Flashcards in Chapter 80 Anticoagulants and Neuraxial and Peripheral Nerve Blocks Deck (115):
The predisposing factors to the development of DVTs
stasis, intimal injury, and hypercoagulability
Some of the risk factors for the development of DVTs are
previous history of DVT or pulmonary embolism,
major surgery, age over 60, obesity, malignancy,
increased duration of surgery, prolonged immobilization,
presence of varicose veins, and the use of estrogen. The
problem is pronounced in total joint operations where
intraoperative factors predispose to the development of DVTs.
The increased coagulability of the
blood is aggravated by
decreases in antithrombin III and tissue plasminogen activator (t-PA).
the most reliable diagnostic test for DVT
Ascending venous contrast venography. It is invasive, requires a radiology suite,
the first-line modality for confirming diagnosis of DVT in
B-mode compression ultrasonography with and without Doppler. It is portable and the most accurate
noninvasive study of DVTs. Failure of the vein to compress
is indirect evidence that a thrombus is present
The prevention of DVT after total joint surgery includes
intraoperative, mechanical, and pharmacologic measures
The use of epidural hypotensive anesthesia is associated with improved
visualization of the operative field, less intraoperative
blood loss, and shorter duration of surgery
Mechanical devices decrease stasis by
augmenting venous flow in the lower legs, and appear to have a fibrinolytic effect through a reduction in plasminogen activator inhibitor. Various types of mechanical devices include calf-length sleeve, thigh-length stockings, and foot pump devices
the most efficacious way of preventing DVT
A combination of mechanical
and pharmacologic measures
The pharmacologic management of DVTs includes
the use of aspirin, warfarin, LMWH, thrombin inhibitors, and the newer drugs including rivaroxaban
For aspirin, most regimens use doses of
325 to 650 mg twice a day. The risks
of aspirin use are gastritis and gastric erosions or ulcers
For warfarin, the usual dosing
mg given the night of surgery, followed by adjustment of the dose to maintain an international normalized
ratio (INR) of 2.0 to 2.5. Higher INRs may result in hemarthromas. The therapy is maintained for 1 month after
ecause of warfarin’s delayed effect and the early
development of postoperative thrombus
add an LMWH as a “bridge therapy” while
the effect of warfarin is commencing
Heparin is not widely used for postoperative prophylaxis
after total joint surgery probably because
of the better bioavailability and predictability of LMWH.
The LMWH therapy
continued for 1 to 2 weeks after the surgery.
a specific Xa inhibitor, is given for 5 to 9 days after surgery
at a daily dose of 2.5 mg. The drug reduces the incidence
of venous thromboembolism by 57%, comparable
an oral thrombin inhibitor. However, its use resulted in severe liver toxicity and this led
to the Food and Drug Administration (FDA) recommending against its approval.
The medication recommendations of
the group for patients at standard risk of both pulmonary
embolism and bleeding, and for patients at elevated risk for
pulmonary embolism and standard risk of major bleeding,
include the following (in alphabetical order):
aspirin; LWMH, pentassacharides, and warfarin (INR goal of
For patients at standard risk of pulmonary embolism
and elevated risk of bleeding, and for patients at elevated
risk of both pulmonary embolism and major bleeding, the group recommended the following medications
and warfarin (INR goal of
In patients with STEMI regardless of whether they undergo reperfusion or fibrinolytic therapy
With regards to anticoagulants, the task force recommended the addition of clopidogrel to aspirin
The ACA/AHA guidelines
recommended that clopidogrel should be discontinued
at least 5 days and preferably 7 days unless the urgency for
revascularization outweighs the risks of excess bleeding.
STEMI patients who do not undergo reperfusion therapy,
the ACA/AHA guidelines stated that
it is reasonable to give
IV or subcutaneous unfractionated heparin (UFH) or subcutaneous
LMWH for at least 48 hr.
For patients who
undergo invasive management, anticoagulant therapy with
unfractionated heparin or LMWH is recommended
After stent placement, it has been recommended that
aspirin be continued for
1 month after a bare-metal stent, 3 months after a sirolimus-eluting stent, and 6 months after a paclitaxel-eluting stent
For clopidogrel, it has been
recommended that the drug be continued for
at least 1 month and ideally up to a year, and for at least 1 year after both sirolimus- and paclitaxel-eluting stent
Problems with warfarin include its
narrow therapeutic range (INR 2–3), unpredictable and patientspecific dose response, delayed onset and offset of action, need for anticoagulation monitoring, slow reversibility,
and many drug–drug and drug–food interactions.
Antiplatelet therapy is highly effective in reducing
the risk of recurrent ischemic stroke or TIA and is recommended over oral anticoagulant for noncardioembolic stroke
irreversibly binds to the platelet COX enzyme inhibiting the formation of thromboxane A2 that causes platelet aggregation, resulting in the formation of an
adequate but fragile clot.
Aspirin Dosing and Effects
Most regimens use doses of 325 to 650 mg twice a day. Lower doses of aspirin are more effective in preventing clot formation, as the platelet COX enzyme is blocked, decreasing the formation of thromboxane A2, which causes platelet aggregation. Higher doses of aspirin inhibit the COX enzyme in the platelets and in the vascular endothelium; this inhibition also results in decreased levels of PGI2, which inhibits platelet aggregation. The ultimate effect of higher dosages is therefore a reflection of the antagonistic effects of reduced levels of
thromboxane A2 and PGI2.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
bind to the platelet COX enzyme but the binding is
reversible; their effect on platelet function usually normalizes within 3 days
platelet function analyzer (PFA).
of in vitro platelet function, as well as a good screening
test for von Willebrand disease, monitoring the effect of
DDAVP administration, and is prolonged after antiplatelet
therapy. The test measures the ability of platelets to occlude a microscopic aperture in a membrane coated with
collagen and epinephrine (C-EPI or PFA-I) or collagen
and adenosine diphosphate (C-ADP or PFA II) under controlled high shear rates. The time required to obtain a
complete platelet plug is the closure time in seconds. The
normal closure times are 60 to 160 s for C-EPI and 50 to
124 s for C-ADP. Aspirin and NSAIDs prolong the closure
time of C-EPI, while clopidogrel, von Willebrand disease, low platelet count, low hematocrit, and renal failure prolong the closure time for C-ADP.
have analgesic effects. They have less gastrointestinal
toxicity and compared to aspirin or NSAIDS,
thienopyridine drugs ticlopidine and clopidogrel
inhibit platelet aggregation by inhibiting ADP receptor mediated platelet activation. These drugs also modulate
vascular smooth muscle reducing vascular contraction.
Clopidogrel is 40 to 100 times more potent than ticlopidine.
ticlopidine and clopidogrel dose
The doses employed are 75 mg daily for clopidogrel and 250 mg twice a day for ticlopidine
Ticlopidine is rarely
used because it causes
hypercholesterolemia, neutropenia, and thrombocytopenic purpura. There is also a possible
delayed antithrombotic effect of ticlopidine and may not
offer protection in the cardiac patient for the first 2 weeks of ticlopidine therapy.
Clopidogrel is preferred because
it has a better safety profile and appears to have a better effect
than aspirin in patients with peripheral vascular disease and
is increasingly used in these patients.
The maximal inhibition of ADP-induced platelet aggregation with clopidogrel
3 to 5 days after initiation of a standard dose (75 mg),
but within 4 to 6 hr after the administration of a large loading dose (300–600 mg). The large loading dose is given to patients before they undergo percutaneous coronary intervention.
neuraxial blocks may be performed in patients on
aspirin or NSAIDs
Neuraxial blocks in patients on COX-2 inhibitors are
safe, although the concomitant use of COX-2
inhibitors and warfarin may increase the risk of bleeding.
For clopidogrel, it is recommended that the drug be discontinued for
7 days before a neuraxial injection. In contrast, a delay of 10 to 14 days is recommended with ticlopidine. This is because the half-life of ticlopidine increases from
12 hr after a single dose to 4 to 5 days after a steady state is reached
Aspirin and NSAIDs alone
do not significantly increase
the risk of spinal hematoma. The combination of these
drugs, however, increases the risk of spontaneous hemorrhagic complications, bleeding at puncture sites, and spinal hematoma. The society cautioned the performance of intraspinal injections in patients who are on combined antiplatelet medications.
For patients on clopidogrel and aspirin, it is recommended
that the clopidogrel be stopped for
7 days and the
patient placed on aspirin therapy. The aspirin is then continued up to the time of injection, after which the patient is switched back on clopidogrel after the block. If the indication for the anticoagulation is very strong then LMWH can be given during the 7 days that the clopidogrel is stopped.
an oral anticoagulant that interferes with the synthesis of the vitamin K–dependent clotting factors II, VII, IX, and X. It also inhibits the anticoagulant protein C. Both factor VII and protein C have short halflives
(6–7 hr) and increase in the INR is the result of the
competing effects of reduced factor VII and protein C
and the washout of existing clotting factors.
after the initial dose of Warfarin Prophylactic anticoagulation (INRs of 2.0–2.5) is
48 to 72 hr after the initial dose
effect of warfarin is primarily dependent on
the levels of factor II that has a half-life of 50 hr. Maximal anticoagulation is reached in 4 to 5 days when factor II is sufficiently reduced
The risks of warfarin usage are
bleeding and the rare occurrence of skin necrosis. Its drawbacks
include the necessity of monitoring its effect with serial INR monitoring, its interaction with a host of other drugs,
and the fact that it has to be stopped a few days before
for safe placement
of the epidural catheter ASRA recommended an INR of
concentrations of factor II in relation to INR
At INR values of 1.5 to 2.0,
the concentrations of factor II were found to be 74% to
82% of baseline while factor VII levels were 27% to 54% of baseline values. Levels of 20% of normal are considered
adequate for normal hemostasis at the time of major
the factor VII activity should be
determined If risk factors such
as low platelets,
advanced age, kidney failure, or intake of other anticoagulants
Warfarin is metabolized primarily by
enzyme of the cytochrome P450 system
glycosaminoglycans that consist of chains
of alternating residues of d-glucosamine and uronic acid,
either glucuronic acid or iduronic acid.
heterogeneous mixture of polysaccharide
chains ranging in molecular weight from 3000 to 30,000.
A unique pentasaccharide sequence
along the heparin chains, binds to antithrombin (AT).The binding of the heparin pentasaccharide to AT causes a conformational change in AT that accelerates its ability to inactivate thrombin, factor Xa, and factor IXa.
UFH releases tissue factor pathway inhibitor from
endothelium, enhancing its activity against factor Xa
The anticoagulant effect of subcutaneous heparin takes
1 to 2 hr but the effect of intravenous heparin is immediate
used to monitor the effect of heparin
anticoagulation is achieved with a prolongation of
the aPTT to greater than 1.5 times the baseline value or a heparin level of 0.2 to 0.4 U/ml. The aPTT is usually not prolonged by the subcutaneous administration of low doses of heparin and is not monitored
for DVT prophylaxis UFH is either administered as
an intravenous injection
or as subcutaneous injection for DVT prophylaxis
The risk factors in the development of intraspinal hematoma
in patients who are given systemic heparin
(1) an interval of less than 1 hr between the lumbar puncture and heparin administration; (2) concomitant use of other
anticoagulants such as aspirin; and (3) traumatic needle placements.
ASRA guidelines on the performance of neuraxial procedures in patients who are anticoagulated with heparin are as follows
(1) the neuraxial technique should be avoided in patients with other coagulopathies;
(2) although the occurrence of bloody or difficult needle placement
increases the risk of hematoma, discussion with the surgeon of the risk/benefit ratio should determine cancellation
or noncancellation of the case;
(3) the heparin administration should be delayed for 1 hr after needle placement;
(4) indwelling neuraxial catheters should be removed 2 to 4 hr after the last heparin dose, and the patient’s coagulation
status is evaluated and reheparinization occurs 1 hr
after catheter removal; and (5) minimal concentrations of local anesthetics should be used for early detection of signs of spinal hematoma and the patient is monitored postoperatively for signs of hematoma
In general surgery and urology, patients who undergo major procedures, the subcutaneous UFH
Is given perioperatively
for DVT prophylaxis.
Heparin, 5000 U, when
given subcutaneously every 12 hr, causes
barely detectable changes in the aPTT; the very few patients that have prolongations of their aPTT do not exceed 1.5 times the normal levels.
debate as to whether
neuraxial procedures should be performed in patients
who undergo cardiopulmonary bypass. In these patients the
following precautions have been recommended
(1) neuraxial procedures should be avoided in patients with a known coagulopathy,
(2) surgery should be delayed 24 hr in the patient with a traumatic tap,
(3) the time from the neuraxial procedure to the systemic heparinization
should exceed 1 hr,
(4) heparinization and reversal should be monitored and controlled tightly, and
(5) the epidural catheter should be removed when normal coagulation is restored and the patient should be monitored closely for signs of spinal hematoma after the catheter is removed
Heparin is not the ideal anticoagulant:
it is a mixture of molecules of which only a fraction has anticoagulant activity. It binds to platelet factor IV, which is released from activated platelets, to a number of plasma proteins, and to high-molecular-weight multimers of von Willebrand factor that are released from platelets and endothelial cells. The heparin–antithrombin complex is also not very effective in neutralizing clot-bound thrombin. These factors result in an unpredictable anticoagulant effect of heparin necessitating careful laboratory monitoring when it is used in therapeutic dosages.
the fractionated forms
of heparin with a mean molecular weight of 5000.
antithrombin, accelerating antithrombin’s interaction with thrombin and factor Xa. LMWH, like unfractionated heparin, also releases tissue factor pathway from the endothelium
compared to heparin
LMWHs have a longer half-life and dose independent
clearance compared to heparin, resulting in a
more predictable anticoagulant response.
The reduced binding with plasma proteins and endothelium of LMWH results in
the LMWHs’ better bioavailability and predictability than
The plasma half-life of the LMWHs ranges from
2 to 4 hr after
an intravenous injection and 3 to 6 hr after a subcutaneous
after injection of LMWH anti-Xa activity is present for
12 hr after injection of LMWH
Laboratory monitoring for LMWH
is not necessary except in patients with renal insufficiency or those with body weight less than 50 kg or more than 80 kg.
The reaction time (r-time) from the thrombelastogram, a test that is easily available, was found to correlate with
the serum anti-Xa concentration
LMWH used a prophylaxis against thromboembolism
in surgical settings such as
general surgery, total hip and knee replacements, surgery for hip fractures, and multiple trauma. Also, LMWHs have been used in unstable angina, acute myocardial infarction, and ischemic stroke
most commonly used LMWHs
enoxaparin (Lovenox) and dalteparin (Fragmin).
enoxaparin (Lovenox) and dalteparin (Fragmin) DOSING
given once daily or every 12 hr (a dosing
that is assocaited with increased risk of spinal hematoma),
while dalteparin is given once a day.
The recommendations of the ASRA for patients receiving
LMWH and neuraxial anesthesia are as follows
l Monitoring of the anti-Xa level is not recommended.
l The administration of antiplatelet or oral anticoagulant medications with LMWHs may increase the risk of spinal hematoma.
l The presence of blood during needle placement and catheter placement does not necessitate postponement of surgery. However, the initiation of LMWH therapy should be delayed for 24 hr postoperatively.
l The first dose of LMWH prophylaxis after twice-daily enoxaparin should be given no earlier than 24 hr postoperatively and only in the presence of adequate hemostasis. It may be given 6 to 8 hr after a once-daily dosing
l In patients who are on LMWH, needle/catheter placement should occur at least 12 hr after the last prophylactic dose of enoxaparin or 24 hr after dalteparin (120 U/kg
every 12 hr or 200 U/kg every 12 hr), or after higher doses of enoxaparin (1 mg/kg every 12 hr; 1.5 mg/kg daily).
l There should be a 12-hr interval between the last
prophylactic dose of enoxaparin and removal of the epidural catheter. For higher doses of enoxaparin, a 24-hr delay is recommended.
l The LMWH may be administered 2 hr after the epidural catheter is removed.
is a synthetic anticoagulant that is a selective
Xa inhibitor. Because it is synthesized chemically, it
exhibits batch-to-batch consistency. The drug is rapidly absorbed, reaching a maximum concentration within 1.7 hr of dosing and has a half-life of 21 hr. It has 100% bioavailability. A dose of 2.5 mg is given subcutaneously
6 hr after surgery, and subsequently once a day.
a direct thrombin inhibitor. Hirudin acts independently of antithrombin and other plasma proteins.
available thrombin inhibitors include
the recombinant hirudin derivatives desirudin (Revasc®), lepirudin
(Refludan®), and bivalirudin (Angiomax®), and the synthetic L-arginine derivative argatroban (Acova®).
thrombin inhibitors MOA
drugs can neutralize free and clot-bound thrombin and are used in the treatment of thrombosis in patients with heparin-induced thrombocytopenia and in the prevention
of thromboembolic complications after total hip replacement
thrombin inhibitors anticoagulant effect is present for
1 to 3 hr and is monitored by the aPTT. There is no pharmacologic reversal to the effect of these drugs
an oral direct thrombin inhibitor. Bioavailability is only 5%, peak plasma levels occur at 2 hr,
and its half-life is 8 hr after a single dose, although it can be up to 17 hr after multiple doses
an oral factor Xa inhibitor. It has an 80% bioavalability; its peak effect occurs after 1 to 4 hr and its duration of effect is 12 hr. It has a half-life of 9 to 13 hr. The drug offers several salutary characteristics including efficacy and simplicity of
once-daily oral dosing
an oral anticoagulant prodrug. Its mechanism
of action is similar to clopidogrel, that is, noncompetitive antagonist of P2Y12, inhibiting the ability of platelet ADP to induce aggregation for the life of the platelet
Prasugrel vs. clopidogrel
Prasugrel has a quicker onset of action, the effect of 60 mg is 1 to 1.5 hr compared to 6 hr with 300 mg clopidogrel. It is 10 times more potent and is less prone to drug–drug
interactions and patient nonresponsiveness
Prasugrel and neuraxial injection
The drug causes 90% platelet inhibition and a 7-day interval between
discontinuation of the drug and neuraxial injection is recommended
inhibits platelet aggregation and its effect on
hemostasis appears to last 7 days
activating factor and its effect lasts 36 hr, while the
effect of ginseng lasts 24 h
herbal drugs and neuraxial block
At this time, there appears to be no specific concerns as to the timing of neuraxial block in relationship to the dosing of herbal therapy, postoperative monitoring, or the timing of neuraxial catheter removal
Pregnancy and puerperium are accompanied by increased risk of
Thromboprophylaxis is recommended in women with
AT deficiency, homozygosity for the factor V Leiden mutation, homozygosity for the prothrombin gene G20210A mutation, or homozygosity for both mutations.
recommendations have been made with
regards to anticoagulation during pregnancy:
(1) oral anticoagulants
should be switched to LMWH or unfractionated
heparin no later than 36 weeks, (2) LMWH should be discontinued and switched to heparin at least 36 hr before induction of labor or cesarean section delivery, (3) IV heparin should be discontinued 4 to 6 hr before the anticipated
The hematomas occurred in patients with abnormal and normal coagulation status, and in patients who were given
LMWH, ticlopidine and clopidogrel, warfarin,
heparin, or a combination of these drugs
The diagnosis of bleeding after peripheral nerve block in patients on anticoagulants include
pain (flank or paravertebral
pain or groin pain in psoas bleeding), tenderness
in the area, fall in hemoglobin/hematocrit, fall in blood pressure, and sensory and motor deficits
definitive diagnosis of bleeding after peripheral nerve block made by
computed tomography, ultrasound can be a diagnostic aid and its increasing use will make this modality a useful tool in diagnosing and following peripheral hematomas
Treatments of peripheral
hematomas usually include
surgical consult, blood
transfusion as necessary, and watchful waiting versus surgical drainage
Aspirin, NSAIDs, COX-2 inhibitors
Pain clinic patients: aspirin preferably stopped 2–3 days in thoracic and cervical epidurals
(a) Clopidogrel (Plavix): discontinue for 7 days.
May perform neuraxial block after 5 days if P2Y12 assay shows less than 10% platelet inhibition.
(b) Ticlopidine (Ticlid): discontinue for 14 days.
Prasugrel: discontinue for 7-10 days.
Do not perform a neuraxial block in patients on more than one antiplatelet drug.
Glycoprotein IIb/IIIa inhibitors: time to normal platelet aggregation
(a) Abciximab (ReoPro) 5 24 to 48 hr
(b) Eptifibatide (Integrilin) 5 4 to 8 hr
(c) Tirofiban (Aggrastat) 5 4 to 8 hr
Check INR (coagulant response time).
INR ,1.5 before neuraxial block or epidural catheter removal.
Subcutaneous heparin (5000 units SC q 12 hr)
Subcutaneous heparin BID is not a contraindication against a neuraxial block.
Neuraxial injection may not be performed in a patient on subcutaneous heparin TID.
Neuraxial block should preferably be performed before SC heparin is given.
Risk of decreased platelet count with SC heparin therapy .5 days
Neuraxial block: 2 to 4 hr after the last intravenous heparin dose
Wait >1 hr after neuraxial block before giving intravenous heparin.
(a) Wait 12 hr before a neuraxial block:
Enoxaparin (Lovenox) 0.5 mg/kg BID (prophylactic dose)
(b) Wait 24 hr before a neuraxial block:
Enoxaparin (Lovenox), 1 mg/kg BID (therapeutic dose)
Enoxaparin (Lovenox), 1.5 mg/kg QD
Dalteparin (Fragmin), 120 units/kg BID
Dalteparin (Fragmin), 200 units/kg QD
Tinzaparin (Innohep), 175 units/kg QD
Twice-daily dosing: LMWH should not be started until after 24 hr after surgery.
Once-daily dosing: LMWH may be given 6 to 8 hr.
LMWH should not be given until >2 hr after epidural catheter removal
Patients with epidural catheter who are given LMWH
The catheter should be removed at the earliest opportunity.
Enoxaparin (0.5 mg/kg): remove the epidural catheter 12 hr after last dose.
Enoxaparin (1 to 1.5 mg/kg), dalteparin, tinzaparin: remove the epidural catheter 24 hr after last dose.
Restart the LMWH 2 hr after the catheter removal.
Summary recommendations for LMWH (preoperative and postoperative): Wait 24 hr except for patients on low-dose enoxaparin (0.5 mg/kg), in which case a 12-hr interval is adequate.
Wait 2 hr after the catheter is removed before starting LMWH.
Specific Xa Inhibitor: Fondaparinux (Arixtra)
Short onset, long duration (plasma half-life: 21 hr)
ASRA: no definite recommendation
If neuraxial procedure has to be performed, recommend single-needle atraumatic placement, avoid indwelling catheter.
Rivaroxaban: a new oral factor Xa inhibitor, half-life of 9–13 hr. Approximately a 24-hr interval, or 23 the drug’s half-life, between the drug and
epidural placement was observed in studies.
No data on safety interval for performance of neuraxial procedure
Follow fibrinogen levels
ASRA: no definite recommendation
Anticoagulant effect lasts 3 hr
Monitored by aPTT
ASRA: no recommendation at this time because of paucity of data
Dabigatran: a new oral direct thrombin inhibitor, half-life of 8-17 hours (recommended interval between drug discontinuation and neuraxial
injections is 2-3 half-lives).
Mechanism of anticoagulant effect and time to normal hemostasis:
Garlic: inhibits platelet aggregation, increased fibrinolysis; 7 days
Ginkgo: inhibits platelet-activating factor; 36 hr
Ginseng: increased PT and PTT; 24 hr
ASRA: neuraxial block not contraindicated for single herbal medication use
The guidelines are the same for the placement and removal of epidural catheters.
Discontinue ticlopidine for
14 days and clopidogrel
contraindication with BID
dosing, contraindicated with
IV: Heparin 1 hr after neuraxial
injection, remove catheter
2–4 hr after heparin
BID dosing: LMWH 24 hr
after surgery, remove catheter 2 hr before LMWH
INR < 1.5
Single injection, atraumatic placement, no indwelling
Suggest avoidance because
of insufficient information