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.
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.