Thrombotic thrombocytopenic purpura (TTP) is a prothrombotic disorder characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. It has been associated with a deficiency or dysfunction of ADAMTS13, an enzyme responsible for cleaving ultra-large von Willebrand factor multimers, thus preventing spontaneous platelet adhesion and aggregation. In its absence, platelet aggregates accumulate in the microvasculature causing neurological symptoms, cardiac ischemia and renal dysfunction. Most cases in adults are idiopathic, and associated with severe ADAMTS13 deficiency (<10%) and anti-ADAMTS13 antibodies. Acquired TTP due to various conditions, such as HIV, drugs, malignancy, collagen disease, bone marrow transplant and acute pancreatitis (AP), have also been described. Some cases of these secondary TTP may be associated with no to moderate ADAMTS13 deficiency and are referred to as thrombotic microangiopathies (TMAs). If plasma exchange (PLEX) has been the treatment of choice for acquired TTP, it has not been shown to be very effective for TMAs. AP-associated MAHA and thrombocytopenia (MAHA-T) might be one exception.
To better understand the relationship between AP and MAHA-T and to evaluate its response to PLEX, we retrospectively reviewed all cases of suspected TTP/ MAHA-T treated by PLEX in the context of AP in our institution from 2005 to 2015. For the purpose of this report, we preferred to use the term MAHA-T to describe this phenomenon since TMA usually refers to a pathologic diagnosis. Finally, a literature review of published cases was also performed.
Five patients were treated with PLEX for suspicion of TTP in the context of AP between January 1st, 2005 and December 31st, 2015 at our centre. Median age was 36 (31-60). Etiologies for pancreatitis were alcohol (3/5) or idiopathic (2/5). Peak lipase level ranged between 426 and 5853 U/L. One patient had 3 episodes of MAHA-T following AP, always in the context of alcohol abuse. Two patients had evidence of MAHA-T on admission, while the remaining 3 patients had an unremarkable CBC at presentation followed by an abrupt drop in platelet count (nadir, 9-23 x 109/L). All patients showed simultaneously signs of MAHA (Hb nadir between 47 and 93 g/L) with fragmentation on the blood smear and abnormal hemolytic parameters: LD level 1104-8097 U/L, bilirubin 36-176 umol/L, reticulocyte count 130-541 x109/L and undetectable haptoglobin. The median time from AP presentation to the development of laboratory or clinical features of MAHA-T in these cases was 2 days (1-3). Acute kidney injury was present in all cases with creatinine levels ranging between 118-906 umol/L. One patient required hemodialysis. Other observed end organ damage included neurologic symptoms (3/5 patients), elevated troponin (5/5 patients) and transaminitis (4/5). One patient experienced a cardiac arrest. All patients had ADAMTS13 activity measured. One patient had severe deficiency on two separate episodes (ADAMTS13 was <1% and 6% respectively). Three other patients had normal ADAMTS13 activity (average 69%) and one had a moderate deficiency by a qualitative assay. In 4 patients, where tests were performed, there was significant heterogeneity in complement protein and function studies between patients ranging from normal to depressed C3 and C4 and normal to elevated CH50. Complement genetics screen was performed in 3 cases and was normal in all 3 cases. PLEX was initiated in all patients and remission (platelet count over 150 x 109/L) was seen for all after a median of 10 daily treatments (2-12). High dose steroids were used in 4 patients. All patients survived to discharge and completely recovered their kidney function.
TTP/MAHA-T precipitated by AP is increasingly recognized and more than 40 cases have been described in the literature. Similar to our findings, time to MAHA-T occurrence is generally reported within the first 4 days after admission for AP, often when markers for pancreatitis are improving, and most patients do not have severe ADAMTS13 deficiency. While many have looked at ADAMTS13 level, to our knowledge, none have yet reported thorough complement studies and genetics. The 3 cases described herein are then the first cases suggesting this is not a complement mediated disorder. Finally, our review and cases confirm that PLEX is effective and prognosis is good in almost all cases.
Pavenski: Alexion Pharmaceuticals Inc.: Honoraria, Other: attended an entity's advisory boards.