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Au nom de Dieu le Tre`s
Mise´ricordieux,
Le Tout Mise´ricordieux
NEW THERAPIES IN VTE
MARYAM MEHRPOOYA MD,
ASSISTANT PROFESSOR OF CARDIOLOGY
TEHRAN UNIVERSITY OF MEDICAL SCIENCE
IMAM KHOMEINI HOSPITAL
VTE, Thrombophilia, Antithrombotic
Therapy, and Pregnancy
Shannon M. Bates, MDCM, MSc
Ian A. Greer, MD, FMedSci, FCCP
Saskia Middeldorp, MD, PhD
David Veenstra, PharmD, PhD
Anne-Marie Prabulos, MD
Per Olav Vandvik, MD, PhD
-----
Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines
Copyright: American College of Chest Physicians 2012©
Endorsing Organizations
This guideline has received the endorsement of the
following organizations:
•
•
•
•
•
•
American for Clinical Chemistry
American College of Clinical Pharmacy
American College of Obstetricians and Gynecologists
American Society of Health-System Pharmacists
American Society of Hematology
International Society of Thrombosis and Hemostasis
CASE 1
A nulliparous 34-year-old patient. At the tenth week
of gestation, she developed phlebothrombosis of
veins of the right leg and massive pulmonary
embolism. After thrombolytic and heparin therapy
she developed rethrombosis.
What's your diagnosis?
BACKGROUND
• The use of anticoagulant therapy during pregnancy is
challenging because of the potential for both fetal and
maternal complications.
• In contrast to anticoagulation of nonpregnant women, the
choice of anticoagulant during pregnancy needs to take into
account fetal safety and maternal peripartum issues (eg,
unpredictable onset of labor, use of neuraxial anesthesia for
management of labor pain).
HEPARINS
Heparins are used for most pregnant women because they do
not cross the placenta and do not result in fetal anticoagulation.
UNFRACTIONATED HEPARIN
Unfractionated heparin is a reasonable alternative to a LMW heparin when
cost or need for rapid reversal is important (eg, for delivery or
perioperatively).
Unfractionated heparin is preferred over LMW heparin in patients with
severe renal insufficiency (eg, creatinine clearance <30 mL/min) because
LMW heparin clearance is almost exclusively renal, while elimination of
unfractionated heparin is renal and hepatic.
LOW MOLECULAR WEIGHT (LMW) HEPARINS
We recommend a LMW heparin rather than unfractionated heparin for all
but the final weeks of the pregnancy, because they are effective and
easier to administer than unfractionated heparin.
LMW heparins produce a more predictable anticoagulant response than
unfractionated heparin and do not require routine monitoring
NEW ANTICOAGULANT
Anti IIa(DIRECT THROMBIN INHIBITORS):
Parentral : Argatroban- Bivalirudin-Hirudin-Lepirudin(A recombinant form of hirudin)
Oral : Dabigatran
Anti Xa :
Parentral : Fondaparinux
Oral : Apixaban-Rivaroxaban-Edoxaban
COAGULATION SYSTEM
Coagulation occurs through the action of discrete enzyme complexes, which
are composed of a vitamin K–dependent enzyme and a nonenzyme
cofactor.
These complexes assemble on anionic phospholipid membranes in a
calcium-dependent fashion. Vascular injury exposes tissue factor (TF), which
binds factor VIIa to form extrinsic tenase.
Extrinsic tenase activates factors IX and X. Factor IXa binds to factor VIIIa to
form intrinsic tenase, which activates factor X. Factor Xa binds to factor Va
to form prothrombinase, which converts prothrombin (II) to thrombin (IIa).
Thrombin then converts soluble fibrinogen into insoluble fibrin.
•
Heparin binds to antithrombin via its
pentasaccharide sequence. This induces a
conformational change in the reactive
center loop of antithrombin that accelerates
its interaction with factor Xa. To potentiate
thrombin inhibition, heparin must
simultaneously bind to antithrombin and
thrombin. Only heparin chains composed of
at least 18 saccharide units, which
corresponds to a molecular weight of 5400,
are of sufficient length to perform this
bridging function. With a mean molecular
weight of 15,000, all the heparin chains are
long enough to do this.
LMWH HAS GREATER CAPACITY TO POTENTIATE
FACTOR XA INHIBITION BY ANTITHROMBIN THAN
THROMBIN BECAUSE, WITH A MEAN MOLECULAR
WEIGHT OF 4500 TO 5000, AT LEAST HALF OF THE
LMWH CHAINS ARE TOO SHORT TO BRIDGE
ANTITHROMBIN TO THROMBIN.
THE PENTASACCHARIDE ONLY ACCELERATES FACTOR
XA INHIBITION BY ANTITHROMBIN BECAUSE THE
PENTASACCHARIDE IS TOO SHORT TO BRIDGE
ANTITHROMBIN TO THROMBIN.
DANAPAROID
Danaparoid sodium (Orgaran) is an anticoagulant that works by
inhibiting activated factor X. Danaparoid is a heparinoid but
considered to be a low molecular weight heparin by some sources.
However it is chemically distinct from heparin, has different protein
binding properties and thus has little cross-reactivity in heparinintolerant patients.
It consists of a mixture of heparan sulfate, dermatan
sulfate, and chondroitin sulfate.
Danaparoid is a low molecular weight heparinoid
(heparan derivative) that is available in many
countries (eg, Canada, Japan, Europe, Australia) but
not the United States. It does not cross the placenta.
High quality data regarding the use of danaparoid in
pregnancy are lacking, and the agent is generally not a
first choice in pregnant women.
Danaparoid is reserved for pregnant women with
acute heparin-induced thrombocytopenia (HIT)
during or immediately preceding pregnancy.
FONDAPARINUX
A synthetic analogue of the antithrombin-binding
pentasaccharide sequence, fondaparinux differs from
LMWH in several ways.
Fondaparinux is licensed for thromboprophylaxis in
medical, general surgical, or high-risk orthopedic patients
and as an alternative to heparin or LMWH for the initial
treatment of patients with established venous
thromboembolism.
Fondaparinux binds only to antithrombin and
is too short to bridge thrombin to
antithrombin. Consequently, fondaparinux
catalyzes factor Xa inhibition by antithrombin
and does not enhance the rate of thrombin
inhibition.
Fondaparinux produces a predictable anticoagulant response
after administration in fixed doses because it does not bind to
plasma proteins.
It is given at a dose of 2.5 mg once daily for prevention of
venous thromboembolism. For initial treatment of established
venous thromboembolism, fondaparinux is given at a dose of
7.5 mg once daily. The dose can be reduced to 5 mg once daily
for those weighing less than 50 kg and increased to 10 mg for
those weighing more than 100 kg..
When given in these doses, fondaparinux is as effective
as heparin or LMWH for the initial treatment of patients
with deep vein thrombosis or pulmonary embolism, and
produces similar rates of bleeding
Experience with fondaparinux during pregnancy is extremely
limited, and data regarding placental passage are mixed. The
American College of Chest Physicians (ACCP) suggests limiting the
use of fondaparinux during pregnancy to women
with severe reactions to heparin (eg, HIT) who are
unable to receive danaparoid.
ARGATROBAN
Argatroban is a parenteral direct thrombin inhibitor reserved for
those with severe reactions to heparins (eg, HIT) who cannot
receive danaparoid or fondaparinux (eg, due to lack of
availability or allergic reactions).
Argatroban requires continuous intravenous administration and
is monitored by the activated partial thromboplastin time (aPTT).
ORAL DIRECT THROMBIN INHIBITORS AND
FACTOR XA INHIBITORS
Oral direct thrombin inhibitors (eg, dabigatran) and
factor Xa inhibitors (eg, rivaroxaban, apixaban ,
edoxaban) are not used during pregnancy due to
increased reproductive risks in animal studies and/or
lack of clinical experience and safety and efficacy data .
Dabigatran etexilate, an oral thrombin inhibitor,
and rivaroxaban, an oral factor Xa inhibitor, are
available in Europe and Canada for short-term
thromboprophylaxis after elective hip or knee
replacement surgery
Warfarin crosses the placenta and can cause fetal
abnormalities or bleeding. The fetal abnormalities
include a characteristic embryopathy, which consists of
nasal hypoplasia and stippled epiphyses.
The risk of embryopathy is highest with warfarin
administration in the first trimester of pregnancy. Central
nervous system abnormalities also can occur with
warfarin exposure at any time during pregnancy.
Finally, maternal administration of warfarin produces an
anticoagulant effect in the fetus that can cause bleeding. This
is of particular concern at delivery, when trauma to the head
during passage through the birth canal can lead to
intracranial bleeding.
Because of these potential problems, warfarin is
contraindicated in pregnancy, particularly in the first and
third trimesters
Instead, heparin, LMWH, or fondaparinux can be
given during pregnancy for prevention or
treatment of thrombosis.
Warfarin does not pass into breast milk, and thus
is safe for nursing mothers
.
We generated strong (Grade 1) and weak (Grade 2)
recommendations based on high quality (Grade A), moderatequality (Grade B), and low-quality (Grade C) evidence.
•
•
Evidence Definitions:
•
Moderate Quality Evidence= Further research is likely to have an important impact
on our confidence in the estimate of effect and may change the estimat
•
Low Quality Evidence = Further research is very likely to have an important impact
on our confidence in the estimate of effect and is likely to change the estimate or
any estimate of effect is very uncertain
High Quality Evidence = Further research is very unlikely to change our confidence
in the estimate of effect
Maternal Consequences of Antithrombotic
Therapy Use During Pregnancy
For pregnant patients, we recommend LMWH for
the prevention and treatment of VTE, instead of
UFH (Grade 1B).
FETAL CONSEQUENCE OF
ANTITHROMBOTIC THERAPY USE IN
PREGNANT WOMEN
For women receiving anticoagulation for the
treatment of VTE who become pregnant, we
recommend LMWH over vitamin K antagonists
during the first trimester (Grade 1A), in the
second and third trimesters (Grade 1B), and
during late pregnancy when delivery is
imminent (Grade 1A).
FETAL CONSEQUENCE OF
ANTITHROMBOTIC THERAPY USE IN
PREGNANT WOMEN
For women requiring long-term VKAs who are
attempting pregnancy and are candidates for
LMWH substitution, we suggest performing
frequent pregnancy tests and substituting LMWH
for VKAs when pregnancy is achieved rather
than switching to LMWH while attempting
pregnancy (Grade 2C).
FETAL CONSEQUENCE OF
ANTITHROMBOTIC THERAPY USE IN
PREGNANT WOMEN
For pregnant women, we suggest limiting the use of
fondaparinux and parenteral direct thrombin inhibitors to
those with severe allergic reactions to heparin (eg, HIT)
who
cannot receive danaparoid (Grade 2C).
FETAL CONSEQUENCE OF
ANTITHROMBOTIC THERAPY USE IN
PREGNANT WOMEN
For pregnant women, we recommend avoiding the use of
oral direct thrombin (eg, dabigatran) and anti-Xa (eg,
rivaroxaban, apixaban) inhibitors (Grade 1C).
USE OF ANTITHROMBOTIC THERAPY IN
NURSING WOMEN
For lactating women using warfarin, acenocoumarol, or UFH
who wish to breast-feed, we recommend continuing the use
of warfarin, acenocoumarol, or UFH (Grade 1A).
USE OF ANTITHROMBOTIC THERAPY IN
NURSING WOMEN
For lactating women using LMWH, danaparoid, or rhirudin who wish to breast-feed, we recommend
continuing the use of LMWH, danaparoid, or r-hirudin
(Grade 1B).
USE OF ANTITHROMBOTIC THERAPY IN
NURSING WOMEN
For breast-feeding women, we suggest alternative
anticoagulants rather than fondaparinux (Grade 2C).
USE OF ANTITHROMBOTIC THERAPY IN
NURSING WOMEN
For breast-feeding women, we recommend
alternative antaicoagulants rather than oral
direct thrombin (eg, dabigatran) and factor Xa
inhibitors (eg, rivaroxaban, apixaban) (Grade 1C).
RISK FACTORS FOR VTE POSTPARTUM
TREATMENT OF PATIENTS WITH PROVEN ACUTE
VTE DURING PREGNANCY
For pregnant women with acute VTE, we recommend
therapy with adjusted-dose SC LMWH over adjusteddose UFH (Grade 1B).
TREATMENT OF PATIENTS WITH PROVEN
ACUTE VTE DURING PREGNANCY
For pregnant women with acute VTE, we recommend LMWH
over vitamin K antagonist treatment antenatally (Grade 1A).
TREATMENT OF PATIENTS WITH PROVEN
ACUTE VTE DURING PREGNANCY
For pregnant women receiving adjusted-dose LMWH therapy
and where delivery is planned, we recommend
discontinuation of LMWH at least 24 h prior to induction
of labor or cesarean section (or expected time of
neuraxial anesthesia) rather than continuing LMWH up until
the time of delivery (Grade 1B).
CRITERIA FOR APLA SYNDROME
• Test positive for lupus anticoagulant (nonspecific inhibitor) or
• Moderate to high titres antibodies to IgG or IgM anticardiolipin (>40 GLL or MPL
or >99th percentile) or
• IgG or IgM β2-glycoprotein I (>99th percentile) on two occasions at least 12
weeks apart and
• Suffer from at least one of
•
•
•
unexplained fetal death (later than 10 weeks of gestation)
three or more unexplained consecutive miscarriages (before 10 weeks of gestation)
one or more premature births of a morphologically normal neonate before the 34th week of
gestation because of eclampsia, severe preeclampsia, or placental insufficiency.
CASE 2
A 24-year-old female (gravida 1, para 1) at 34
weeks of gestation was referred due to acute
PE. One month before the hospitalization, the
patient was prescribed bed-rest due to
threatened premature labour. Moreover,
saddle pulmonary embolus was revealed.
On admission to the Intensive Care Unit, she was moderately
dyspneic, with preserved systemic blood pressure (110/70 mmHg)
and moderate tachycardia 98/min.
D-dimer plasma level was 5226 μg/ml (normal values <500
μg/ml)Therefore, a diagnosis of intermediate-risk acute PE was made.
Initially, for 4 days the patient was treated with APTT adjusted
intravenous infusion of unfractionated heparin (UFH) followed by a 2day treatment with enoxaparin in a dose of 1 mg/kg.
The initial platelet count was 200×109/L. Platelet count was
monitored every other day during the first days of therapy and always
exceeded 100×109/L.
On the seventh day of anticoagulation therapy, a rapid decline in the
platelet count, reaching 44×109/L, was observed. LMWH was stopped
immediately.
The following causes of thrombocytopenia in
our pregnant patient were considered:
heparin-induced thrombocytopenia (HIT),
thrombotic thrombocytopenic purpura (TTP),
disseminated intravascular coagulation (DIC),
preeclampsia-eclampsia and HELLP
syndrome.
HIT was diagnosed on the basis of antiplateletheparin binding antibodies presence in serum (GTI
Diagnostics’ PF4 Enhanced Solid Phase ELISA),
while other causes were excluded.
A prior episode of heparin-induced thrombocytopenia (HIT)
that has been adequately treated is not an indication for
anticoagulation during pregnancy.
However, if a pregnant patient with a history of HIT
requires anticoagulation for another reason, or if a patient
develops HIT immediately prior to or during pregnancy, an
anticoagulant other than heparin should be used. All
sources of heparin (including heparin flushes) should be
avoided.
The 2012 American College of Chest Physicians (ACCP)
guidelines recommend danaparoid as the preferred alternative
to heparin for pregnant patients; this agent is not available in
the United States .
For patients who cannot receive danaparoid, argatroban or
fondaparinux can be used. We generally use fondaparinux
because of the ease of administration during pregnancy. Other
aspects of the management of HIT are discussed separately.
Yesterday is past, it is history.
Tomorrow is future, it is a mystery.
Today is present, it is a gift!
‫ دیگر باز نمی گردد‬،‫دیروز گذشته است‬
‫ رازی بیش نیست‬،‫فردا آینده است‬
‫ هدیه ای است گران بها‬،‫امروز حال است‬
THE END