VWF, ADAMTS13, and acute coronary syndromes

In this issue of Blood, Pedrazzini et al¹  have taken an important step toward revitalizing our view of coronary artery thrombosis and providing a new target for the pharmacologic treatment of acute coronary syndromes (ACS).

In the United States, ∼660 000 new and 305 000 recurrent myocardial infarctions (MIs) occur yearly.²  The number of therapeutic options for treatment of ACS has remained limited to thrombin antagonists since 1981,³  aspirin since 1983,⁴  and P2Y12 antagonists since 2000.⁵  Despite the development of new P2Y12 inhibitors prasugrel, ticagrelor, and more recently cangrelor, progress in reducing morbidity and mortality for these syndromes has been incremental rather than groundbreaking. A key part of the treatment of ACS is prompt revascularization to reduce or eliminate local arterial stenosis and restore perfusion of the myocardium. However, even with currently available pharmacologic and mechanical reperfusion strategies, intraprocedural thrombotic events occur in nearly 8% of patients who undergo intracoronary stent placement for ACS; these events explain approximately two thirds of the 30-day morbidity and mortality among patients with ACS.⁶ 

In the current paper, Pedrazzini et al¹  turn their attention to the von Willebrand factor (VWF)–a disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) axis, a mechanism of thrombosis that has remained relatively unexplored in the cardiology community. The relationship between VWF and ADAMTS13, the metalloproteinase principally responsible for its cleavage, is well known to readers of Blood. VWF is produced in megakaryocytes and endothelial cells, stored as a multimer in Weibel-Palade bodies, and is rapidly secreted in the form of high-molecular-weight strings on the surface of activated endothelial cells, where it plays a key role in initiating platelet adhesion. ADAMTS13 is produced in largely in hepatic stellate cells but is also released by endothelial cells, where it has been shown to cleave VWF multimers on the cell surface.⁷  Pedrazzini et al sampled blood systemically as well as proximal and distal to the culprit coronary narrowing in patients undergoing coronary interventional procedures for acute ST segment elevation MI. The key observation is that compared with the systemic circulation, ADAMTS13 antigen and activity were reduced in the distal coronary artery, as was the ratio of ADAMTS13 to VWF.¹  Thus, at the site of coronary occlusion, less ADAMTS13 is available to modulate the promotion of shear-induced platelet adhesion and aggregation by VWF. What is important in the current report is that the balance between VWF and ADAMTS13 appears to be altered locally rather than (or perhaps in addition to) systemically in patients with MI. In order to interpret these observations, it is critical to recognize that the areas of the vasculature sampled in this study do not represent normally functioning arteries that happen to have discrete areas of narrowing that produce shear. ACS in general and MI in particular result from abrupt disruption of an atherosclerotic plaque that is characterized by dysfunctional endothelium, local and systemic inflammatory changes, and possibly alterations in mechanical stress.⁸ 

If confirmed, the current observations should invite further investigation of the altered balance between VWF and ADAMTS13 in diseased blood vessels and might ultimately be directed at developing new antithrombotic therapeutics to restore the balance between them. The secretion of VWF is relatively rapid, whereas investigations in human umbilical vein endothelial cells suggest that ADAMTS13 release is relatively slow,⁷  and its activity is altered by flow conditions,⁹  which can change rapidly in patients with ACS. Understanding the timing of this derangement might prove to be particularly important to determine the optimal duration of treatment.

Manipulating the VWF–ADAMTS13 axis must be approached cautiously. Patients undergoing treatment of acute coronary syndromes are currently treated with a thrombin (or FXa) antagonist, aspirin, a P2Y12 antagonist, and sometimes an antagonist of integrin α_2Bβ₃. Adding another class of antithrombotic is likely to increase the risk of serious bleeding. On the other hand, most ischemic complications of ACS occur relatively soon after presentation, implying that it may be possible to limit the duration of exposure to the most aggressive portion of the antithrombotic regimen. Detailed characterization of this pathophysiologic derangement might lead to investigation of new antithrombotic strategies to inhibit VWF or promote the local activity of ADAMTS13 that might be applicable during the acute phases of ACS.