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 α2Bβ3. 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.

Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

REFERENCES
1
Pedrazzini
G
Biasco
L
Sulzer
I
, et al. 
Acquired intracoronary ADAMTS13 deficiency and VWF retention at sites of critical coronary stenosis in patients with STEMI.
Blood
2016
 
127(23):2934-2936
2
Mozaffarian
D
Benjamin
EJ
Go
AS
, et al. 
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association.
Circulation
2016
, vol. 
133
 
4
(pg. 
e38
-
e360
)
3
Telford
AM
Wilson
C
Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome.
Lancet
1981
, vol. 
1
 
8232
(pg. 
1225
-
1228
)
4
Lewis
HD
Jr
Davis
JW
Archibald
DG
, et al. 
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
N Engl J Med
1983
, vol. 
309
 
7
(pg. 
396
-
403
)
5
Yusuf
S
Zhao
F
Mehta
SR
Chrolavicius
S
Tognoni
G
Fox
KK
Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
N Engl J Med
2001
, vol. 
345
 
7
(pg. 
494
-
502
)
6
Wessler
JD
Généreux
P
Mehran
R
, et al. 
Which intraprocedural thrombotic events impact clinical outcomes after percutaneous coronary intervention in acute coronary syndromes? A pooled analysis of the HORIZONS-AMI and ACUITY trials.
JACC Cardiovasc Interv
2016
, vol. 
9
 
4
(pg. 
331
-
337
)
7
Turner
NA
Nolasco
L
Ruggeri
ZM
Moake
JL
Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage.
Blood
2009
, vol. 
114
 
24
(pg. 
5102
-
5111
)
8
Bentzon
JF
Otsuka
F
Virmani
R
Falk
E
Mechanisms of plaque formation and rupture.
Circ Res
2014
, vol. 
114
 
12
(pg. 
1852
-
1866
)
9
Dong
JF
Moake
JL
Nolasco
L
, et al. 
ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.
Blood
2002
, vol. 
100
 
12
(pg. 
4033
-
4039
)