A delay in diagnosis: thrombotic thrombocytopenia purpura occurring in systemic lupus erythematous

Thrombotic thrombocytopenia purpura (TTP) in the background of systemic lupus erythematous (SLE) remains rare with an incidence of about 2%. Both conditions have overlapping features and can thus be difficult to differentiate and diagnose. A careful review of the peripheral blood smear remain essential often providing many clues. The diagnosis of TTP is a medical emergency and therapy should be instituted immediately. We present one such challenging case where a delay in diagnosis due to limited resources could have proven fatal for our patient.


Introduction
Thrombotic thrombocytopenia purpura (TTP), is a rare life threatening disease presenting with microangiopathic haemolytic anaemia, thrombocytopenia, renal abnormalities, neurological abnormalities and a fever. However, the urgency for treatment of patients with plasma exchange has resulted in a change in the diagnostic criteria.
It has been revised from the earlier classic pentad, found in only 5% of cases, to the current dyad of thrombocytopenia and microangiopathic hemolytic anaemia, with no clinically apparent alternative explanation for thrombocytopenia and anaemia [1]. TTP occurring in the background of systemic lupus erythematous (SLE), remains rare. The incidence of TTP in SLE is thought to be approximately 2% [2]. The pathophysiologic feature of TTP has been described as severe deficiency of von Willebrand Factor (vWF) cleaving metalloproteinase (ADAMTS-13), which normally cleaves the unusually large vWF into smaller and less adhesive vWF moiety. This deficiency is thought to be possibly secondary to the presence of an IgG antibody inhibiting ADAMTS-13 activity, inhibition that finally allows the presence of units of unusually large vWF which is responsible for the microvascular thrombosis, hemolysis, and thrombocytopenia [3]. TTP is difficult to differentiate from a flare of SLE because of overlapping features. Both can present with haemolytic anaemia, thrombocytopenia, fevers, renal and neurological dysfunction, often complicating the diagnosis. The haemolytic anaemia in TTP is microangiopathic while in a flare of SLE autoimmune haemolytic anaemia is the commonest cause. In the background of SLE, a number of disease entities can cause microangiopathic haemolytic anaemia and thrombocytopenia including antiphospholipid syndrome, disseminated intravascular coagulation, malignant hypertension, systemic vasculitis as well as a HELLP syndrome in any female of child bearing age [4]. The mainstay of treatment of TTP even in the background of SLE remains plasma exchange [5].
Corticosteroids are used initially to achieve relatively rapid immunosuppression. There is some prospective evidence that higher doses of methylprednisolone (10 mg/kg/day) are more effective than lower doses (1 mg/kg/day) [6]. Rituximab is effective in patients who have failed to respond to plasma exchange and steroids [7].

Patient and observation
A 40-year-old female of Asian origin, known to have SLE diagnosed three years ago, presented to our institution with a three-day history of jaundice, gross hematuria and bleeding from her gums. Apart from generalized weakness and intermittent headaches, the patient denied any other symptoms including abdominal pain, diarrhea, vomiting, dysuria, frequency, fever or chills, neck stiffness, photophobia or seizures. She denied any travel history especially to areas endemic of malaria. She also denied any prior or current history of easy bruising or bleeding tendencies. Her past medical history was significant for systemic lupus erythematous with a flare treated with high dose steroid one year ago. Her current medications included: prednisolone 2.5mg once a day. She was a mother of two healthy children and was currently not on any contraception. Her menstrual cycle was regular and denied any previous miscarriages. She denied any alcohol or tobacco history and was active with daily household chores. Her were gradually tapered and she was scheduled to follow in our outpatient clinic. Figure 1 represents the platelet count from admission to discharge of the patient.

Discussion
The initial diagnosis in our patient was thought to be a flare of SLE leading to the autoimmune mediated destruction of red blood cells and platelets. However, the peripheral blood smear was remarkable for schistocytes and not spherocytes. In addition, our patient had a Normal ADAMTS-13 activity should clue one into looking at other causes of MAHA and low platelets [9]. Interestingly, in patient with SLE, especially with a positive anti-dsDNA, and concomitant TTP, less than 10% showed ADAMTS-13 activity [8]. In addition, the decreased level of ADAMTS-13 activity correlated with increased SLE related tissue damage [10]. The diagnosis of TTP is a medical emergency with plasma exchange being the mainstay of treatment. Plasma exchange should be started immediately and has shown to decrease mortality for an estimated 90% to less than 10% [11]. Hence now the dyad of microangiopathic haemolytic anaemia and thrombocytopenia with no clinically apparent explanation should be treated as TTP [1].
Unfortunately, in our patient's case the diagnosis of TTP was delayed by a week due to the delay in the report of the peripheral blood film.
Plasma exchange is usually given concomitantly with steroid [4]. Once the platelets have normalized for 48 hours, the plasma exchange can be halted and steroid gradually tapered [4,12]. Cyclophosphamide and rituximab (anti-CD 20) have been reportedly used as a salvage treatment in refractory TTP [12,13]. This case report demonstrates that not all hemolytic anaemia in SLE is immune mediated. Peripheral blood film is mandatory to evaluate anemias even though it is often

Conclusion
Hemolytic anemia and thrombocytopenia must always raise the suspicion on TTP especially in the appropriate clinical setting. SLE and