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Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. METHODS AND RESULTS
  5. DISCUSSION
  6. REFERENCES

Arterial thrombotic events, thrombocytopenia, and hemolytic anemia with schistocytes may be encountered in the setting of both thrombotic thrombocytopenic purpura (TTP) and primary antiphospholipid syndrome (APS). We report 2 cases of TTP occurring in patients with definite primary APS. We also describe the results of tests for ADAMTS-13 activity in 20 consecutive patients with primary APS, as well as tests for antiphospholipid antibodies in 26 patients who had TTP, severe ADAMTS-13 deficiency, and ADAMTS-13–inhibiting antibodies. In both of the patients with primary APS and TTP, ADAMTS-13 activity was undetectable, and ADAMTS-13–inhibiting antibodies were present. None of the 26 patients with TTP and severe ADAMTS-13 deficiency was positive for the lupus anticoagulant. One of these patients had a low level of anticardiolipin antibodies (22 IgG phospholipid units). In the 20 patients with primary APS, mean ADAMTS-13 activity was 116% (range 44–250%), and no severe deficiency (<5%) was observed. Our findings suggest that primary APS must be added to the list of autoimmune disorders that can be complicated by TTP.

Thrombotic thrombocytopenic purpura (TTP) is characterized by hemolytic anemia with schistocytes on blood smears, thrombocytopenia, fever, renal abnormalities, and neurologic disturbances. A major breakthrough in the understanding of TTP pathophysiology occurred with the discovery of deficient activity of the von Willebrand factor–cleaving protease (ADAMTS-13) (1, 2), which was shown to be attributable to inhibition of ADAMTS-13 activity by IgG antibodies (1, 2).

A peculiar presentation of the antiphospholipid syndrome (APS) named catastrophic antiphospholipid syndrome (CAPS) (3, 4) features widespread microvascular thrombosis, at times in conjunction with thrombocytopenia and microangiopathic hemolytic anemia with schistocytes. TTP and APS (especially the CAPS variant) may be difficult to discriminate (5). It is likely that some cases of TTP have been harbored under the diagnosis of CAPS. TTP has been reported in patients with systemic lupus erythematosus (SLE), regardless of the presence of associated APS (6–8). In contrast, only 4 cases of TTP associated with primary APS have been described (9–11), and in none of these cases was ADAMTS-13 activity determined. We report 2 cases of TTP in patients with definite primary APS. In both patients, ADAMTS-13 activity was undetectable, and an inhibitor was present.

CASE REPORTS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. METHODS AND RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient 1.

The patient, a 22-year-old woman, was admitted to a local hospital in July 1999, because of the acute onset of dysarthria and right hemiparesis. The week before admission, she had noticed repeated and transient right homonymous hemianopsia. Her medical history was unremarkable. Her blood pressure was 120/60 mm Hg, and her temperature was 37°C. Physical examination revealed a systolic heart murmur, right facial nerve palsy, and right hemiparesis. The reflexes of her right arm were increased. Babinski's sign was negative, and Hoffman's reflexes were absent. There was no manifestation suggestive of SLE.

Laboratory studies revealed the following values: hemoglobin 7.3 gm/dl, mean corpuscular volume (MCV) 66 μm3 with 102 × 109 reticulocytes, lactate dehydrogenase (LDH) 900 units/liter (normal range 220–440 units/liter), haptoglobin 0.3 gm/liter (normal range 0.5–1.4 gm/liter), and platelets 76,000/mm3. The presence of iron deficiency was determined by a low serum ferritin level and increased serum transferrin concentrations. Schistocytes were present on peripheral blood smears. Results of the direct Coombs' test were negative, and antinuclear antibodies (ANAs) were absent. Lupus anticoagulant (LAC) was detected. The patient's activated partial thromboplastin time (APTT) was 44 seconds, compared with 30 seconds for normal control and 40 seconds after mixing. High titers of anticardiolipin antibody (aCL) IgG (92 IgG phospholipid units [GPL units]; normal <15) were detected. The VDRL test was positive, and the Treponema pallidum hemagglutination test was negative. Magnetic resonance imaging (MRI) of the brain revealed left parietal and occipital infarcts. A carotid ultrasonic duplex examination was normal. Echocardiography revealed mitral valve thickening. Blood cultures were negative. Results of electroencephalography and cerebrospinal fluid examination were normal. An abdominal computed tomography (CT) scan revealed triangular lesions of the spleen and the right kidney, suggestive of arterial infarcts. Primary APS was diagnosed. The patient received intravenous heparin followed by oral anticoagulants. Her neurologic status returned to normal within a few days. She was discharged, and at that time was receiving oral anticoagulants and iron.

The patient was admitted again in September 1999, with easy bruising, mild headache, a systolic murmur, a platelet count of 17,000/mm3, and an international normalized ratio (INR) of 2.07. Her hemoglobin concentration was 11 gm/dl, and the haptoglobin concentration remained low. Repeated direct Coombs' tests were negative. Peripheral blood smears revealed schistocytes. A bone marrow aspirate showed a normal number of megakaryocytes. High-dose intravenous methylprednisolone infusion followed by oral prednisone (1 mg/kg/day) improved the platelet count up to 133,000/mm3. Oral anticoagulation was increased in order to reach an INR of 3–3.5. The patient was discharged, and at that time she was receiving fluindione and prednisone.

The patient was hospitalized in February 2000, with exacerbation of severe headaches and fluctuating neurologic symptoms. Her temperature and blood pressure were normal. Physical examination revealed multiple bruises, a petechial rash, and various transient (i.e., lasting a few minutes) neurologic deficits (perioral numbness, alternating hemiparesis with aphasia). The systolic murmur remained unchanged, but the examination was otherwise normal. The INR was 3.4, and the platelet count was 26,000/mm3. She had hemolytic anemia (hemoglobin 7.9 gm/dl, LDH 1,849 units/liter, low level of serum haptoglobin) with numerous schistocytes on blood smears and repeatedly negative direct Coombs' tests. The creatinine level was normal. MRI of the brain was normal except for a previous left parietooccipital infarct. Full-dose anticoagulation with heparin was ineffective for stopping the occurrence of transient focal neurologic deficits. The diagnosis of TTP was considered. ADAMTS-13 activity was 0%, and ADAMTS-13–inhibiting antibodies were present.

The patient was treated with daily plasmapheresis for 4 days, using 4 liters of fresh-frozen plasma as replacement fluid. This regimen resulted in the disappearance of new neurologic symptoms and a complete normalization of the platelet count and LDH level. The frequency of plasmapheresis was then reduced to 3 times weekly. After a total of 8 cycles, the platelet count progressively decreased to 88,000/mm3. Plasmapheresis was intensified, and a splenectomy was performed. Within a few days, the patient's platelet count reached 1,000,000/mm3, and schistocytes were no longer observed. The patient was discharged, and at that time was receiving warfarin and prednisone. Within 2 weeks, complete normalization of the LDH, haptoglobin, and hemoglobin levels was achieved. Prednisone was tapered and stopped, and therapy with fluindione was continued. Six months after the patient underwent splenectomy, her ADAMTS-13 activity was 60%, and no inhibitor was detected. Four years later, she remained in good condition.

Patient 2.

The patient, an 18-year-old girl, was admitted in August 1996 with headaches and right upper extremity clumsiness and numbness. She was an active smoker and was taking estrogen-containing oral contraceptives. Her medical history and her family history were unremarkable. Physical examination revealed a mild systolic murmur. Besides minor arthralgias without arthritis, she had no signs of SLE.

Laboratory studies revealed the following values: platelets 69,000/mm3, hemoglobin 9.1 gm/dl, MCV 91 μm3 with 31 × 109 reticulocytes, LDH 710 units/liter, and haptoglobin 0.01 gm/liter. Results of a direct Coombs' test were negative, and ANAs were absent. LAC was detected (the patient's APTT was 54 seconds versus 32 seconds for normal control and 50 seconds after mixing) and was associated with a high titer of aCL IgG (>100 GPL units). The VDRL test was positive, and the T pallidum hemagglutination test was negative. MRI of the brain revealed a left parietal infarct. An abdominal CT scan showed spleen infarction. An echocardiogram showed mitral valve thickening. The patient was diagnosed as having primary APS, and she was treated with intravenous heparin followed by oral anticoagulants, with a target INR of 3–3.5. Her neurologic status returned to normal.

The patient was hospitalized in November 1998 with multiple cutaneous hematomas, purpura, and abdominal pain with diarrhea. Except for the finding of a systolic murmur, the clinical examination was unremarkable. Laboratory studies revealed the following values: INR 2.4, platelets 14,000/mm3, hemoglobin 9.3 gm/dl, LDH 1,030 units/liter, and reticulocytes 145 × 109. The serum creatinine level was normal, ANAs were absent, and results of the direct Coombs' test were negative. The peripheral blood smear showed rare schistocytes. Blood and stool cultures were negative. A bone marrow aspirate showed a normal number of megakaryocytes. The patient was treated with high-dose intravenous methylprednisolone and gamma globulin for suspected idiopathic thrombocytopenic purpura. Oral anticoagulants were replaced by low molecular weight heparin.

After 5 days of treatment, the patient became anxious, and she developed expressive aphasia lasting 30 minutes, right hemiparesis lasting 1 hour, and a left facial deficit lasting a few minutes. Her hemoglobin concentration had decreased to 5 gm/dl, the LDH level was 2,111 units/liter, and the platelet count was 16,000/mm3. The serum creatinine level remained normal. Results of the direct Coombs' test remained negative. A peripheral blood smear now revealed numerous schistocytes. A CT scan and MRI of the brain showed only the sequela of a left parietal infarct. ADAMTS-13 activity was 0%, and ADAMTS-13–inhibiting antibodies were present. The diagnosis of TTP was considered. Daily plasmapheresis with 4 liters of fresh-frozen plasma as replacement fluid was initiated. The patient had no further neurologic symptoms, and her platelet count reached normal values within 3 days. The LDH level, haptoglobin level, and hemoglobin concentration progressively returned to normal. Plasmapheresis was performed 3 times weekly for 1 month and then was stopped. The patient was discharged, and at that time was receiving fluindione and prednisone. Her hemoglobin concentration was 10.5 gm/dl, the LDH level was 313 units/liter, the platelet count was 223,000/mm3, and the INR was 3.2. The dosage of prednisone was tapered, and after 6 months prednisone treatment was stopped. Therapy with fluindione was continued. ADAMTS-13 activity was 31%, and no inhibitor could be detected at that time. For the following 4 years, the patient did not experience any symptoms of TTP or primary APS.

METHODS AND RESULTS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. METHODS AND RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients.

All of the patients were referred to the Service de Médecine Interne, Hôpital Pitié-Salpêtrière, Paris, France. Definite APS was diagnosed according to the Sapporo criteria (12). APS was classified as primary according to strict exclusion criteria (13).

Assay for ADAMTS-13 activity.

Measurement of ADAMTS-13 activity was performed by immunoradiometric assay, as previously described (14, 15). Platelet-poor plasma from 25 healthy volunteers was arbitrarily defined as containing 100% ADAMTS-13 and was used as an internal control. ADAMTS-13 inhibitor was assayed by measuring the residual ADAMTS-13 activity in mixtures of patient plasma and plasma from healthy volunteers at 3 different volume/volume ratios (1:1, 2:1, and 3:1) after a 30-minute preincubation at room temperature.

Protease activity in patients with primary APS.

Levels of ADAMTS-13 activity were assessed in 20 consecutive patients with primary APS. The mean ADAMTS-13 activity was 116% (range 44–250%). No severe deficiency (<5%) was observed (see Table 1).

Table 1. ADAMTS-13 activity in 20 consecutive patients with primary antiphospholipid syndrome
PatientSexAge, yearsADAMTS-13 activity, %*
  • *

    Normal range 50–150%.

1F5344
2M5358
3F4459
4F3365
5F6468
6F2378
7M3696
8F19100
9F74105
10M40114
11F20117
12M32125
13F45129
14M28130
15M22143
16M38149
17F49150
18F38153
19F54193
20F52250

Antiphospholipid antibodies in patients with TTP.

We next studied the presence of aCL and LAC in 26 consecutive patients with well-defined TTP. All of the patients had severe ADAMTS-13 deficiency (activity of 0%), with ADAMTS-13–inhibiting antibodies. None of the patients was positive for LAC, and 1 patient was positive for aCL IgG (22 GPL units).

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. METHODS AND RESULTS
  5. DISCUSSION
  6. REFERENCES

Our 2 patients fulfilled the criteria for definite APS (12). Both had persistently high titers of aCL IgG, a positive VDRL test, LAC, and mitral valve thickening. Both had brain infarcts due to large-vessel thrombosis, a finding regarded as frequent in APS but unusual in TTP (16, 17). Neither patient had clinical or biologic features suggestive of any associated autoimmune disease, especially SLE. Therefore, the diagnosis of primary APS could be firmly established for these 2 patients. The diagnosis of associated TTP was, for both patients, sustained by the presence of thrombocytopenia, hemolytic anemia with schistocytes, a severe decrease in ADAMTS-13 activity, and the presence of an inhibiting antibody. In this regard, severe (<5%) deficiency in ADAMTS-13 activity is regarded as highly specific for TTP (18–23).

Because TTP and primary APS can share clinical and biologic features, the simultaneous presence of these 2 disorders within the same individual must be interpreted cautiously. Only 4 cases of TTP associated with primary APS have been reported to date (9–11). However, a determination of ADAMTS-13 activity was not available in these early reports, and therefore the diagnosis of TTP was questionable. To exclude the possibility that a severe decrease in ADAMTS-13 activity could be commonly observed in primary APS, we assessed ADAMTS-13 activity in 20 consecutive patients with primary APS. ADAMTS-13 activity was normal in 19 of these patients. In 1 patient, ADAMTS-13 activity was decreased to 44%. Such a slight decrease has been observed in idiopathic thrombocytopenic purpura, SLE, heparin-induced thrombocytopenia, as well as in physiologic conditions (pregnancy and neonatal period) and, therefore, cannot be considered as specific for TTP (18–23). Conversely, among the 26 patients with well-defined TTP, none had LAC. Anticardiolipin antibodies were weakly positive in 1 patient only. This finding, which is consistent with a report by Montecucco et al (24), who did not find any aCL in 8 patients with primary TTP, seems to favor the unusual presence of antiphospholipid antibodies in primary TTP. However, the total number of patients with TTP evaluated for antiphospholipid antibodies is small, and no conclusions can be definitively drawn.

Our findings suggest that primary APS should be added to the list of autoimmune disorders that can be complicated by TTP. Further studies are needed to determine ADAMTS-13 activity in patients with APS, especially the CAPS variant.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. METHODS AND RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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