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34.
https://t.me/med1917
FUNDAMENTAL MECHANISMS IN VENOUS
THROMBOSIS
Jose A. Diaz , Daniel D. Myers Jr., and omas W. Wake eld
INTRODUCTION
Venous thromboembolism (VTE) comprises deep vein
thrombosis (DVT) and pulmonary embolism (PE). VTE
occurs worldwide, in all age groups and socioeconomic
populations in North America and Western Europe.
recent study by Heit etal., the estimated total annual number of VTE events in the United States exceeded 900,000.
Symptomatic VTE accounted for two-thirds of the cases
reported. Interestingly, no changes in the incidence of VTE
were noted during this 25-year cohort study.
and its sequelae remain an important health care problem
that demands coordination between the e orts of clinicians, surgeons, and investigators. In this setting, venous
thrombosis research plays a pivotal role in the process of
elucidating the intrinsic mechanisms involved in thrombogenesis and thrombus resolution. Only by understanding
VTE pathophysiology will we be able to identify potential
therapeutic targets to aid the patient population a ected
by VTE. In this chapter, the authors will summarize the
mechanisms involved in VTE as well as potential therapeutic targets.
PATHOPHYSIOLOGY
E N D O T H E L I U M
e endothelium forms the inner cell lining of all blood vessels in the body and is a spatially distributed organ. In an
average individual, the endothelium weighs approximately
1kg and covers a total surface area of 4,000 to 7,000 square
4
meters.
e endothelium has been described as a primary
determinant of pathophysiology or as a target for collateral
damage in most, if not all, disease processes.
1,4
cells (ECs) play a critical role in the balance between procoagulant and anticoagulant mechanisms in healthy individuals. e ECs’ anticoagulant properties involve supporting
1,2
In a
3
us, VTE
Endothelial
3
local brinolysis, in which coagulation (platelet activation
and adhesion) and in ammation (leukocyte activation)
5
remain suppressed.
In contrast, a procoagulant e ect is
observed during states of EC activation and disturbance,
either physical (vascular trauma) or functional (sepsis;
5
Figure34.1 ).
It is widely known that, under normal conditions,
cellular blood components interact with the vessel wall
promoting vascular repair. Activated or dysfunctional
ECs trigger a mechanism of rapid deposition of platelets, erythrocytes, leukocytes, and insoluble brin, which
establishes a mechanical barrier to blood ow, termed
4
thrombosis.
I N F L A M M A T I O N A N D
THROMBOGENESIS
Arterial thrombosis requires EC disruption with collagen
exposure, as it occurs in atherosclerotic plaque rupture.
the contrary, in venous thrombosis the ECs are “intact” (at
least at the initiation of the thrombus formation), and no
collagen exposition is needed in order to generate thrombi.
ECs play a pivotal role in venous thrombosis. us, during a
normal EC response to a stimulus, the balance between anticoagulant and procoagulant mechanism is altered toward
1,7,8
the ECs procoagulant activity.
In ammation and vein
thrombosis were linked in a publication by Stewart, Ritchie,
and Lynch in 1974 demonstrating leukocyte migration into
9
the vein wall with an intact layer of ECs.
Since then, several
studies demonstrated the interaction between in ammation
5,10–13
and thrombosis.
e question of what alters the EC
toward a procoagulant e ect is fundamental to understanding the pathophysiology of VTE. In ammatory cytokines
such as tumor necrosis factor alpha (TNF-α), interleukin 1
(IL-1). and interleukin 6 (IL-6), induce EC activation and
8,14
contribute to venous thrombosis
( Figure 34.2 ). Once
ECs are activated, cell interaction between ECs, leukocytes,
5,6,10,15
monocytes, and platelets occurs.
6
On
6
268
Anti- and pro-thrombogenic mechanisms of endothelial surface
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Endothelial surface
Antithrombogenic
• Endothelial production of thrombomodulin and
subsequent activation of protein C
• Endothelial expression of heparin sulfate and
dermatan sulfate (which accelerate antithrombin
and heparin cofactor activity)
• Constitutive expression of tissue factor pathway
inhibitor (TFPI)
• Local production of tissue-type plasminogen
activator (tPA) and urokinase-type plasminogen
activator (uPA)
• Production of NO, prostacyclin, and interleukin
10 which, inhibits the adhesion and activation of
leukocytes and produces vasodilatation
mechanisms
Endothelial surface
Prothrombogenic
mechanisms
• Release of platelet activating factor (PAF)
and endothelin-1 promotes
vasoconstriction
• Production of von Willebrand factor
(vWF) tissue factor (TF), plasminogen
activator inhibitor type 1 (PAI-1) and
Factor V augment thrombosis
• Increased surface expression of cell
adhesion molecules (P-selectin or E selectin) promoting the adhesion and
activation of leukocytes
Figure34.1 Anti- and prothrombogenic mechanisms of the endothelial surface. One of the main functions of the ECs is to maintain the balance
between the procoagulant and anticoagulant mechanisms in healthy individuals. e anticoagulant properties of the ECs involve supporting
local brinolysis, suppressing coagulation and in ammation. e procoagulant e ect of the ECs is observed during states of EC activation and/or
disturbance.
P-Selectin, P-Selectin Receptor, Leukocytes, and
Platelets in Vein rombosis
Selectins are cell adhesion molecules that have critical roles
in in ammation and thrombogenesis
P-selectin is involved in leukocyte rolling and adhesion,
an early in ammatory mechanism that facilitates leuko-
9,16
cyte transmigration.
Animal studies that utilized rat and
mouse thrombosis models have demonstrated the upregulation of P-selectin in the vein wall at 6 hours a er throm-
16
bus induction.
us, it has been shown that P-selectin is
a common molecule that links in ammation and thrombosis in vivo. e P-selectin receptor, P-selectin glycoprotein
ligand 1 (PSGL-1), is a glycoprotein expressed on the surface of leukocytes and platelets that plays a critical role in
the recruitment of leukocytes and platelets into in amed
5,10,16
( Figure 34.3 ).
tissue. e interaction of PSGL-1 with P-selectin (the
EC P-selectin:PSGL-1-leukocyte complex and the EC
P-selectin:PSGL-1-platelet complex) promotes rolling and
adhesion of leukocytes and platelets respectively, which
ultimately results in increased vein wall cell in ltration
( Figure34.3 ).
It is widely known that the initiation of in ammation and/or the thrombosis processes occurs, chronologically, almost immediately a er EC activation. is could
be possible only if the ECs have stored P-selectin that
could be released upon stimulation, as secretory cells do.
Weibel-Palade bodies (WPBs) are the EC-speci c storage
organelles for regulated secretion of von Willebrand factor
(vWF) and P-selectin on their cell surface membrane.
15,19–21
Wagner etal. demonstrated that the increase in the number
17,18
15
Figure34.2 I n ammatory cytokines such us tumor necrosis factor alpha (TNF-α)and interleukins 1 and 6 (IL-1 and IL-6), induce EC activation and
contribute to venous thrombosis. Once ECs are activated, cell interaction between ECs, leukocytes, and platelets occurs.
Inammatory cytokines facilitate initiation of vein thrombosis process
Endothelial cells
References
PMN with
PSGL-1
P Selectin
PSGL - 1
Platelet with
PSGL - 1
Inammatory cytokines
Platelets
Increase Tissue Factor Expression
TNFα
Activate Endothelial Cell
Increase Platelets Reactivity
Increase Fibrinogen Expression
IL-6
Increase PAI-1 Expression
IL-1
Activate Endothelial Cell
Leukocytes
FUNDAMENTAL MECHANISMS IN VENOUS THROMBOSIS • 269
Vein
https://t.me/med1917
Wall
Vein
Lumen
P-selectin facilitates leukocyte rolling, adhesion, and transmigration
References
PMN with PSGL-1
P Selectin
PSGL - 1
Endothelial
surface
Endothelial
surface
Rolling
Adhesion
Vein
Wall
Inltration
Figure34.3 P-selectin is involved in leukocyte rolling and adhesion, an early in ammatory mechanism that facilitates leukocyte transmigration. e
interaction of P-selectin glycoprotein Ligand 1 with P-selectin on ECs and leukocytes promotes rolling and adhesion of leukocytes and platelets,
which ultimately results in increased vein wall cell in ltration.
of P-selectin molecules present on the EC surface is due to
15,21
its release from the WPB.
us, the exocytosis of WPBs
initiates a rapid translocation of P-selectin to the EC surface, resulting in the EC’s adhesiveness for leukocytes and
platelets ( Figure34.4 ).
e role of platelets in arterial thrombosis is well known,
but how platelets participate in venous thrombosis remains
unclear. Platelets are anucleate circulating blood particles
derived from bone marrow megakaryocytes, initially called
2
Osler, Hayam, and Bizzonero initially described
plates.
them as small particles in the blood until the Wright
2
blood staining method clearly identi ed the platelets.
P-selectin expression on the endothelial surface
e
megakaryocytes extend their cytoplasm into the bone marrow sinusoid and release a small portion of cytoplasm containing alpha granules and dense granules surrounded by a
bilipid membrane into the blood circulation.
Under physiological conditions, circulating platelets are
15,22
resting or nonactivated and express PSGL-1.
let’s PSGL-1 allows an EC-platelet interaction.
e plate-
15,17
Once
activated, platelets excrete the contents of the granules,
which increases their adhesiveness and ultimately poten-
22
tiates platelet aggregation.
Particularly, alpha granules
contain P-selectin, and its expression on platelet surface
favors leukocyte-platelet crosstalk as a direct consequence
Figure34.4 Weibel-Palade bodies are the endothelial-speci c storage organelle for regulated secretion of von Willebrand factor and P-selectin onto
its membrane. us the exocytosis of WPBs initiates a rapid translocation of P-selectin to the endothelial surface, resulting in augmented endothelial
adhesiveness for leukocytes and platelets.
Injury
Endothelial cell
References
P-selectin
Weibel-Palade body
von Willebrand
Factor
270 • VENOUS THROMBOEMBOLISM
of platelet activation.
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platelets release a greater amount of P-selectin than ECs.
15,17
In addition, it has been shown that
15
us, once platelets are attached to the vein wall, the concentration of P-selectin available increases dramatically,
improving the leukocyte recruitment e ciency of the vein
15
It was elegantly demonstrated by Frenette etal. in a
wall.
mouse model that platelets roll on the vein wall, as leuko-
17
cytes do, when EC activation occurs.
Microparticles
Circulating cell-derived microparticles (MPs) contribute to
coagulation and ampli cation of thrombosis. ey are present in the blood of healthy individuals and increase under
certain circumstances including DVT.
small vesicles (less than 1 micrometer) consisting of a plasma
membrane surrounding a small amount of cytoplasm that
contains cell-speci c surface molecules.
esis, MPs are associated with ECs, leukocytes, and platelets,
carrying membrane proteins that characterize their cell of
2,24,26
origin.
ECs, leukocytes, and platelets have a very well
structured plasma membrane characterized by a controlled
transverse lipid distribution termed “ra s.”
of these cells promotes a general membrane content redistribution, during which ra s concentrate in areas of the cell
that will ultimately produce MPs ( Figure34.5 ).
the MP membrane is rich in lipid ra s.
derived MPs concentrate tissue factor (TF).
MPs with activated platelets promotes thrombus formation
in a TF-dependent manner. In addition to TF, the expression
Rafts re-distribution and microparticle formation
Activation
Endothelial cell
Leukocyte
Platelet
Raft Raft
Figure34.5 ECs, leukocytes, and platelets have a very well structured
plasma membrane characterized by ra s. Ra s are a particular
membrane structure with a controlled transverse protein-lipid
distribution. e activation of these cells promotes a general membrane
ra redistribution that concentrates in areas of the cell that will
ultimately produce MPs. erefore, the MP membrane is rich in
lipidra s.
2,23
MPs are de ned as
24,25
In thrombogen-
27
e activation
27
27
Raft redistribution
erefore,
Also, lipid ra –
27
e fusion of
Microparticle
of prothrombinase activity on the membrane and PSGL-1
are involved in the procoagulant activity of MPs.
5,28
During in ammation, the activation of ECs upregulates the expression of P-selectin on their surface, leading
to the formation of the EC P-selectin:PSGL-1-leukocyte
complexes. ese complexes stimulate the production of
MPs from leukocytes, particularly monocytes, along with
platelets and ECs. In addition, the accumulation of leukocyte markers expressed on the surface of MPs in the growing
thrombus is mediated by the P-selectin:PSGL-1 complex.
e MP concentration increases dramatically at the area
10
of vein wall injury and in ammation.
MPs also possess a
phosphatidylserine-rich anionic surface capable of assembling complexes of the coagulation cascade. Another molecule expressed on the MPs’ membrane surfaces is PSGL-1,
which then can bind to upregulated P-selectin on platelet surfaces in the thrombus. ere is even evidence that
the macrophage-1 antigen (Mac-1) on leukocyte-derived
MPs can allow interactions between MPs and inactivated
platelets using “glycoprotein Ib (platelet) alpha polypeptide” (GP1bα), resulting in further platelet activation with
29,30
P-selectin upregulation.
All of these events, which are
occurring in the area of thrombus formation, lead to thrombus ampli cation. e increase of circulating MPs with the
onset of in ammation adds to the proposed mechanisms
linking vein wall in ammation and thrombogenesis.
Platelet-Activating Factor (PAF) and
Endothelin-1(ET-1) Play a Role in In ammation
PAF, also known as PAF-acether or AGEPC (acetylglyceryl-ether-phosphorylcholine), is produce by EC, mac-
31
rophages, mast cells, and leukocytes.
One of the central
functions of PAF during in ammation is to activate the
leukocytes adhered to the vessel wall via the adhesion mol-
31,32
ecules expressed by ECs.
ET-1 is a 21-amino-acid pep-
tide produced in a variety of tissues including endothelial
33
and smooth muscle cells.
33,34
.
ET
Speci c locations have also been proposed for ET-1
B
receptors:vein EC (ET
cell (ET
). 33 When ET-1 binds to its receptors (which are
B1
ET-1 receptors include ET A and
) and vein vascular smooth muscle
B1
Gq-proteins) on the vascular smooth muscle, this induces
an increase of inositol 1,4,5 phosphate levels, leading to
calcium release and subsequent muscle contraction.
Particularly, it has been shown that endothelial dysfunction
and in ammation contribute to overproduction of ET-1 in
35
humans.
cells.
In addition, ET A is expressed in in ammatory
35
Future directions include elucidating the role of PAF
and ET-1 in venous thrombosis.
Molecules at Participate as Inhibitors of
Coagulation:Natural Anticoagulants
Circulating inhibitory molecules regulating the process
of thrombogenesis include: antithrombin III (ATIII),
5
33
FUNDAMENTAL MECHANISMS IN VENOUS THROMBOSIS • 271
proteinC, protein S, and tissue factor pathway inhibitor
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(TFPI). Antithrombin III, a plasma glycoprotein synthesized in the liver, is a serine protease inhibitor (SERPIN)
structurally related to other plasma protease inhibitors such
as alpha 1-antichymotrypsin, alpha 2-antiplasmin, and hep-
2
arin cofactor II.
Antithrombin III acts as a pseudosubstrate
for the inhibition of intrinsic pathway (Factors IIa [thrombin], IXa, Xa, XIa, XIIa) and extrinsic pathway (Factor
2
VII), kallikrein, and plasmin.
Other targets of antithrom-
bin III include trypsin and the C1s subunit, which are
36
involved in the classical complement pathway.
e plasma
half-life of antithrombin III is 60 to 70 hours, while the
thrombin:antithrombin (TAT) complex is cleared by the
1,36
liver and its inhibitory activity is increased by heparin.
Protein C, a vitamin K–dependent plasma glycoprotein,
is synthesized as a single chain and cleaved prior to secre-
37
tion by the liver.
Plasma protein C consists of a two-chain
molecule, light and heavy chain. Its plasma half-life is 6 to
2
7hours.
Once protein C binds to its receptor, EC protein C
receptor, it is activated by the thrombin:thrombomodulin
complex on the EC surface, resulting in activated protein
2,38
C (APC).
In the presence of calcium and protein S,
APC inactivates Factor Va and Factor VIIIa of the “protein
2
C anticoagulant pathway”
( Figure34.6 ).
Protein S, a vitamin K–dependent plasma glycopro-
tein, is synthesized by the liver, the endothelial, cells and
39
the megakaryocytes.
protein C anticoagulant pathway.
Protein S is a cofactor of APC in the
38
In addition, protein S
exhibits APC-independent anticoagulant activity by bind-
1
ing to Factors Va, VIIIa, and Xa.
In serum, protein S is
found in two forms:free (active) and bound (inactive) protein. Almost 70% of protein S circulates bound to a com-
2
plement protein (C4b-binding protein).
e remaining
protein S circulates as “free protein S,” which has a half-life
1
of 96 hours, and acts as a cofactor for proteinC.
TFPI is a single chain plasma polypeptide that inhibits
Factor Xa and TF:Factor VIIa complex catalytic activity.
40,41
Plasma contains a minor fraction of TFPI, 20 to 30 % of
intravascular distribution, which is largely bound to lipo-
2,40
proteins.
normally bound to the vascular endothelium.
e major proportion of TFPI (60 to 70%) is
40
is pool of
TFPI is released into the blood ow a er an injection of
1,40,41
heparin.
Finally, prostacyclin and nitric oxide (NO) are secreted
42
by ECs.
ese compounds synergistically contribute to
vessel homeostasis by reducing the tone and growth of
vascular smooth muscle cells, platelet aggregation, and leukocyte adhesion to endothelium, and thus decreasing the
2,42
vessel’s susceptibility to form thrombus.
Interestingly,
Osanai etal. demonstrated that vessel homeostasis might
be maintained through an increase in prostacyclin production in vascular ECs when nitric oxide (NO) synthesis is
43
impaired.
e endothelial NO synthase (eNOS) function
has been widely studied in arterial ECs, but there is also evidence suggesting that decreased NO production may play a
44–46
role in the development of venous disease.
PLASMINOGEN ACTIVATORS
ANDTHROMBOLYSIS
Venous thrombosis is a dynamic process, with thrombus
formation (thrombogenesis) and dissolution (thrombolysis) occurring almost simultaneously under normal condi-
1
tions in a healthy individual.
multiple physiological processes, including brinolysis.
rombolysis depends on
47
In response to thrombus formation, natural anticoagulants
37,39
such as protein C and protein S are activated.
Similarly,
circulating plasminogen is activated to plasmin, which is
5,47
the main brinolytic enzyme.
e substrates of plasmin
substrates include brin, brinogen, other coagulation
Figure34.6 Protein C anticoagulant pathway. Once protein C binds to its receptor, endothelial protein C receptor, it is cleaved by the
thrombin:thrombomodulin complex on the endothelial surface, resulting in activated protein C (APC). In the presence of calcium and protein S,
APC inactivates Factor Va and Factor VIIIa.
Protein C
rombomodulin
rombin
Protein C anticoagulant pathway
Factor Va
Factor VIIIa
APC
Protein S
Protein C
Endothelial protein C
receptor
272 • VENOUS THROMBOEMBOLISM
APC
Factor V
Factor VIII
+
Ca
+
Endothelial cell
factors, procollagenases, and latent transforming growth
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factor beta (TGFβ).
vWF-mediated platelet adhesion by proteolysis of GpIb.
47
In addition, plasmin interferes with
48
Plasminogen activators are serine proteases that acti-
vate plasminogen by the proteolytic cleavage of a single
47
arginine-valine peptide bond.
Plasminogen activator
inhibitor-type 1 (PAI-1) is the primary inhibitor of the
plasminogen activators, both tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator
5,47,49
(u-PA), and hence of brinolysis.
e primary function
of PAI-1 is to inhibit plasminogen activators from converting plasminogen to plasmin, which is responsible for
2
initiating brinolysis.
PAI-1 is produced by the EC but is
also secreted in an active form by the liver and adipose tis-
47,50
Increased PAI-1 levels are found in various disease
sue.
states such as cancer, obesity, and metabolic syndrome.
51
us, it has been suggested that the increased occurrence of
thrombosis in patients with these conditions could be asso-
51
ciated with elevated PAI-1 levels.
to synergize with Factor V Leiden genetic abnormalities.
PAI-1 elevation appears
5
Elevated PAI-1 may suppress brinolysis and increase
thrombosis, hence increasing the clinical manifestations
of VTE, although studies on the role of elevated levels of
PAI-1 in venous thrombosis have been contradictory.
52
Particularly, it has been published that increased serum
levels of PAI-1 and impaired brinolysis is associated with
53
hyperlipidemia in humans.
is relationship suggests that
hyperlipidemic patients have an increased risk to develop
cardiovascular diseases, including VTE related to impaired
53
brinolysis.
Polymorphism in the PAI-1 gene has been suggested
54,55
to be associated with an increased risk of VTE.
Human
studies have evaluated the role of genetic polymorphisms,
particularly the 4G/5G insertion/deletion in the promoter
region, which a ects transcription rates. e highest levels
of PAI-1 have been noted in those individuals carrying the
55
4G/4G polymorphism.
Akar etal. reported an increased
odds ratio of 5.5× for DVT with the 4G allele. is
increase was even greater when the 4G allele coexisted with
55
Factor-V-Leiden.
Another study, by Zoller etal., showed
an 8.14× increased risk of PAI-1 elevation in individuals
carrying the 4G allele in combination with other thrombophilic markers, while PE was increased in 4G/4G patients
54
with protein S de ciency (odds ratio 4.5×).
Fibrin degradation products (FDPs) result from the
action of plasmin on deposited brin. FDPs include the
fragment E and fragment D, which, during physiological thrombolysis, are released as a covalently linked dimer,
5
the D-dimer.
Clinically, the level of circulating D-dimers
is used as a surrogate marker for the diagnosis of ongoing
56
DVT and/or PE.
In addition, the presence of elevated
D-dimer levels a er successful treatment of DVT has a high
positive predictive value for recurrent VTE.
5
D-dimer levels
may also aid in the diagnosis of disseminated intravascular
coagulation.
THROMBUS RESOLUTION AND VEIN
WALL REMODELING
DVT resolution is a brotic process that mimics wound
healing. is process involves pro brotic growth factors,
collagen deposition, and matrix metalloproteinase (MMP)
57
expression and activation.
e kinetics of leukocytes in
the vein wall follows the same pattern as that observed in
57
thrombi.
us, immediately a er thrombus formation,
an early in ux of polymorphonuclear (PMN) cells is fol-
5
lowed by a migration of monocytes.
Leukocyte migration,
rst from the blood into the vein wall and then from the
vein wall into the thrombus, follow a speci c sequence of
5
events leading to thrombus resolution.
e rst cell type
that migrates as described above is the PMN leukocyte.
PMNs are essential for early thrombus resolution as they
promote both brinolysis and collagenolysis.
5
In support of
this concept, a study using a rat model of stasis DVT showed
that neutropenia increased both thrombi size, at 2 and 7 d,
and intrathrombus collagen deposition. It also signi cantly
lowered intrathrombus levels of both uPA and MMP-9.
Chronologically, the second cell type observed in the
59
thrombus is the monocyte.
in the chronic stages of thrombus resolution.
Monocytes are important cells
59
Monocyte
in ux into the thrombus is detected at day 8, a er thrombus
generation, which correlates with elevated levels of monocyte chemotactic protein-1 (MCP-1), a CC chemokine that
5
promotes monocyte chemotaxis and activation.
has been associated with DVT resolution.
MCP-1
5
In a study
using a mouse model of stasis thrombosis, chronic stages of
thrombus resolution were tested using target deleted CC
60
receptor-2 (CCR-2 KO) mice.
In this study, late impair-
ment of thrombus resolution appeared to be mediated via
5,60
impaired MMP-2 and MMP-9 activity.
rombus resolution involves a number of proin am-
matory factors that are released into the local environment.
5,8,14
ese factors include IL-1β and TNFα.
It has been suggested that these mediators are released by leukocytes and
smooth muscle cells found within the resolving thrombus,
although the speci c mechanisms involved in this process
have yet to be elucidated. Henke etal. observed that elastinolysis occurs early in a mouse model of stasis-induced DVT.
In this model, the evaluation of elastinolysis was determined
by tensiometry and was associated with an increase in vein
wall sti ness. Elastinolysis persisted for 14 d, together with
60
elevated MMP-2 and MMP-9 activity.
In the same model,
vein wall collagenolysis was observed within the rst 7 d,
60
representing an acute response to injury.
e elevation of pro brotic mediators, including TGFβ,
IL-13, and MCP-1, have been associated with early biome-
61
chanical injury during DVT.
ese mediators are present
in the vein wall, and thrombus and may drive the brotic
61
response.
lution as it also promotes organ brosis in vivo.
Exogenous MCP-1 may accelerate DVT reso-
61
TGFβ
is also present in the thrombus and is activated during
5,8–10
58
60
FUNDAMENTAL MECHANISMS IN VENOUS THROMBOSIS • 273
thrombolysis. 61 is factor appears to be critical in the
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mechanisms promoting vein wall brosis. In mice, late
brosis has been associated with a signi cant increase in
57
vein wall collagen a er stasis thrombogenesis.
Increased
gene expression and activity of collagen types I and III,
10,57
MMP-2, and MMP-9 has also been observed.
us, vein
wall injury is associated with active matrix remodeling that
57
seems to promote net brosis.
Myers etal. demonstrated that inhibition of the in amma-
16
tory response can decrease vein wall brosis.
ese data add
to the evidence of the close interaction between in ammation
16
and brosis.
In another study using an inferior vena cava
stenosis model in rats, animals were treated with either low
molecular weight heparin or an oral P-selectin inhibitor start-
18
ing 2 d a er thrombus initiation.
In this study, the P-selectin
inhibitor signi cantly decreased vein wall injury (independent
of thrombus size), which was assessed by vein wall tensiometry
(sti ness), intimal thickness score, IL-13 levels, MCP-1 levels,
18
and platelet-derived growth factor-β levels.
In summary, venous thrombosis is a complex and
dynamic process that involves at least two phases:thrombus
formation and thrombus resolution.
rombus formation :In ammation appears to be closely
involved in thrombus formation. ECs, platelets, and leukocytes (PMNs and monocytes) are the main circulatory
elements involved in venous thrombosis. In ammatory
cytokines orchestrate this early phase. us, preventive or
prophylaxis therapeutic approaches should be directed to
these potential targets.
rombus resolution :Vein wall remodeling is a complex
process that varies as the thrombus ages. Pro brotic mediators play an important role in this phase, leading to brosis. e severity of this brosis will determine the outcome
a er an episode of DVT (i.e., postthrombotic syndrome or
thrombus recanalization with or without valve insu ciency).
Novel therapeutic approaches aimed to alleviate postthrombotic cell wall damage and focused on the sequence of events
occurring during thrombus aging are warranted.
R E F E R E N C E S
1 . K i t c h e n s C S , A l v i n g B M , K es sl er C M . Consultative hemostasis and
thrombosis . Philadelphia : W.B. Saunders. 2002 .
2. Heith JA . rombophilia: Clinical and laboratory assessment
and management. In: Kitchens CS , Alving BM , Kessler CM , eds.
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FUNDAMENTAL MECHANISMS IN VENOUS THROMBOSIS • 275
35.
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CONGENITAL AND ACQUIRED
HYPERCOAGULABLE SYNDROMES
Jocelyn A. Segall and Timothy K. Liem
INTRODUCTION
A ne balance exists between anticoagulant, procoagulant,
and brinolytic factors. Intravascular thrombosis represents a shi in this balance, and may occur as the result of
many factors in conjunction with a congenital or acquired
abnormality in coagulation. An understanding of the differing hypercoagulable syndromes is important to appreciate the complexity of hemostasis and the factors that may
o set normal clotting and anticoagulant mechanisms (see
Figure 35.1). In addition, methods of prophylaxis and
treatment of venous thromboembolism (VTE) are increasingly being strati ed based, in part, on the presence or
absence of a thrombophilic state. e presence of a hypercoagulable state does not imply that the patient will have
thrombosis of a vessel. It does suggest that the individual
is at a higher risk for thrombosis especially when the other
factors of Virchow’s triad (endothelial injury and stasis) are
involved.
Some congenital hypercoagulable states place the individual at higher risk for thrombosis than others. Most genetic
abnormalities in existence have clinically imperceptible
consequences.
tiple genetic abnormalities, increasing their risk of thrombosis.
are listed in Table35.1.
and some congenital hypercoagulable states may exist as
acquired states as well. For instance, protein C and protein S
de ciencies may occur secondary to decreased protein production from liver failure, sepsis, and/or malnutrition and
increased protein loss secondary to nephrotic syndrome
and in ammatory states.
emia may occur because of enzymatic defects or because of
1
C O N G E N I T A L
VERSUS ACQUIRED
HYPERCOAGULABLESTATES
2,3
Additionally, some individuals have mul-
4
e common congenital hypercoagulable disorders
Many causes exist for acquired hypercoagulable states,
5
In addition, hyperhomocystein-
de ciencies in Vitamins B
and B 12 and folate. e acquired
6
hypercoagulable disorders are listed in Table35.2.
T H E C O N G E N I T A L
HYPERCOAGULABLE
DISORDERS
ANTITHROMBIN DEFICIENCY
Antithrombin is a serine protease inhibitor of thrombin
and also inhibits factors IXa, Xa, XIa, and XIIa. rombin
is irreversibly bound by antithrombin and prevents thrombin’s action on brinogen, on factors V, VIII, and XIII,
6
and on platelets.
liver and endothelial cells, and has a half-life of 2.8days.
is anticoagulant is synthesized in the
7
Antithrombin de ciency has a prevalence of 1:5,000 with
more than 100 genetic mutations and an autosomal domi-
8
nant inheritance pattern.
Homozygotes typically die in
utero, whereas heterozygotes typically have an antithrombin level that is 40 to 70% of normal.
Antithrombin de ciency is associated with lower
extremity venous thrombosis as well as mesenteric venous
thrombosis, and there are two clinical types. Individuals
with Type Ide ciency have a reduced number and function
of antithrombin, and individuals with Type II have normal
production but a reduction in function. Additionally, the
heparin-binding site of the antithrombin may be mutated.
9
e risk of thrombosis increases as the functional antithrombin activity decreases to less than 80% of normal levels. e highest risk for thrombosis occurs when the activity
1
is less than 60% of normal.
e most common presentation in those with antithrombin de ciency is deep venous thrombosis (DVT)
10
with or without pulmonary embolism.
e frequency of
thromboembolism is unusual before the late teenage years
11
and plateaus around the age of 40.
romboembolism
may occur spontaneously but is o en precipitated by other
factors such as pregnancy, oral contraceptive use, estrogen
12
replacement, trauma, surgery, or infection.
276
A
X
https://t.me/med1917
XII
Figure35.1 e coagulation cascade (light gray) and the sites of action for the natural anticoagulants (black). PC=protein C, APC=activated
protein C.Protein S (PS) is a cofactor for the inhibition of factors V and VIII. TFPI (tissue factor pathway inhibitor) levels increase severalfold in
response to heparin. TFPI binds to factor VIIa, inhibiting the conversion of factor X to Xa, and factor IX toIXa.
Table35.1 THE MOST COMMON CONGENITAL
HYPERCOAGULABLE DISORDERS
CONGENITAL HYPERCOAGULABLE DISORDERS
Antithrombin De ciency
Protein C De ciency
Protein S De ciency
Factor V Leiden
Prothrombin G20210A Polymorphism
Hyperhomocysteinemia
Dys brinogenemia and Abnormal Fibrinogens
XIIa
XI
IX
brinogen
Antithrombin·heparin
IX
XIa
IXa
Ca • VIIIa • PL
X
IIa II
Cross-linked brin
VIIa
Ca • TF • Xa
Xa
Ca • Va • PL
brin
B
XII XIIa
XI
IX
X
brinogen
PC
rombomodulin
IX
XIa
IXa
Ca • VIIIa • PL
X
IIa II
PS
APC
Cross-linked brin
Xa
Ca • Va • PL
brin
PS
Va and VIIIa, thereby inhibiting the generation of throm-
4
bin.
Additionally, activated Protein C (APC) stimulates
the release of tissue-type plasminogen activator (t-PA). It
is produced in the liver and is the dominant endogenous
anticoagulant with an 8-h half-life. Protein C de ciency
has a prevalence of 1 in 200–300 with more than 150 mutations and an autosomal dominant inheritance.
to antithrombin de ciency, protein C de ciency has two
types:Type Iis associated with decreased production and
Heparin
·TFPI
VIIa
Ca • TF • Xa
4,7
Similar
function and Type II is associated with a low functional
8
Type Ide ciency predominates.
Table35.2 ACQUIRED HYPERCOAGULABLE
DISORDERS
ACQUIRED HYPERCOAGULABLE DIS
Heparin-Induced rombocytopenia/
Heparin-Induced rombocytopenia
and rombosis Syndrome
Lupus Anticoagulant/Antiphospholipid
Antibody Syndrome
Smoking
Warfarin
Pregnancy
Oral Contraceptive Pills/Hormone
Replacement erapy
Mechanical Injury/Trauma/Surgery
Diabetes Mellitus
Hyperlipidemia
Polycythemia vera
ORDERS
Hyper brinogenemia
Nephrotic Syndrome
Renal Failure
Vasculitis
Malignancy
rombocythemia
Homocysteinemia
Sepsis
Obesity
Immobility
Antithrombin de ciency should be suspected in a
patient with spontaneous thrombosis, in a patient who cannot be anticoagulated adequately on heparin or in a patient
who develops thrombosis while on heparin. To detect this
de ciency, antithrombin levels should be measured when
13,14
the patient has not been exposed to heparin.
level.
Protein S is also a vitamin K–dependent anticoagulant
protein that is a cofactor to APC. e actions of protein
S are regulated by complement C4b binding protein and
only the free form of protein S serves as an APC cofac-
15
Additionally, protein S appears to have independent
tor.
anticoagulant function by directly inhibiting procoagulant
7,16
enzyme complexes.
e prevalence of protein S de ciency
is about 1:500 with an autosomal dominant inheritance.
ree types of protein S de ciencies exist:Type Iis associated with low levels of free and total protein S antigen and
decreased APC activity; Type II has normal levels of protein S antigen but low levels of APC cofactor activity; and
Type III has normal to low levels of total protein S, low free
protein S, and an increased proportion of protein S bound
8
to complement C4b.
In addition, many patients with pro-
tein S de ciency also have resistance to APC, which may be
1
the reason for the thrombosis.
Clinically, protein C and protein S de ciencies are
essentially identical. With homozygous protein C and protein S de ciencies, infants typically will succumb to purpura
fulminans, a state of unrestricted clotting and brinolysis.
In heterozygotes, venous thromboses may occur at an early
17
age especially in the lower extremity.
rombosis may
also occur in mesenteric, renal, and cerebral veins. Protein
PROTEIN C AND PROTEIN S
DEFICIENCY
Protein C is a vitamin K–dependent anticoagulant protein
that, once activated by thrombin, will inactivate factors
C and protein S de ciencies usually become clinically evident when the levels of these proteins are less than 50% of
normal.
Plasma protein C and S concentrations may be obtained
to diagnose de ciencies of these proteins. Antigen and
CONGENITAL AND ACQUIRED HYPERCOAGUABLE SYNDROMES • 277
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