Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.

Keywords: ADAMTS13; TTP; caplacizumab; diagnosis; follow-up; review; thrombotic thrombocytopenic purpura; treatment.

Figure 1

Mode of action of ADAMTS13. (a) Under normal circumstances, multimeric von Willebrand factor (VWF) circulates in the plasma in a globular conformation, in which its A1 domains are concealed, and so does not interact with platelets. ADAMTS13 circulates in a “closed” conformation stabilized through the interaction of the C-terminal CUB domains with the central Spacer domain. The MP domain of ADAMTS13 also has a latent conformation in which the active site cleft is occluded by the Ca2+-binding loop. This prevents ADAMTS13 from proteolyzing off-target substrates and confers resistance to plasma inhibitors. (b) Following vessel damage, the endothelium (EC) is disrupted to reveal subendothelial collagen. Globular VWF binds to this surface via its A3 domain and unravels into an elongated conformation in response to the shear forces exerted by the flowing blood. This reveals the A1 domain that can then capture platelets via the GPIbα receptor on the platelet surface. Unravelling of VWF also unravels the VWF A2 domain into a linear polypeptide conformation that reveals the binding sites for ADAMTS13 and the Tyr1605-Met1606 cleavage site, making it susceptible to proteolysis by ADAMTS13. (c) ADAMTS13 recognizes unfolded VWF through multiple interactions. (1) The CUB domains bind the VWF D4-CK domains, which (2) induces their dissociation from the Spacer domain. (3) The Spacer and (4) cysteine (Cys)-rich domain exosites recognize the C-terminal region of the unfolded A2 domain to bring the enzyme and substrate into proximity. (d) Once bound, (5) the disintegrin-like (Dis) domain exosite engages VWF residues Asp1614–Asp1622. This interaction (6) induces an allosteric change in the MP domain. This causes a conformational change, disrupting the “gatekeepertriad” that otherwise occludes the active site cleft, to reveal the S1′ pocket. Once allosterically activated, (7) the MP domain proteolyzes the scissile bond. Petri et al. [54], pp. 1–16. The corresponding author, James Crawley agreed to use of the Figure. No changes were made to the original figure. Creative Commons License: http://creativecommons.org/liceses/by/4.0/.

Figure 2

Flowchart for ADAMTS13 investigation in TTP. Severely deficient ADAMTS13 activity of <10% is required to establish a diagnosis of TTP. Further investigation of anti-ADAMTS13 IgG inhibitory autoantibodies are required to document the mechanism of ADAMTS13 deficiency. ADAMTS13 gene analysis for biallelic mutations is reserved for selected situations to confirm a diagnosis of cTTP. In some cases, the underlying mechanism of ADAMTS13 activity deficiency is not immediately clear and repeated measurements of ADAMTS13 activity in remission and anti-ADAMTS13 IgG during relapse events can help establish a diagnosis.