Arteriosclerosis, Thrombosis, and Vascular Biology

ATVB IN FOCUS
Dynamic Functionality of Apolipoproteins
Series Editor: Mary Sorci-Thomas

Clot or Not? Reviewing the Reciprocal Regulation

Between Lipids and Blood Clotting
Ziyu Zhang , Maya Rodriguez , Ze Zheng

ABSTRACT: Both hyperlipidemia and thrombosis contribute to the risks of atherosclerotic cardiovascular diseases, which are
the leading cause of death and reduced quality of life in survivors worldwide. The accumulation of lipid-rich plaques on
arterial walls eventually leads to the rupture or erosion of vulnerable lesions, triggering excessive blood clotting and leading
to adverse thrombotic events. Lipoproteins are highly dynamic particles that circulate in blood, carry insoluble lipids, and are
associated with proteins, many of which are involved in blood clotting. A growing body of evidence suggests a reciprocal
regulatory relationship between blood clotting and lipid metabolism. In this review article, we summarize the observations that
lipoproteins and lipids impact the hemostatic system, and the clotting-related proteins influence lipid metabolism. We also
highlight the gaps that need to be filled in this area of research.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.

Key Words: cardiovascular diseases ◼ coagulation ◼ fibrin ◼ fibrinolysis ◼ lipid ◼ lipoproteins

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A
therosclerotic cardiovascular diseases, including myo-
cardial infarction and ischemic stroke, are the leading
causes of death and reduced quality of life in survivors
worldwide.1,2 These diseases share common features in
their pathological progression from hyperlipidemia to lipid-
rich plaques building up on arterial walls to the rupture
or erosion of vulnerable lesions. Eventually, this triggers
excessive clotting, leading to adverse thrombotic events
that block or reduce blood flow and cause tissue ischemia.
Growing evidence suggests that these common features
are not happening as a coincidence but rather have mech-
anistic links between hyperlipidemia and thrombosis.
Please see www.ahajournals.org/atvb/atvb-focus for all
articles published in this series.
Hemostasis is the mechanism that forms blood clots to
stop bleeding. Blood clotting follows 4 steps: vasoconstric-
tion, platelet plug formation, coagulation, and fibrinolysis.
Thrombosis occurs when excessive blood clots extend and
block blood flow. Lipoproteins are highly dynamic particles
that circulate in blood and carry both insoluble lipids and are
associated with proteins, many of which are involved in blood
clotting. In this article, we will review insights into how the
blood clotting system intertwines with lipoproteins based on
evidence from both clinical observations and mechanistic
studies, with perspectives toward future research directions.
OVERVIEW OF HEMOSTATIC SYSTEM AND
LIPOPROTEINS
Primary Hemostasis
Upon vascular injury, activated endothelial cells secrete
VWF (von Willebrand factor) onto the surface of
lesioned endothelium and the subendothelial extracel-
lular matrix.3,4 Platelets adhere to VWF at the injury site,
before becoming activated and forming aggregates that
lead to platelet plug formation.
Secondary Hemostasis
These platelet plugs are loose and require stabilization
by cross-linked fibrin clots, which are generated through

Correspondence to: Ze Zheng, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, Email zzheng@mcw.edu; or Ziyu Zhang, Versiti Blood
Research Institute, 8733 Watertown Plank Rd, Milwaukee, WI 53226, Email zzhang@versiti.org
For Sources of Funding and Disclosures, see page 541.
© 2024 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at www.ahajournals.org/journal/atvb

Arterioscler Thromb Vasc Biol. 2024;44:533–544. DOI: 10.1161/ATVBAHA.123.318286 March 2024   533
 Zhang et al Reciprocal Regulation of Lipids and Blood Clotting

Nonstandard Abbreviations and Acronyms Highlights

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ABCG4 ATP-binding cassette subfamily G4 • Clotting-related proteins are associated with lipo-
CETP cholesteryl ester transfer protein proteins by proteomics.
FI factor I • LDL (low-density lipoprotein)-apheresis reduces
clotting-related protein levels in plasma.
FII factor II
• Dyslipidemia is associated with increased plate-
FIIa activated factor II let count, platelet activity, hypercoagulability, and
FV factor V impaired fibrinolysis.
FVa activated factor V
FVII factor VII
pathway can be initiated with the sequential activation of
FVIIa activated factor VII
the serine proteases factor XII (FXIIa [activated factor
FVIII factor VIII
XII]), FXIa (activated factor XI), and FIXa. FXIIa activates
FVIIIa activated factor VIII FXI (factor XI) to FXIa and prekallikrein to kallikrein,
FIX factor IX which subsequently activates more factor XII, generat-
FIXa activated factor IX ing more FXa.8 Subsequently, FXa forms a 1-to-1 com-
FX factor X plex with FVa (activated FV) in the presence of calcium
FXa activated factor X and phospholipids.9 This complex, also called prothrom-
FXI factor XI binase, converts prothrombin (FII [factor II]) to thrombin
FXIa activated factor XI (FIIa [activated factor II]).10 Upon activation of FX to FXa,
FXII factor XII TFPI (tissue factor pathway inhibitor) strongly inhibits
FXIIa activated factor XII extrinsic pathway,11,12 without inhibition on the intrinsic
FXIII factor XIII pathway. Therefore, the intrinsic pathway plays a signifi-
cant role in the amplification of the coagulation cascade.
FXIIIa activated factor XIII
Thrombin is the enzyme that converts fibrinogen to fibrin,
GP1bα glycoprotein-1b-α
which is then cross-linked by a transglutaminase, factor
HDL high-density lipoprotein XIIIa (FXIIIa [activated factor XIII]), eventually generat-
IDL intermediate-density lipoprotein
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ing stable insoluble fibrin clots.13 Thrombin also amplifies

LDL low-density lipoprotein its own production, through feedback activation of FVa,
Lp(a) lipoprotein(a) FVIIIa, and FXIa. The anticoagulation system naturally
MTP microsomal triglyceride transfer protein exists and is an important part of the hemostatic system
PAI-1 plasminogen activator inhibitor 1 to check and balance the coagulation cascade. The major
PF4 platelet factor 4 players in the anticoagulation system include the protein
TF tissue factor C, protein S, antithrombin, and the abovementioned TFPI.
TFPI tissue factor pathway inhibitor
tPA tissue-type plasminogen activator Fibrinolysis
uPA urokinase plasminogen activator
After the cross-linked fibrin stabilized the clot, fibrinoly-
VLDL very-low-density lipoprotein
sis gradually removes the clot, allowing blood to reflow.
VWF von Willebrand factor tPA (tissue-type plasminogen activator) initiates fibri-
nolysis by binding to fibrin, where it converts the zymo-
gen plasminogen to the active enzyme plasmin. Plasmin
coagulation. Under physiological conditions, following cleaves the insoluble cross-linked fibrin to soluble fibrin
vascular injury, extravascular TF (tissue factor) comes in degradation products.14,15 As a positive feedback loop,
contact with blood and forms a 1-to-1 complex with the plasmin also activates uPA (urokinase plasminogen acti-
serine protease FVIIa (activated factor VII),5 initiating the vator) to produce more plasmin and amplify fibrinolysis.15
extrinsic coagulation pathway, also called the TF pathway PAI-1 (plasminogen activator inhibitor 1), a serine pro-
(Figure 1). This TF-FVIIa complex then activates FX (fac- tease inhibitor (serpin), inactivates tPA or uPA by form-
tor X) to the serine protease FX (FXa [activated factor ing tPA–PAI-1 or uPA–PAI-1 complex, thereby inhibiting
X]).6 The TF-FVIIa complex also feeds into the intrinsic fibrinolysis.15
pathway by activating FIX (factor IX) to FIXa (activated
FIX), which is a part of the intrinsic pathway. FIXa forms
an enzymatic complex with its cofactor FVIIIa (activated Lipoproteins
FVIII) upon activation by thrombin. The FIXa-FVIIIa com- Abundant lipid-bound proteins are carried on lipoproteins
plex rapidly converts FX to FXa.7 The alternative intrinsic in circulation, including many involved in blood clotting.

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 Zhang et al Reciprocal Regulation of Lipids and Blood Clotting

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Figure 1. Summary of the hemostatic system.

Upon vascular injury, endothelial cells secrete VWF (von Willebrand factor), which platelets bind to, forming long strings and aggregates
(platelet plugs). The extrinsic and intrinsic coagulation pathways work in concert to activate FX (factor X) to FXa (activated FX). FXa activates
prothrombin to thrombin, which cleaves fibrinopeptides from the N-terminus of fibrinogen to form fibrin. Fibrin polymerizes and is cross-linked by
activated FXIIIa (activated FXIII). The polymerized fibrin stabilizes the blood clot. FII indicates factor II; FIIa, activated factor II; FV, factor V; FVa,
activated factor V; FVII, factor VII; FVIIa, activated factor VII; FVIII, factor VIII; FVIIIa, activated FVIII; FIX, factor IX; FIXa, activated factor IX;
FX, factor X; FXa, activated factor X; FXI, factor XI; FXIa, activated factor XI; FXII, factor XII; FXIIa, activated factor XII; FXIII, factor XIII; FXIIIa,
activated factor XIII; and TF, tissue factor.

Lipoproteins are primarily known for their functions of car-
rying various insoluble lipids traveling through bloodstream.
Regardless of the heterogeneity of lipoproteins, all contain
a core with cholesterol-esters and triglycerides, surrounded
by free cholesterol, phospholipids, and apolipoproteins.
All apoB-containing lipoproteins are atherogenic, includ-
ing chylomicron, VLDL (very-low-density lipoprotein), IDL
(intermediate-density lipoprotein), LDL (low-density lipopro-
tein), and Lp(a) (lipoprotein[a]). In contrast, apoA1-containing
HDL (high-density lipoprotein) is atheroprotective.
CONNECTIONS BETWEEN LIPOPROTEINS
AND HEMOSTATIC SYSTEM
Clotting-Related Proteins Are Associated With
Lipoproteins by Proteomics
VLDL, LDL, HDL, and Lp(a) are composed of 7%, 20%,
40% to 55%, and 25% proteins by weight, respectively.16
Proteomic analyses of isolated lipoproteins identified
proteins outside of those that regulate lipid metabolism,
including many proteins involved in blood clotting (Fig-
ure 2). VLDL fractions have VWF, PF4 (platelet factor
4), FV (factor V), fibrinogen-α/γ, prothrombin, protein S,
TFPI, plasminogen, α-2-macroglobulin, complement C3,
C4B, and C9. LDL factions have VWF, platelet GP1bα
(glycoprotein-1b-α), PF4, FXIII (factor XIII)-α, fibrinogen-
α/β/γ, prothrombin, TFPI, plasminogen, complement
C3, C4B, and C9. HDL fractions have PF4, FXII (fac-
tor XII), fibrinogen-α/β/γ, prothrombin, antithrombin-III,
and plasminogen. Lp(a) fractions have VWF, fibrinogen-
α/β/γ, FXIII-β, plasminogen, kallikrein, complement C2/
C3/C5, C6/C7/C9, and C4B.17–23
The proteins on lipoproteins are not always consistent.
Many factors contribute to the variation: (1) the conditions
in which the blood samples are collected; (2) how lipopro-
teins are isolated; and (3) how lipids are removed before
analyzing protein content. Due to similar density between

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 Zhang et al Reciprocal Regulation of Lipids and Blood Clotting
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Figure 2. Hemostasis-related proteins identified in human lipoprotein fractions by proteomic studies.

This figure summarizes the findings from several proteomic studies that isolated lipoproteins from human plasma or serum, revealing the presence
of various hemostasis-related proteins. Notably, FXIII (factor XIII), prothrombin, fibrinogen, and plasminogen were detected across all lipoprotein
fractions, including VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), Lp(a) (lipoprotein[a]), and HDL (high-density lipoprotein).
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However, it is important to note that the absence of certain proteins in this figure does not necessarily imply a lack of association with lipoproteins due
to limited sensitivity by mass spectrometry, particularly for proteins with low plasma concentrations. FV indicates factor V; FVII, factor VII; FVIII, factor
VIII; FX, factor X; FXI, factor XI; FXII, factor XII; GPIbα, glycoprotein Ib alpha; TFPI, tissue factor pathway inhibitor; and VWF, von Willebrand factor.

Lp(a) and HDL, and similar size between Lp(a) and LDL,
without further purification, Lp(a) contamination could be
found in HDL fractions isolated by fast protein liquid chro-
matography–size exclusion chromatography. In proteomic
studies of lipoproteins isolated by size exclusion–fast pro-
tein liquid chromatography and density gradient ultracen-
trifugation, protein S, prothrombin, and fibrinogen-γ were
found on VLDL and LDL fractions.19,21 In contrast, lipopro-
teins isolated by density gradient followed by lower-speed
centrifugation, protein S, prothrombin, and fibrinogen-γ
were found only on VLDL fractions.18 However, most stud-
ies did not report the donors’ age, gender, and metabolic
information, which contributed to the variation. Further
investigations are required to understand how lipoprotein
protein contents vary in dyslipidemia in humans.
LDL-apheresis is a procedure to remove circulating
apoB-lipoproteins, including VLDL, LDL, and Lp(a), from
patients with severe hypercholesterolemia that is resis-
tant to lipid-lowering therapies, such as familial hyper-
cholesterolemia. In addition to reducing cholesterol and
triglyceride, LDL-apheresis therapy also lowers clotting-
related proteins carried on apoB-lipoproteins.24 Fibrino-
gen and TF decreased by 66% and 27%, respectively,
in 22 patients with coronary artery disease undergoing
heparin-mediated extracorporeal LDL-precipitation-
apheresis.25 PAI-1 decreased by 72%, 58%, and 30%
in 3 patients with familial hypercholesterolemia who
received 6 consecutive LDL-apheresis treatments,
respectively.26 Another study of 9 patients with severe
familial hypercholesterolemia, all received LDL-apheresis
using either immunoadsorption apheresis method (n=5),
or dextran-sulfate absorption method (n=4). Regard-
less of the LDL-apheresis method used, all patients had
decreased fibrinogen, FV, FVII (factor VII), FVIII (factor
VIII), VWF, FXI, FXII, prekallikrein, antithrombin-III, pro-
tein C, protein S, α-2-macroglubolin, plasminogen, and
PAI-1, with the highest reduction in FVIII by 72% after
immunoadsorption apheresis, and by 98.5% by dextran-
sulfate absorption.27 Although many hemostasis-related
proteins are present in both apoB-lipoprotein fractions
and HDL fractions, the mechanism of how these pro-
teins are associated with lipoproteins and the functional
impact of the associate remain unexplored. The differ-
ent core apolipoproteins and lipids content may impact
lipoprotein function and carrying capacity. In the case of
HDL, its high radius of curvature enables hydrophobic
stretches of plasma proteins to associate.28 Therefore,
the mechanism contributing to the interaction between

536   March 2024 Arterioscler Thromb Vasc Biol. 2024;44:533–544. DOI: 10.1161/ATVBAHA.123.318286
 Zhang et al
the hemostasis proteins and different types and sizes of
lipoproteins are likely varied.
Procoagulant Roles of Phospholipids on
Lipoproteins
Lipoprotein is the major carrier of circulating neutral
phospholipid, such as phosphatidylcholine.29 Coagula-
tion cascade requires an appropriate surface area, such
as that provided by phospholipid vesicles from platelets,
which reduces the Km of prothrombinase for prothrom-
bin by 1400-fold.30–33 Lipoproteins do not contain the
negatively charged phosphatidylserine, which is essential
for coagulation cascade. Normally, phosphatidylserine is
located on the inner leaflet of the cell membrane. During
platelet activation and cellular apoptosis, phosphatidyl-
serine flips to the outer leaflet of the membrane (inside
out). When phosphatidylserine is exposed on the outer
membrane of a platelet during blood clotting, the nega-
tively charged phosphatidylserine provides a surface
that supports coagulation cascade and promotes clot
formation.34 Instead, the surface of lipoproteins is made
of a monolayer of phosphatidylcholine.35 Experimental
evidence showed VLDL promotes clotting by providing
physiological surfaces, abundant in phospholipids, to sup-
port extrinsic pathway.36 In the presence of prothrombi-
nase complex, VLDL yields thrombin at a rate 6× slower
than synthetic phosphatidylcholine/phosphatidylserine
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vesicles. However, the binding affinity between pro-
thrombin and VLDL is slightly higher than that between
prothrombin and phosphatidylserine vesicles.36
The oxidation of LDL and phospholipids begins when
free radicals, which are highly reactive molecules with
unpaired electrons, attack the unsaturated fatty acids
present in LDL and phospholipid.37 These oxidized LDL
and oxidized phosphatidylcholines are accumulated in
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Reciprocal Regulation of Lipids and Blood Clotting
atherosclerotic plaques.38 Recent studies showed oxi-
dized phosphatidylcholines are also capable of enhanc-
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ing thrombin generation.39 In humans, elevated oxidized
phosphatidylcholine in apoB-lipoproteins is associated
with higher cardiovascular risk.40 Additionally, oxidized
LDL induces platelet aggregation through multiple mech-
anisms,41–43 which will be discussed in the following sec-
tions. However, whether oxidized phosphatidylcholines in
apoB-lipoprotein directly interact with coagulation fac-
tors is undetermined and requires future investigation.
Functional Impact of Lipoproteins and
Hemostatic System on Each Other
Although lipoproteins may play a role in hemostasis, the
mechanisms by which they serve as hemostatic regula-
tors are poorly understood. Pioneer studies have shed
light on potential function of lipoprotein in association
with these clotting-, or clot lysis–related proteins (Fig-
ure 3). Hepatocytes are the main source of circulating
lipoproteins. Our previous studies found that hepatocytes
also synthesize tPA.44,45 Moreover, our recent findings
reveal a novel role of intracellular tPA–PAI-1 interac-
tion in determining VLDL assembly and production in
hepatocytes.46 We found that tPA, partially through the
lysine-binding site on its Kringle 2 domain, binds to the
N terminus of apoB, blocking the interaction between
apoB and MTP (microsomal triglyceride transfer pro-
tein) in hepatocytes, thereby reducing VLDL assembly
and plasma apoB-lipoprotein cholesterol levels. PAI-1
sequesters tPA away from apoB and increases VLDL
assembly. Our study establishes a link between tPA, PAI-
1, and plasma levels of atherogenic apoB-lipoproteins,
beyond the well-known roles of tPA and PAI-1 in the
occlusive thrombus that is the ultimate manifestation
of atherosclerotic vascular disease.46 These findings
Figure 3. Functional impact of lipids
and fibrinolysis on each other.
Plasminogen promotes ABCA1 (ATP-
binding cassette transporter A1)-
dependent cholesterol efflux to export
cholesterol out of macrophages. Both
Lp(a) (lipoprotein[a]) and plasminogen
have serine protease domains, while the
one in Lp(a) is inactive. Lp(a) also inhibits
the conversion of plasminogen to plasmin.
Therefore, Lp(a) is antifibrinolytic. Beyond
the well-known roles of tPA (tissue-
type plasminogen activator) in initiating
fibrinolysis, and PAI-1 (plasminogen
activator inhibitor 1) as tPA’s serpin
protease inhibitor, we found that tPA
interacts with apoB in the haptocytes
and blocks apoB lipidation and VLDL
(very-low-density lipoprotein) production.
PAI-1 sequesters tPA away from apoB and
increases VLDL assembly.
March 2024   537
 Zhang et al
provide a possible mechanistic explanation behind the
correlation between high apoB cholesterol and low tPA
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in patients with atherosclerotic cardiovascular disease.
Plasminogen, found in VLDL, LDL, HDL, and Lp(a) frac-
tions, promotes ABCA1 (ATP-binding cassette transporter
A1)-dependent cholesterol efflux capacity, transferring
cholesterol out of macrophages. Plasminogen-promoted
ABCA1-mediated cholesterol efflux capacity is indepen-
dent of apoA1, HDL’s core apolipoprotein47 but can be
inhibited by Lp(a).47 Both Lp(a) and plasminogen have
serine protease domains, while the one in Lp(a) is inac-
tive, followed by Kringle domain repeats.48 Lp(a) inhibits
the conversion of plasminogen to plasmin and, there-
fore, inhibits fibrinolysis and exacerbates thrombosis.49,50
Moreover, the Kringle domains have abundant lysine-
binding sites, allowing Lp(a) to promote coagulation by
inhibiting an anticoagulant, TFPI, by blocking its lysine
residues in the carboxy-terminus.51,52 LDL also promotes
thrombosis by enhancing VWF self-association and sub-
sequent platelet adhesion, leading to increased size and
persistence of VWF-platelet thrombi.53 In contrast, HDL,
or apoA1, prevents VWF self-association and adsorption
onto vessel walls, inhibiting platelet activation and adhe-
sion.54,55 HDL also enhances the anticoagulant activity of
protein C and protein S.56 These findings show reciprocal
regulation between these 2 systems (Table).
THROMBOTIC TENDENCY IN OBESITY
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AND DYSLIPIDEMIA
Obesity has become a pandemic, increasing risks for
arterial, venous, and microvascular thrombosis, includ-
ing myocardial infarction, ischemic stroke, venous
Table. Effect of Lipids or Lipoproteins on Hemostasis-Related Proteins
Clinical observations
VWF Obesity and dyslipidemia: associates with higher
VWF57–59
Platelet LDL cholesterol: associates with higher platelet count60,61
HDL cholesterol: associates with lower platelet count60,62
Total cholesterol/triglycerides: associates with higher
platelet count,60,61 shorter platelet life span,63,64 and higher
platelet activation65–67
Coagulation Obesity: associates with higher monocyte TF activity,71
higher FVII,59,72 higher thrombin,73 and denser clots.74,75
High triglyceride: associates with higher activation of
platelets,76 higher FVII and FX77
Fibrinolysis Obesity: associates with higher PAI-1,85,86 higher tPA87
High triglyceride: higher PAI-186,88
CD36 indicates cluster of differentiation 36; FVII, factor VII; FX, factor X; HDL, high-density lipoprotein; HepG2, hepatoma G2; LDL, low-density lipoprotein; Lp(a),
lipoprotein(a); oxLDL, oxidized low-density lipoprotein; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor; TFPI, tissue factor pathway inhibitor; tPA, tissue-type
plasminogen activator; VLDL, very-low-density lipoprotein; and VWF, von Willebrand factor.
538   March 2024 Arterioscler Thromb Vasc Biol. 2024;44:533–544. DOI: 10.1161/ATVBAHA.123.318286
Reciprocal Regulation of Lipids and Blood Clotting
thromboembolism, and thrombotic thrombocytopenic
purpura.93 Seventy percentage of obese people have
dyslipidemia,94 which is independently associated with
thrombosis,95–97 suggesting dyslipidemia could be one
of the causal mechanisms driving thrombosis in obe-
sity. Obesity-associated dyslipidemia is characterized
by higher plasma apoB-lipoproteins cholesterol and tri-
glyceride, due to increased hepatic and intestinal apoB-
lipoprotein production,98,99 decreased apoB-lipoprotein
clearance, and reduced HDL cholesterol.100 The CETP
(cholesteryl ester transfer protein) facilitates transfer
of cholesteryl esters from HDL to apoB-lipoproteins.
Increased CETP activities and protein mass have been
observed in obese subjects, contributing to a decrease in
HDL cholesterol levels.101
Chylomicron and VLDL contain 90% and 60% tri-
glycerides, respectively.16 These lipoproteins are assem-
bled in intestinal epithelial cells and liver hepatocytes
to transport triglyceride to other organs and tissues.
Dietary lipid overloading to the intestinal epithelial cells
and hepatocytes promotes the assembly and secre-
tion of chylomicrons and VLDL to circulation, leading
to higher circulating apoB-lipoproteins, triglyceride, and
cholesterol.102,103
Increased Platelet Count, Activation, and
Aggregation in Dyslipidemia
Cholesterol homeostasis has impacts on hematopoiesis,
platelet biogenesis, and platelet activation. Megakaryocyte
progenitors give rise to megakaryocytes during hemato-
poiesis (megakaryopoiesis) in the bone marrow. ABCG4
(ATP-binding cassette subfamily G4) is a transporter that
Mechanistic studies
LDL: promotes VWF self-association53
HDL: inhibits VWF self-association54
oxLDL: induces platelet activation through CD3642
HDL/apoA1: suppresses platelet production through increased cholesterol
efflux in megakaryocytes progenitor cells68,69; reduces platelet activation and
aggregation55,68,70
oxLDL: increases TF expression in monocytes/macrophages78,79 and in vascular
smooth muscle cells80
Lp(a): inhibits TFPI through blocking its lysine residues in the carboxy-terminus51,52
HDL: enhances the anticoagulant activities of protein C and protein S56
Obesity: higher TF in obese mice81
Cholesterol: increases TF expression in monocytes/macrophages78,79,82,83;
decreases TF activity by depletion of cholesterol in human fibroblast84
VLDL: stimulates PAI-1 secretion in human umbilical vein endothelial cells or
HepG2 cells89,90
Lp(a): inhibits conversion of plasminogen to plasmin by tPA91,92
Obesity: higher PAI-1 and tPA,44 lower tPA activity44 in obese mice
Fatty acids: increases hepatocyte PAI-144 and tPA,44 decreases hepatocyte
PAI-1–free tPA44
 Zhang et al
facilitates cholesterol efflux to HDL and is expressed in
megakaryocyte progenitor cells.68,69 ABCG4 deficiency
led to defective cholesterol efflux to HDL and increased
free cholesterol accumulation in megakaryocyte progeni-
tor cells in association with increased megakaryopoiesis
and higher platelet counts.68 Moreover, infusion of recon-
stitute HDL reduced megakaryocyte progenitor cell pro-
liferation and platelet counts in wild-type mice, but not in
Abcg4−/− mice.68 Taken together, those findings indicate
HDL/ABCG4-mediated cholesterol efflux in megakaryo-
cyte progenitor cells suppresses megakaryocytes and
platelet production.68 However, whether apoB-lipoproteins
have an impact on megakaryopoiesis is undetermined and
is worthy of investigation in future studies.
Platelets are budding off from megakaryocytes through
a process called platelet biogenesis. Specifically, mega-
karyocytes extend proplatelet pseudopodia into blood ves-
sels, where shear forces break off small fragments that
become platelets. Plasma LDL cholesterol is positively
correlated with platelet counts in humans.60,61 The find-
ings in humans have been recapitulated in animal stud-
ies, which show diet-induced hypercholesterolemia led to
thrombocytosis in mice.104 However, hypercholesterolemia
is also associated with a shortened platelet life span and
increased turnover rate.63,64,105 Therefore, these findings
suggest the net increased platelet numbers in hypercho-
lesterolemia are due to enhanced platelet biogenesis,
which exceeds the shorter platelet life span and clearance
rate. In contrast, HDL cholesterol levels are negatively
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associated with platelet count in humans,62 and infusion of
reconstitute HDL reduced platelet counts in mice.68
Familial hypercholesterolemia, a genetic disorder char-
acterized by high levels of LDL cholesterol, is associ-
ated with an abnormal platelet function, including higher
platelet activation, platelet-releasing 12-HETE and
thromboxane B2, cell-free nucleotide, impaired vasodila-
tor responses, and enhanced platelet aggregation.65–67,106
Hypercholesterolemia increases platelet activation through
multiple mechanisms. Increased oxidized LDL and oxidized-
phosphatidylserine in hypercholesterolemia induce plate-
let activation through the engagement of their receptor
CD36.42 This process leads to the inhibition of nitric oxide
synthase,43 activation of phospholipase A2,41 and surface
expression of activated GPIIb/IIIa (glycoprotein IIb/IIIa)
and P-selectin.107 Contrary to the role of LDL cholesterol,
which increases platelet activity, the infusion of reconstitute
HDL in individuals with type 2 diabetes is associated with
>50% reduction in platelet aggregation.70 The depletion of
cholesterol in platelet membranes via HDL-dependent cho-
lesterol efflux mechanism may contribute to the reduced
platelet aggregation by reconstitute HDL.
Hypercoagulability in Obesity and Dyslipidemia
The connection between thrombosis and obesity,
or dyslipidemia, also involves elevated levels of the
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Reciprocal Regulation of Lipids and Blood Clotting
prothrombotic molecules. Obese patients or patients
with dyslipidemia have higher plasma concentrations of
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VWF,57 FVII,72 thrombin,73 circulating monocyte TF proco-
agulant activity,71 and also have denser clots, packed with
thin fibers that are lysed slower than the light and loosely
packed fibrin clots in nonobese patients.74,75,108,109 Higher
serum triglyceride levels also associate with a higher risk
of thrombosis, higher VWF levels,58 and higher activation
of platelets, FVII and FX.76,77
TF is ubiquitously expressed across many organs and
various cell types, including smooth muscle cells in blood
vessels, astrocytes in the brain, epithelial cells encom-
passing organs, cardiomyocytes in the heart, and circulat-
ing monocytes.110 High levels of TF have been detected
in brain, lung, and placenta; moderate levels in heart, kid-
ney, intestine, testes, and uterus; and lower levels in the
spleen, thymus, and liver.110 TF is known to play a critical
role as the primary cellular initiator of coagulation cas-
cade. Deficiencies in TF are lethal in mice, and there are
no reported instances of human TF deficiency.111
High TF level is associated with intravascular throm-
bosis in various diseases, such as sepsis, cancer, and
atherosclerosis.112–114 Several studies reported high lev-
els of TF antigen in human atherosclerotic plaque.115–118
TF is higher in lesions from patients with unstable
coronary syndrome compared with patients with sta-
ble coronary syndrome.117 These findings suggest TF
contributes to the atherothrombosis events. Interest-
ingly, cholesterol also induces TF expression. Patients
with hypercholesterolemia showed higher TF levels in
circulating monocytes compared with the control sub-
jects.119,120 Similarly, in obese mice, adipose TF mRNA
is upregulated and associated with the increased cir-
culating TF.81 Experimental evidence demonstrates
both cholesterol loading and incubating oxidized LDL
with monocytes or macrophages result in increased
TF expression.78,79,82,83 Lysophosphatidic acid, which
is a component of oxidized lipoprotein, increased TF
expression and activity in vascular smooth muscle cells
prepared from explants of excised aortas of rats.80 In
contrast, depletion of membrane cholesterol of human
fibroblasts with methyl-β-cyclodextrin reduced TF activ-
ity, while treating the cholesterol-depleted cells with
cholesterol restored TF expression and activity.84 How-
ever, the underlying mechanism remains uncertain and
requires further investigation.
Coagulopathies are frequently seen in severe SARS-
CoV-2 virus infections121–123 with both arterial and
venous thrombosis outcomes, including myocardial
infarction, pulmonary embolism, and deep vein thrombo-
sis.124,125 The incidence of thrombotic and thromboem-
bolic complications in patients with moderate and severe
COVID-19 ranges from 21% to 49%, while even higher
in nonsurviving patients.121,126–128 Development of hyper-
triglyceridemia is independently correlated with thrombo-
sis incidence and inpatient mortality in those with severe
March 2024   539
 Zhang et al
COVID-19 infection, after adjusting for age, gender, and
obesity.129,130 Lp(a) is a risk factor for thrombotic car-
ATVB IN FOCUS - T
diovascular disease, including myocardial infarction and
ischemic stroke.131–134 In patients with COVID-19, higher
Lp(a) was reported to be positively associated with isch-
emic heart disease and venous thromboembolism.135,136
Our recent study also showed higher Lp(a) in hospi-
talized COVID-19 patients with high tPA antigen level
and low tPA enzymatic activity level.137 Further research
regarding the mechanism behind severe COVID-19 with
dyslipidemia and thrombotic outcomes is needed.
Impaired Fibrinolysis in Obesity and
Dyslipidemia
Among the myriad metabolic abnormalities related to
obesity, impaired fibrinolysis has been recognized as a
mechanistic pathway for obesity-associated thrombosis.
tPA initiates fibrinolysis by catalyzing the conversion of
the inactive zymogen plasminogen into plasmin, which is
a serine protease responsible for breaking down fibrin
clots.14 PAI-1, a fast-acting suicidal serpin (serine prote-
ase inhibitor), inactivates tPA by forming a complex with
it, leading to the inhibition of the fibrinolysis.15 Total PAI-1
antigen is higher in obese patients,85,86 or those with high
triglyceride levels.86,88,138 Incubating human umbilical vein
endothelial cells or HepG2 hepatoma cells with purified
human VLDL stimulates PAI-1 secretion.89,90 Although
Downloaded from http://ahajournals.org by on February 22, 2024
tPA also increased in obesity,87 the increase of PAI-1 is
higher than tPA in obesity, leading to a net reduction in
tPA activity and fibrinolytic potential, delaying fibrin clot
removal. Therefore, it is the PAI-1-free tPA levels that
reflect fibrinolytic potential.139 In dyslipidemia, tPA anti-
gen is positively correlated with PAI-1,140 suggesting
compensatory feedback when there is insufficient active
tPA. Furthermore, plasma tPA antigen level is negatively
associated with tPA activity shown by several indepen-
dent studies.137,141–143 These observations suggest that
impaired fibrinolysis could be a link between dyslipidemia
and an increased risk of thrombosis.
Our previous studies revealed that hepatocytes are
an unappreciated source of tPA that contribute ≈40%
to 50% plasma basal tPA concentration, which is impor-
tant for fibrinolysis when a vessel injury occurs.44,45 We
further investigated how hepatocytes sense metabolic
stresses and imbalance of production of tPA and its ser-
pin inhibitor PAI-1.44 Lipid-overloaded hepatocytes have
reduced transcription co-repressor Rev-Erbα, leading to
increased PAI-1, which then stimulates tPA synthesis via
a PAI-1-LRP1-PKA-p-CREB1 (low-density lipoprotein
receptor-related protein–protein kinase A–phosphorylated
cAMP-responsive element-binding protein 1) pathway.44
This PAI-1-stimulating tPA production mechanism func-
tions as a compensatory pathway to compete with the
large increase of PAI-1. However, the small induction of tPA
synthesis is limited by its transcription repressor DACH1
540   March 2024 Arterioscler Thromb Vasc Biol. 2024;44:533–544. DOI: 10.1161/ATVBAHA.123.318286
Reciprocal Regulation of Lipids and Blood Clotting
(dachshund homolog 1), which is induced in obese livers. In
hepatocytes, where lipids are loaded and incorporated into
lipoproteins, this PAI-1-tPA regulatory network influences
the degree of impaired fibrinolysis in obesity.
Another potential link between impaired fibrinolysis and
dyslipidemia is Lp(a).144 Lp(a) contains 1 LDL-like particle
and 1 apo(a). Apo(a) is encoded by LPA gene, which is
only expressed in primates.145 This gene is evolved from
the plasminogen gene through duplication and remodeling
over millennia, leading to the structural similarity between
Lp(a) and plasminogen.145 Like other apoB-lipoproteins,
Lp(a) also carries cholesterol.144,146 Clinical studies dem-
onstrate that Lp(a) levels are associated with atheroscle-
rotic cardiovascular disease risk quantitatively.147 Plasma
Lp(a) level is genetically determined, with ≈25% of popu-
lation having high Lp(a) >30 mg/dL.147 People with Lp(a)
higher than 30 mg/dL have 2× higher risk of coronary
artery diseases.148 Lp(a) becomes a significant contribu-
tor to the plasma total cholesterol and the risk of athero-
sclerotic cardiovascular disease when its levels rise above
30 mg/dL.149 Unlike plasminogen, apo(a) cannot be con-
verted to an active protease because a serine substitution
to arginine at the position that can be cleaved by tPA.91,150
Therefore, Lp(a) competes with plasminogen and inhibits
fibrinolysis by binding to lysine-binding sites within Krin-
gle IV domains of Lp(a), thereby increasing thrombosis
risk.91,92 In addition to inhibiting fibrinolysis, the Women’s
Healthy Study with 25 131 White women participants,
showed that individuals with high Lp(a) levels have greater
benefits in lowering atherothrombotic events by low-dose
aspirin compared with those with low Lp(a) levels (median
Lp[a], 153.9 versus 10.0 mg/dL).151 Over the 9.9 years of
follow-up, the use of aspirin reduced cardiovascular risk
in individuals with high Lp(a) levels (age-adjusted hazard
ratio, 0.44 [95% CI, 0.20–0.94]) but not in those with
low Lp(a) (HR, 0.91 [95% CI, 0.77–1.08]). The potential
mechanisms underlying this effect are not yet clear and
require validation.
CONCLUSIONS
As summarized in this review, lipoproteins are associated
with proteins related to blood clotting by proteomics.
Obesity or dyslipidemia is associated with impaired fibri-
nolysis and hypercoagulable tendencies and increased
risk of ischemic stroke, deep vein thrombosis, and pul-
monary embolism in men and women across all ethnic
groups.152,153 However, the distribution of specific risk
factors mentioned above is poorly studied in all eth-
nicity groups and requires further investigation. More
studies are required to understand the link between
lipoproteins and the hemostatic system regarding the
functional impact of lipoprotein-associated clotting fac-
tors on hemostasis and thrombosis, and strategies to
improve clinical care to balance the risk of thrombosis
and bleeding.
 Zhang et al
ARTICLE INFORMATION
Affiliations
Thrombosis & Hemostasis Program, Versiti Blood Research Institute, Milwaukee
(M.R., Z. Zhang, Z. Zheng). Department of Medicine (Z. Zheng), Cardiovascular
Center (Z. Zheng), and Department of Physiology (Z. Zheng), Medical College of
Wisconsin, Milwaukee.
Acknowledgments
The authors thank Wen Dai and Mark Castleberry at Versiti Blood Research In-
stitute, Hayley Lund and Mahi Besur at the Medical College of Wisconsin, and
Jeremy Wood at the University of Kentucky for helpful discussion and editing
the article.
Sources of Funding
This work was funded by National Institutes of Health R01HL163516 to Z.
Zheng, a Collaborative Sciences Award from the American Heart Association to
Z. Zheng, a Career Development Award from the National Hemophilia Foundation
to Z. Zheng, a Joan Gill Pilot Award from Versiti CCBD to Z. Zheng, and a Startup
Fund from the MCW and Versiti BRI to Z. Zheng.
Disclosures
None.
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