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activity levels of protein C are measured, whereas for pro-
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tein S, only antigen levels are measured. ese measurements should be made prior to starting anticoagulation
8,13,18
therapy with either heparin or warfarin.
FACTOR V LEIDEN MUTATION AND
APC RESISTANCE
Factor V is a glycoprotein synthesized in the liver. With
Factor V Leiden, a point mutation occurs when arginine
is substituted by glutamine at position 506. is point
mutation causes the activated Factor V to be resistant to
inactivation by APC, thus causing a procoagulant state.
e mutation appears almost exclusively in the Caucasian
population, and inheritance is autosomal dominant. e
relative risk of a thromboembolic event in a heterozygous
carrier is increased ve- to seven-fold over the general population and increased up to eighty-fold in a homozygous car-
4
e risk of thrombosis also increases with combined
rier.
genetic defects and/or additional acquired risk factors and
15
will exceed the sum of the separate risks.
Clinically, patients may present with DVT in the lower
extremities, or less commonly in the portal vein, cerebral
vein, or super cial venous system. Laboratory testing for
the diagnosis of APC resistance and Factor V Leiden may
be performed using functional clotting-based assays or by
genetic testing. Factor V Leiden is the most common cause
for APC resistance. Other less common causes include
Factor V Cambridge, HR2 haplotype, Factor V Hong Kong,
and Factor V Liverpool. e functional clotting-based
assays include a modi ed activated partial thromboplastin time (aPTT) test, which dilutes the patient’s plasma in
Factor V–de cient plasma or incorporates dilute Russell’s
viper venom in the assay. e presence of APC resistance
is then determined by measuring the aPTT in the presence
and absence of APC. is modi ed test may be used in the
presence of heparin, warfarin, and lupus anticoagulant. e
genetic test relies on DNA ampli cation using PCR and is
18
the most reliable test.
PROTHROMBIN G20210
POLYMORPHISM
Prothrombin (Factor II) is a zymogen synthesized in the
liver and dependent on vitamin K. When prothrombin is
activated, it forms thrombin (Factor IIa). Asingle mutation where adenine is substituted for guanine occurs at the
20210 position. e mechanism for increased thrombotic
risk is not well understood, but individuals with this genetic
variant have supranormal levels of prothrombin. e mutation is inherited as an autosomal dominant trait and is
associated with both arterial and venous thrombosis. Like
Factor V Leiden, this mutation occurs almost exclusively in
the Caucasian population. Individuals with the prothrom-
7
bin gene variant are typically heterozygous.
Heterozygosity
confers a two-fold increase in the risk of thrombosis, and
homozygosity confers approximately a ten-fold increase in
the risk of thrombosis.
13
Clinically, patients may present with DVT of the lower
extremity, cerebral venous thrombosis, and arterial thrombosis. e risk of thrombosis increases in the presence of
other genetic coagulation defects and with acquired risk
1,7
factors.
Detection of the prothrombin G20210 polymorphism is by genetic analysis alone, as no correlation exists
between functional prothrombin levels and those individu-
13
als with the genetic mutation.
HYPERHOMOCYSTEINEMIA
Homocysteine is an amino acid formed during the metabolism of methionine and may be elevated secondary to inherited defects in two enzymes that are part of the conversion
of homocysteine to cysteine. e two enzymes involved are
5
,N 10 –methylene tetrahydrofolate reductase (MTHFR)
N
or cystathionine beta-synthase. Hyperhomocysteinemia has
been shown to increase the risk of atherosclerosis, atherothrombosis, and venous thrombosis.
Elevated plasma homocysteine levels cause various dysfunctions of endothelial cells leading to a prothrombotic
state. With the oxidation of homocysteine, superoxide radicals are formed, which cause endothelial damage, smooth
muscle proliferation, and activation of platelets and leukocytes. Additionally, hyperhomocysteinemia augments factor V and VII activity and decreases the activation of protein
C, indirectly stimulates platelet aggregation, decreases the
production of endothelium-derived nitric oxide, and inter-
1,19
feres with the binding of t-PA.
In patients with unexplained VTE, homocysteine levels
should be measured. Levels may be measured by obtaining a
fasting plasma homocysteine or a er giving a standardized
methionine-loading test. In patients who have been given
the loading dose of methionine, hyperhomocysteinemia is
present if the level of homocysteine is two standard deviations above themean.
In patients with hyperhomocysteinemia, folate, B
can be given with normalization of homocysteine lev-
or B
12
, and/
6
els a er several weeks of therapy. Whether this treatment
has any a ect on the prothombotic e ects of hyperhomo-
19
cysteinemia remains to be proven.
ACQUIRED HYPERCOAGULABLE
DISORDERS
ere exist far more known causes of acquired hypercoagulable disorders than inherited disorders. Additionally, several of the congenital hypercoagulable states may be seen as
acquired states attributable to a change in the production or
consumption of various factors. Many of the common causes
of acquired hypercoagulable disorders will be discussed.
278 • VENOUS THROMBOEMBOLISM
HEPARININDUCED
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THROMBOCYTOPENIA HIT
AND HEPARININDUCED
THROMBOCYTOPENIA AND
THROMBOSIS SYNDROME HITTS
Approximately 2 to 3% of patients who undergo heparin
therapy will develop HIT or HITTS. Patients with HIT
will have thrombocytopenia (characterized by a platelet
3
count less than 100,000/mm
or a decrease in the baseline count by more than 30%), will be resistant to anticoagulation with heparin, and may develop arterial or venous
thromboses.
Two types of HIT exist. e rst type is not associated with an immune mediated response and typically is
seen in the rst few days a er initiation of heparin therapy. Typically, platelet levels do not fall below 100,000/
3
. Type II is immune-mediated with patients producing
mm
immunoglobulin G (IgG) antibodies against complexes of
heparin and platelet factor 4.Antibody formation usually
occurs between the 5th and 10th day a er the rst heparin
exposure. e formation of these immune complexes creates a hypercoagulable state by activating platelets and the
8,20
endothelium.
Antibodies may develop against any form of heparin,
and the formation of antibodies is independent of the age
or sex of the patient, the route of administration of heparin, or the amount of heparin administered. Clinically, a
patient will have a declining platelet count, may have an
increasing resistance to anticoagulation therapy with heparin, and may develop a new thrombosis. Laboratory testing
may be performed, which includes testing for antibodies to
1
heparin.
Functional assays to detect platelet aggregation or
activation in the presence of heparin-associated antibodies
are well established. Enzyme-linked immunosorbent assays
(ELISA) are readily available, but there is up to 40% discordance in the results of these antigenic assays, when compared with the functional platelet aggregation tests. e
ELISA may detect IgM and IgA varieties, whereas platelet
aggregation assays detect only the IgG antibodies.
e treatment of HIT includes the prompt discontinuation of heparin or low molecular weight heparin, and the
administration of alternative anticoagulants, such as recombinant hirudin or argatroban (both direct thrombin inhibitors). Danaparoid (a low molecular weight heparinoid),
has been used in the past as an alternative anticoagulant in
patients with HIT. However, danaparoid production was
discontinued in 2002 because of a shortage in the drug substance. Fondaparinux (a pentasaccharide that inactivates factor Xa via an antithrombin-dependent mechanism) has had
recent success as another alternative anticoagulant. As with
hirudin and argatroban, there are no reliable agents that can
reverse the anticoagulant e ect of fondaparinux. Hirudin
and fondaparinux are metabolized primarily via renal excretion, whereas argatroban is metabolized primarily by theliver.
Patients with heparin-induced thrombocytopenia are at
high risk for the development of subsequent thromboses,
and the discontinuation of heparin alone is usually not suf cient. Warfarin may be used for prolonged anticoagulation
in patients with acute thromboses, but its initiation should
be delayed until the platelet count has substantially recovered. In addition, warfarin therapy should overlap with
the administration of a direct thrombin inhibitor until the
platelet count normalizes.
L U P U S A N T I C O A G U L A N T /
ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
e term “antiphospholipid syndrome” was developed to
describe the clinical manifestations of a hypercoagulable
state associated with antiphospholipid antibodies. e
most commonly identi ed antiphospholipid antibodies are lupus anticoagulant, anticardiolipin antibody, and
-glycoprotein I antibodies. 21
anti-β
2
is syndrome is divided into primary and secondary
syndromes. e primary syndrome occurs in patients without associated autoimmune disorders, and the secondary
syndrome occurs in patients with systemic lupus erythematosus (SLE) and/or other autoimmune disorders. e procoagulant e ects of the antiphospholipid antibodies leading
to thrombosis include inhibition of the APC pathway, inhibition of antithrombin activity, inhibition of anticoagulant activity of β
-glycoprotein I, inhibition of brinolysis,
2
potentiation of platelet activation, and enhanced platelet
8,21
activation, among others.
Antiphospholipid antibodies are found in 1 to 5% of
the population, and their prevalence increases with age.
Among patients with SLE, the prevalence of antiphospholipid antibodies is much higher, with 12 to 30% having anticardiolipin antibodies and 15 to 34% having lupus
anticoagulant antibodies. In patients with SLE and an
antiphospholipid antibody, 50 to 70% may develop the
1
antiphospholipid syndrome.
In order for the diagnosis of
antiphospholipid syndrome to be made, the patient must
meet the criteria of the international consensus statement. Ade nitive diagnosis may be made if the patient
has at least one of the clinical criteria and one of the
laboratory criteria. e consensus statement is de ned in
22
Table35.3.
Clinically, the most common manifestation of the
antiphospholipid syndrome is DVT of the legs. Arterial
thrombosis also may be seen but less o en than venous
thrombosis. Laboratory tests to detect the antiphospholipid antibodies include the aPTT test, performed with and
without exogenous normal plasma to detect the presence of
an inhibitor. Other tests include the kaolin clotting time,
and dilute Russell’s viper venom time (dRVVT). ELISA
tests are performed to detect anticardiolipin antibodies and
-glycoprotein Iantibodies. 21
anti-β
2
CONGENITAL AND ACQUIRED HYPERCOAGUABLE SYNDROMES • 279
Table35.3 CRITERIA FOR THE CLASSIFICATION OF
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THE ANTIPHOSPHOLIPID SYNDROME
INTERNATIONAL CONSENSUS STATEMENT ON PRELIMINARY
CRITERIA FOR THE CLASSIFICATION OF THE ANTIPHOSPHO
Clinical Criteria:
Vascular thrombosis:1 or more clinical episodes of arterial, venous,
or small vessel thrombosis, occurring within any tissue or organ.
Complications of Pregnancy:
1 or more unexplained deaths of morphologically normal fetuses
at or a er the 10th week of gestation; or
1 or more premature births of morphologically normal neonates at
or before the 34th week of gestation; or
3 or more unexplained consecutive spontaneous abortions before
the 10th week of gestation.
Laboratory Criteria:
Anticardiolipin antibodies
Anticardiolipin IgG or IgM antibodies present at moderate or high
levels in the blood on 2 or more occasions at least 6 weeks apart.
Lupus anticoagulant antibodies
Lupus anticoagulant antibodies detected in the blood on 2 or more
occasions at least 6 weeks apart.
(From Reference22)
LIPID SYNDROME
Aspirin and hydroxychloroquine have been used in subsets of patients with the antiphospholipid syndrome for
prophylaxis against thrombotic events. e treatment of
established VTE in these patients consists of acute heparinization and longer-term (possibly lifelong) vitamin K
antagonists. e optimal intensity of warfarin anticoagulation (international normalized ratio [INR] 2.0–2.9 versus
21
3.0–3.9) has not been determined.
WARFARININDUCED SKIN
NECROSIS
is disorder is the most severe nonhemorrhagic complication of oral anticoagulation. Although rare, it seems to
show a predilection for perimenopausal obese women who
are being anticoagulated. Venules and capillaries within the
subcutaneous fat and overlying skin thrombose, leading to
necrosis. is typically is seen in the subcutaneous fat of the
breasts, thighs, buttocks, and legs. Clinically, the patient
may initially have paresthesias, which are then followed by
painful, erythematous lesions. When hemorrhagic bullae
are present, this is indicative of full thickness skin necrosis.
e pathogenesis for this process is the depletion of protein C prior to the other vitamin K–dependent coagulation
factors. As the half-life of protein C is only 8 h, its rapid
depletion causes a transient hypercoagulable state until the
rest of the vitamin K–dependent factors also are reduced to
levels that produce anticoagulation.
e primary treatment is prevention with heparin or low
molecular weight heparin anticoagulation for the rst 48 to
72 h of anticoagulation with warfarin. If skin necrosis develops, warfarin needs to be discontinued, and anticoagulation
may continue with heparin or a direct thrombin inhibitor.
8
SURGERY/TRAUMA
e risk of thrombosis is dependent on the type of surgery
and the presence of additional risk factors. is risk may
persist for up to several months a er surgery. Patients who
are at particularly high risk include those who undergo hip
fracture surgery, hip or knee arthroplasty, neurosurgical procedures, and patients with major trauma. Injury to tissues
and vessels during the procedure may enhance thrombogen-
8,23
Operative dissection, thermal injuries, and so tissue
esis.
trauma activate the coagulation cascade by inducing tissue
factor release, thereby increasing the thrombogenicrisk.
With a major traumatic injury, risk for venous thrombosis is highest in patients with spinal injuries, pelvic fractures,
and lower extremity fractures. e risk of thrombosis also
increases with greater injury severity. In part, this may be
due to the accompanying systemic in ammatory response
(another prothrombotic state, covered later).
P R E G N A N C Y
During pregnancy, there is an associated hypercoagulable
state due to the increase in factors I, VII, VIII, IX, X, XI,
and XII. Additionally, platelet counts increase and concentrations of protein S and antithrombin decrease. e
brinolytic system also may be inhibited secondary to the
increased production of plasminogen-activated inhibitors
1 and 2 by the placenta. Compounding this risk is the
degree of stasis that occurs as a result of compression of
the lower extremity veins by the gravid uterus. In the postpartum period, the risk for thrombosis is up to ve times
greater than during pregnancy. Approximately 2months
a er delivery, the coagulation and brinolytic systems will
1
return to normal.
e risk of thrombosis is increased further in pregnant
women who have a genetic risk for thrombosis. Depending
on the inherited thrombophilia, a woman with a thrombophilia who becomes pregnant may have a risk of venous
thrombosis up to eight times higher than those without a
4
thrombophilia.
In addition, women with a genetic risk for
thrombosis are also at an increased risk for fetal loss and preeclampsia. Many women with a history of thrombophilia or
thromboembolism are treated with heparin, low molecular
24
weight heparin, and/or aspirin while pregnant.
ORAL CONTRACEPTIVERELATED
THROMBOSIS
Oral contraceptives are among the drugs most frequently
used by women. e use of oral contraceptives initially was
associated with a three-fold increased risk of venous thrombosis. With the decrease in the amount of estrogen placed
in the pill, a subsequent decrease in the incidence of venous
thrombosis was seen. With lower levels of estrogen, the risk
of thrombosis is 1.5 to 2 times that over control patients.
280 • VENOUS THROMBOEMBOLISM
Additionally, newer oral contraceptives using newer proges-
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terones have shown an increased risk of thromboembolism.
25
e risk for venous thrombosis is highest during the
1st year of use of the oral contraceptive, and the risk is not
cumulative with prolonged use. Once the pill is discontin-
25,26
ued, the risk returns to baseline for that patient.
Oral contraceptives in uence the plasma levels of nearly
every protein involved in coagulation. Factors VII, VIII,
IX, X, and XI increase, and the natural anticoagulants antithrombin and protein S decrease. However, oral contraceptive administration is associated with elevated protein C,
-antitrypsin, and brinolytic proteins, producing an anti-
α
1
thrombotic e ect. Additionally, the pill has been associated
with an acquired APC resistance occurring within 3days
of initiation of the pill and reversing with discontinuation.
is resistance has been shown to have a more pronounced
increase in those women using third-generation oral contraceptives. e combination of APC resistance, increased
prothrombin levels, and decreased protein S levels produces
a net prothrombotic a ect and confers the prothrombotic
27,28
risk of oral contraceptives.
In women with inherited thrombophilias who also take
oral contraceptives, the risk for thrombosis increases thirtyto y-fold. For example, women who take oral contraceptives and are heterozygous for the Factor V Leiden mutation
have been shown to have an increased risk of venous thrombosis by a factor of approximately thirty- ve. is increased
relative risk for venous thrombosis is in the same order of
magnitude as patients who are homozygous for the Factor
V Leiden mutation (almost y-fold increased risk). e
women who have other inherited thrombophilias also
4,25
appear to have a remarkably increased risk.
H O R M O N E R E P L A C E M E N T
THERAPYRELATED THROMBOSIS
Historically, hormone replacement therapy (HRT) has
been used to reduce the progression of osteoporosis, relieve
the symptoms of menopause, and reduce the cardiovascular
risk pro le. Several studies including the Heart Estrogen/
Progestin Replacement Study (HERS) and the Women’s
Health Initiative (WHI) have shown an increased risk of
VTE with the use of HRT. Atwo- to four-fold increased
26,29
risk, compared with nonusers, has been shown.
Similar to oral contraceptives, the risk of VTE is highest
during the rst year of HRT. Once HRT is discontinued,
the risk of thrombosis returns to baseline. Additionally,
increasing age has been associated with an increased risk
of venous thrombosis. Several studies also have shown an
increased risk in patients using HRT who had lower extremity fractures, recent surgery, previous VTE, cancer, and obe-
29
Also similar to oral contraceptive pills, patients on
sity.
HRT with thrombophilias have a signi cantly increased
4
risk of VTE.
e coagulation factor changes that occur
as a result of hormone replacement therapy are similar to
those changes that occur with oral contraceptive pills, but
to a lesser degree.
SYSTEMIC INFLAMMATORY
RESPONSE SIR ANDSEPSIS
With the SIR, cytokines and other in ammatory mediators are released causing a prothrombotic state. Speci cally,
tumor necrosis factor α (TNFα) and interleukin-1α (IL-1α)
are increased. ese factors activate the coagulation cascade,
cause an increase in tissue factor expression, and decrease levels of protein C and protein S.Fibrinogen synthesis also will
increase as part of the in ammatory response. Additionally,
the in ammatory response is enhanced by thrombin, which
augments leukocyte adhesion and activates platelets. Platelet
activation in turn, further promotes tissue factor expression
and increases cytokine release. All these factors contribute
to the hypercoagulable state seen with SIRs and sepsis and
30
predispose the patient to thrombosis.
MALIGNANCY
VTE is a common complication of cancer. In 10% of
patients who present with an idiopathic VTE, malignancy
will be discovered. e majority of thrombotic episodes
occur spontaneously, although patients with cancer o en
have other concurrent risk factors (inherited thrombophilias, immobilization, major surgical procedures, chemotherapy, and central venous catheters) that place them at high
risk forVTE.
Tissue factor and cancer procoagulant are produced
by tumor cells. e cancer procoagulant directly activates
factor X independently of factor VII. Additionally, tumor
cells produce proteins that may regulate the brinolytic
system. ese proteins impair brinolytic activity, lead-
31
ing to a prothrombotic state.
Tumor cells also produce
various cytokines and a ect the coagulation cascade and
induce a thrombogenic state in a similar manner as SIRS.
TNF-α and IL-1β are released by cancer cells and induce
tissue factor expression and downregulate thrombomodulin. Furthermore, tumor cells activate other cytokines and
several di erent types of leukocytes, which also increase tissue factor expression and activate platelets. e interaction
of all these processes lead to a prothrombotic condition.
TESTING FOR INHERITED
THROMBOPHILIC CONDITIONS
We perform testing for inherited thrombophilic conditions in the following clinical circumstances: idiopathic
DVT, recurrent DVT, DVT with young age at onset, and
venous thromboses in unusual locations (mesenteric or
portal venous thrombosis, cerebral vein thrombosis). Many
hospitals provide testing with a “hypercoagulable panel.”
However, the clinician should ascertain that the following
31
CONGENITAL AND ACQUIRED HYPERCOAGUABLE SYNDROMES • 281
tests are performed:antithrombin activity, protein C activ-
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ity, protein S activity, testing for either APC resistance or
Factor V Leiden, prothrombin gene mutation, homocysteine levels, anticardiolipin antibody and lupus anticoagulant
testing, and factor VIII activity. Antithrombin, protein C,
and protein S levels may be depressed by the presence of
acute thrombosis. Protein C and S may be similarly a ected
by warfarin administration. erefore, an abnormal test
result drawn during these time periods does not necessarily
signify the presence of an inherited thrombophilic condition. Repeat testing is required.
OTHER ACQUIRED
HYPERCOAGULABLE CONDITIONS
AND TREATMENT STRATIFICATION
Patients are predisposed to thrombosis via many other clinical conditions. ese conditions may a ect the coagulation
cascade, the brinolytic system, and/or platelet function,
thereby increasing the risk of thrombosis. With two or
more conditions that predispose to thrombosis, the patient
is at a higher risk for su ering a thrombosis.
e objectives for treating acute VTE include the prevention of death from pulmonary embolism, reduction of
lower extremity symptoms, prevention of the postphlebitic
syndrome, and prevention of recurrent VTE. By limiting
the propagation of thrombus, anticoagulation potentially
has a role in achieving all of these objectives. Initial anticoagulation with unfractionated heparin or low molecular
weight heparin, followed by 6 weeks to 6months of oral
vitamin K antagonists has been the mainstay of therapy.
More recently, the American College of Chest Physicians
Consensus Statement has strati ed the type and duration of
anticoagulation, based in part on the whether the patient has
32
a concurrent thrombophilic condition (see Table35.4).
In
general, the overall trend is to extend the duration of anticoagulation, especially in patients with recurrent DVT,
antiphospholipid syndrome, and patients with multiple
thrombophilic conditions. In patients with malignancy and
VTE, the recommended duration of low molecular weight
heparin therapy has been extended to 3to6months, followed by long-term vitamin K antagonists.
C O N C L U S I O N
A clear understanding of the various conditions and situations in which a patient may have a hypercoagulable state
is important for the ability to manage and appropriately
treat patients in whom the risk of thrombosis exists. Once
that risk is recognized, appropriate observation, prophylaxis, and treatment may ensue. It must be recognized that
the number of acquired disease processes that predispose
patients to thrombosis far outweighs the number of patients
with congenital thrombophilias. Although a large portion
Table35.4 AMERICAN COLLEGE OF CHEST
PHYSICIANS RECOMMENDATIONS FOR
DURATION OF ANTICOAGULATION FOR VENOUS
THROMBOEMBOLISM
CLINICAL SUBGROUP TREATMENT DURATION
First episode DVT/transient
risk
First episode DVT/concurrent
cancer
Inde nite anticoagulation until
cancer resolves
First episode idiopathic DVT UH/LMWH followed by 6–12
First episode DVT/
thrombophilia
antithrombin de ciency
protein C and S de ciency
factor V leiden
prothrombin 20210
homocysteinemia
factor VIII elevation
(>90th %)
First episode DVT/
thrombophilia
Antiphospholipid antibodies
2 or more thrombophilias
Recurrent DVT UH or LMWH followed by
UH=unfractionated heparin, LMWH=low-molecular-weight heparin,
VKA=vitamin K antagonist.
32
UH/LMWH followed by
3 mos VKA
3–6 mos LMWH
mos VKA (suggest inde nite)
UH or LMWH followed by
6–12 mos VKA (suggest
inde nite if idiopathic)
UH or LMWH followed by 12
mos VKA (suggest inde nite)
inde nite VKA
of the population may have a thrombosis, few thromboses
are caused by an inherited thrombophiliaalone.
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31. Prandoni P , Falanga A , Piccioli A . Cancer and venous thromboembolism , Lancet . 2005 . 6 : 401–410 .
32. Buller HR , Agnelli G , Hull RD , et al. Antithrombotic therapy
for venous thromboembolic disease: e seventh ACCP conference on antithrombotic and thrombolytic therapy , Chest . 2004 .
126 : 401S–428S .
1 :
CONGENITAL AND ACQUIRED HYPERCOAGUABLE SYNDROMES • 283
36.
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NEW WAYS TO PREVENT VENOUS THROMBOEMBOLISM
INHIBITION OF FACTOR XA AND THROMBIN
David Bergqvist
n prevention of postoperative venous thromboembolism one of the low molecular weight heparins has been
I
dominating the market since the early 1990s. ere
is, however, room for improvement, especially in patients
undergoing high-risk surgery such as major orthopedic surgery and surgery for abdominal/pelvic malignancies. For
the clinician, and for the patient, new methods should be
either more e ective or safer than low molecular weight
heparins and be more cost-e ective or easier to administer (i.e., be available for oral administration). e latter is
especially true as long-term prophylaxis will undoubtedly
increase in volume.
e various low molecular weight heparins have a rather
complex mechanism of action, inhibiting activated factor X
to a higher degree than inhibiting thrombin. is has been
considered necessary for the good prophylactic e ect.
In search of new agents overcoming some of the drawbacks with heparins, there have been two important developments within the eld of antithrombotic substances.
One development was to use the heterogeneous heparin
molecule as a basis, and, working with the relation between
structure and function, Lindahl etal. in Uppsala, Sweden,
de ned the speci c antithrombin-binding pentasaccharide
sequence. e research group of Choay in Paris was able to
synthesize this pentasaccharide as fondaparinux—a selective Xa inhibitor.
size small direct thrombin inhibitors, knowing the pivotal
role thrombin plays within the hemostatic system and
knowing that the thrombin inhibitor hirudin (originally
from the saliva of medicinal leeches) had a good thromboprophylactic e ect.
synthesize such small selective thrombin inhibitors and the
rst with clinical documentation was ximelagatran/mela-
6–8
gatran.
a er approval because of liver toxicity.
bolism with molecules that are more selective and structurally more homogeneous have been investigated in large
clinical trial programs and both have got an approval in
major orthopedic surgery.
However, this substance was withdrawn shortly
ese two new ways of preventing venous thromboem-
3,4
e other development was to synthe-
5
Many attempts have been made to
9
1,2
When evaluating new thromboprophylactic substances
and principles in the clinical setting, there should ideally be
a three-step research program:
1. Studies on mechanism of action, pharmacokinetics, and
pharmacodynamics.
2. Proof of principle with phlebographic evaluation of the
antithrombotic e ect in highrisk
a. major orthopedic surgery
b. major abdominal/pelvic surgery (especially cancer)
3. Proof of clinical importancein
a. large studies with a simple protocol on clinical venous
thromboembolism
b. meta-analyses.
Regarding step 2, although elective hip surgery is a
well-established clinical model, it is important also to evaluate other high-risk surgical procedures. is is to make conclusions and clinical use more generalizable. From a practical
point of view it is not ideal to have di erent prophylactic
programs for various surgical procedures in a hospital or a
surgical department. Prophylaxis must be simple to obtain
widespread and well-accepted use. e manufacturers of the
substances discussed in this chapter have rst focused on
and obtained approval for major orthopedic surgery.
F O N D A P A R I N U X
Fondaparinux is a synthetic analogue of the natural pentasaccharide sequence of the heparin molecule, which mediates its interaction with antithrombin.
weight is 1,728 D, with a very high batch-to-batch consistency. e reversible binding, to a speci c site on antithrombin, results in a 300-fold increase in the rate of factor
Xa inhibition by antithrombin. A er subcutaneous administration with a 100% bioavailability, the peak plasma level
is obtained in about 2 h with an elimination half-life of
about 17–21 h, longer in elderly, which allows once-daily
administration.
9,10
e elimination is mainly unchanged
4
e molecular
284
through the renal route. e drug is therefore contraindi-
https://t.me/med1917
cated in patients with renal failure, de ned by a creatinine
clearance of less than 30 ml/min. If used there is a potential for bleeding complications. Apeak steady state plasma
level is reached a er 3–4 d (dose 2.5 mg daily). ere is no
speci c antidote to fondaparinux, but in case of emergency
11
recombinant factor VIIa may be used.
is could be the
case in accidental overdosing with clinical hemorrhage.
A large phase III clinical program was performed to evaluate the e ect of fondaparinux in major orthopedic surgery
of the lower limbs. e studies conducted used various acronyms:EPHESUS (European Pentasaccharide Hip Elective
12
SUrgery Study with 2,309 patients
), PENTATHLON
(PENTAsaccharide in Total Hip Replacement Surgery
13
with 2,275 patients
in MAjor Knee Surgery with 1,049 patients
), PENTAMAKS (PENTAsaccharide
14
) and
PENTHIFRA (PENTasaccharide in HIp FRActure sur-
15
gery with 1,711 patients
). e studies were consistently
performed using 2.5 mg fondaparinux daily starting postoperatively. e comparator was enoxaparin:in EPHESUS
and PENTHIFRA with 40 mg once daily with preoperative start as used in Europe and in PENTATHLON and
PENTAMAKS with 30 mg twice daily with postoperative
start as used in North America. Phlebography was used
for end-point assessment and the studies were evaluated
16
in a meta-analysis.
e primary e cacy outcome is summarized in Table36.1, the common odds reduction being
55% in favor of fondaparinux (p < 0.001). e incidence
of symptomatic venous thromboembolism was low without
di erence between the groups (0.6% in the fondaparinux
group and 0.4% in the enoxaparin group; p=0.25). Fatal
pulmonary embolism was diagnosed in two and three
patients respectively. e bene cial e ect of fondaparinux
was consistent regarding sex, age, body mass index, type
of anesthesia, use of cement for xation of prosthesis, and
duration of the surgical procedure.
ere were 2.7% adjudicated major bleedings in the
fondaparinux group versus 1.7 in the enoxaparin group
(p = 0.008). is di erence was mainly due to a di erence in bleeding index, whereas fatal bleedings, bleedings
in critical organs, and bleeding leading to reoperation did
not di er. ere was a signi cant relation between the incidence of major bleeding and the timing of the rst injection of fondaparinux (between 3 and 9 h postoperatively,
p =0.008), whereas the thromboprophylactic e ect was
not in uenced by timing (p = 0.67). rombocytopenia
was not reported (there is no binding to platelet factor 4).
18
In the PENTHIFRA Plus study
the e ect of prolonged
17
prophylaxis with fondaparinux was evaluated in patients
undergoing hip fracture surgery. All 656 patients received
fondaparinux for 6 to 8 d, wherea er they were randomized
to placebo or fondaparinux for another 19 to 23 d.Venous
thromboembolism (bilateral phlebography or symptomatic
venous thromboembolism) di ered signi cantly, being 35%
in the placebo group and 1.4% in the fondaparinux group, a
Table36.1 FREQUENCY OF VENOUS
THROMBOEMBOLISM UP TO DAY 11 PERCENT
WITHIN BRACKETS.
FONDAPARINUX
N=2,682
Venous
thromboembolism
Any DVT 174 (6.5) 363 (13.5)
Any proximal DVT 35 (1.3) 81 (2.9)
(From Reference17)
182 (6.8) 371 (13.7)
ENOXAPARIN
N=2,703
reduction that is highly remarkable. e e ect was also signi cant when symptomatic venous thromboembolism was
used as end point (2.7% vs. 0.3%; p=0.02).
In a multicenter, double-blind study (PEGASUS trial)
on 2,048 patients undergoing high-risk abdominal surgery,
17
fondaparinux was noninferior to dalteparin.
In the subgroup operated on for cancer the di erence was signi cant
in favor of fondaparinux (Table36.2).
In another trial in elective abdominal surger y (APOLLO
study) fondaparinux combined with intermittent pneumatic
compression was signi cantly more e ective than intermittent compression alone. e frequency of venous thromboembolism was reduced from 5.3 to 1.7% (p<0.004).
19
bleeds occurred in 0.2% and 1.6% respectively (p=0.006);
none of them fatal or in a criticalorgan.
Fondaparinux is safe, the main concern being bleeding, which in some studies have been signi cantly higher
than with the comparator. One important nding in a
post hoc analysis of the orthopedic trials was the signi cantly increased frequency of major bleeding when the
rst fondaparinux injection was given within 6 h a er
wound closure instead of more than 6 h a er (3.2% vs. 2.1
16
%; p=0.045).
In case of serious bleeding complications
recombinant factor VIIa may be used to reverse the antico-
11,20
agulant e ect, also adding tranexamic acid.
rombocytopenia is seen at a similar frequency as
following low molecular weight heparins, and there are
no reports of heparin-induced thrombocytopenia (HIT).
ere does not seem to be an increase in liver enzymes.
R I V A R O X A B A N
Rivaroxaban is an oral direct factor Xa inhibitor with a
molecular mass of 436 D. e bioavailability exceeds 80%.
Table36.2 FONDAPARINUX IN HIGHRISK ABDOMINAL
SURGERY PEGASUS. VENOGRAPHICDVT.
FONDAPARINUX DALTEPARIN
Primary e cacy analyses 47/1,027 (4.6%) 62/1,021 (6.1%)
Patients with cancer 37/696 (4.7%) 55/712 (7.7%)
(From Reference 20)
Major
NEW WAYS TO PREVENT VENOUS THROMBOEMBOLISM • 285
e half-life is 7–11 h, and it is to about 65% excreted via
https://t.me/med1917
the kidneys.
21–23
ree phase II trials
als ( e RECORD program)
and four phase III clinical tri-
24–27
have evaluated its e cacy
and safety in orthopedic surgery. As comparator enoxaparin has been used. e two phase II trials were designed to
allow pooling of the results, which showed that rivaroxaban
in a total daily dose of 5–20 mg had the most favorable bal-
28
ance between e ect and safety.
In RECORD 1 rivaroxaban was shown superior to enoxaparin in reducing the primary end point of any DVT, nonfatal
pulmonary embolism, or death (1.1% vs. 3.7 % respectively;
p < 0.001), but not in symptomatic venous thromboembolism (0.3% vs. 0.5%). In RECORD 2 both total and symptomatic venous thromboembolism were signi cantly lower
in the patients treated with rivaroxaban (2.0% vs. 9.3% and
0.2% vs. 1.2% respectively, p=0.004), but the study did not
compare similar prophylactic routines, rivaroxaban given for
35 d versus enoxaparin for 12 d.In the RECORD 3 and 4
rivaroxaban was superior to enoxaparin. e incidence of
major and clinically signi cant nonmajor hemorrhage was
increased across the rivaroxaban treatment groups, although
not statistically signi cant. e RECORD trials with 12,500
patients demonstrated a more than 50% reduction compared with enoxaparin in the composite primary e cacy end
point (symptomatic venous thromboembolism and death).
Bleeding did not di er from that in the enoxaparin groups.
APIXABAN
Apixaban is a reversible direct oral factor Xa inhibitor. It
has a bioavailability of 51–85% and reaches a Tmax a er 3
h. e half life is 9–14 h, 25% being excreted by the kidneys
and 65% viafeces.
In the ADVANCE program apixaban was tested against
enoxaparin in major orthopedic surgery with altogether
around 11,600 patients. e apixaban dose is 2.5 mg twice
daily. ADVANCE 1 and 2 used elective knee arthroplasty as
29–30
the study population.
In the American way of dosing enoxaparin (30 mg
× 2) apixaban was noninferior, but when the European
administration was used (40 mg × 1) apixaban was signi cantly better than enoxaparin. In both studies prophy-
31
laxis was given for 10–14 d.In ADCANCE 3
extended
prophylaxis was studied in patients undergoing total hip
replacement, 40 mg, and again apixaban was superior (1.4%
vs. 2.9%). In all three studies apixaban prophylaxis started
12–24 h post surgery. In ADVANCE 1, major bleeding was
signi cantly lower in the apixabangroup.
e ADVANCE 2 and 3 studies have been pooled in an
analysis, apixaban being more e ective than enoxaparin 40
32
mg once daily.
In the ADOPT study
Bleeding did not di er.
33
the patient group consisted
of medically ill patients (congestive heart failure, acute
respiratory failure, infection, acute rheumatic disorder,
or inflammatory bowel disease) with additional risk
factors: age greater than or equal to 75years, previous
venous thromboembolism, cancer, body mass index
greater than or equal to 30, estrogen therapy, or chronic
heart or respiratory failure. Of 4,495 available patients
2.7% of apixaban patients and 3.1% of enoxaparin
patients reached the primary composite efficacy outcome
(30-d death related to venous thromboembolism, pulmonary embolism, symptomatic DVT, or proximal DVT
detected with bilateral ultrasonography). Major bleeding
was significantly more common in the apixaban patients
(0.5% vs.0.2%).
D A B I G A T R A N
Dabigatran etixilate is the oral prodrug form of the
active direct factor IIa (thrombin) inhibitor dabigatran.
Absorption and conversion are rapid. It is a small (molecular mass 472 D) synthetic molecule, the oral bioavailability
being around 6.5%. e half-life in patients is 14–17 h, 85%
34
being excreted via the kidneys.
Data from two phase II
als, RE-NOVATE, RE-MODEL, and RE-MOBILIZE
35,36
and three phase III clinica l tri-
37–39
have been published. ey deal with e cacy and safety
in major orthopedic surgery. e RE-NOVATE and
RE-MODEL studies compared two dabigatran dose regimens (150 mg and 220 mg once daily starting with half the
dose 1–4 h postoperatively) with the European regimen of
enoxaparin (40 mg × 1)in patients operated on with total
hip or total knee replacement. In both trials dabigatran was
as e ective and safe as enoxaparin. In the RE-MOBILIZE
trial in total knee replacement dabigatran in the same doses
was less e ective than the American regimen of enoxaparin
(30 mg × 2), but safety was similar. e three phase III trials
have been meta-analyzed with the total of 8,210 patients.
40
No signi cant di erences were seen between dabigatran
220 mg once daily and enoxaparin in any of the end points
regarding thrombosis prevention and safety.
LIMITATIONS OF NEW
ANTICOAGULANTS
ere are no available antidotes to dabigatran, rivaroxaban,
or apixaban. is is a concern in patients who may require
urgent reversal of the e ect for emergency surgical procedures, in the case of trauma or a hemostatic emergency such
as cerebral bleeding or overdosage.
ere is still very limited experience in patients with
decreased renal function as well as in pregnancy.
With the liver toxicity of ximelagatran such an e ect
has been a concern with the new oral substances, but so far
there is no indication that this may be a problem.
286 • VENOUS THROMBOEMBOLISM
C O N C L U D I N G R E M A R K S
https://t.me/med1917
Today, there are synthetic substances inhibiting very well
de ned steps or speci c factors in the hemostatic system,
showing a clear e ect in prevention of postoperative venous
thromboembolism in major orthopedic surgery. Apart from
being of practical importance, the principal mechanisms of
action are of great theoretical interest. e target for optimal clotting factor inhibition is still a matter for discussion.
e substances have been extensively evaluated in clinical
studies of high quality with large sample sizes. e e ect is at
least as e ective as or more e ective than today’s dominating
prophylactic method (low molecular weight heparin). Data
are largely lacking on prophylaxis in nonorthopedic surgery,
but the few results there are seem promising.
41
Another direct oral factor Xa inhibitor—apixaban
—
has also recently been evaluated in a large phase III program
(ADVANCE), the e ect being promising at least comparable to enoxaparin, which has led to approval as prophylaxis
in major orthopedic surgery in several countries.
One important issue in studies on new anticoagulants
in surgical prophylaxis is the de nition of bleeding and the
42,43
impact that has on major bleeding outcome.
None of
the new oral substances have any speci c antidote. Another
concern with the oral substances is the question of compliance outside a strict trial situation. is is important to
evaluate as an oral substance would be of value in situations
44
where extended out-of-hospital prophylaxis is indicated.
e new anticoagulants are indeed promising, but it is
important to study other risk groups than orthopedic surgery and to follow the e ect in routine clinical care outside
strict clinical trial situations. Heparins and low molecular
weight heparins also have nonanticoagulant e ects, which
are used therapeutically, and whether the new substances
45
can totally replace heparins needs to be shown.
R E F E R E N C E S
1. Lindahl U , Backstrom G , Hook M , u nb er g L , F r a n ss on L A , L i n k e r
A . Structure of the antithrombin-binding site in heparin , Proc Natl
Acad Sci USA. 1979 . 76 ( 7 ): 3198–3202 .
2. Lindahl U , Bäckström G , unberg L , Leider I . Evidence from a
3–0-suphated D-glucosamine residence in the antithrombin binding
sequence of heparin , Proc Natl Acad Sci USA. 1980 . 77 : 6651–6655 .
3. Choay J , Petitou M , Lormeau J , Sinay P , Casa B , Gatti G .
Structure-activity relationship in heparin:Asynthetic pentasaccharide with high a nity for antithrombin III and eliciting high antifactor Xa activity , Biochem Bioph Res Co. 1983 . 116 : 492–499 .
4. Petitou M , Lormeau JC , Choay J . Chemical synthesis of glycosami-
noglycans:New approaches to antithrombotic drugs , Nature. 1991 .
350 ( Suppl 6319 ): 30–33 .
5. Eriksson BI , Wille-Jorgensen P , Kalebo P , et al. A comparison of
recombinant hirudin with a low-molecular-weight heparin to prevent
thromboembolic complications a er total hip replacement, N Engl J
Med. 1997 . 337 ( 19 ): 1329–1335 .
6 . G u s ta f s s o n D , E lg M . e pharmacodynamics and pharmacokinetics of
the oral direct thrombin inhibitor ximelagatran and its active metabolite
melagatran:Amini-review , romb Res. 2003. 109 ( Suppl 1) : S9–S15 .
7. Crowther MA , Weitz JI . Ximelagatran: e rst oral direct thrombin inhibitor, Expert Opin Investig Drugs. 2004. 13 ( 4 ): 403–413 .
8. Eriksson BI , Dahl OE . Prevention of venous thromboembolism following orthopaedic surgery:Clinical potential of direct thrombin
inhibitors , Drugs. 2004 . 64 ( 6 ): 577–595 .
9. Bauer KA , Hawkins DW , Peters PC , et al. Fondaparinux, a synthetic pentasaccharide: e rst in a new class of antithrombotic
agents: e selective factor Xa inhibitors , Cardiovasc Drug Rev.
2002. 20 ( 1 ): 37–52 .
10. Boneu B , Necciari J , Cariou R , etal. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with
high a nity to antithrombin III in man , romb Haemost. 1995.
74 ( 6 ): 1468–1473 .
11. Bijsterveld NR , Moons AH , Boekholdt SM , etal. Ability of recombinant factor VIIa to reverse the anticoagulant e ect of the pentasaccharide fondaparinux in healthy volunteers, Circulation. 2002.
106 ( 20 ): 2550–2554 .
12. Lassen MR , Bauer KA , Eriksson BI , Turpie AG . Postoperative
fondaparinux versus preoperative enoxaparin for prevention
of venous thromboembolism in elective hip-replacement surgery: A randomised double-blind comparison, Lancet. 2002.
359 ( 9319 ): 1715–1720 .
13. Turpie AG , Bauer KA , Eriksson BI , Lassen MR . Postoperative
fondaparinux versus postoperative enoxaparin for prevention
of venous thromboembolism a er elective hip-replacement
surgery: A randomised double-blind trial , Lancet.
359 ( 9319 ): 1721–1726 .
14. Bauer KA , Eriksson BI , Lassen MR , Turpie AG . Fondaparinux
compared with enoxaparin for the prevention of venous thromboembolism a er elective major knee surgery , N Engl J Med. 2001.
345 ( 18 ): 1305–1310 .
15. Eriksson BI , Bauer KA , Lassen MR , Turpie AG . Fondaparinux
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345 ( 18 ): 1298–1304 .
16. Turpie AG , Eriksson BI , Lassen MR , Bauer KA . A meta-analysis of
fondaparinux versus enoxaparin in the prevention of venous thromboembolism a er major orthopaedic surgery , J South Orthop Assoc.
2002. 11 ( 4 ): 182–188 .
17. Agnelli G , Bergqvist D , Cohen A , Gallus A , Gent M . PEGASUS
investigations: Postoperative fondaparinux versus preoperative
dalteparin for prevention of venous thromboembolism in hip-risk
abdominal surgery: A randomized double-blind trial , Br J Surg.
2005 . 92 : 1212–1220 .
18. Eriksson BI , Lassen MR . Duration of prophylaxis against venous
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study , Arch Intern Med. 2003. 163 ( 11 ): 1337–1342 .
19. Turpie AG , Bauer KA , Caprini JA , Comp PC , Gent M , Muntz JE .
Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of
venous thromboembolism a er abdominal surgery: Arandomized,
double-blind comparison, J romb Haemost. 2007. 5 ( 9 ): 1854–1861 .
20. Huvers F , Slappendel R , Benraad B , van Hellemondt G , van Kraaij
M . Treatment of postoperative bleeding a er fondaparinux with
rFVIIa and tranexamic acid, Neth J Med. 2005. 63 ( 5 ): 184–186 .
21. Turpie AG , Fisher WD , Bauer KA , etal. BAY 59–7939: An oral,
direct factor Xa inhibitor for the prevention of venous thromboembolism in patients a er total knee replacement: A phase II
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114 ( 22 ): 2374–2381 .
23. Eriksson BI , Borris L , Dahl OE , etal. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism a er total hip replacement , J romb Haemost. 2006.
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NEW WAYS TO PREVENT VENOUS THROMBOEMBOLISM • 287
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