A case of severe refractory thrombotic thrombocytic purpura responding to treatment with 13‐CIS retinoic acid (2002)

Thrombotic thrombocytic purpura (TTP) is characterized by microangiopathic haemolytic anaemia, thrombocytopenia, acute thrombotic complication central nervous system abnormalities, renal dysfunction and fever. Both acquired and congenital forms are recognized. We report here a case of a patient with acquired severe TTP refractory to plasma exchange, steroids and vincristine who finally responded to a combination of vincristine and retinoic acid. A 25-year-old woman was admitted to hospital with haematomas, severe menstrual bleeding, fatigue and generalized malaise following an upper respiratory tract infection. Blood analysis showed severe thrombocytopenia and signs of microangiopathic haemolytic anaemia, as demonstrated by fragmented erythrocytes, elevation of serum bilirubin and lactate dehydrogenase. Coagulation indices and renal function were normal. Past history revealed no disease of any relevance, but she was taking oral contraceptives. TTP was diagnosed and a standard therapy with plasmaphereses combined with corticosteroids (hydrocortisone 100 mg/d) was initiated on d 6 after the first symptoms occurred (Fig 1). Using this combination, an overall rate of complete responses of 70–85% has been reported (Rock et al, 2000). In addition, the contraceptive was discontinued as several reports have described an association between TTP and oral contraceptives (Kwaan, 1987; Lopez Izquierdo et al, 1999). Course of the platelet count in a 25-year-old woman with TTP. TTP was refractory to first-line treatment consisting of plasmaphereses and steroids. After an initial response to vincristine the platelet count declined again. A second dose of vincristine combined with retinoic acid resulted finally in a complete and continuing response. Despite this treatment the patient developed right-sided hemiparesis and coma, signs of haemolysis progressed and the platelet count dropped to 6 × 109/l (normal range: 150–440 × 109/l). The frequency of plasmapheres was increased from every second day to daily but the thrombocyte count remained low. Several events of generalized epileptic convulsions developed on d 6 and 7. Therefore, the patient was intubated and treated with phenytoin and clonazepam. The daily plasmapheres were continued and vincristine (1·4 mg/m2) was added on d 8. A few days later the platelet count increased, seizure activity stopped and the patient could be weaned off mechanical ventilation. Unfortunately, the haemolysis continued and after 48 h the platelets started to drop again. Owing to relapse, the patient received a second dose of vincristine (1·4 mg/m2) on d 18. She was then started on 13-cis retinoic acid 80 mg/m2 twice daily on d 22. Within 3 d the thrombocyte count normalized, the haemoglobin level increased within 6 d from 6·0 g/dl to 8·4 g/dl and the number of fragmented erythrocytes decreased significantly. The patient was discharged on d 33 and is currently followed in our outpatient clinic without any signs of disease recurrence to date. Prednisone 100 mg/d (started on d 6) could be tapered off, and retinoid acid was continued for 6 months. Despite the severe course, von Willebrand factor-cleaving protease activity in our patient has been within the normal range throughout the observation period, which is a well described phenomenon in idiopathic forms of TTP, while an increase in protease activity is more common in patients with secondary TTP, i.e. after bone marrow transplantation or associated with HIV-infection (Rock et al, 1991). There are no clear treatment recommendations for patients with TTP refractory to ‘standard therapy’ with plasma exchange either alone or in combination with steroids. Our patient was given vincristine, as this chemotherapeutic agent is thought to cause an immunomodulatory effect on the endothelium whose disruption seems to be a key in TTP (Ferrara et al, 1999). Owing to relapse, a second dose of vincristine was given and retinoids added. Retinoids are supposed to exert effects in cell differentiation and haemostasis by induction of thrombomodulin and tissue plasminogen activator and might therefore prevent acute thrombotic complications. (Gudas et al, 1994). A case report on a 9-year-old boy with TTP who was refractory to all conventional treatment modalities and who achieved remission after treatment with retinoic acid suggests a beneficial effect of retinoids in refractory TTP (Raife et al, 1998). Although the various pretreatment modalities our patient received preclude a conclusive statement on her recovery being as a result of administration of retinoic acid, our observation indicates that retinoic acid could be a safe and novel approach for patients with refractory TTP.