Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3656_Библиотеки_им_академика_М_И_Перельмана
.pdf
https://t.me/med1917
11
https://t.me/med1917
Evaluation of hypercoagulable states and
molecular markers of acute venous thrombosis
DIANE M. NITZKI-GEORGE AND JOSEPH A. CAPRINI
11.1 Introduction 131
11.2 Markers of thrombotic risk 131
11.3 Thrombophilia 132
11.4 Predisposing conditions 135
11.1 INTRODUCTION
Normal hemostasis provides a balance between clot formation and dissolution. Vessel injury, venous stasis, and
thrombophilias favor thrombosis. ese three factors,
described as Virchow’s triad, represent a disruption in the
normal hemostatic processes.1 e risk of venous thromboembolism (VTE) increases in proportion to the presence of
these predisposing risk factors.
detailed discussion on the epidemiology and risk factors
forVTE.)
Hypercoagulable states can be categorized as inherited,
acquired, or mixed.4 rombophilic patients most commonly present with characteristic features such as thrombosis at a young age, recurrent thrombosis, resistance to
heparin, warfarin-induced skin necrosis, purpura fulminans, family history of thrombosis, or thrombosis that
develops at an unusual site. e identication of an inherited or acquired thrombophilic defect is most essential when
the information obtained would aect clinical management
of the patient or of a family member.
2,3
(See Chapter 9 for a more
5
11.2 MARKERS OF THROMBOTIC RISK
11. 2.1 β2-glycoprotein
β2-glycoprotein I (β2-GPI) is a major antigen found in
patients who have circulating antiphospholipid antibodies.6
β2-GPI removes microparticulates from the circulation,
including anionic and lipopolysaccharide cellular remnants.6 Repeated exposure and binding of β2-GPI to cellular
phosphatidylserine has been theorized as a mechanism for
11.5 Best demonstrated practices 136
Acknowledgments 137
References 137
the formation of anti-β2-GPI antibodies. ese antibodies
appear to be more specic for antiphospholipid antibody
syndrome (APS) and can cause activation of the dierent
cell types involved in the regulation of hemostasis.
6
11.2.2 D-dimer
Elevated D-dimer is not necessarily a risk factor causing VTE,
but it should be used and interpreted as a marker of hypercoagulability. D-dimer is formed when brin is proteolysed
by plasmin.7 e presence of elevated levels of D-dimer in
the circulation signies brinolysis.8 e degree of D-dimer
elevation with VTE may depend on the extent of disease, the
duration of symptoms, and the use of anticoagulants, with
lower D-dimer levels being associated with less extensive disease, longer duration of symptoms, and anticoagulant use.
Elevated D-dimer levels can also result from recent
major surgery, hemorrhage, trauma, pregnancy, cancer,
or acute arterial thrombosis.9 Dierent assays vary with
respect to sensitivity and specicity, speed of testing, and
the labor involved in performing the assay.7 Moderately and
highly sensitive assays range from about 85% to at least 95%,
respectively, but specicity can be as low at 40% depending on the assay used.9 Other issues with the D-dimer
assays include dierences in the specicity of the antibody
to the various binding sites on the D-dimer molecule, lack
of a denitive cut-o value between abnormal and normal
results, lack of a reference standard assay, and lack of a
standard unit of measurement.7 One brinogen-equivalent
unit is approximately half of a D-dimer unit. Because the
D-dimer assay has a high negative predictive value, it is used
to help “rule out” VTE.
9
7
131
132 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis
https://t.me/med1917
In patients with a normal D-dimer at 1 month aer discontinuing anticoagulation, repeat D-dimer testing every
few months for 1 year can be used to identify the risk for
recurrence.
10–12
Repeat D-dimer tests have not only been
used to identify people who are at risk for recurrent VTE,
but have identied dierences in recurrence rates based
on gender, with men being at greater risk.13 e Vienna
Prediction Model uses a web-based calculator to stratify
VTE recurrence risk based on gender, location of VTE, and
D-dimer results 3 weeks aer anticoagulation is stopped.14
Other D-dimer-based rules to predict VTE recurrence
include the age-adjusted D-dimer and DASH (D-dimer,
Age, Sex, Hormonal) therapy.
15–17
11.2.3 Factor VIII
Elevated plasma levels of factor VIII (FVIII), one of ve
cofactors that control the generation of thrombin, have
been associated with an increased risk of recurrent VTE.18
is risk was initially identied in patients who had a FVIII
level in about the 90th percentile. A more recent study
found an adjusted multivariate hazard ratio (HR) of 4.5
(95% CI: 1.7–12.2) in patients with a FVIII level above the
75th percentile compared with a normal D-dimer.19 When
compared with an abnormal D-dimer, the HR of an elevated FVIII (>75th percentile) was 7.1 (95% CI: 2.8–17.6).19
However, since FVIII is activated during an acute phase,
these results demand careful interpretation. In a followup study of people who presented with an initial VTE
and FVIII levels >230 IU/dL, the probability of recurrent
thrombosis at 2 years aer discontinuing anticoagulation
was 30% (95% CI: 13%–46%).
20
11.2.4 Hyperhomocysteinemia
on the endothelium, factor V, thrombomodulin, and tissue
21,22
factor.
For arterial thrombosis, the authors of the randomized,
double-blind Vitamin Intervention for Stroke Prevention
(VISP) trial found that, despite reducing levels of homocysteine, high-dose vitamin therapy had no eect on
stroke, coronary heart disease events, or death.27 In addition, the Norwegian Vitamin (NORVIT) trial also demonstrated that folate plus vitamin B12 with or without
vitamin B6 does not lower cardiovascular disease or death
aer acute myocardial infarction, and actually led to a
non-statistically signicant increase in events, despite a
reduction in homocysteine.28 Heart Outcomes Prevention
Evaluation 2 (HOPE 2) also found that folic acid and vitamins B6 and B12 did not reduce cardiovascular events in
5522 patients.29 Of note, the NORVIT and HOPE 2 trials
included patients without regard to baseline homocysteine
levels. Furthermore, the china stroke primary prevention
trial (CSPPT) found that patients who took folic acid in
combination with enalapril demonstrated a signicant risk
reduction in rst stroke.
30
11.2.5 P-selectin
P-selectin, an adhesion molecule expressed on the surfaces
of activated platelets and endothelial cells, is increased in
the presence of acute VTE, and is therefore used to aid in the
diagnosis of DVT and pulmonary embolism.31 P-selectin is
a mediator of leukocyte recruitment that promotes the formation of pro-coagulant microparticles, and directly aects
thrombus stabilization.32 Evidence from basic and clinical
studies has suggested that P-selectin can be used as a marker
for reecting a pro-thrombotic state, and has demonstrated
value in cancer patients.
33,34
Hyperhomocysteinemia (HHC) refers to an elevation of the
plasma homocysteine levels, a metabolic substrate derived
from the amino acid methionine.
21,22
HHC may occur in
certain medical conditions, such as renal insuciency,
hypothyroidism, or deciencies in folate, vitamin B6, or
vitamin B12, since these vitamins are important in the
metabolism of homocysteine. Warfarin use has also been
suggested to contribute to HHC, since patients oen avoid
green vegetables that supply these necessary vitamins.
23
HHC may also be suggestive of a mutation in the methylenetetrahydrafolate reductase (MTHFR) gene, an inherited
thrombophilia.
HHC has been correlated with a greater occurrence
of idiopathic deep vein thrombosis (DVT).24 A 4.8-fold
increase risk of VTE has been found in people with HHC.25
Unlike other thrombotic conditions, except for antiphospholipid antibody syndrome, HHC is associated with both
arterial and venous thrombosis. In fact, fasting homocysteine levels have been positively associated with myocardial
infarction risk in women (relative risk [RR]: 3.37, 95% CI:
26
1.30–8.70, P = 0.014).
e mechanism of HHC-associated
thrombosis is not fully elucidated, but may involve eects
11.3 THROMBOPHILIA
Most thrombophilias are inherited, with antiphospholipid
syndrome representing an acquired thrombophilia.35 Other
disease states, conditions, and laboratory abnormalities that
predispose patients to thrombosis
be true thrombophilias, but are discussed elsewhere in this
chapter.
Inherited thrombophilias may be classied into two or
more groups (Table 11.1).21 Group 1 disorders are dened as
deciencies of coagulation factor inhibitors, while group 2
disorders represent an increased level or function of coagulation factors.21 Other inherited thrombophilias include
rare disorders of the brinolytic system.
In general, the group 1 disorders are less common, but
more thrombogenic than the group 2 disorders. e group 2
disorders, although likely risk factors for single thrombotic
events, may not be strong risk factors for subsequent throm-
21
Patients with group 1 disorders usually present at
bosis.
a younger age with idiopathic or recurrent VTE, have a
higher likelihood of recurrent VTE, and are more likely to
have a family history of VTE.
4,5,36
are not considered to
37
36
11.3 Thrombophilia 133
https://t.me/med1917
Table 11.1 Classification of inherited thrombophilias
Group 1 inherited thrombophilia Group 2 inherited thrombophilia
• Antithrombin deficiency
• Protein C deficiency
• Protein S deficiency
• Activated protein C resistance with or without factor V Leiden mutation
• Prothrombin G20210A mutation
• Factor elevation
• Methylenetetrahydrafolate reductase (MTHFR) gene mutation
11.3.1 Activated protein C resistance with or
without the factor V Leiden mutation
28
Antiphospholipid antibodies are reported in up to 10% of
healthy subjects and in 30%–50% of patients with systemic
lupus erythematosus.45 In patients with thrombotic events,
Activated protein C resistance (APC) refers to the resistance of factor V to cleavage by APC, slowing down factor
V cleavage by about 10-fold and thus increasing thrombin
production.
21,37,38
Factor V Leiden (FVL) is the most common inherited thrombophilia, aecting approximately 5% of
Caucasians, 1.2% of African–Americans, 2.2% of Hispanic–
Americans, 1.2% of Native Americans, and 0.45% of
Asian–Americans.
21,37–39
Compared with group 1 disorders
(deciencies of antithrombin, protein C, and protein S), APC
resistance is a relatively weak risk factor for thrombosis.21 e
lifetime probability of symptomatic VTE in patients with a
heterozygous FVL mutation is approximately 10%; thus, the
vast majority of patients will not develop complications due
to this mutation.38 Adjusted HRs of 2.2 (95% CI: 2.0–2.5) for
people with heterozygous mutations and 7.0 (95% CI: 4.8–10)
for those with homozygous mutations have been reported.40
e risk of recurrent VTE is higher in people with heterozygous FVL (odds ratio [OR]: 2.4, 95% CI: 1.6–3.6, P < 0.01).
41
the prevalence is higher, being in the range of 4%–21%, suggesting a potential association between antiphospholipid
antibodies and thrombosis.
When screening for lupus anticoagulants, current guidelines recommend using two or more phospholipid-dependent coagulation tests.
therapy, particularly heparin, the accuracy of the test may be
aected. Anticardiolipin antibodies—immunoglobulin (Ig)
isotypes IgG, IgM, and IgA—are detected by using enzymelinked immunosorbent assays, and are usually reported as
a titer that is specic to each isotype. It is believed that the
IgG isotype is most strongly linked with the development of
thrombosis.
e incidence of recurrent VTE in patients with APS has
been reported to be in the range of 52%–69%, appearing to
be highest in the rst few months of stopping anticoagula-
44
Patients who are at higher risk for a thrombotic event
tion.
are those who have triple positivity consisting of conrmed
positive anticardiolipin, anti-β2-glycoprotein antibodies,
and lupus anticoagulant.
11.3.2 Antiphospholipid antibody syndrome
11.3.3 Antithrombin deficiency
Antiphospholipid antibodies are a heterogeneous family
of autoantibodies, including the lupus anticoagulants and
anticardiolipin antibodies, and are directed against the
phospholipid binding proteins that are important for coagulation.42 APS is an antibody-mediated hypercoagulable
state, dened by the combination of clinical and pathological characteristics as detailed by the Sydney classication.
43
e laboratory criteria are anchored on persistently positive
antibodies: anticardiolipins, β2-glycoprotein, and lupus
anticoagulant testing. Primary APS includes patients with
the syndrome but without lupus or other autoimmune conditions, whereas secondary APS includes patients who also
have systemic lupus erythematosus.44 Catastrophic APS, the
most severe form, is denitive in the presence of four clinical–pathological features: multi-organ involvement, the
development of manifestations in less than a week, the presence of antiphospholipid antibodies (persistence of antibodies is not mandatory for the diagnosis), and small vessel
occlusion.43 e presence of antiphospholipid antibodies
can also develop during treatment with certain medications
and also during periods of infection, but their clinical signicance in these scenarios is not known.
45,46
Antithrombin (formerly termed “antithrombin III”) is a
natural anticoagulant that binds and inactivates factors
IIa (thrombin), IXa, Xa, XIa, and XIIa in order to reduce
clot formation.21 More than 100 mutations may result in
antithrombin deciency, which is inherited as an autosomal dominant trait.37 Antithrombin deciency is classied into two types: type I indicates reduced levels of both
functional (activity) and antigenic antithrombin, while
type II indicates reduced functional but preserved antigenic levels.
21, 37, 50
A deciency in antithrombin is present in 0.07%–0.2%
of the general population and 0.5%–8% of patients presenting with VTE.
21, 37, 50
during an acute thrombotic event, so laboratory diagnosis
should occur at least 3 months aer the event. Diagnosis
should also be deferred until at least 5 days aer the cessation of heparin therapy, as antithrombin levels may be low
during therapy.
zygous antithrombin deciency is increased by 5–50 times.
Most (>50%) patients with heterozygous mutations will
develop VTE by 30 years of age.
45,47
45,48
In patients taking anticoagulant
49
Antithrombin levels can be decreased
37, 50
e VTE risk in patients with hetero-
50
134 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis
https://t.me/med1917
11.3.4 Factor elevations
e prevalence of elevated factor levels ranges from 10% to
20% for factors VIII and IX.51 Elevated plasma concentrations of coagulation factors V, VII, VIII, IX, X, and XI are
potentially induced by regulatory proteins or by unidentied mutations in the factor genes. Whether the elevated
levels contribute to thrombosis or a reection of another
thrombophilic process is not known; however, persistent
factor level elevations are more common in patients with a
history of VTE.
21,51
Factor levels can be measured using functional or antigenic tests. Levels of factors VII, IX, and X may be reduced
in conditions that are associated with vitamin K deciency,
such as vitamin k antagonists (VKAs), malnutrition, and
hepatic or biliary disease. Other conditions associated with
changes in factor levels include oral contraceptive use, pregnancy, dyslipidemia, obesity, aging, acute stress, chronic
inammation, recent aerobic exercise, and blood type.
51
11.3.5 Fibrinolytic system disorders
Emerging laboratory markers suggesting defects in the
brinolytic system include heparin cofactor II deciency
and deciencies in contact factors.
brinogen, changes in brinogen structure, plasminogen
deciency, elevated plasminogen activator inhibitor-1
(PAI-1), and tissue plasminogen activator (tPA) deciency
could all increase the thrombotic risk.
increasing brin levels, an elevated brinogen level may
enhance platelet binding to the glycoprotein IIb/IIIa
receptor and increase plasma viscosity. An acquired or
inherited change in brinogen structure—dysbrinogenemia—may result in abnormal brinogen function and
either hemorrhagic or thrombotic complications. Testing
for any of the brinolytic system defects is not routine, as
the tests are not standardized, the thrombotic risk is not
established, and it is unclear how treatment would change
because of a positive result.
51,55
51–56
Intuitively, elevated
21,51,55,57
Besides
elevated homocysteine level, not the underlying mutation,
is associated with thrombosis, measuring the total plasma
homocysteine level (tHcy) is more useful than testing for
genetic mutations.
8,22
Reasonable denitions for moderate,
intermediate, and severe elevations are tHcy 15–30 μmol/L,
31–100 μmol/L, and 100 μmol/L, respectively.21 e relative
risk for arterial thrombosis, according to a meta-analysis,
was 1.3 (95% CI: 1.1–1.5); data showing an increased risk
of recurrent VTE are more substantial than those for rst
22
VTE.
11.3.7 Protein C deficiency
Similar to antithrombin deciency, protein C deciency is
classied into two types: type I implies a reduction in both
functional and antigenic levels, usually due to low protein C
production, and type II implies a reduced functional level
but a normal antigenic level. More than 160 mutations result
in protein C deciency, which makes genetic testing imprac-
21, 37, 50
tical.
Protein C deciency is present in approximately
0.17%–0.4% of the general population, with the majority
being type I deciency. Heterozygous deciency is present
in 1.5%–11.5% (mean: 4%) of patients with VTE.
21, 37, 50
Protein C deciency should be diagnosed with a func-
tional protein C level.
37, 43
is level is not elevated during
an acute VTE episode, which enables testing to be done at
any time.58 A nding of a normal protein C level during
an acute event would rule out deciency.50 Warfarin and
other vitamin K antagonists are the most common reasons
for low protein C functional or antigenic levels; thus, waiting to test until 2–4 weeks aer warfarin is discontinued is
prudent.
37, 50
e OR of VTE in patients with protein C deciency is
3.1. By 40 years of age, about 50% of patients with heterozygous protein C deciency will have an episode of VTE, and
the risk is increased by an additional concurrent inherited
or acquired thrombophilia.
50
11.3.8 Protein S deficiency
11.3.6 MTHFR gene mutation
Inherited HHC can result from mutations in the genes
coding enzymes involved in homocysteine metabolism:
MTHFR, cystathione b synthase (CBS), or methionine
synthase.
21,22
ese mutations may or may not lead to
HHC, depending on the homozygosity or heterozygosity
of the mutations, co-inheritance with another mutation,
or the presence of concurrent B vitamin deciency.37 e
most common known mutations resulting in HHC are the
MTHFR C677T (“thermolabile”) and the MTHFR A1298C
mutations. Although these mutations may result in HHC,
they are not directly associated with thrombosis.
e prevalence of the heterozygous MTHFR C677T
mutation is 34%–50% and the prevalence of the homozygous
mutation is 12%–15%, depending on the population. e
MTHFR A1298C mutation is less common.
21,22,37
21,22
Since an
Like protein C, protein S is a vitamin K-dependent endogenous anticoagulant that is primarily produced in the
37, 59
liver.
Protein S is a cofactor for APC’s inactivation of factors Va and VIIIa; therefore, protein S deciency is phenotypically similar to protein C deciency. Protein S deciency
diers from the other two deciencies of natural anticoagulants in that 60%–70% of the total protein S is bound to the
transport protein C4b-binding protein and is not available
as a cofactor for APC. More than 131 mutations are associated with protein S deciency.
21, 37, 59
Protein S deciency is classied into three types based
on free, total, and functional tests. Type I deciency denotes
low levels of both free and total antigen, type II denotes
low activity but normal free and total levels, and type III
denotes low free but normal total levels. Type III deciency
usually results from abnormal binding of protein S to C4bbinding protein.
37, 59
11.4 Predisposing conditions 135
https://t.me/med1917
Approximately 0.03%–0.2% of the general population have protein S deciency, but the true prevalence is
unknown due to the diculty in making an accurate diagnosis. Diagnosing protein S deciency is challenging due to
multiple factors aecting the free protein S level. Total protein S level is not a clear predictor of VTE risk.
57
e available tests for the diagnosis of protein S deciency
are free antigen level, total antigen level, and functional
(APC cofactor activity) level. Routine testing of antigenic
total protein S is not usually necessary. e functional test
is inuenced by factors other than protein S activity, and
should be interpreted with caution. Fluctuations in protein S levels have been noted over time. us, the diagnosis
should be conrmed with a second test.
37, 59
e rates of VTE being associated with protein S deciency have been reported to range from zero to 11.5-fold.37
A familial study showed that 50% of patients with protein S
deciency develop VTE by 45 years of age, but populationbased studies show a weaker or no association, possibly due
to the diculty in reaching statistical signicance with the
low incidence of protein S deciency.
59
11.3.9 Prothrombin defects: Prothrombin
gene 20210A mutation
e prothrombin G20210A (P20210) mutation is a G to
A point mutation on the factor II gene at position 20210,
which results in higher circulating levels of functionally
normal prothrombin.
21, 37, 60
P20210 is the second most common inherited thrombophilia. e prevalence in the United
States is 1%–2%. About 5%–10% of patients with VTE have
P20210.
21,60
Since P20210 is a mutation, it is diagnosed with
a genetic test, and can be tested without regard to a patient’s
current conditions.
37, 60
e adjusted risk for VTE in people
with homozygous prothrombin P20210 is higher (HR: 11,
95% CI: 2.8–44) than for those with a heterozygous mutation (HR: 1.5, 95% CI: 1.2–1.9).40 e risk of recurrent VTE
is less signicant, with an OR of 1.72 (95% CI: 1.27–2.31) for
recurrence aer a rst event in patients who are heterozygous for P20210, which is lower than the risk for rst VTE,
but higher than the risk for non-carriers.
61
11.4 PREDISPOSING CONDITIONS
11.4.1 Blood groups
Patients who have type 0 blood appear to be at lower risk
for developing DVT. High levels of factor VIII and von
Willebrand factor are associated with certain genotypes,
specically the A1 and B alleles, of the ABO blood system.
e O1 and O2 alleles impart a lower VTE risk.62 Data on
the VTE risk associated with the A2 allele are conicting
and require further investigation.
consecutive patients who presented with DVT, the OR of
having a non-O blood type was 2.21 (95% CI: 1.78–2.75).
e combination of a non-O blood type plus thrombophilia is an even greater risk for DVT (OR: 7.06, 95% CI:
62–64
In a series of 712
4.85–10.28).
homozygous FVL.
40,64,65
is is especially true in patients with
66
11.4.2 Cancer
VTE is a major cause of morbidity and mortality in cancer
patients. Pulmonary embolism is the cause of death in one
of every seven hospitalized cancer patients who dies.
67,68
e frequency of new and recurrent VTE is much higher in
cancer patients than in non-cancer patients, and the majority of the events occur spontaneously without the presence
of other triggering risk factors, as in the case of non-cancer
patients. e reverse association is also true, as evidenced by
the high rate of cancer development in patients with VTE,
especially idiopathic thrombosis.67 Some common risk factors that further heighten the risk of VTE in cancer patients
include surgery, chemotherapy, the insertion of central
venous catheters, and immobility. Treatment of VTE should
be continued indenitely until the cancer is in remission and
the patient is no longer receiving chemotherapy. Treatment
with low-molecular-weight heparin is more eective than
warfarin, and it is the preferred treatment approach for the
rst 3–6 months aer an acute event.
67,69
11.4.3 Family history
Patients who have one rst-degree relative with a history of
VTE are at a two-fold greater risk of developing VTE (OR: 2.2,
95% CI: 1.9–2.6), and those who have more than one aected
relative have up to a four-fold increased risk of VTE (OR: 3.9,
95% CI: 2.7–5.7).70 ese ndings apply to siblings, parents,
children, maternal and paternal half-siblings, nieces, nephews, cousins, and spouses of those diagnosed with VTE.
71
11.4.4 Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a severe pathological adverse eect of heparin that involves an immunoglobulin-mediated response to the heparin molecule,
leading to platelet activation and thrombin generation.
Although heparin-induced antibody formation occurs in
10%–20% of patients treated with heparin, the vast majority of these patients never develop HIT. Antibodies to the
heparin/PF-4 complex are transient and have been reported
to disappear from the circulation within a median of 85
72,73
days.
Low-molecular-weight heparins are associated
with a signicantly lower risk of HIT than unfractionated
heparin (UFH) (<1%).
72
11.4.5 Pregnancy
In patients who are pregnant, the risk for arterial thrombosis is four-fold greater compared to non-pregnant women.
e risk of VTE during pregnancy is four- to ve-fold
74
greater.
in factors VII, VIII, and X, as well as brinogen, von
Willebrand factors, and PAI-1. ese changes in hemostasis,
Pregnancy is normally associated with increases
136 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis
https://t.me/med1917
in addition to the physically decreased venous capacity and
outow imposed by the pregnancy, are implicated as contributing to the VTE risk, and are not expected to normalize
until 8 weeks post-partum.
74
Of the VTEs, about 80% present as a DVT, while 20%
are pulmonary embolisms. Recurrent VTE accounts for
15%–25% of the events that occur during pregnancy, representing a three- to four-fold increase in risk (RR: 3.5, 95%
CI: 1.6–7.8). e most important risk factor is the presence
of a thrombophilia, which has been found in 30%–50% of
women who have a VTE during pregnancy.
11.4.6 Surgery
In patients with past thrombosis or thrombophilic defects,
BOX 11.1: Patients who may be considered
for thrombophilia work-up
Unexplained or “idiopathic” thromboembolism (first
event)
Secondary, non-cancer-related first event and age
<50 years (includes thrombosis on oral contraceptives and hormone-replacement therapy)
Recurrent “idiopathic” or secondary non-cancer-
related events
Thrombosis at unusual sites (portal vein, sinus
veins, etc.)
Extensive thrombosis
Strong family history of venous thromboembolism
the chance of recurrent thrombosis post-operatively may
be well over 50%.8 It is most important that patients with
known thrombophilic defects or related positive family
members are carefully screened and counseled pre-operatively.75 is knowledge will enable proper selection, onset,
dosage, and duration of thromboprophylaxis, as well as
justifying the addition of physical methods of prophylaxis,
despite their added costs.
causing a thrombotic event. In studies conducted to date,
the total score was compared to the actual development of a
thrombotic event within 30–60 days post-operatively. is
system has been tested in over 25,000 patients worldwide in
more than 15 trials of medical and surgical patients. e risk
of a clinical event is <1.0% in those with a score of 4 or less. e
clinically relevant VTE rate increases parallel to rising scores.
11.5 BEST DEMONSTRATED PRACTICES
11.5.1 Testing
Scores of 9 or more increase the VTE risk to 18% aer some
operations. e concept seems to hold true regardless of the
specialty tested. Boston University has shown the best results
using this score tied to a mandatory prophylaxis schema.
e combination of a genetic thrombophilic defect and one
or more acquired risk factor(s), such as surgery or oral contraceptive use, lead to a higher risk of VTE than the separate eects of these single factors.36 Universal testing for an
inherited thrombophilia is inappropriate and not recommended. A negative test only rules out the presence of the
thrombophilic defects for which the patient has been tested,
and is not necessarily proof that an unidentiable defect
does not exist. us, in each case, evaluating and documenting a detailed initial clinical history are crucial.
4
Currently, there are no consistent guidelines in the literature by which patients should be considered for thrombophilia work-up and for which specic tests should be included
if patients are tested. Box 11.1 gives some practical recom-
mendations regarding these issues. Many of the function and
antigen assays for thrombophilias can be aected by a variety
of external factors, such as medications, acute thrombosis,
and other acquired conditions. us, these assays should be
repeated aer ruling out any external factors and before a
nal diagnosis of an inherited thrombophilia is made.
76
Patients with a score of 4 or less can receive prophylaxis at
the discretion of the treating physician (low to moderate risk)
during hospitalization. Many of these low-risk patients are not
given anticoagulant prophylaxis, since the risk of a clinical
bleeding event is greater than the chance of a clinically evident
thrombosis. On the other hand, those with a score of 5–8 are
considered to be in the high-risk group and need to be protected for the period of time shown in clinical trials in order
to prevent post-operative thrombosis. is time period is 7–10
days regardless of their length of hospital stay. Finally, patients
with a score of 9 or more (highest risk) are given prophylaxis
for 30 days, since the incidence of real thrombotic events is
6%–18%. ese rules are mandatory, but the physicians can
opt out if they feel that there is a high bleeding risk. Physician
compliance in high-risk patients was 89%, and it was 77% in
the highest-risk group. e VTE rate in general surgery was
0.2%, and the pulmonary embolism rate approached zero during this time. is system at Boston University has recorded
the lowest VTE event rates ever seen in the National Surgical
Quality Improvement Project (NSQIP) database.
7,62
78
78
11.5.2 Risk assessment using scoring
systems
ere are many scoring systems for evaluating the thromboembolic risk in surgical patients, and the most widely validated is the Caprini score.
of common risk factors, each of which is assigned a numerical weight. is number reects the likelihood of each factor
77
is system consists of a number
11.5.3 The importance of scoring
inpatients with thrombophilia
Patients with a history of thrombosis receive a score of 3
points, with an additional 3 points for those with a thrombophilic defect. Family history of thrombosis increases the
score to 9. is means that in some patients who are contemplating elective quality-of-life procedures, a high score may
References 137
https://t.me/med1917
cause them to rethink the advisability of going ahead with
the planned surgery. e risk of major or fatal complications
in this small subset of patients may be as high as 5%.
Since more than one thrombophilic defect can be present in a given patient, testing for additional inherited or
acquired thrombophilias should be considered, even aer
the identication of a single thrombophilic defect. Consider
11.5.4 General recommendations
repeating function or antigen diagnostic assays aer ruling
out interfering factors such as medications and acquired
Informed consent should be obtained from patients, and
especially asymptomatic family members, before thrombo-
conditions, and before a denite diagnosis of an inherited
thrombophilia is made.
4,36,37,76
philia testing is performed. Counseling should be provided
to patients who test positive for one or more thrombophilias
ACKNOWLEDGMENTS
regarding their risk of thrombosis, the signs and symptoms of
VTE, and the benets of antithrombotic prophylaxis in highrisk situations such as elective surgery or pregnancy.
Guidelines 2.1.0 of the American Venous Forum on the evaluation of hypercoagulable states and molecular markers of
acute venous thrombosis
No. Guideline
2.1.1 Patients with the following conditions are considered for
evaluation for thrombophilia:
1. Unexplained or “idiopathic” thromboembolism (first event)
2. Secondary, non-cancer-related first event and age <50
years (includes thrombosis on oral contraceptives and
hormone-replacement therapy)
3. Recurrent “idiopathic” or secondary non-cancer-related
events
4. Thrombosis at unusual sites (portal vein, sinus veins, etc.)
5. Extensive thrombosis
6. Strong family history of venous thromboembolism
2.1.2 Testing for thrombophilia is recommended to most patients
2–4 weeks after completing the typical course (usually 6
months) of anticoagulant therapy.
2.1.3 Long-term, primary pharmacologic thromboprophylaxis of
asymptomatic thrombophilic patients is not recommended.
2.1.4 Patients with thrombophilia should be considered for
thromboprophylaxis at times of high thrombotic risk such
as surgery, trauma, prolonged immobility, pregnancy, or
acute illness.
2.1.5 Patients with thrombophilia should be considered for
prolonged anticoagulation following acute deep vein
thrombosis.
4,36,37,76
e authors would like to thank Dr. Alfonso J. Tafur for his
review and comments.
Grade of evidence
Grade of
recommendations
(1:strong; 2: weak)
1 C
1 C
2 B
1 A
1 B
(A:high quality;
B:moderate quality;
C:low or very low quality)
REFERENCES
●
= Key primary paper
★
= Major review article
1. Wolberg AS, Aleman MM, Leiderman K, and
Machlus KR. Procoagulant activity in hemostasis and
thrombosis: Virchow’s triad revisited. Anesth Analg
2012;114(2):275–85.
●
2. Heit JA, O’Fallon WM, Petterson TM etal. Relative
impact of risk factors for deep vein thrombosis and
pulmonary embolism: A population-based study.
Arch Int Med 2002;16 2:1245 – 8.
3. Rosendaal F. Risk factors for venous thrombosis:
Prevalence, risk and interaction. Semin Hematol
19 97; 3 4 :171– 8 7.
★
4. Haemostasis and Thrombosis Task Force, British
Committee for Standards. Investigation and management of heritable thrombophilia. Br J Haematol
2001;114:512–28.
5. Middeldorp S, Buller H, Prins M etal. Approach
to the thrombophilic patient. In: Coleman R, ed.
138 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis
https://t.me/med1917
Hemostasis and Thrombosis: Basic Principles and
Clinical Practice. Philadelphia, PA: Lippincott,
Williams & Wilkins, 1994, 1085–100.
6. de Groot PG and Meijers JC. β(2)-glycoprotein I:
Evolution, structure and function. J Thromb Haemost
2011;9 ( 7):12 75 – 84.
7. Lensing AWA, Hirsh J, Ginsberg JS, and Büller HR.
Diagnosis of venous thrombosis. In: Colman RW,
Hirsh J, and Marder VJ etal., eds. Hemostasis and
Thrombosis. Philadelphia, PA: Lippincott Williams &
Wilkins, 2001, 1277–301.
★
8. Caprini JA, Glase CJ, Anderson CB, and Hathaway K.
Laboratory markers in the diagnosis of venous thromboembolism. Circulation 2004;109(Suppl. I):I-4–I-8.
9. Wells PS, Owen C, Doucette S etal. Does this
patient have deep vein thrombosis? JAMA
2006;295:199–207.
10. Palareti G, Cosmi B, Legnani C etal.; DULCIS
(D-dimer and ULtrasonography in Combination
Italian Study) Investigators. D-dimer to guide the
duration of anticoagulation in patients with venous
thromboembolism: A management study. Blood
2014;124(2):196–203.
11. Tamizifar B, Oghab P, and Esfahani MA. The prediction role of D-dimer in recurrence of venous
thromboembolism 1-year after anticoagulation discontinuing following idiopathic deep vein thrombosis. J Res Med Sci 2014;19(7):586–91.
●
12. Cosmi B, Legnani C, Tosetto A etal.; PROLONG
Investigators (on behalf of Italian Federation of
Anticoagulation Clinics). Usefulness of repeated
D-dimer testing after stopping anticoagulation for
a first episode of unprovoked venous thromboembolism: The PROLONG II prospective study. Blood
2010;115(3):481–8.
13. Kearon C, Spencer FA, O’Keeffe D etal.; D-dimer
Optimal Duration Study Investigators. D-dimer
testing to select patients with a first unprovoked
venous thromboembolism who can stop anticoagulant therapy: A cohort study. Ann Intern Med
2015;162(1):27–34.
●
14. Eichinger S, Heinze G, and Kyrle PA. D-dimer levels
over time and the risk of recurrent venous thromboembolism: An update of the Vienna prediction
model. JAm Heart Assoc 2014;3(1):e000467.
15. Di Marca S, Cilia C, Campagna A etal. Comparison
of wells and revised Geneva rule to assess pretest probability of pulmonary embolism in highrisk hospitalized elderly adults. J Am Geriatr Soc
2015;63(6):1091–7.
●
16. Righini M, Van Es J, Den Exter PL etal. Age-adjusted
D-dimer cutoff levels to rule out pulmonary embolism: The ADJUST-PE study. JAMA 2014;311(11):1117–
24. Erratum in: JAMA. 2014;311(16):1694.
17. Tosetto A, Iorio A, Marcucci M etal. Predicting
disease recurrence in patients with previous unprovoked venous thromboembolism: A proposed
prediction score (DASH). J Thromb Haemost
2012;10(6):1019– 25.
18. Kyrle PA and Eichinger S. Clinical scores to predict recurrence risk of venous thromboembolism.
Thromb Haemost 2012;108(6):1061– 4.
19. Cosmi B, Legnani C, Cini M, Favaretto E, and Palareti
G. D-dimer and factor VIII are independent risk factors for recurrence after anticoagulation withdrawal
for a first idiopathic deep vein thrombosis. Thromb
Res 2008;122(5):610–7.
20. Eischer L, Gartner V, Schulman S, Kyrle PA, and
Eichinger S; AUREC-FVIII Investigators. 6 versus 30
months anticoagulation for recurrent venous thrombosis in patients with high factor VIII. Ann Hematol
2009;88(5):485–90.
★
21. Crowther MA and Kelton JG. Congenital thrombophilic states associated with venous thrombosis:
A qualitative overview and proposed classification
system. Ann Intern Med 2003;138:128 – 34.
22. Key NS and McGlennen RC. Hyperhomocyst(e)
inemia and thrombophilia. Arch Pathol Lab Med
2002;126:1367–75.
23. Sobczyń ska-Malefora A, Harrington DJ, Rangarajan
S, Kovacs JA, Shearer MJ, and Savidge GF.
Hyperhomocysteinemia and B-vitamin status after
discontinuation of oral anticoagulation therapy in
patients with a history of venous thromboembolism.
Clin Chem Lab Med 2003;41(11):1493–7.
24. Omar S, Ghorbel IB, Feki H etal.
Hyperhomocysteinemia is associated with deep
venous thrombosis of the lower extremities in
Tunisian patients. Clin Biochem 2007;40 (1–2):41– 5.
25. Köktürk N, Kanbay A, Aydoğdu M, Özyılmaz E,
Bukan N, and Ekim N. Hyperhomocysteinemia
prevalence among patients with venous thromboembolism. Clin Appl Thromb Hemost 2011;17(5):487–93.
●
26. Page JH, Ma J, Chiuve SE etal. Plasma total cysteine and total homocysteine and risk of myocardial
infarction in women: A prospective study. Am Heart
J 2010;159(4):599–604.
27. Toole JF, Malinow MR, Chambless LE etal. Lowering
homocysteine in patients with ischemic stroke to
prevent recurrent stroke, myocardial infarction, and
death: The vitamin intervention for stroke prevention (VISP) randomized controlled trial. JAMA
20 04;291:565–75.
28. Bønaa KH, Njølstad I, Ueland PM etal. Homocysteine
lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578–88.
29. The Heart Outcomes Prevention Evaluation (HOPE) 2
Investigators. Homocysteine lowering with folic acid
and B vitamins in vascular disease. N Engl J Med
2006;354:1567–77.
●
30. Huo Y, Li J, Qin X etal.; CSPPT Investigators. Efficacy
of folic acid therapy in primary prevention of stroke
among adults with hypertension in China: The CSPPT
randomized clinical trial. JAMA 2015;313(13):1325–35.
31. Antonopoulos CN, Sfyroeras GS, Kakisis JD,
https://t.me/med1917
Moulakakis KG, and Liapis CD. The role of soluble P
selectin in the diagnosis of venous thromboembolism. Thromb Res 2014;13 3(1):17– 24.
32. André P. P-selectin in haemostasis. Br J Haematol
2004;126(3):298–306.
33. Pabinger I and Ay C. Biomarkers and venous
thromboembolism. Arterioscler Thromb Vasc Biol
2009;29(3):332–6.
●
34. Ay C, Simanek R, Vormittag R etal. High plasma
levels of soluble P-selectin are predictive of venous
thromboembolism in cancer patients: Results from
the Vienna Cancer and Thrombosis Study (CATS).
Blood 2008;112(7):2703–8.
35. Cavenagh JD and Colvin BT. Guidelines for the
management of thrombophilia. Department
of Haematology, The Royal London Hospital,
Whitechapel, London, UK. Postgrad Med J
1996;72(844):87–94.
36. Cushman M. Inherited risk factors for venous thrombosis. Hematology (Am Soc Hematol Educ Program)
20 0 5 ; 4 5 2 – 7.
37. Moll S. Thrombophilias —Practical implications and
testing caveats. J Thromb Thrombolysis 2006;21:7–15.
38. Press RD, Bauer KA, Kujovich JL, and Heit JA.
Clinical utility of factor V Leiden (R506Q) testing for
the diagnosis and management of thromboembolic
disorders. Arch Pathol Lab Med 2002;126:1304 –18.
39. Mazoyer E, Ripoll L, Gueguen R etal.; FITENAT
Study Group. Prevalence of factor V Leiden and
prothrombin G20210A mutation in a large French
population selected for nonthrombotic history:
Geographical and age distribution. Blood Coagul
Fibrinolysis 2009;20(7):503–10.
40. Sode BF, Allin KH, Dahl M, Gyntelberg F, and
Nordestgaard BG. Risk of venous thromboembolism
and myocardial infarction associated with factor V
Leiden and prothrombin mutations and blood type.
CMAJ 2013;185(5):E229–37.
41. Sveinsdottir SV, Saemundsson Y, Isma N, Gottsäter
A, and Svensson PJ. Evaluation of recurrent venous
thromboembolism in patients with factor V Leiden
mutation in heterozygous form. Thromb Res
2012;130(3):467–71.
42. Giannakopoulos B and Krilis SA. The pathogenesis
of the antiphospholipid syndrome. N Engl J Med
2013;368(11):1033–44.
43. Asherson RA, Cervera R, de Groot PG etal.;
Catastrophic Antiphospholipid Syndrome Registry
Project Group. Catastrophic antiphospholipid
syndrome: International consensus statement on
classification criteria and treatment guidelines. Lupus
2003;12(7):530–4.
44. Ortel TL. The antiphospholipid syndrome: What
are we really measuring? How do we measure it?
And how do we treat it? J Thromb Thrombolysis
2006;21:79–83.
References 139
★
45. Lim W, Crowther MA, and Eikelboom JW.
Management of antiphospholipid antibody syndrome: A systematic review. JAMA 2006;295:1050–7.
46. von Landenberg P, Döring Y, Modrow S, and
LacknerKJ. Are antiphospholipid antibodies an
essential requirement for an effective immune
response to infections? Ann N Y Acad Sci.
2007;1108:578–83.
47. Galli M, Luciani D, Bertolini G, and Barbui T. Lupus
anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: A systematic review of the
literature. Blood 2003;101:1827–32.
48. Keeling D, Mackie I, Moore GW, Greer IA, and
Greaves M; British Committee for Standards in
Haematology. Guidelines on the investigation and
management of antiphospholipid syndrome. Br J
Haematol 2012;157(1):47–58.
●
49. Pengo V, Ruffatti A, Legnani C etal. Incidence of
a first thromboembolic event in asymptomatic
carriers of high-risk antiphospholipid antibody
profile: A multicenter prospective study. Blood
2011;118(17):4714–8.
50. Kottke-Marchant K and Duncan A. Antithrombin
deficiency: Issues in laboratory diagnosis. Arch
Pathol Lab Med 2002;126:1326–36.
51. Chandler WL, Rodgers GM, Sprouse JT, and
Thompson AR. Elevated hemostatic factor levels as
potential risk factors for thrombosis. Arch Pathol Lab
Med 20 02;126:1405–14.
52. Tollefsen DM. Heparin cofactor II deficiency.
ArchPathol Lab Med 2002;126:1394– 4 0 0.
53. Brandt J. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for
thromboembolic disease. Arch Pathol Lab Med
20 02;126:1376 – 81.
54. Francis CW. Plasminogen activator inhibitor-1
levels and polymorphisms: Association with
venous thromboembolism. Arch Pathol Lab Med
20 02;126:14 01– 04.
55. Hayes T. Dysfibrinogenemia and thrombosis. Arch
Pathol Lab Med 2002;126:1387–90.
56. Kitchens C. The contact system. Arch Pathol Lab
Med 20 02;126:1382– 6.
57. Pintao MC, Ribeiro DD, Bezemer ID etal. Protein
S levels and the risk of venous thrombosis: Results
from the MEGA case–control study. Blood
2013;122(18):3210 –9.
58. Minuk L, Lazo-Langner A, Kovacs J, Robbins M,
Morrow B, and Kovacs M. Normal levels of protein C
and protein S tested in the acute phase of a venous
thromboembolic event are not falsely elevated.
Thromb J 2010;8:10.
59. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, and
Bovill E. A review of the technical, diagnostic, and
epidemiologic considerations for protein S assays.
Arch Pathol Lab Med 2002;126:1349– 66.
Соседние файлы в папке Библиотека им академика М.И. Перельмана