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125
N.S. Sadick et al. (eds.), Practical Approach to the Management and Treatment of Venous Disorders,
DOI 10.1007/978-1-4471-2891-5_13, © Springer-Verlag London 2013
1 3
Introduction
The three aspects in fl uencing risk of clotting—
Virchow’s Triad—include venous stasis, vessel
injury, and hypercoagulable states or thrombo-
philias (Fig. 13.1 ).
The occurrence of a venous thrombosis (VT)
is a consequence of the presence of various envi-
ronmental (advanced age, obesity, immobility,
cancer, etc.) and genetic risk factors. The pres-
ence of genetic risk factors increases the risk of
VT during certain periods of risk (surgery, air
travel, pregnancy, etc.).
The hereditary thrombophilias may be classi fi ed
into Group 1 and Group 2 disorders. Group 1 disor-
ders are de fi ciencies of coagulation factor inhibitors
and include de fi ciencies of antithrombin, protein C,
and protein S. An increased level or function of
coagulation factors are classi fi ed as Group 2 disor-
ders, and include activated protein C resistance/fac-
tor V Leiden polymorphism, prothrombin G20210A
polymorphism, and elevated levels of factors VIII,
IX, and XI. Other hereditary thrombophilias include
disorders of the fi brinolytic system and hyperhomo-
cysteinemia [ 1 ] (See Fig. 13.2 ).
As a generalization, Group 1 disorders are less
common and more thrombogenic, especially with
regard to recurrent VT, than Group 2 disorders [ 1 ]
(Fig.
13.3 ). Compared to patients with Group 2
disorders, patients with Group 1 disorders typi-
cally present at a younger age with idiopathic or
recurrent VT and are more likely to have a family
history of VT [
2 ] (Fig. 13.4 ). Most thrombophilias
Genetic Thrombophilias:
When to Consider and What to Do
Edith A. Nutescu , Jessica B. Michaud ,
and Joseph A. Caprini
E. A. Nutescu , Pharm.D. () • J. B. Michaud , Pharm.D.
Clinical Professor and Director and
Antithrombosis Center,
University of Illinois at Chicago,
College of Pharmacy and University of Illinois Hospital
and Health Sciences System ,
833 S. Wood Street; M/C 886 ,
Chicago , IL 60612 , USA
e-mail: enutescu@uic.edu; jbmitche@uic.edu
J. A. Caprini , M.D., M.S., FACS, RVT
Louis W. Biegler Chair of Surgery,
Department of Vascular Surgery ,
Northshore University Health System ,
Evanston , IL , USA
Clinical Professor of Surgery , The University of Chicago
Pritzker School of Medicine, Chicago , IL , USA
e-mail: j-caprini@northwestern.edu, jcaprini2@aol.com
Virchow
,
s
Triad
Circulatory
Stasis
Endothelial
Injury
Hypercoagulable
State
Fig. 13.1 Virchow’s triad of factors in fl uencing initiation
of VTE
https://t.me/med1917
126
E.A. Nutescu et al.
are associated with venous thromboembolism,
with less or no evidence for arterial thromboembo-
lism. Table 13.1 details the relatively wide ranges
for the prevalence of thrombophilia in the general
population and in patients that present with VT.
Diagnostic Testing
Testing for thrombophilias is complicated since
there are many thrombophilias and several tests
for each thrombophilia. Numerous interactions
with testing can occur which further complicates
diagnosis. Table
13.2 details the tests that are
available for the thrombophilias and the ones that
are recommended as routine tests for diagnosis.
Patients with more than one thrombophilia have
higher thrombosis risk than those with one disor-
der, so including all recommended labs in the
hypercoagulable workup is prudent [ 3 ].
Figure 13.5 lists important anticoagulant drug
interactions with the laboratory tests. Close
examination of the timing of all thrombophilia
laboratory tests is recommended to avoid under- or
Fig. 13.2 Thrombophilia
categories
Group 1: Deficiencies of natural
anticoagulants
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Group 2: increased levels or function of
procoagulant factors
Activated protein C resistance (including factor V
leiden mutation)
Prothrombin G20210A mutation
Elevated levels of factors VIII, IX, and XI
Other
Hyperhomocysteinemia
Antiphospholipid antibody (APLA) syndrome
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12713 Genetic Thrombophilias: When to Consider and What to Do
LOW
heterozygous factor V leiden
heterozygous protein C deficiency
heterozygous protein S deficiency
heterozygous AT deficiency
dysfibrinogenemia, APLA
homozygous factor V leiden
homozygous prothrombin gene mutation
homozygous protein C deficiency
homozygous protein S deficiency
homozygous AT deficiency
heterozygous prothrombin gene mutation
hyperhomocysteinemia, elevated FVIII, IX, XI
MODEST
HIGH
EXCESSIVE
Fig. 13.3 Relative risk of
thrombosis
1. Family history of venous thrombosis
Thrombosis is at age< 40
Thrombosis in infants
Thrombosis at unusual sites
Unexplained recurrent pregnancy loss
Recurrent venous thrombosis
Id iopathic venous thrombosis
Venous thrombosis with minimal provocation
Heparin resistance
Coumarin skin necrosis
2.
3.
4.
5.
6.
7.
8.
9.
10.
Fig. 13.4 Clinical
manifestations:
hypercoagulable states
Table 13.1 Prevalence of thrombophilias in the general population and in patients with venous thromboembolism
(VTE) [
1, 4 ]
Thrombophilia Prevalence in the general population Prevalence in patients with VTE (%)
Antithrombin de fi ciency 0.07–0.2% 0.5–8
Protein C de fi ciency 0.17–0.4% 1.5–11.5
Protein S de fi ciency 0.03–0.2% 1.3–5
Factor V Leiden polymorphism Heterozygous: 5% of Caucasians,
1.2% of African Americans
10–20
Homozygous: 1% of Caucasians
Prothrombin G20210A
polymorphism
1–2% 5–10
Factor elevations 10–20%
MTHFR C677T polymorphism 34–50% heterozygous
12–15% homozygous
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128
E.A. Nutescu et al.
over-diagnosing thrombophilias, and performing
a con fi rmatory test is often prudent. For example,
warfarin may reduce levels of the vitamin-K-
dependent protein C, and therefore any protein C
levels checked during warfarin may inappropri-
ately lead to a diagnosis of protein C de fi ciency,
which would strongly in fl uence the recommended
duration of anticoagulation. Sometimes impor-
tant information can still be obtained for a poorly
timed laboratory test; for example, a normal pro-
tein C level during warfarin would exclude pro-
tein C de fi ciency. Of course, testing for genetic
mutations is not in fl uenced by any medication or
disease state.
Table 13.2 Laboratory tests for thrombophilia
Thrombophilia
Laboratory tests
Available assays by type
Recommended
Functional
(activity)
Antigenic
(levels) Genetic
Antithrombin de fi ciency X X Functional amidolytic
assay
± antigenic assay
Protein C de fi ciency X X Functional
Protein S de fi ciency X X (total, free) Free antigenic and/or
functional
± total antigenic
APC resistance X (clotting assay,
with or without
addition of factor
V-de fi cient plasma)
X (factor V Leiden
genetic test)
APC resistance assay with
factor V-de fi cient plasma
or FVL genetic test
Prothrombin G20210A
mutation
X Genetic test
Elevated factors VIII, IX,
and XI
X X either
Hyperhomocysteinemia X (tHcy) X (MTHFR genetic
test)
tHcy
tHcy total plasma homocysteine levels
Antithrombin levels
decreased
decreased
decreased
altered altered
warfarin heparin
Protein C levels
Protein S levels
APC Resistance clotting Assay
Factor V leiden DNA Assay
Prothrombin Gene Mutation
.....
.....
.....
.....
.....
.....
.....
Fig. 13.5 Effect of
anticoagulants
on screening tests
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12913 Genetic Thrombophilias: When to Consider and What to Do
Thrombophilias due to De fi ciencies
of Natural Anticoagulants
(Group 1 Disorders)
Antithrombin De fi ciency
Antithrombin (formerly called “antithrombin III”)
is a natural anticoagulant that binds and inacti-
vates factors IIa (thrombin), Xa, IXa, XIa, and
XIIa [ 1 ] (See Fig . 13.6 ). De fi ciency of antithrom-
bin results from more than 100 mutations that can
be heterozygous or homozygous [ 4 ] . The risk of
VT is up to 5–50 times higher in patients with
antithrombin de fi ciency [ 5 ] .
In the acute thrombosis phase, massive hep-
arin doses may be required in patients with
antithrombin de fi ciency since heparins work
by increasing the activity of antithrombin.
Patients may require the use of an anticoagu-
lant that does not depend on antithrombin to be
effective (i.e. direct thrombin inhibitors).
Warfarin is recommended as a long-term anti-
coagulant, usually inde fi nitely, due to the rela-
tively high likelihood of recurrence ( Dager
2004; [ 6 ] ).
Protein C and S De fi ciencies
Activated protein C, with its cofactor protein S,
inactivates factors Va and VIIIa, thus inhibiting
thrombin formation [ 1, 4 ] . Because both protein
C and protein S are required to inactivate coagu-
lant factors, the phenotypic presentation of the
de fi ciency of these proteins is similar [ 1 ] . Protein
C de fi ciency confers a VT risk of 3.1-fold [ 5 ] ,
and protein S de fi ciency has shown a risk ranging
from no association to 2.4–11.5-fold [ 4 ] . About
half of patients with protein C or S de fi ciency will
develop VT by their 40s [ 7, 5 ] A homozygous
Hyperhomocysteinemia
Inhibits activation
of protein C
ACTIVATED PROTEIN C
Protein S
deficiency
PROTEIN S PROTEIN S
Inactivates
factor Va
Factor V Leiden mutation
Factor V resistant to
degradation by protein C
Controls thrombin
generation
Antithrombin deficiency
Decreased thrombin
neutralization
PROTHROMBIN THROMBIN COAGULATION
G20210A mutation
Increased prothrombin
levels
Inactivates
factor VIIIa
Thrombin binds to
thrombomodulin on
endothelial cells
Protein C
deficiency
PROTEIN C
Fig. 13.6 Simpli fi ed coagulation cascade with effects of thrombophilia
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130
E.A. Nutescu et al.
mutation or multiple heterozygous mutations
generally cause very low levels (~20%) and in
newborns may cause fatal neonatal purpura fulmi-
nans characterized by diffuse venous thrombosis
[ 1, 4, 5, 7 ]
Because proteins C and S are vitamin-K-
dependent, their levels are reduced by (Vitamin
K antagonists), which can be dangerous in
patients with underlying de fi ciency. This reduc-
tion in protein C or S can precipitate intravas-
cular coagulation, or warfarin-induced skin
necrosis (See Fig. 13.7 ). Patients with protein C
de fi ciency are especially at risk due to the short
half-life of protein C (~5–10 h), causing a rapid
decline in levels. Patients with warfarin-induced
skin necrosis should be tested for protein C or
S de fi ciency. Heparin or low molecular weight
heparin should be used concurrently with war-
farin, overlapped for at least 5 days and until
the INR is therapeutic and stable, in order to
prevent this complication. Avoiding “loading”
doses of VKAs is also prudent in these patients
to minimize the reduction in protein C or S.
Fresh frozen plasma may be used to replenish
protein C in the postoperative period when hep-
arin use may be contraindicated [ 4– 7 ] .
Thrombophilias due to Increased
Level or Function of Coagulation
Factors (Group 2 Disorders)
Activated Protein C Resistance/Factor
V Leiden Polymorphism
Activated protein C (APC) resistance is the most
common hereditary thrombophilia [ 8 ] , occurring
in up to 5% of Caucasians ( [ 8 ] (3–7%), [ 1 ] (5%)).
Because the factor V Leiden (FVL) polymor-
phism is the mutation responsible for 90% of
APC resistance cases, this thrombophilia is often
referred to as “factor V Leiden” [ 1, 4, 8 ] .
Distinguishing between the positive results is
important, since homozygous mutation results in
an approximately 50–100-fold ( [ 8 ] increase in
VTE risk, compared with the 3–7-fold [ 4 , 8 ]
increase caused by heterozygous FVL mutation.
The VTE risk is further increased in patients with
other hypercoagulable states such as prothrombin
G20210A mutation, pregnancy, and oral contra-
ception use [ 8 ] .
Approximately 10% of patients with heterozy-
gous FVL mutation will develop symptomatic
VT in their lifetime [ 8 ] . This relatively low
Fig. 13.7 Warfarin induced skin necrosis
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13113 Genetic Thrombophilias: When to Consider and What to Do
probability is in contrast to the Group 1 disor-
ders, in which a majority of patients are likely to
develop VT in their lifetime. Another feature of
APC resistance, distinct from Group 1 disorders,
is that the risk of initial VT is more established
than the risk of recurrent VT [
4, 8 ] .
Prothrombin Defects: Prothrombin
G20210A Polymorphism
In this thrombophilia, A is substituted for G at
position 20210 on the prothrombin gene, result-
ing in higher circulating levels of functionally
normal prothrombin [ 1, 4, 9 ] .
The prothrombin G20210A polymorphism is
similar to APC resistance in its:
Primary cause (genetic mutation) •
Prevalence (second most common hereditary •
thrombophilia)
Risk of VT ( approximately two to three times •
increased risk [ 4 , 9 ]
More established risk of initial versus recur-•
rent VT
Low lifetime chance of VT compared to Group •
1 disorders [ 1 ]
Established increase in VT risk with preg-•
nancy, oral contraceptive use, or coinheritance
with another thrombophilia [ 9 ]
Elevated Coagulation Factors
Patients with recurrent VT are more likely to have
persistently elevated coagulation factor levels [
1 ] ;
however, it is unclear what causes factor levels to
increase, and whether this increase is a source or
a marker of hypercoagulability [ 10 ] . The eleva-
tion of some factors (factors V and VII) has been
more associated with arterial thrombosis; whereas,
the elevation of other factors (factors VIII, IX, and
XI) has been more associated with VT [
1 , 10 ] .
Hyperhomocysteinemia
A high plasma level of the amino acid homo-
cysteine has been clearly associated with both
venous and arterial thrombosis (with relative risk
of arterial events approximately 1.3) [ 1, 11 ] .
Hyperhomocysteinemia can be acquired from:
B vitamin (folate, vitamin B6, and/or vitamin B12) •
de fi ciency
Renal insuf fi ciency •
Hypothyroidism •
Other medical conditions •
Or inherited via mutations in genes coding
enzymes involved in homocysteine metabolism:
Methylene-tetrahydrofolate reductase (MTHFR) •
gene
Cystathione • b synthase gene
Methionine synthase gene [ • 1, 11 ]
The foremost consideration is whether the
homocysteine level ought to be lowered with B
vitamin supplementation. Several trials (VITRO,
VISP, NORVIT, and HOPE-2) have suggested
that although B vitamin supplementation lowers
homocysteine level, it does not reduce thrombotic
events [ 12– 15 ] . For this reason, we do not recom-
mend routine B vitamin supplementation to lower
homocysteine-associated thrombotic events.
Other Hereditary Thrombophilias
The hereditary thrombophilias discussed in this
chapter are the most recognized thrombophilias, but
other hypercoagulable laboratory tests will likely
emerge as clinically important. Laboratory tests are
also available to test for defects in the fi brinolytic
system, heparin cofactor II de fi ciency, and
de fi ciencies of contact factors [ 10, 16– 20 ] .
Combination of Thrombophilic Defects
In cases where a combination of thrombophilic
defects is present, the risk of thrombosis can be
extremely high. Thus, in cases where a known
hereditary thrombophilia is present, consideration
should be given to test for other potential defects or
risk factors. In addition, the combination of a genetic
thrombophilic defect and one or more acquired risk
factors, such as surgery or oral contraceptive use,
lead to a higher risk of VTE then the separate effects
of these single factors [ 1, 4 ] .
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132
E.A. Nutescu et al.
Clinical Practice Considerations
Currently, there are no consistent guidelines in the
literature on which patients should be considered
for thrombophilia work-up and what speci fi c tests
should be included if patients are tested. The ini-
tial evaluation of patients presenting with a strong
clinical case suggesting thrombophilia must
include a detailed family and personal history.
Identi fi cation of high-risk patients with under-
lying genetic thrombophilic disorders is espe-
cially important in cases of elective surgery and
invasive procedures and prior to prescribing birth
control or hormone replacement therapy. In addi-
tion to the presence of one or more thrombophilic
defects, the presence of risk factors such as preg-
nancy, estrogen containing oral contraceptives,
hormone replacement therapy, surgery, cancer,
advanced age, medical illness, further compound
and markedly increase the risk of thrombosis,
and should be considered as part of the patients
overall thrombotic-risk evaluation.
Venous Thrombosis Prophylaxis and
Treatment Considerations [
21– 24 ]
1. Prophylaxis of VTE
(a) Asymptomatic patients without a prior VTE:
Long-term, primary pharmacologic throm-
boprophylaxis of asymptomatic thrombo-
philic patients is not recommended, as the
risk of major and fatal bleeding outweighs
the risk of fatal VTE even in patients
with most severe types of thrombophilia.
However, these patients should be consid-
ered candidates for prophylaxis at times of
high thrombotic risk such as surgery, inva-
sive procedures, trauma, prolonged immo-
bility, pregnancy, acute illness, etc.
(b) Patients with prior VTE:
Patients with documented thrombophilia
and history of a prior VTE, are candidates
for short-term thromboprophylaxis during
times of heightened thrombotic risk such
as surgery, invasive procedures, trauma,
prolonged immobility, pregnancy, acute
illness, etc.
There is no evidence to suggest that patients
with thrombophilia would bene fi t from more
intense anticoagulant regimens or longer dura-
tion of prophylaxis.
2. Treatment of VTE
The initial treatment of an acute VTE (deep
vein thrombosis and/or pulmonary embolism)
in patients with thrombophilia is similar to the
treatment approach used in all other patients
presenting with VTE. The acute treatment phase
of VTE is typically accomplished by admin-
istering a fast acting parenteral anticoagulant
such as unfractionated heparin, low-molecular-
weight heparin, or fondaparinux. The sub-acute
and chronic treatment phase of VTE is usually
accomplished using oral anticoagulant agents,
such as warfarin. In certain populations, such as
patients with cancer and women who are preg-
nant, the low-molecular-weight heparins are the
preferred agents. The injectable agent should
be overlapped with warfarin therapy for a mini-
mum of 5 days. Warfarin should be dosed to
achieve a goal INR of 2.5 (range 2–3). Once the
INR is stable and above 2, the injectable antico-
agulant is discontinued.
3. Duration of therapy
Anticoagulation therapy is usually given for
3–6 months but should be given longer depend-
ing on the underlying etiology of the VTE and
patient’s risk factors. In cases of unprovoked
events and persistent risk factors such as
thrombophilic defects, the duration of therapy
should be extended beyond the usual period of
anticoagulation.
References
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135
N.S. Sadick et al. (eds.), Practical Approach to the Management and Treatment of Venous Disorders,
DOI 10.1007/978-1-4471-2891-5_14, © Springer-Verlag London 2013
1 4
Treatment of Acute DVT
Indications
Provide relief of acute symptoms •
Prevent thrombus propagation •
Prevent Pulmonary Embolism (PE) •
Prevent recurrent Venous Thromboembolism •
(VTE)
Prevent the Post-Thrombotic Syndrome (PTS) •
Contraindications (Absolute or
Relative)
Active internal bleeding (for anticoagulant •
and thrombolytic drugs)
Documented bleeding complication with •
therapeutic-level anticoagulation
Heparin induced thrombocytopenia (for heparin). •
Allergy or known hypersensitivity to speci fi c •
anticoagulant/thrombolytic drug
Conditions which increase bleeding risk: •
intracranial/intraspinal bleeding; gastrointesti-
nal bleeding; known bleeding diathesis; recent
history of major surgery, trauma, or obstetrical
delivery (for anticoagulants and thrombolytics)
Renal failure (for full-dose low molecular •
weight heparins)
Pregnancy (full-dose LMWH and warfarin) •
Bleeding-prone lesion in critical anatomic •
location: central nervous system tumor, aneu-
rysm, or arteriovenous malformation; recent
non-hemorrhagic stroke; recent eye operation
or hemorrhagic retinopathy; advanced age (for
thrombolytic drugs)
Introduction
First-episode deep vein thrombosis (DVT) occurs
in 250,000–300,000 patients in the U.S. each
year [ 1 ] and leads to a number of important
complications: (1) pulmonary embolism (PE),
which causes at least 50,000 deaths each year;
(2) paradoxical systemic embolization through
an intracardiac defect, which can cause stroke;
(3) phlegmasia cerulea dolens, which can lead to
limb amputation or death; and (4) the post-
thrombotic syndrome (PTS), which causes
chronic, lifestyle-limiting symptoms including
limb swelling, pain, venous claudication, and/or
stasis dermatitis with ulcer formation [
2 ] . In
addition, recurrent symptomatic venous throm-
boembolism (VTE) occurs in 5–10% of patients
per year and signi fi cantly increases the risk of
Deep Vein Thrombosis: What to Do
Karun Sharma and Suresh Vedantham
K. Sharma , M.D., Ph.D.
Assistant Professor of Radiology Interventional
Radiology, Georgetown University Hospital ,
Washington , DC 20007
e-mail: kvs102@gunet.georgetown.edu
S. Vedantham , M.D. ()
Washington University School of Medicine,
Mallinckrodt Institute of Radiology ,
510 S. Kingshighway ,
Box 8131 , St. Louis , MO 63110 , USA
e-mail: vedanthams@mir.wustl.edu
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