Alloantibody Sensitization after PLASMA Exchanges for Relapsed Thrombotic Thrombocytopenic Purpura (TTP

Deficiency of ADAMTS-13, (A Disintegrin And Metalloprotease with 8 Thrombospondin like Domains), a Von Willebrandt Factor (VWF) cleaving protease, may be congenital (Upshaw Shulman syndrome) or acquired due to inhibitory autoantibodies and leads to the syndrome of Thrombotic Thrombocytopenic Purpura. Plasma exchange (PE) therapy is efficacious in therapy of TTP as it replenishes the deficient protease and at the same time removes the inhibitory antibody responsible for the enzyme deficiency. Few data exist effect of rising ADAMTS-13 inhibitor titers on the success of TTP therapy.

We report a case of a 59 yr old African American woman who was diagnosed with TTP in October 2000 when she presented with altered mental status and focal weakness in right upper extremity. Initial labs showed Hemoglobin of 5.5 gm/dl, platelet count of 21,000/mm3, LDH of 4295. Peripheral smear showed moderate schistocytes and serum haptoglobin levels were decreased, renal function was normal. The patient received a total of 6 PE with FFP along with steroids and subsequently went into remission.

The patient had a relapse after 10 months. She achieved remission with 5 PE. She was started on azathiaprine as an outpatient that was continued for five months. The patient remained asymptomatic for 5 years till her next relapse in the postoperative period after elective knee replacement surgery. The hospital course was complicated by development of transfusion related acute lung injury after receiving FFP. The patient again responded to PE (total 8 sessions) and IV steroids and went into remission.

Prior to initiation of PE for this third relapse, tests showed ADAMTS -13 activity level was <5% indicating severe deficiency of the enzyme; inhibitor titer was 3.2 Bethesda units (BU). Follow up testing after completion of PE and remission revealed persistently low ADAMTS 13 activity of <5% with paradoxically higher inhibitor titers of 8 BU. Repeat testing after 16 months shows ADAMTS 13 activity of <5% with inhibitor titers of 0.9 BU.

Conclusion: Our patient developed rising titer of inhibitory antibodies to ADAMTS 13 post Plasma exchange during the second relapse of TTP; Pre and post plasma exchange autoantibody titers were 3.2 and 8.0 BU respectively. She was started on azathioprine after the third TTP relapse, which she took for 2 months and the therapy was then discontinued. She has remained in remission since then and repeat testing reveled ADAMTS 13 activity continues to be <5% with the inhibitor titer decreasing to 0.9 BU. We postulate that the high inhibitor titers post plasma exchange could be the result of alloantibody formation as a result of FFP transfusions and the subsequent low level (0.9BU) inhibitor detected could be related to waning of alloantibody titers in the absence of further FFP exposure. Rising antibody titers post FFP exposure after PE therapy do not preclude a successful outcome with PE therapy with FFP replacement. Further study on the significance of rising antibody titers post PE therapy is required. Epitope mapping and idiotype analysis may be helpful in future studies.