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SECTION C: MANAGEMENT OF DEEP VENOUS THROMBOSIS
11
The Pathophysiology of Deep
Venous Thrombosis
Ahmad Bhatti
Division of Vascular Surgery, Loyola University Medical Center, Maywood, Illinois,
U.S.A.
Nicos Labropoulos
Vascular Laboratory, Division of Vascular Surgery, New Jersey Medical School, Newark,
New Jersey, U.S.A.
BACKGROUND
Venous thromboembolism (VTE) is a common event. It may be asymptomatic or lead to
pulmonary embolism (PE), which may be fatal. In the eighteenth and nineteenth centuries,
pulmonary arterial thrombosis was first recognized as an entity. While some attributed
death and causality to this finding on autopsy, others merely commented on it incidentally.
The fact that pulmonary arterial thrombosis may occur from a venous VTE, an extra-
pulmonary source, was not entertained. In 1858, Rudolf Virchow recognized that the
aforementioned phenomenon might occur from a pulmonary, or an extra-pulmonary
source. He stated the importance of thrombi in remote venous systems that may dislodge
and cause secondary occlusion such as PE. It is during this time that he postulated the
etiologies of deep vein thrombosis (DVT) and proposed what is today called “Virchow’s
triad” as follows: hypercoagulability, blood stasis, and vessel injury(1).
In most patients, the etiology of DVT is multifactorial. It is important to recognize
which of these etiologic factors are transient (e.g., immobility) and which are long-
standing (e.g., malignancy). The anatomic location, extent and type of symptomatology of
DVT increase the risk of VTE or PE to varying degrees (2). Many, if not all, of the
pathophysiologic factors for DVT exert their effect through one or more of Virchow’s
triad. Hence, in every DVT there exists at least one of these factors as an initiating event.
STASIS
Venous stasis has received the most attention as the main reason for causing DVT (3).
Although it may be simplistic to view stasis as the leading or sole cause in DVT formation,
its contribution is substantial. Conditions of stasis are common and often are transient:
immobility (e.g.,cessation of calf-pump mechanism), outflow compression (e.g.,pregnancy),
or vasodilation/decreased flow (e.g., general anesthesia). Various randomized controlled
studies have shown that simple intermittent pneumatic compression devices that prevent or
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reduce stasis reduce the incidence of DVT (4–8). There is a belief that these devices also act
via stimulation of the endogenous fibrinolytic system. Research in this area is inconclusive,
as there are studies in the literature to argue for and against this theory (9–12).
While it is well accepted and intuitive that blood stasis leads to thrombosis, the basic
mechanisms are poorly understood. It is felt that cessation of flow causes upregulation of
cell adhesion molecules (CAMs) by endothelial cells (ECs). This upregulation of CAMs
increases leukocyte and platelet adherence, while the decreasing flow limits the
hemodynamic clearance of adherent leukocytes or platelets (13). Animal models have
demonstrated such adherence and accumulation of leukocytes and platelets with simple
venous stasis in a time-dependent manner. Adhesion, accumulation, and transmigration
result in EC sloughing and exposure of the highly thrombogenic basement membrane.
Leukocytes are thought to play the primary role in this series of events, and regulation of
these CAMs could, in theory, modulate damage to ECs, prevent basement membrane
exposure, and/or thrombosis formation (13–15). Animal models have also shown that
leukocyte adherence, EC sloughing, and thrombus formation first occurs behind valve
cusps (13,14). While this may or may not be macroscopically apparent, this series of
events occurs shortly after stasis. Contrast venography studies have shown delayed
clearance of contrast in valve sinuses/cusps in non-excercised limbs (16). Even with
normal flow in a vein, there may be local stasis that occurs behind the valve cusps. This
local stasis is a result of eddy currents or vortices that occur behind these cusps, and these
are known to increase the risk of thrombus formation (17,18).
Major causes of stasis include excessive bed rest (e.g.,hospitalization), paralysis, long
air-travel times and prolonged sitting. DVT associated with air-travel has a variable
incidence with case reports of sudden death from PE after trans-atlantics flights (19,20). One
large extensive prospective study showingthe incidence to be zero regardless of the class of
travel (business versus economy), once hyper-coaguable patients were excluded (21). This
study did, however, demonstrate an elevation of D-dimers, compared with pre-flight levels,
in 10% of travelers, suggesting activation of the thrombolytic system. With an increasingly
technologically advancedsociety requiring less physical demand, case reports of DVT from
prolonged sitting at computer terminals (work, recreational, or personal), and the like, are
now being reported. The term “eThrombosis” has been used to describe this etiology (22).
Stasis can also result from position independent factors by varying degrees of venous
obstruction. Common examples wouldinclude pregnancy, with the gravid uterus impinging
on the iliac veins, or pelvic tumors by a similar mechanism. Low hemodynamic flow rates
can also result in a relative stasis of venous blood such as in hypotension or congestive heart
failure (CHF). One outpatient study of patients with CHF showed an inverse ratio between
cardiac ejection fraction and DVT/VTE rates (23). Although inherently intuitive, these
in vivo flow and DVT correlations have not been well studied clinically. Venodilation that
occurs with epidural or spinal analgesia or spinal trauma may also predispose to stasis and
thereby to DVT formation. This potential cause of stasis has been acknowledged and
attempts to modulate it clinically have been reported (24).
HYPERCOAGULABILITY
This condition occurs when the coagulation is promoted or anticoagulation is impaired.
Acquired or inherited clotting cascade mutations, imbalances, or activation produce
hypercoaguable states (Table 1). While there are many specific factors that may be
implicated, a small subset has been established and their relationships with DVT formation
have been well studied.
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Table 1 Factors that Promote Coagulation or Impair Anticoagulation
Factor
Prevalence in patients
with DVT or VTE
Prevalence in general
population Risk for DVT or VTE Comments
Factor V Leiden
(APCR)
20–60% (40) 5% (61) Hetero: 3!; Homo
50–80!(29)
Most common heritable thrombophilia in DVT/VTE
patients; majority of APCR is from Factor V Leiden
Malignancy 30–35% (62) U.S.: 9.6 million cur-
rent cases (63)
2–3! (38) Risk varies with type of malignancy
Factor VIII 17–25% (48,49) 10%
a
5–7! (45–47) For increased (idiopathic) levels: O90
th
percentile
Plasminogen activator
inhibitor (PAI)
22% (64) 7.6–44.8% (65) Unclear (43,61,62) Lowest in African Americans,
highest in Caucasians and Japanese
Prothrombin 20210A
(Factor IIA)
4–20% (26) 2% (37) Hetero: 2–3! (31,32) Homozygotes rare (case reports); 2
nd
most common
heritable thrombophilia in DVT/VTE patients
Antiphospolipid Anti-
bodies (LA, ACA,
etc.)
15% (36) Unknown (37) 1/3 lifetime VTE risk (36) May exist without SLE
Protein C&S
deficiency
5–10% (38,40,66) 0.2–0.7% (37) Hetero: 50% risk of VTE
by age 50 (37)
Protein S deficiency more common
Hyperhomocystein-
emia
10%(67) 5%
a
2.5! (38) For increased levels: O95
th
percentile
Antithrombin III
deficiency
0.5–5% (38) 0.02 (37) 85% VTE risk by age
50 (38)
Factor XI Low (38) 10%
a
2.5! (38) For increased levels: O90
th
percentile
Factor IX Low (38) 10%
a
2.5! (38) For increased levels: O90
th
percentile
Polycythemia vera Low 1.9 per 100,000 (68) 3.4%/yr (arterial and
venous) (69)
Risk felt to be related to cell volume
Dysfibrinogenemias Rare (0.8%) (70) Case reports
Unclear (42,65)
a
By definition.
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The two most common factors for hypercoagulability in the veins are the mutations
of factor V and the Prothrombin 20210A (25,26). A large risk for DVT formation occurs
with activated protein C resistance (APCR) (27,28). Factor Va acts as a co-factor for the
prothrombin activating complex. Activated protein C (APC) neutralizes Factor Va thereby
inhibiting prothrombin activation. An abnormal/mutated factor Va called Factor V Leiden
will resist APC resulting in sustained prothrombin activation and increased thrombotic
risk (29). In patients with venous thrombosis 20–60% are positive for this mutation (40).
Factor V heterozygotes are at three times the risk of venous thrombosis compared with the
normal population, and homozygotes are at 50–80! higher risk (30). In addition to DVT
formation, Factor V and prothrombin gene mutations are also associated with a high risk
for VTE recurrence (31). The Prothrombin 20210A mutation results in hypercoagulability
via increased prothrombin levels. This is the second most common genetic mutation
(Factor V Leiden being the first) in patients with venous thrombosis (32). It increases the
risk of a DVT two to threefold (31,33). Most cases are heterozygous for this mutation, and
homozygous patients are rare but have been reported (34,35).
Antiphospholipid antibodies, hyperhomocysteinemia and deficiencies of anti-
thrombin III are also major risk factors for DVT formation. Antiphospolipid antibodies
are a broad class of reactive autoimmune antibodies that include anticardiolipin antibody
(ACA) and lupus anticoagulant (LA). ACA and LA were first recognized in patients with
systemic lupus erythematosus (SLE). These antibodies can exist without the presence of
SLE (36). Up to 15% of DVT may involve antiphospholipid antibodies and one third of
patients with antiphoshpolipid antibodies will have a thromboembolic event (37).
Protein C and Protein S are two anticoagulant proteins that are implicated in DVT
formation (38,39). Deficiency in either may produce a procoagualant state. This deficiency
may be functional, as may be in the case of mutations, or it may be relative as with
induction of warfarin anticoagulation. In patients with venous thrombosis 10% have
inherited deficiencies of Protein C or Protein S (40).
Malignancy is associated with an increased incidence of DVT. Certain malignancies,
such as gastric or pancreatic cancer may have a higher association with DVT (41). The
mechanisms by which procoagulant states are created vary from tumor to tumor. These
mechanisms are variable, but examples include tumors creating cysteine protease proco-
agulants (which activate Factor X), or tumors activating the extrinsic pathway, or altering
EC anticoagulant activity. In some patients, idiopathic VTE or DVT may be the presenting
symptom for an undiagnosed malignancy (37).
Thrombus formation and degradation are the result of an ongoing balance of
coagulation and fibrinolysis. Alterations mayoccur toform procoagulant states as discussed
above, or in fibrinolysis leading to impairments of thrombus degradation. Imbalances in,
or dysfunction of, tissue plasminogen activator and inhibitor, Factor XIIa (Hageman
factor), and prekallikrein defeciences may upset this balance of thrombus formation
and degradation (42–44). The association between impairments of the fibrinolytic
system and symptomatic thrombosis remain controversial, with one critical review of the
literature showing no association (45). Increased Factor VIII levels increase the risk of
DVT, with various studies showing a five times toseven timeshigher recurrencerate ofVTE
for with patients with elevated (in or O than the 90th percentile) factor VIII levels (46–48).
The incidence of elevated FVIII has been reported in the range from 17–25%, making this an
important contributor to DVT and VTE in the population (49,50).
Other contributors to hypercoaguability exist. Factors that increase viscosity, such as
polycythemia vera, have been implicated in DVT formation (51). Polymorphisms that allow
over expression of plasminogen activator inhibitor (PAI) inhibit fibrinolysis and are
associated with higher DVT rates (52,53). The significance (statistical and otherwise) of this
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has not been well established, as reported in several studies (43,54,55). Platelet dysfunction
or thrombocytosis, however have little association with venous thrombosis (56). HIV also
predisposes patients to venous thrombosis, however the mechanism remains unclear (57).
Dysfibrinogenemia is a rare cause of venous thrombosis, accounting for 0.8% of patients
with DVTs (58). It should, however, be considered in the differential diagnosis in patients
that are young or have familial histories of DVTs, as with all potentially heritable
thrombophilias. Oral contraceptives (OCs) have been well known to increase the incidence
of DVT in patients who take them. The mechanisms are multifactorial, but with regards to
thrombophilic states, this may occur via reduction in ATIII, reduction in Protein S, or
induction of APCR (50,59,60). While both estrogens and progesterones in OCs contribute to
DVT formation, it is felt that the latter may have a larger role.
VESSEL INJURY
Various degrees of gross or microscopic trauma and/or disruption to the vein’s architecture
may produce DVT. ECs act as a physical barrier by covering the prothrombogenic
basement membrane. They also actively participate in thrombus formation and
degradation (71). As mentioned earlier, CAMs are expressed with stasis or EC injury
and induce leukocyte adhesion, migration, and eventual EC sloughing (13–15). This
exposes the collagen rich thrombogenic basement membrane inducing thrombus
formation via platelet activation (72). ECs also express plasminogen activators thereby
inducing thrombus lysis (43). Focal vessel injury should not impair fibrinolysis. This is
because ECs and plasminogen activators may locally/remotely act upon distant thrombi.
Focal vessel injury will, however, produce thrombi, for the aforementioned reasons. Any
exogenous or endogenous agent that may cause EC and/or basement membrane damage,
irritation, injury, or simple exposure of the basement membrane can result in thrombosis.
This includes physical injury (e.g., blast, thermal, or shear), anoxia, stasis, mechanical
injury (e.g., catheters, venoplasty, or stents), exposure to non-iso-osmolar agents
hyperlipidemia, and hyperhomocysteinemia (58,73–78). Extravascular tissues and vessel
adventitia all contain varying degrees of tissue factor (TF). TF binds factor VIIa (FVIIa) to
activate the clotting cascade. Vessel injury exposes TF to flowing blood thereby inducing
thrombus formation (79). This TF/FVIIa complex is postulated to be formed and released
during surgery (cutting through tissue and vessels). It exerts effects at remote sites causing
DVT. Pharmacologic inhibitors of TF/FVIIa complexes have been used clinically to
reduce post-operative DVT rates with initial success (80–82).
OTHER CAUSES
Estrogens, OCs, and hormonal therapies exert their influence by creating a hypercoaguable
state, increasing calf venous volume, and decreasing venous velocity (50,56,57). Obesity,
possibly from decreased mobility and increased hormonal production, increases the risk of
DVT formation two-fold, and is a co-morbidity in 27% of patients with DVT (83,84). It is
difficult to separate the effects of anesthesia and surgery on DVT formation. Several
studies are suggestive that anesthetic induction alone results in venous distension,
decreased muscle tone, increased stasis, or decreased venous flow (85–88). There is data to
suggest that general anesthesia may be a greater risk factor than regional anesthesia
(74,75). Surgery or incision itself activate the extrinsic coagulation cascade or inhibit such
factors as fibrinolysis, thereby making the patient hypercoaguable (89–91). These cascade
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of events during surgery result in a peak period of hypercoagulability from 24 to 48 hours
postoperatively. Prolonged immobility may also occur during surgery, resulting in
increased risk for DVT. Increasing age is a risk factor for DVT. One prospective cohort
followed from age 50 to 80 years found that the incidence of DVT 0.5% at 50 years of age,
and 10.7% at 80 years of age (92,93). This has been confirmed in other cross-sectional
studies. Pregnancy and puerperium also predispose to venous thrombosis. This may occur
from increased pelvic pressure on iliac and pelvic veins, increased hormonal levels/
hypercoaguability, and possibly decreased ambulation (94,95). Blood surface antigens
(ABO blood-grouping) have been implicated as a risk factor, with Type O being
protective, although there are some conflicting reports (96,97). Spinal fractures or cord
injuries increase the risk of DVT 2–3! (98). This may be the result of immobility,
venodilation, and venous stasis that occurs with these conditions. Previous history of DVT
or VTE is a known risk factor as well. Recurrent episodes may or may not have similar
etiology (85). Inflammatory bowel disease (IBD) has also been shown to have an
association with venous thrombosis, the exact mechanism, however, remains unclear
(99,100). Superficial venous thrombosis (SVT) and varicose veins (VVs) are additional
risk factors for DVT and probably share similar etiology (101). Venous malformations
such as Klippel–Trenaunay and possibly venous angiomas have a higher incidence of
DVT/VTE than the general population but the etiology is unclear (102–104).
NATURAL HISTORY OF DVT
The natural history of a DVT consists of thrombus formation, propagation, and
recanalization that may be partial or complete. In 1978 Aschoff et al. described the
histopathology of venous thrombi (105). Thrombus typically starts by amorphous platelet
adhesions to the vessel wall. This is then covered by coralline (corral like) thrombus, which
is laminar. Layers of fibrin and blood cells alternate with layers of platelets. These layers
form visible lines that are called the “lines of Zahn” after the man who discovered them in
1872 (92). As the thrombus extends, it alters the blood flow which reciprocally shapes the
thrombus formation. This causes the lines of Zahn to form bending and swirling in the
direction of the blood flow. Once the vessel becomes occluded, the static column of blood
turns into a red amorphous jelly-like thrombus consisting offibrin and red blood cells. This
then propagates to the nearest tributary to where flow may be sufficient enough to prevent
stasis and clotting. At this point, the thrombus becomes adherent to the vessel wall.
Recanalization occurs in the majority of cases within three months (106). Resolution then
ensues with thrombus resorption/lysis, but up to 50% oflimbs still may have some degree of
partial occlusion at three years (94). Propagation of thrombus, in this same study, occurred
in 15% of cases regardless of anticoagulation status. This waslimited to one or twoadjacent
segments (94). Propagation can occur distally and proximally. In one study of isolated calf
DVT, proximal propagation occurred in 13% of limbs, and distal propagation occurred in
4%, and both directions in 10% (107). Different segments of thrombus may propagate and
lyse at the same time. Resolution occurs at an exponential rate, regardless of the vein
segment. Recanalization rate and thrombus resolution rate, through endogenous
fibrinolysis, are proportional with initial thrombus load (108). Calf DVT tend to have
small thrombus loads, and therefore resolve faster, and this has been shown clinically (95).
This remodeling and resorption of thrombus can destroy the valves involved and lead to
reflux. Reflux or residual obstruction, along with pain, edema, and pigmentation changes
are features of post-thrombotic syndrome (PTS). One study reported PTS at two years
from DVT formation and found that 50% of patients had sonographic obstruction or reflux
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(109). Only 27% of post-DVT limbs were asymptomatic at two years, and subjective
findings were common: pain 62%, edema 46%, and pigmentation 35%. Another study found
the incidence of phelobrgraphically proven PTS to be 56% at one year (110). The actual
incidence is not well documented, with rates varying in the literature from 17% to 56% at
one year (98,111).
Recurrence of DVT, with or without a specific etiology, should be considered as
part of the natural history of DVT. One study cites the incidence of VTE in patients with
thrombophilia (Protein C, Proteins S, and antithrombin deficiencies) at 1.4% per year
with anticoagulation, and 2.7% per year without (112). Another study of a prospective
cohort of 528 patients with a first episode of DVT from any etiology was followed for eight
years. The study found the cumulative incidence of DVT 17.2%, 24.3%, and 29.7% at two,
five, and eight years, respectively (113). In this same study, the incidence of PTS was
22.8% and 28% at two and five years respectively. The incidence of PTS increased by
six times after a recurrent ipsilateral DVT. These contrasting studies, and many others,
provide arguments for and against life-long or long-term anticoagulation for various DVT
etiologies. Symptomatic DVT itself is a risk factor for recurrent VTE (114). The incidence
of PE, symptomatic, or subclinical, with DVT is quite high, with studies citing rates of
40%–50% (115,116).
KEY POINTS
† Deep venous thrombosis is an inflammatory process, that occurs from
hypercoagulability, blood stasis, and vessel injury.
† Factors may be transient (e.g., stasis due to bed rest) or permanent
(e.g., inherited coagulapathies).
† Stasis, which is a common, contributes by initiating a cellular prothrombotic
state.
† Hypercoaguability is largely a permanent factor, with most hypercoagulable
states being inherited (e.g., Factor V Leiden), while others are transient
(e.g., oral contraceptive use).
† Vessel injury is usually transient and may occur as a result of many factors
including stasis, mechanical, or chemical injury.
† Deep venous thrombosis is multifactorial.
† The natural history consists of thrombus formation, propagation, embolization
and recanalization.
REFERENCES
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