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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5524_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug
Mechanism
of action
Table 3 (Continued)
Indications (FDA
approved) Dose Route Half-life Metaboilism Excretion
Detection
of anti-
coagula-
tion
Drug
interactions
†
Unique issues
398 E. Gonzalez and E. E. Moore
Argatroban Thrombin
inhibition
— HIT tx.
— PCI for ACS in
HIT or HIT-risk
patients.
— HIT tx and prophylaxis: 0.5–2.0 mcg/kg/
min continuous i.v.
infusion (goal PTT
2.0–2.5 times control)
(start warfarin once
therapeutic goal
reached and PLT count
9
≥150 × 10
and con-
tinue argatroban until
INR is ≥4; stop argatroban and check INR
in 4 h, if INR is below
desired range then
resume argatroban and
repeat until desired
INR is reached on
warfarin alone).
— PCI for ACS:
350 mcg/kg bolus i.v.,
25 mcg/kg/min continuous i.v. infusion.
parenteral
(intravenous)
45 min (up to
2 h in hepatic
impairment)
hepatic 22% renal,
65% fecal
PTT No significant
interactions
—Transition to
warfarin may be
delayed based on
bleeding risk and
need for interventional procedures.
— Will also
significantly
increase INR.
— No renal dose
adjustment needed.
— Avoid with
impaired liver
function.
— Can be used
(off-label) for
pre-filter
administration
during CRRT in
HIT patients.
Diagnosis and Management of Coagulopathy 399
Dabigatran Thrombin
inhibition
Fondaparinux Factor Xa
inhibition
(indirect)
— Stroke and
systemic embolism
prevention in
non- valvular AF.
— VTE prophylaxis.
— DVT and PE tx
(only for acute management, transition to
warfarin for post-VTE
risk reduction).
— HIT tx.
150 mg q12h oral 16h hepatic 80% renal,
20% fecal
— VTE prophylaxis:
2.5 mg/d.
— DVT or PE tx:
7.5 mg/d (weight
50–100 kg), 10 mg/d
parenteral
(subcutaneous)
20h unknown
(non-hepatic)
77% renal anti-Xa No significant
(weight >100 kg).
— HIT tx: 7.5 mg/d
(weight 50–100 kg),
10 mg/d (weight >100
kg) (start warfarin
once PLT count ≥150
9
and continue fon-
x 10
daparinux for at least 5
days, and until INR is
≥2 for at least 24h).
Ecarin
clotting
time
(ECT) or
thrombin
time (TT)
P-glycoprotein
inhibitors,
PPI**
interactions
— Avoid if Cr
clearance
<30mL/min or with
impaired liver
function.
— Dialyzable.
— Contraindicated
if body weight
<50 kg.
— Long-term use
(>14 days) has not
been studied.
— Avoid if
CrCL<30mL/min.
— Dialyzable.
— Anti-Xa prophylactic goal
(measured 3 h after
dose): 0.3–0.5.
— Anti-Xa
therapeutic goal
(measured 3h after
dose): 1.2–1.3.
(Continued )
Drug
Mechanism
of action
Table 3 (Continued)
Indications (FDA
approved) Dose Route Half-life Metaboilism Excretion
Detection
of anti-
coagula-
tion
Drug
interactions
†
Unique issues
400 E. Gonzalez and E. E. Moore
Rivaroxaban Factor Xa
inhibition
(direct)
— VTE prophylaxis
(only for post-op knee
and hip replacement).
— DVT or PE tx.
— Stroke and
systemic embolism
prevention in nonvalvular AF.
— VTE prophylaxis:10
mg/d (14 d for knee,
35d for hip)
— DVT or PE tx:
15 mg Q12 h for 3
weeks then 20 mg/d
(duration of tx per
ACCP 9th Ed.).
oral 8h
(12h in elderly)
hepatic 66% renal,
33% fecal
anti-Xa P-glycoprotein
inhibitors,
CYP-3A4
inhibitors
— Avoid if
CrCL<30mL/min or
with impaired liver
function.
— Not dialyzable
— Stroke and systemic
embolism prevention
in non-valvular AF:
20 mg/d.
Apixaban Factor Xa
inhibition
(direct)
— Stroke and
systemic embolism
prevention in nonvalvular AF.
5 mg Q12 h (2.5 mg if 2
of the following present:
≥80 y.o, weight ≤60 kg,
or Cr≥1.5 mg/dL)
oral 12h hepatic 25% renal,
75% fecal
anti-Xa CYP-3A4
inhibitors
— Avoid if
CrCL<30mL/min or
with impaired liver
function.
— Not dialyzable
P-glycoprotein inhibitors*: rifampin, amiodarone, verapamil. CYP-3A4 inhibitors*: ketoconazole, itraconazole, voriconazole, fluconazole (mostly 2C9 inhibitor, weak 3A4), ciprofloxacin, metronidazole, erythromycin, ritonavir, amiodarone.
CYP-1A2 inhibitors*: ciprofloxacin, ethanol. CYP-2C9 inhibitors*: amiodarone, TMP/SMX, metronidazole, fluconazole, fluvastatin, isoniazid, lovastatin, setraline, gemfibrozil.
CYP-2C9 inducers**: rifampin, carbamazepine, phenytoin, phenobarbital.
U.S. brand names: enoxaparin (Lovenox), dalteparin (Fragmin), bivalirudin (Angiomax), dabigratan (Pradaxa), fondaparinux (Arixtra), apixaban (Eliquis), rivaroxaban (Xarelto).
* May increase anti-coagulant concentration and/or effect.
** May decrease anti-coagulant concentration and/or effect.
†
Combination of any two medications that affect hemostasis is considered a significant interaction as they increase bleeding risk.
tx: treatment, DVT: deep vein thrombosis, PE: pulmonary embolism, VTE: venous thrombo embolism, MI: myocardial infarction, STEMI: ST-segment elevation myocardial infarction,
NSTEMI: non-ST-segment elevation myocardial infarction, PTT: partial thromboplastin time, LMWH: low molecular weight heparin, PCI: percutaneous coronary intervention, ACS:
Diagnosis and Management of Coagulopathy 401
Review of Current Literature with References
• In a prospective cohort study of major trauma patients studied upon ED
arrival, Brohi, Cohen, et al. (Ann Surg 2007; 245: 812–818) identified that
patients without tissue hypoperfusion were not coagulopathic, irrespective of
the amount of thrombin generated. Prolongation of PT and PTT was only
observed with an increased base deficit (BD). An increasing BD was associated with high soluble thrombomodulin and increased protein-C activity.
High thrombomodulin and increased protein-C activity were significantly
associated with increased mortality, blood transfusion requirements, acute
renal injury, and reduced ventilator-free days.
• The Ben-Taub group studied outcomes before and after implementation of a
TEG-guided MTP (Tapia, Mattox et al., J Trauma Acute Care Surg 2013; 74:
378–385). These investigators compared outcomes of a fixed 1:1:1
(RBC:FFP:PLT) ratio MTP to a goal-directed TEG-guided MTP. A significant survival benefit was identified in penetrating trauma patients receiving
>10 units of RBC in the TEG-guided MTP group compared to the fixed-ratio
MTP group. Blunt trauma patients who received >10 units of RBC received
less FFP when a TEG-guided MTP protocol was used compared to a fixedratio MTP, with no difference in mortality. There was no difference in
volume of blood products or mortality in patients receiving <10 units of
blood.
• In two studies that used a statistical analysis technique of pattern-finding
and data reduction, known as principal components analysis (Kutcher,
Cohen et al., J Trauma Acute Care Surg 2013 74: 1223–1230)(Chin, Moore
et al. Surgery 2014;156(3): 570–577), patterns of TIC based on coagula-
tion factors, endogenous anticoagulants, and VHA parameters were
identified. Two distinct patterns of TIC were described: (1) global coagulation factor depletion, which was associated with penetrating injury as well
as injury severity, and predicted coagulopathy and mortality; (2) hyperfibrinolysis, which was associated with hemorrhagic shock, and predicted
mortality. These data suggests distinct and possibly overlapping patterns of
TIC; however their biological mechanisms remain to be understood,
particularly regarding fibrinolysis.
• In the clinical randomization of an anti-fibrinolytic in significant hemorrhage
(CRASH-2) trial (Lancet 2010; 376: 23–32), an absolute mortality reduction
of 1.5% was identified in trauma patients receiving empiric tranexamic acid
(TXA) compared with placebo. Enrollment criteria included adult trauma
patients within eight hours of injury with a SBP < 90 mmHg or HR>110, or
402 E. Gonzalez and E. E. Moore
those who were considered to be at risk of significant hemorrhage. Early TXA
(<1h from injury) administration was associated with the greatest reduction in
hemorrhage-related mortality. TXA given 3h after injury was associated with
an increased risk of death (4.4% vs. 3.1%; RR, 1.44; 95% CI, 1.1–1.8). No
coagulation assays were used to describe the degree of coagulopathy and/or
fibrinolysis of the patients enrolled, or to characterize the effect of the studied
drug. The characteristics of the population studied are the primary criticism
of this trial; only 50% of patients met inclusion criteria and only half of those
received a blood transfusion. Furthermore, there was no significant reduction
in transfusion requirements in the treatment arm of the study.
• In a comprehensive analysis of the data of all clinical studies using TXA as
an anti-fibrinolytic in trauma patients performed by Napolitano, Moore et al.
(J Trauma Acute Care Surg 2013; 74: 1575–1586), only a modest effect on
the overall population treated was observed; all-cause mortality was reduced
from 16.0% to 14.5%(number-needed-to-treat, 67), and the risk of death
caused by bleeding overall was reduced from 5.7% to 4.9%(number-neededto-treat, 121). TXA’s greatest impact on mortality was in those in the
severe shock group (SBP<75 mmHg). Furthermore, the mechanism by
which TXA reduced mortality in the CRASH-2 trial (Lancet 2010; 376:
23–32) remains unclear given that fibrinolysis and coagulation assessments
were not part of the study design. This calls for caution of indiscriminate use
of anti- fibrinolytic drugs and raises the question of whether coagulation
assessments should be performed prior to their administration.
Chapter 9-(iii)
Prevention and Management
of Venous Thromboembolism
Eduardo Gonzalez, MD* and Ernest E. Moore, MD
†
Professor of Surgery and Vice-Chair of Surgical Research, University of Colorado
*Surgical Resident, University of Colorado School of Medicine
School of Medicine
†
Take Home Points
• Surgical intensive care unit patients by definition are at the highest risk for
venous thromboembolic events (VTE) and should be managed with pharmacologic and mechanical prophylaxis if no contraindications exist.
• High-risk conditions independently associated with VTE: increasing age,
trauma (spinal fracture or cord injury, pelvic fracture, vascular injury), cancer,
total knee arthroplasty, total hip arthroplasty, and presence of an indwelling
central venous catheter. History of a VTE is the strongest predisposing risk
factor.
• The choice of prophylactic anticoagulant agent should be made based on the
evidence available for each high-risk group (e.g., trauma, orthopedic surgery,
surgical oncology patients).
Contact information: (Eduardo Gonzalez) 777 Bannock St. MC 0206, Denver, CO 80204;
(Ernest E. Moore), 655 Broadway, Ste. 365, Denver, CO 80203; Tel.: 303-602-1820,
Fax: 303-602-1817, email: ernest.moore@dhha.org; Eduardo.Gonzalez@dhha.org
403
404 E. Gonzalez and E. E. Moore
• The timing at which pharmacologic VTE prophylaxis benefits patients with
traumatic brain injury over an increased risk of intracranial hemorrhage progression has not been adequately studied. The decision of when to start
prophylaxis should be made on a case-by-case basis.
• Duplex ultrasound is the diagnostic test of choice when there are clinical find-
ings of deep vein thrombosis.
• Computed tomography (CT) angiography is the diagnostic test of choice
when there are clinical findings of a pulmonary embolism (PE) in a normotensive patient, while other diagnostic strategies are available for patients with
contraindications for CT, or those who are hypotensive.
• The presence of hypotension associated with a PE has been defined as a
threshold for thrombolysis. A careful consideration of contraindications due
to bleeding risk should be had.
• If there is a high index of suspicion for PE, anticoagulation should be started
while proceeding with diagnostic testing.
• Intravenous unfractionated heparin is the anticoagulant agent of choice for
treatment of a DVT or PE in surgical ICU patients.
• Post-VTE risk reduction therapy should be continued with warfarin for at
least three months in most cases.
• Heparin induced thrombocytopenia typically causes a >50% decrease in
platelet count, that usually occurs 5–10 days after heparin exposure. It is
associated with a 50% incidence of thrombotic complications, and should be
treated with anticoagulation using a non-heparin agent.
Background
• Despite implementation of guidelines for the prevention and treatment of
venous thromboembolisms (VTE), pulmonary embolisms (PE) remain the
most common preventable cause of hospital death (appx. 150,000–200,000
deaths/year in the United States).
• Virchow’s triad, consisting of stasis, endothelial injury, and hypercoagulability
(inherited or acquired), is the basic pathophysiological process driving VTE.
• Mechanisms of activation of the coagulation system following critical illness,
surgery, or trauma are incompletely understood, but may include decreased
venous blood flow in the lower extremities, immobilization, release or exposure of tissue factor, increased platelet activity, endothelial cell activation,
depletion of endogenous anticoagulants such as antithrombin and protein C,
and compromised fibrinolysis.
• The reported incidence of clinically diagnosed VTE in intensive care unit
(ICU) patients ranges from 1.3 to 7.6% despite administering recommended
Prevention and Management of Venous Thromboembolism 405
pharmacological and/or mechanical prophylaxis. However, the true incidence of all VTE’s is substantially higher if routine screening with imaging
is performed:
A 10% prevalence of VTE upon ICU admission has been reported.
In trauma patients, screening with venography detected a DVT incidence
of 58% in patients who were not receiving VTE prophylaxis.
A single-center study that used computed tomography (CT) scanning to
screen for asymptomatic PE in trauma patients (ISS ≥9) detected an incidence of 24% (54% of patients with a detected asymptomatic PE were
receiving pharmacologic prophylaxis).
• Failure to significantly decrease the incidence of VTE despite adopting the
recommended prophylactic strategies may be due to inadequate heparin dosing, failure to address platelet activation, and shutdown of fibrinolysis.
The lack of efficacy of thromboprophylaxis with heparin has been largely
attributed to decreased bioavailability due to peripheral edema, vasoconstriction, decreased cardiac output, and obesity.
Studies have shown anti-Xa levels to be below recommended thresholds
for prophylaxis despite using recommended doses.
ICU patients experience a substantial progressive increase both in the
concentration as well as the function of fibrinogen, which independently
enhances coagulation.
Fibrinogen binds heparin and reduces its bioactivity; there is an inverse
correlation between fibrinogen levels and the efficacy of heparin.
Activated platelets also contribute to hypercoagulability, and heparin
administration appears to paradoxically increase platelet activation.
Suppressed endogenous fibrinolytic activity, also referred to as fibrinoly-
sis shutdown, has been documented in ICU patients, and may be
implicated in driving VTE formation.
• Characterization of hypercoagulability has been achieved clinically with
thrombelastography (TEG) in ICU trauma patients.
Both enzymatic (driven by fibrinogen and coagulation factors) and plate-
let hypercoagulability are concomitantly present.
Citrated-kaolin TEG values of clot strength maximum amplitude (MA)
>72 mm, and shear elastic modulus strength (G) >12.4 dynes/cm2, have
been established as markers of post-injury hypercoagulability associated
with increased risk of VTE.
This hypercoagulable threshold is reached by 48 h from ICU admission in
most trauma patients.
406 E. Gonzalez and E. E. Moore
Main Body
• VTE risk assessment
Risk assessment should be performed upon every patient’s admission
to the ICU. When contraindications for VTE prophylaxis exist, a daily
re-assessment of bleeding and thrombosis risk should be performed.
Omission of prophylaxis at 24 h from ICU admission has been associated
with a 3-fold increase in VTE incidence, and with an estimated attributable mortality effect of 3.9 to 15.4%.
DVT event rates in the absence of prophylaxis based on systematic screen-
ing studies with imaging: acute spinal cord injury 90%, trauma 58%, elective
hip surgery 50%, major general surgery 25%, neurosurgical patients 22%.
The Caprini Risk Assessment Model, described in Table 1, is the most
commonly utilized VTE risk assessment tool in surgical patients and has
been modified for its use in the 2012 American College of Chest
Physician’s VTE prophylaxis guidelines.
Although this tool is useful to identify those patients who will benefit
from VTE prophylaxis, surgical ICU patients by definition are high
risk (mostly due to a major surgical procedure, central venous catheter
[CVC], immobility, and/or trauma) and should be managed as such.
Of note, this model was not developed using rigorous statistical meth-
ods, and includes some variables that were later found not to be
associated with VTE risk. Furthermore, it does not include specific
criteria for trauma patients.
In trauma patients, the Greenfield risk assessment profile (RAP) score has
been developed to identify those patients at high risk for VTE (≥5 points)
who will benefit from VTE prophylaxis. Table 2 describes the RAP score.
Hereditary hypercoagulable disorders: activated protein-C resistance from
factor V Leiden (most common, 5% general population), prothrombin gene
mutation 20210A, protein C and S deficiency, elevated homocysteine, antithrombin deficiency, and elevated coagulation factors VIII, IX, and XI.
The total incidence of one of these inherited thrombophilias in
subjects with a VTE range from 24% to 37% compared with approximately 10% in controls.
The Asian population has a lower incidence of VTE compared to other
ethnicities.
Acquired hypercoagulable disorders: anti-phospholipid antibody syndrome,
polycythemia vera, essential thrombocytosis, paroxysmal nocturnal hemoglobinuria, Cushing syndrome.
Prevention and Management of Venous Thromboembolism 407
Polycythemia vera patients have a high incidence of portal and mesenteric
vein thrombosis, mostly due to hypercoagulability resulting from increased
blood viscosity. Hence, adequate hydration perioperatively is crucial in
preventing thrombosis in these patients.
Malignancy is the most common acquired condition predisposing to VTE.
Major risk factors that have been independently associated with increased
VTE incidence: increasing age, spine fracture, spinal cord injury, pelvic
fracture, severe femur or tibial fracture, vascular injury (risk highest with
venous repair or ligation), sepsis, >72 hours of mechanical ventilation,
prolonged neuromuscular blockade (repeated dosing or continuous infusion), indwelling central venous catheters (CVC), prolonged vasopressor
requirements, obesity, congestive heart failure, and end-stage renal disease.
History of a previous VTE is the strongest risk factor.
Medications associated with a hypercoagulable state: oral and transder-
mal contraceptives, estrogen (+/− progestin) replacement therapy,
tamoxifen, raloxifene, L-asparaginase, chemotherapeutic agents, bevacizumab (Avastin; VEGF monoclonal antibody used in colon cancer).
In ICU patients with CVC, there is a 33% prevalence of catheter-related
DVT reported by studies using ultrasound (US) screening.
Incidence of CVC-related DVT by catheter location: femoral vein >
internal jugular vein > subclavian vein.
Peripherally inserted central venous catheters (PICC) are associated
with an increased risk of catheter related DVT’s compared to that of
CVC’s (OR 2.55) (80% of PICC-related DVT’s occurred within
14 days from insertion).
Prevalence of a CVC-related DVT is elevated when a central line asso-
ciated blood stream infection (CLABSI) is present, and conversely there
is a 2.6-fold higher risk of sepsis when CVC related DVT is present.
Misplaced CVC (catheter tip in the innominate vein or junction of the
innominate vein with the superior vena cava) are associated with a
higher risk of CVC related DVT than properly positioned catheters
(catheter tip in distal superior vena cava or junction with right atrium).
• VTE prophylaxis
Anticoagulant medications and dosing are described in Table 3.
Very-low, low, and moderate VTE risk patients should be managed
according to Table 1.
High-risk patients, in addition to pharmacologic prophylaxis, should
receive lower extremity intermittent pneumatic compression (IPC) if no