Surge of anti-SS-A antibody associated with fulminant thrombotic thrombocytopenic purpura in pregnancy.
ABSTRACT: Thrombotic thrombocytopenic purpura thrombotic thrombocytopenic purpura
A disease of unknown origin, characterized by abnormally low levels of platelets in the blood, the formation of blood clots in the arterioles and capillaries of many organs, and neurological damage. (TTP TTP (thymidine triphosphate): see thymine. ) is an uncommon clinical syndrome and is rarely associated with systemic lupus erythematosus Systemic Lupus Erythematosus Definition
Systemic lupus erythematosus (also called lupus or SLE) is a disease where a person's immune system attacks and injures the body's own organs and tissues. Almost every system of the body can be affected by SLE. (SLE SLE systemic lupus erythematosus.
systemic lupus erythematosus
Systemic lupus erythematosus (SLE) ). Diagnosis of TTP in patients with SLE, especially those who are pregnant, is challenging. We report the case of a pregnant woman with a high level of anti-SS-A antibody (162,143 U/mL) and fulminant ful·mi·nant
Occurring suddenly, rapidly, and with great severity or intensity, usually of pain.
ful TTP. The patient responded to plasma exchange treatment. Recent studies indicate that patients with SLE and another serologic abnormality, such as the presence of antiphospholipid antibody, may be at high risk for TTP. We explore the possible pathogenesis of acute TTP in patients with SLE and summarize the risk factors for acute TTP in patients with SLE and the current treatments for SLE-associated TTP.
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 mic·ro·an·gi·o·path·ic hemolytic anemia
The fragmentation of red blood cells because of narrowing or obstruction of small blood vessels. , 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 hemolysis (hĭmŏl`ĭsĭs), destruction of red blood cells in the bloodstream. Although new red blood cells, or erythrocytes, are continuously created and old ones destroyed, an excessive rate of destruction sometimes occurs. 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 Nausea and Vomiting Definition
Nausea is the sensation of being about to vomit. Vomiting, or emesis, is the expelling of undigested food through the mouth. but unremarkable for cardiovascular disease, hemorrhage (no hemoptysis Hemoptysis Definition
Hemoptysis is the coughing up of blood or bloody sputum from the lungs or airway. It may be either self-limiting or recurrent. Massive hemoptysis is defined as 200-600 mL of blood coughed up within a period of 24 hours or less. , hematemesis hematemesis /he·ma·tem·e·sis/ (he?mah-tem´e-sis) the vomiting of blood.
The vomiting of blood. , or melena melena /me·le·na/ (me-le´nah) the passage of dark stools stained with altered blood.
n. ), infectious diseases, and hematologic hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. 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 afebrile /afe·brile/ (a-feb´ril) without fever.
afebrile adjective Feverless . Vital signs were stable, and there was no orthostatic hypotension. No skin rash, ecchymosis ECCHYMOSIS, med. jur. Blackness. It is an extravasation of blood by rupture of capillary vessels, and hence it follows contusion; but it may exist, as in cases of scurvy, and other morbid conditions, without the latter. Ryan's Med. Jur. 172. , splenomegaly splenomegaly /sple·no·meg·a·ly/ (-meg´ah-le) enlargement of the spleen.
congestive splenomegaly Banti's disease; splenomegaly secondary to portal hypertension. , or hepatomegaly hepatomegaly /hep·a·to·meg·a·ly/ (hep?ah-to-meg´ah-le) enlargement of the liver.
The abnormal enlargement of the liver. Also called megalohepatia. 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 hemolytic uremic syndrome
A syndrome in which hemolytic anemia and thrombocytopenia occur with acute renal failure, marked in children by sudden gastrointestinal bleeding, urine that contains red blood cells and is scanty in volume, and , HELLP syndrome, preeclampsia-eclampsia, and disseminated intravascular coagulation disseminated intravascular coagulation
Abbr. DIC A hemorrhagic disorder that occurs following the uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels, resulting in tissue necrosis and .
The laboratory studies showed a normal white blood cell count white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. (WBC WBC white blood cell; see leukocyte.
white blood cell
n stands for white
cell. ) 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 red blood cell: see blood. (RBC RBC red blood cell.
RBC or rbc
red blood cell
n See red blood cell count.
red blood cells; red blood (cell) count (see blood count). ) 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 transaminase /trans·am·i·nase/ (-am´i-nas) aminotransferase.
See aminotransferase. levels were normal. The hepatitis panel yielded negative results. Lactate dehydrogenase (LDH LDH -lactate dehydrogenase.
lactic acid dehydrogenase; see lactate dehydrogenase. ) level was 1,411 U/L. Prothrombin time was 14.8 sec (normal, 11.5 to 14.5 sec), and partial thromboplastin time Partial Thromboplastin Time Definition
The partial thromboplastin time (PTT) test is a blood test that is done to investigate bleeding disorders and to monitor patients taking an anticlotting drug (heparin). was 32.0 seconds (normal, 21.5 to 34.7 sec) with an international normalized ratio International Normalized Ratio Hematology A method of reporting prothrombin time–PT results for Pts receiving oral anticoagulant therapy; the INR is defined by the formula, PTPatient/PTMNPT 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 human chorionic gonadotropin (HCG): see gonadotropic hormone. .
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 DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. , anti-DS DNA, Smith antibody, and RNP/SM antibody, were within normal limits. Rapid plasma reagin Rapid Plasma Reagin (RPR) refers to a type of test that looks for non-specific antibodies in the blood of the patient that may indicate that the organism (Treponema pallidum) that causes syphilis is present. was nonreactive. An assay for human immunodeficiency virus human immunodeficiency virus
Human immunodeficiency virus (HIV)
A transmissible retrovirus that causes AIDS in humans. 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 chilblain /chil·blain/ (chil´blan) a recurrent localized itching, swelling, and painful erythema of the fingers, toes, or ears, caused by mild frostbite and dampness. Called also chilblains . 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 cyclophosphamide /cy·clo·phos·pha·mide/ (-fos´fah-mid) a cytotoxic alkylating agent of the nitrogen mustard group; used as an antineoplastic, as an immunosuppressant to prevent transplant rejection, and to treat some diseases , 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 vincristine /vin·cris·tine/ (vin-kris´ten) an antineoplastic vinca alkaloid; used as the sulfate salt in the treatment of various neoplasms, including Hodgkin's disease, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Kaposi's , 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.
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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.