Surge of anti-SS-A antibody associated with fulminant thrombotic thrombocytopenic purpura in pregnancy.
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) is a rare clinical scenario. The diagnosis of TTP can be made by recognizing the clinical characteristic pentad of thrombocytopenic purpura, microangiopathic hemolytic anemia, renal failure, neurologic abnormalities, and fever. (1-3) However, the diagnosis of TTP in pregnant women is sometimes difficult, especially in pregnant women with systemic lupus erythematosus (SLE), because TTP, pregnancy-associated microangiopathies such as HELLP (hemolysis with elevated liver enzymes and low platelet count) syndrome, and lupus-associated microangiopathy share many features. The outcome for patients with lupus-associated TTP is usually fatal if this clinical scenario is not recognized and treated in time. (4,5) We successfully treated a pregnant patient who had fulminant TTP at 10 weeks' gestation. An extremely high level of anti-SS-A antibody was seen at the beginning of fulminant TTP. She responded to the treatment of plasma exchange. The fetus did not have any sign of compl ete heart block, one of the lethal complications in neonatal lupus syndrome. (6)
A 34-year-old African American woman with a history of SLE and a 10-week pregnancy was admitted to our hospital due to altered mental status, severe anemia, renal failure, and thrombocytopenia. Review of systems was positive for nausea and vomiting but unremarkable for cardiovascular disease, hemorrhage (no hemoptysis, hematemesis, or melena), infectious diseases, and hematologic malignant diseases. The patient had no known drug allergy and did not take any prescribed drugs at home. Social history was positive for heroin abuse, and the last heroine abuse had been 2 weeks earlier. There was no history of SLE in the family.
The physical examination was significant for pale appearance. The patient was afebrile. Vital signs were stable, and there was no orthostatic hypotension. No skin rash, ecchymosis, splenomegaly, or hepatomegaly was found. Stools were negative for occult blood. The pelvic examination was unremarkable, and no evidence of bleeding was found. Neurologic examination revealed a slightly confused woman without any focal defects. Differential diagnoses initially included TTP, hemolytic uremic syndrome, HELLP syndrome, preeclampsia-eclampsia, and disseminated intravascular coagulation.
The laboratory studies showed a normal white blood cell count (WBC) of 10.5 x [10.sup.9]/L with normal differential counts, hemoglobin level of 4.5 g/dL, hematocrit of 13.5%, and platelet count of 8,000/[micro]L. Reticulocyte count was 9% and red blood cell (RBC) distribution width index was 28.9. The patient had normal electrolyte values, but both serum urea nitrogen and creatinine levels were elevated (40 mg/dL and 2.2 mg/dL, respectively). Urinary analysis revealed 11 RBCs per high-power field. Total bilirubin value was slightly elevated (1.6 mg/dL), and transaminase levels were normal. The hepatitis panel yielded negative results. Lactate dehydrogenase (LDH) level was 1,411 U/L. Prothrombin time was 14.8 sec (normal, 11.5 to 14.5 sec), and partial thromboplastin time was 32.0 seconds (normal, 21.5 to 34.7 sec) with an international normalized ratio of 1.2. Fibrinogen level was 462 mg/dL. Results of both the direct and indirect Coombs' tests were negative. The patient's pregnancy test was positive for human chorionic gonadotropin.
The anti--SS-A value was 162,143 U/mL (normal, 0 to 91 U/mL). Antinuclear antibody panel results were interpreted as consistent with Sjogren's syndrome. Results of all other serologic tests, such as those for anti--SS-B, histone antibody, SCL70 antibody, anti-SS DNA, anti-DS DNA, Smith antibody, and RNP/SM antibody, were within normal limits. Rapid plasma reagin was nonreactive. An assay for human immunodeficiency virus was nonreactive. The complement (C3, C4, and GH50) levels were within normal limits. Anticardiolipin antibodies (IgM, IgA, and IgG) were not present. The lupus inhibitor was not detected. Total [alpha]-fetoprotein level was 85 ng/mL, with a maternal [alpha]-fetoprotein level of 2.4 ng/mL. On the peripheral blood smear, RBC morphology showed slight anisocytosis with few ovalocytes and many schistocytes, WBC morphology was within normal ranges, and platelet morphology was normal.
Thrombotic thrombocytopenic purpura was diagnosed, and the treatment of plasma exchange was initiated immediately. The patient also received supportive care, such as blood transfusions and corticosteroid treatment for lupus. The patient responded to the treatments (Figure). Mental status improved shortly after plasma exchange. Hemoglobin level stabilized around 10 g/dL after transfusion of 4 units of blood. Renal function returned to normal range in a few days. Platelet count gradually rose to normal range, with a prolonged treatment of plasma exchange. The LDH level dropped to normal range after the plasma exchange treatment. Interestingly, the anti-SS-A antibody level dropped to 16,439 U/mL (from 162,143 U/mL) 2 weeks after starting plasma exchange treatment, and dropped to 257 U/mL when the platelet count returned to normal range after the completion of plasma exchange treatment. The patient was discharged home without any signs of active TTP or complete heart block of the fetus.
Despite the fact that both TTP and SLE share many similar clinical features, TTP and SLE are two separate clinical scenarios. (2) The diagnosis of TTP in patients with SLE is challenging. As a matter of fact, TTP rarely occurs in patients with SLE. (7) In a review of 103 patients with TTP, about 4% of the patients had SLE. (8) Thrombotic thrombocytopenic purpura associated with subtype SLE, such as positive anti--SS-A serology in pregnant women (as in our patient's case), has not been reported.
Anti-SS-A antibody has been reported to be associated with a subtype of lupus erythematosus, chilblain lupus erythematosus, which is characterized by erythematosus lesions induced by a cold, damp climate and positive anti-SS-A serology. (9) Also, similar to other neonatal lupus syndromes, anti-SS-A antibody in pregnant women places the fetus at high risk for development of complete heart block, one of the possibly fatal complications in neonatal lupus syndrome with an estimated mortality rate of more than 30%. (6) In our patient, there was no sign of complete heart block in the fetus throughout the entire hospital stay. However, another possibly fatal complication, TTP, developed in our patient at 10 weeks of pregnancy.
Thrombotic thrombocytopenic purpura is an uncommon clinical syndrome. It is estimated that in the United States the new cases of TTP annually total approximately 3,000. (3) Although it is rare, TTP can occur during pregnancy. The outcome of TTP in pregnancy could be fatal if the condition is not
recognized and treated in time. (10,11)
Several proposed etiologies for the pathogenesis of TTP include nonspecific tissue factors, damaged endothelial cells, and abnormal platelet aggregation activities due to either the lack of the endogenous inhibitors or the inhibition being disrupted by abnormal proteins or immunoglobulins. (1) Recent studies implicate the inhibition of von Willebrand's factor (vWF)--cleaving protease by abnormal antibodies as the possible etiology of acute TTP. (12,13) In fact, data indicate that patients with a history of SLE, especially SLE with another serologic abnormality, such as antiphospholipid antibody, (14) C2 deficiency, (15) or abnormally large forms of vWF, (16) may be at higher risk of having acute TTP, since abnormal antibodies in these patients may interfere with the normal inhibition of platelet aggregation or inhibit the activity of vWF-cleaving protease (Table 1).
The mechanism for SLE-associated TTP in pregnant women is not known. Abnormal immunoglobulins in these patients may contribute to the pathogenesis of acute TTP, since the abnormal immunoglobulins (such as anti-SS-A antibody) may interrupt the normal inhibition of platelet aggregation or inhibit the activity of vWF-cleaving protease. In our patient, the level of anti-SS-A antibody was high at the beginning of fulminant TTP and dropped dramatically after the patient responded to the treatment of plasma exchange. Therefore, the anti-SS-A antibody may have played a role in triggering TTP in our patient. In clinical practice, we could consider these abnormal serologic findings in patients with SLE, especially in pregnant women with SLE, as the risk factors for TTP development (Table 1). Thus, early diagnosis of TTP in these patients may be possible, and prompt treatment such as plasma exchange may change the possibly fatal outcome in these patients.
Since TTP could occur in patients with either active SLE or inactive SLE, Snicker et al (2) proposed that TTP and SLE were two distinct clinical scenarios. They recommended the use of plasma exchange rather than immunologic intervention based on the fact that the treatment of plasma exchange usually resulted in better survival outcomes in these patients.
In pregnant women, TTP sometimes has a fatal outcome, especially in patients with a history of SLE in whom the correct diagnosis is not made and therapeutic intervention is not initiated in time. (4,5) Despite the fact that physicians treat patients with SLE-associated TTP with multiple modalities, such as corticosteroids, antiplatelet agents, danazol, cyclophosphamide, vincristine sulfate, and intravenous IgG as well as plasma exchange, (1,2) the most effective treatment is plasma exchange, especially in TTP patients with quiescent SLE. (2,3) In TTP patients with active SLE, the benefit from the addition of immunosuppressive agents such as corticosteroids, vincristine, or cyclophosphamide to the plasma exchange needs further confirmation. (11,14) The current management of SLE-associated TTP is summarized in Table 2.
In summary, the diagnosis of TTP should be considered in patients with SLE who have thrombocytopenic purpura, microangiopathic hemolytic anemia, neurologic symptoms, and renal failure. In those patients, TTP can be fatal. Proper therapeutic interventions such as plasma exchange can improve the possibly fatal outcome. Whether abnormal serologic findings such as anti-SS-A antibody play a role in triggering TTP is the subject of future study.
Acknowledgment. We thank Stanley Schade, MD, professor of hematology, for his review and critical comments during manuscript preparation.
(1.) Schmidt J: Thrombotic thrombocytopenic purpura: successful treatment unlocks etiologic secrets. Mayo Clin Proc 1989; 64:956-961
(2.) Stricker RB, Davis JA, Gershow J, et al: Thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus. case report and literature review from the plasmapheresis era. J Rheumatol 1992; 19:1469-1473
(3.) Lankford KV, Hillyer CD: Thrombotic thrombocytopenic purpura: new insight in disease pathogenesis and therapy. Transfus Med Rev 2000; 14:244-257
(4.) Jorfen M, Callejas JL, Formiga F, et al: Fulminant thrombotic thrombocytopenic purpura in systemic lupus erythematosus. Scand J Rheumatol. 1998; 27:76-77
(5.) Caramaschi F, Riccetti MM, Pasini AF, et al: Systemic lupus erythematosus and thrombotic thrombocytopenic purpura. report of three cases and review of the literature. Lupus 1998; 7:3741
(6.) Finkelstein Y, Adler Y, Harel L, et al: Anti-Ro (SSA) and anti-La (SSB) antibodies and complete congenital heart block. Ann Med Interne (Paris) 1997; 148:205-208
(7.) Musio F, Bohen EM, Yuan CM, et al: Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus. Semin Arthritis Rheum 1998; 28:1-19
(8.) Porta C, Bobbio-Pallavicini E, Centurioni R, et al: Thrombotic thrombocytopenic purpura in systemic lupus erythematosus. J Rheumatol 1993; 20:1625-1626
(9.) Franceschini F, Calzavaza-Pinton P, Quinzanini M, et al: Chilblain lupus erythematosus is associated with antibodies to SSA/Ro. Lupus 1999; 8:215-219
(10.) Kemp WL, Barnard JJ, Prahlow JA: Death due to thrombotic thrombocytopenic purpura in pregnancy: case report with review of thrombotic microangiopathies of pregnancy. Am J Forensic Med Pathol 1999; 20:189-198
(11.) Perez-Sanchez I, Anguita J, Pintado T: Use of cyclophosphamide in the treatment of thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus: report of two cases. Ann Hematol 1999; 78:285-287
(12.) Tsai HM, Lian EC: Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339:1585-1594
(13.) Furlan M, Robles R, Galbusera M, et al: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339:1578-1584
(14.) Hess DC, Sethi K, Awad E: Thrombotic thrombocytopenic purpura in systemic lupus erythematosis and antiphospholipid antibodies: effective treatment with plasma exchange and immunosuppression. J Rheumatol 1992; 20:1625-1626
(15.) Dixit R, Krieg AM, Atkinson JP: Thrombotic thrombocytopenic purpura developing during pregnancy in a C2-deficient patient with a history of systemic lupus erythematosis. Arthritis Rheum 1985; 28:34 1434
(16.) Cockerelt CJ, Lewis JE: Systemic lupus erythematosus-like illness associated with syndrome of abnormally large von Willebrand's factor multimers. South Med J 1993; 86:951-953
TABLE 1 Summary Data of SLE Patients With Serologic Abrnormalities and Acute TTP Serologic Reference Abnormality SLE Pregnancy Hess et al (14) Antiphospholipid antibody + - Dixit et al (15) C2 deficiency + + Cockerell and Lewis (16) Abnormally large forms of vWF + - Our report Anti-SS-A antibody + + Reference TTP Hess et al (14) + Dixit et al (15) + Cockerell and Lewis (16) - Our report + SLE = Systemic lupus erythematosus TTP = thrombotic thrombocytopenic purpura vWF = von Willebrand's factor. TABLE 2 Management of SLE-Associated TTP Treatment of choice: Plasma exchange Immunosuppressive agents: Vincristine and cyclophosphamide Other drugs: Corticosteroids, danazol, and intravenous IgG SLE = Systemic lupus erythematosus; TTP = thrombotic thrombo-cytopenic purpura.
RELATED ARTICLE: KEY POINTS
* Thrombotic thrombocytopenic purpura (TTP) in pregnant women with systemic lupus erythromatosus may be triggered by the surge of the lupus antibody.
* Patients with abnormal antibodies have high risk for TTP.
* The treatment choice for such a clinic scenario is plasma exchange.