Pathophysiology of thrombotic thrombocytopenic purpura

Abstract

The discovery of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) revolutionized our approach to thrombotic thrombocytopenic purpura (TTP). Inherited or acquired ADAMTS13 deficiency allows the unrestrained growth of microthrombi that are composed of von Willebrand factor and platelets, which account for the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury that characterize TTP. Most patients with acquired TTP respond to a combination of plasma exchange and rituximab, but some die or acquire irreversible neurological deficits before they can respond, and relapses can occur unpredictably. However, knowledge of the pathophysiology of TTP has inspired new ways to prevent early deaths by targeting autoantibody production, replenishing ADAMTS13, and blocking microvascular thrombosis despite persistent ADAMTS13 deficiency. In addition, monitoring ADAMTS13 has the potential to identify patients who are at risk of relapse in time for preventive therapy.

Figure 1.

Structure of VWF and ADAMTS13. VWF multimers may contain ≥40 ∼250 kDa subunits linked together by disulfide bonds between C-terminal cystine-knot (CK) domains and N-terminal D3 domains. The VWF subunit is composed mostly of repeated A, C, and D domains and has binding sites for many proteins, including factor VIII, platelet GPIb, and collagens (Col) 1, 3, and 6. The A2 domain has a globular structure in native VWF, but unfolds in response to fluid shear stress to expose a Tyr-Met bond (red triangle) that is cleaved by ADAMTS13. ADAMTS13 is a multidomain protein with metalloprotease (M), disintegrin-like (D), thrombospondin type 1, Cys-rich, spacer, 7 more thrombospondin type 1 repeats, and 2 CUB domains. A molecular model of the proximal domains shows sites (shaded red) that interact with the extended sequence of the A2 domain.

Figure 2.

Role of VWF and ADAMTS13 in platelet adhesion. VWF multimers may adhere to endothelial cells or to connective tissue in the vessel wall. Platelet GPIb binds to the VWF A1 domain. Flowing blood applies force to the platelets that stretches VWF and exposes a cleavage site for ADAMTS13 in the A2 domain (thin lines in VWF multimers attacked by ADAMTS13). Cleavage of VWF limits the growth of intravascular thrombi. Congenital or acquired ADAMTS13 deficiency allows excessive platelet deposition, causing microvascular thrombosis and TTP.

Figure 3.

Targeting the pathophysiology of TTP. Anti-CD20 agents, such as rituximab, kill B cells and prevent their differentiation into plasma cells. Long-lived plasma cells may be targeted by agents with activity against multiple myeloma, such as bortezomib. Anti-ADAMTS13 autoantibodies are removed by plasma exchange. ADAMTS13 can be replaced by plasma exchange and potentially by recombinant ADAMTS13 (indicated by triangles marked with “r”). Large thrombogenic VWF multimers can be shortened by reducing agents like N-acetylcysteine. The thiol (SH) of N-acetylcysteine attacks and cleaves disulfide bonds of VWF, making smaller VWF multimers disulfide-linked (S) to the cysteine moiety. Inhibitors of VWF-platelet interactions, such as caplacizumab, can stop the progression of TTP in the absence of ADAMTS13.