In this issue of Blood, Chung and colleagues demonstrate in vitro and in an animal model that von Willebrand factor (VWF) self-association under shear stress can be modulated by the high-density lipoprotein and apolipoprotein A-I (HDL/ApoA-I) complex, with significant reduction in the length and thickness of VWF fibers. These antiadhesive and antithrombotic properties of HDL/ApoA-I may connect the pathology of microvasculature with that of large vessels (atherosclerosis with arterial thrombosis) and might suggest novel approaches to these thrombotic disorders.1 

During shear VWF-dependent platelet adhesion (A), the VWF A1 domain binds first to GPIb; then, after initial tethering, the platelet becomes activated and promotes binding between VWF released from ECs and additional platelets, supporting thrombus formation. In the case of normal HDL/ApoA-I levels, VWF fibers are less extended with the normal size of platelet thrombi (B). In the case of reduced HDL/ApoA-I levels, VWF fibers are longer and thicker and generate larger platelet thrombi (C). These antithrombotic effects of HDL/ApoA-I are reported for the first time. Illustration by Luigi Flaminio Ghilardini, University of Milan.

During shear VWF-dependent platelet adhesion (A), the VWF A1 domain binds first to GPIb; then, after initial tethering, the platelet becomes activated and promotes binding between VWF released from ECs and additional platelets, supporting thrombus formation. In the case of normal HDL/ApoA-I levels, VWF fibers are less extended with the normal size of platelet thrombi (B). In the case of reduced HDL/ApoA-I levels, VWF fibers are longer and thicker and generate larger platelet thrombi (C). These antithrombotic effects of HDL/ApoA-I are reported for the first time. Illustration by Luigi Flaminio Ghilardini, University of Milan.

Close modal

VWF is a multimeric glycoprotein that plays a major role in hemostasis and thrombosis by promoting adhesion to platelet receptors and platelet-platelet interactions under high shear stress conditions. VWF is synthesized by vascular endothelial cells (ECs) and megakaryocytes in ultra-large (UL) molecular weight multimers that can be stored in Weibel-Palade bodies and platelet granules.2,3  After secretion, UL-VWF remains on the cell surface as very long strings that may interact actively with circulating platelets. UL-VWF in circulation is converted to the smaller and less thrombogenic forms of VWF by the metalloprotease ADAMTS13, which cleaves the Tyr1605-Met1606 bond of the VWF A2 domain. Quantitative VWF defects and/or qualitative abnormalities of VWF structure cause bleeding disorders such as inherited von Willebrand disease whereas increased levels of VWF and/or the persistence of the UL-VWF in circulation are responsible for thrombotic disorders such as thrombotic microangiopathies (TMAs) and other arterial thrombosis.2,3 

Platelet adhesion and aggregation at sites of vascular injury under shear stress conditions such as those found in microcirculation and in large arteries with lumen restrictions are dependent on the normal multimeric VWF. In blood flow, the VWF A1 domain mediates platelet adhesion by interacting with the glycoprotein (GP) V receptor. Platelets become activated following the initial tethering which allows their irreversible adhesion followed by binding to GP αIIbβ3 of the VWF released by ECs. Once immobilized on the membrane of adherent platelets, VWF promotes the recruitment of additional platelets supporting platelet-platelet aggregation with formation of platelet thrombi.4,5  Indeed, shear stress should be considered the most important regulator of the VWF binding to platelet receptors because high shear can unfold the globular VWF with formation of VWF fibers.6 

Arterial thrombosis is the acute complication that develops on the chronic lesions of atherosclerosis. This may cause heart attack and stroke in a large number of individuals in developed countries.4  Plasma levels of HDL are negatively correlated with the incidence of atherosclerosis and the mechanisms of the antiatherogenic effects of HDL are mainly related to its involvement in the pathways of reverse cholesterol transport (RCT). ApoA-I, the major protein component of HDL, plays pivotal roles throughout the RCT process as follows: (1) formation and stabilization of HDL particle structure; (2) activation of lecithin cholesterol acyl transferase; (3) binding to the hepatic scavenger receptor (SRB1). ApoA-I exists in lipid-free, lipid-poor, and lipid-bound states and therefore has an adaptable structure. However, a lipid-free ApoA-I in full-length is crucial to understand HDL formation and atherosclerosis development.7  In the last 2 decades, several authors have demonstrated in animal models the major roles of VWF in the localization of atherosclerosis8  and in the recruitment of platelets to atherosclerotic sites in response to hypercholesterolemia.9 

With this background information, Chung and colleagues demonstrated in vitro and in vivo using animal models that VWF self-association under shear stress can be modulated by HDL/ApoA-I, with significant reduction in length and thickness of VWF fibers. In their in vitro techniques, when they applied fluid shear stress in a flow chamber where cultured human ECs were activated, the hyperadhesive VWF strings were able to bind large numbers of platelets. If HDL was present during EC stimulation, fewer and shorter platelet-decorated VWF strings were formed. According to Chung and colleagues, this HDL effect on the reduced platelet deposition might be attributed to the binding of HDL particles to the scavenger receptor SRB1,7  activating EC nitric oxide synthase and inhibiting Weibel-Palade body secretion. The presence of HDL during both stimulation and platelet perfusion further reduced the number and length of platelet decorated strings. Their results obtained in vitro showed that HDL dampened VWF adhesive impact both by reducing its secretion and by interfering with its ability to form hyperactive strands. In another set of experiments, using endothelialized in vitro microvessels, they could demonstrate that ApoA-I prevents the incorporation of fluid-phase VWF multimers into preformed VWF fibers under flow but does not compete with platelets in the binding to these fibers.1 

To determine whether HDL could modulate VWF function in vivo, Chung and colleagues used a model of TMA induced by injections of high concentrations of human VWF into ADAMTS13-deficient mice. The protective effects of HDL on thrombocytopenia were accompanied by higher circulating VWF compared with the mice that received only VWF. These results may suggest that HDL stabilizes VWF in circulation, prevents the VWF self-association and binding to the vessel wall, and therefore reduces VWF-induced thrombocytopenia.1 

Based on these results obtained in both in vitro and in vivo models, the authors conclude that HDL/ApoA-I may have potent antithrombotic effects, clearly unrelated to reverse cholesterol transport (see figure). When HDL concentrations drop, the equilibrium shifts in favor of VWF self-association, especially in the setting of the rapid VWF secretion from the Weibel-Palade bodies. This unexpected and novel antithrombotic property of HDL/ApoA-I might have several important implications in both cardiovascular diseases and TMA as well as in sepsis, malaria, and sickle cell disease. The role of this novel antithrombotic effect of the HDL/ApoA-I in venous thrombosis needs further investigation.

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

1
Chung
 
DW
Chen
 
J
Ling
 
M
, et al. 
High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion.
Blood
2016
 
127(5):637-645
2
Sadler
 
JE
von Willebrand factor: two sides of a coin.
J Thromb Haemost
2005
, vol. 
3
 
8
(pg. 
1702
-
1709
)
3
Huang
 
J
Roth
 
R
Heuser
 
JE
Sadler
 
JE
Integrin αvβ3 on human endothelial cells binds von Willebrand factor strings under fluid shear stress.
Blood
2009
, vol. 
113
 
7
(pg. 
1589
-
1597
)
4
Ruggeri
 
ZM
Platelets in atherothrombosis.
Nat Med
2002
, vol. 
8
 
11
(pg. 
1227
-
1234
)
5
Savage
 
B
Sixma
 
JJ
Ruggeri
 
ZM
Functional self-association of von Willebrand factor during platelet adhesion under flow.
Proc Natl Acad Sci USA
2002
, vol. 
99
 
1
(pg. 
425
-
430
)
6
Zheng
 
Y
Chen
 
J
López
 
JA
Flow-driven assembly of VWF fibres and webs in in vitro microvessels.
Nat Commun
2015
, vol. 
6
 (pg. 
7858
-
7867
)
7
Mei
 
X
Atkinson
 
D
Lipid-free apolipoprotein A-I structure: insights into HDL formation and atherosclerosis development.
Arch Med Res
2015
, vol. 
46
 
5
(pg. 
351
-
360
)
8
Methia
 
N
André
 
P
Denis
 
CV
Economopoulos
 
M
Wagner
 
DD
Localized reduction of atherosclerosis in von Willebrand factor-deficient mice.
Blood
2001
, vol. 
98
 
5
(pg. 
1424
-
1428
)
9
Theilmeier
 
G
Michiels
 
C
Spaepen
 
E
, et al. 
Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia.
Blood
2002
 
99(12):4486-4493

Sign in via your Institution