiorgan failure, and patients no. 4 and 5 died of acute myocardial infarctions. Patient no. 7 was lost to follow-up, and at the time of this report, patient no. 1 remained well and patient no. 2 continued to have thrombocytopenia and intermittent ischemic disease of the central nervous system.
PATHOLOGY
For two patients, tissue samples were ob- tained during the acute illnesses. Patient no. 6 underwent autopsy, and examination of the kidney showed diffuse rnembranoproliferative glomerulonephritis. Thrombi as well as frag- mented red blood cells were visualized within renal vascular lumens but were not seen in
JAIN ET AL
other vascular beds (Fig 2). In addition, an interlobar artery was totally occluded by a recanalized thrombus (Fig 3). Patient no. 2 had a kidney biopsy, which showed concentric hyper- trophy of the walls of arterioles and arteries, marked intimal proliferation, and occlusion of some vascular lumens. The patient also had evidence of mild mesangial proliferation consis- tent with lupus glomerulonephritis.
DISCUSSION
We report seven patients with pre-existing SLE or related syndromes who had MAHA. The patient with primary antiphospholipid syn- drome was included in this series because the identical complication arose in this patient whose premorbid condition resembled but did not fulfill criteria for SLE. MAHA accompanied by thrombocytopenia and acute organ dysfunction suggested a microvascular thrombotic process as the cause of the patients’ clinical phenom- ena. Symmers2” introduced the term thrombotic microangiopathy to denote conditions in which microvascular thrombosis occurs. Such disor- ders include TTP, hemolytic-uremic syndrome, postpartum renal failure, pre-eclampsia, sclero- derma renal crisis, and malignant hyperten- sion.** Typical histological findings in these syndromes include hyaline thrombi composed of fibrin and platelets that occlude the microvas-
Fig 2: An intraglomeru-
lar arteriole is markedly
distended and occluded by a recent thrombus. The dark structures within the
center of the thrombus represent fragmented red
blood cells (original mag-
nification 500x).
SLE COMPLICATED BY THROMBOTIC MICROANGIOPATHY 179
Fig 3: An interlobar ar-
tery is occluded by a re-
canalized thrombus. An
adjacent artery has a patent lumen (original
magnification 50X).
culature. Patients may have hemolytic anemia, thrombocytopenia renal, or neurological involve- ment but need not have all of these manifesta- tions. For this reason, thrombotic microangiopa- thy is preferred to TTP to describe our patients because it is a more inclusive term. However, in previous reports of such phenomena occurring in patients with SLE, nearly all authors used the diagnosis of TTP to describe the clinical events.
In an effort to determine the frequency with which thrombotic microangiopathy has been reported to complicate SLE, we evaluated pub- lished series of patients with TTP, series of patients with SLE, and previously reported cases of coexistent TTP and SLE. A total of 546 patients were reported in two major reviews of TTP.‘“,?” Although 16 patients had positive LE preps or ANAs and histological evidence sugges- tive of SLE was found in 13 autopsies, few patients carried the diagnosis of SLE before death. In contrast, an autopsy series of patients with TTP performed by Levine and ShearG was notable for histological findings consistent with but not specific to SLE in 23% of patients. These discordant findings are best explained by the criteria used to diagnose SLE, which were not standardized and would not meet current recommendations.
The incidence of thrombotic microangiopa- thy complicating SLE was reported to be ap-
proximately 0.5% based on the observations of Rothfieldz6 that 2 of 433 SLE patients devel- oped TTP. Devinsky et al*’ performed an au-
topsy review of 50 SLE patients and noted that clinical features of TTP developed during the terminal illnesses of 14 (28%) patients. How- ever, the diagnosis of TTP was suspected ante- mortem in only 1 patient; all other patients were believed to have exacerbations or complications of SLE. Histological findings at autopsy re- vealed microvascular thrombosis in 7 patients. As thrombocytopenia, hemolytic anemia, and microvascular occlusive disease are not re- stricted to TTP, alternative disorders such as DIC may have been responsible for some of the findings. From these reviews, it appears that thrombotic microangiopathy may complicate SLE, but the frequency with which this occurs appears low.
In a review of the literature, 19 case reports of TTP occurring in association with SLE were found.‘-‘” In 5 reports published before 1967, it could not be determined from the clinical de- scriptions whether the patients would meet current criteria for SLE. In the reports since 1967, 16 patients were diagnosed with SLE an average of 9 years before the occurrence of TTP. In only two cases was SLE diagnosed after TTP, and in another case the two conditions occurred simultaneously. Although it was difh-
180 JAIN ET AL
cult to evaluate SLE activity at the time of onset of TTP in these cases, assessments of clinical parameters or laboratory values such as anti- DNA antibody titers or complement levels sug- gested that SLE activity ranged from quiescent to highly active. Of these 24 patients previously described in the literature, therapy included steroids alone in 25%, steroids with another therapeutic intervention in 71%, plasma ex- change or infusion in 50%, splenectomy in 16%, and antiplatelet agents in 25%. Although the overall mortality was 25%, mortality in those patients who did not receive plasma exchange was 42% compared with a mortality of just 9% in those patients treated with plasma exchange or infusion.
In our series of seven patients, all patients but two were diagnosed with rheumatic illness within 1 year of the development of thrombotic micro- angiopathy. Although the patients had estab- lished diagnoses, each patient at the time of presentation with microangiopathy posed major diagnostic and therapeutic dilemmas. The pri- mary issue was whether the observed manifesta- tions reflected active SLE or whether a coexist- ent disorder was responsible for the acute illness. Consideration was given to the possibil- ity that an underlying vasculitis was responsible for the observed complications. However, cuta- neous evidence of vasculitis was not present, organ involvement was highly restricted, and histological evidence of vasculitis was lacking in the two cases where tissue was available for examination. Traditional laboratory markers of SLE activity, including anti-DNA antibodies and complement levels, suggested that SLE was no more active than usual because five of the patients had elevations of anti-DNA antibodies similar to their baseline values and only two patients were hypocomplementemic during their acute illnesses. SLE appeared to be clinically inactive in some patients but was judged to be active in others. For example, those patients with coexistent glomerulonephritis were be- lieved to have active disease, whereas activity assessments were less clear in those patients with other manifestations such as thrombocyto- penia or neurological disease. Regardless of the status of the patients’ SLE, the superimposed acute complications were thought to result from
a noninflammatory microvasculopathy in con- trast to the more typical inflammatory processes of SLE that may yield similar clinical features.
Several different medical therapies were ad- ministered either simultaneously or in rapid succession, but it is our contention that several of the patients who received plasma exchanges or infusions improved as a result of these interventions as opposed to the other therapies that were coadministered. This is based on the lack of response to the initial therapy, which included corticosteroids in each patient and more significantly on the temporal relationship between improvement and the initiation of plasmapheresis. The courses of patients no. 1,3, 5, and 7 best show this observation. Patient no. 1 had improvement of hematologic abnormalities and neurological status within 1 day of begin- ning plasmapheresis. Although patient no. 3 had a decline in creatinine before plasmapher- esis, it was’not until the 3rd day after plasma- pheresis was begun that he regained conscious- ness. Patient no. 5, who received different therapies for over 2 months, had rapid resolu- tion of hemolytic anemia and thrombocytopenia following the institution of plasmapheresis. The course of patient no. 7 shows partial improve- ment of hemolytic anemia and thrombocytope- nia before plasma infusion, but coma did not resolve until approximately the 8th day after plasma infusion was begun. Patient no. 6 ex- pired before adequate data could be collected; however, the platelet count rose threefold within 3 days of initiating plasmapheresis. Patient no. 4 received nearly all therapies simultaneously. The single patient (patient no. 2) who did not undergo plasmapheresis was treated with ste- roids and aspirin, and although she partially improved, she had residual renal insufficiency, hemolytic anemia, and mild thrombocytopenia. Patients no. 4 and 5 relapsed after discontinua- tion of plasmapheresis despite remaining on corticosteroids and cyclophosphamide. Treat- ment outcomes of those patients with coexistent TIP and SLE previously reported in the litera- ture revealed a reduced mortality in patients who received plasmapheresis. Randomization to different treatment protocols was not pos- sible because of the limited number of patients and their critical conditions.
SLE COMPLICATED BY THROMBOTIC MICROANGIOPATHY 181
It is unknown whether a pathogenetic relation- ship exists between the vasculopathy and the autoimmune disease. Most authors have gener- ally viewed these disorders as independent con- ditions, although others proposed mechanisms to explain their coexistence. It has been hypoth- esized that microvascular thrombosis results from enhanced endothelial-platelet interac- tions either from direct vascular injury or from antiplatelet antibodies. 2~11 An additional expla- nation may lie in the observation that patients with SLE and antiphospholipid antibodies are at increased risk for thrombotic events. In contrast to the occlusions, which are generally regional and occur in isolated arterial or venous beds, several recent articles have described a syndrome in patients with antiphospholipid an- tibodies who have acutely developed wide- spread noninflammatory arterial thromboses. Greisman et a128 documented two patients with SLE and antiphospholipid antibodies who pre- sented with multiorgan failure. Histological ex- amination revealed bland fibrin thrombi with- out vasculitis. One patient responded to plasmapheresis and high-dose corticosteroids, whereas the other patient expired despite corti- costeroids and antiplatelet agents. Perez et al?” as well as Ingram et al”” described similar patients with antiphospholipid antibodies who acutely developed multiorgan failure from wide- spread arterial thromboses. In addition to the reports of diffuse microvascular thrombosis, there have been several reports of localized microvascular thrombosis occurring in patients with antiphospholipid antibodies. D’Agati et a13’ and Magi1 et al?* reported patients with antiphospholipid antibodies and renal insuffi- ciency whose renal biopsy specimens showed microvascular thrombosis without vasculitis.
Six of the seven patients in our series were noted to have antiphosphoiipid antibodies. This frequency is significantly higher than that re- ported in surveys of SLE patients.“” Of the prior reports of coexistent SLE and TTP, lupus anti- coagulants were documented in 2 of 12 patients examined8.10 and anticardiolipin antibodies were documented in 4 of 5 patients examined.l”,il Biologic false positive syphilis serologies were positive in just one patient and negative in five.25 Data from these reports is insufficient to incrimi-
nate antiphospholipid antibodies as a possible cause of the thrombotic microangiopathy. How- ever, our observations as well as those of Hess et all” who described two patients with TIP, SLE, and antiphospholipid antibodies support a pos- sible association between antiphospholipid anti- bodies and the development of thrombotic mi- croangiopathy.
Many of the clinical features of thrombotic microangiopathy such as thrombocytopenia, he- molytic anemia, renal disease, and neurological dysfunction mimic typical manifestations of SLE. Therefore, diagnosis of this rare syndrome is dependent on the suspicion of a microangio- pathic process and the recognition of schisto- cytes on peripheral smear. From our series and a review of similar cases, it appears that SLE patients with thrombotic microangiopathy may require plasmapheresis in addition to other therapies. The presence of anticardiolipin anti- bodies, lupus anticoagulant, or biologic false positive syphilis tests in all but one of these patients, and a resemblance of some of the clinical events to the recently described wide- spread occlusive disease of the antiphospho- lipid antibody syndrome, suggest a possible association between thrombotic microangiopa- thy and antiphospholipid antibodies. Patients with this complication posed diagnostic and therapeutic dilemmas for all clinicians. The patients were gravely ill at presentation, and one patient expired during the initial hospitaliza- tion. Despite nearly full recovery, three addi- tional patients died within 1 year of presenta- tion. Whether their deaths were related to the prior development of thrombotic microangiopa- thy is unknown. However, this series as well as the experience with the vasculopathies of the antiphospholipid syndrome emphasizes the exis- tence of noninflammatory vascular disease that can be equally devastating as vasculitis. A better understanding of this syndrome may result in more timely recognition and improved outcomes.
ACKNOWLEDGMENTS
The authors thank Drs Robert Greenwald, Kenneth Miller, and Richard Blau for allowing us to include their patients. We also acknowl- edge the clinical assistance provided by the numerous consultants from neurology, hematol- ogy, and nephrology.
182 JAIN ET AL
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