However, there is little correlation between peak anti-factor Xa activity and
the dosing interval. Like other measures of hemostasis, results vary considerably,
requiring both instrument-specific and method-specific determination of therapeutic
1,000 mg PO twice daily, and atorvastatin 80 mg PO every evening. Initial laboratory values include:
What signs and symptoms demonstrated by J.T. are consistent with DVT?
Optimal Therapeutic Range and Duration of Anticoagulation
Indication INR Goal Minimum Duration
Prophylaxis of VTE (DVT, PE) 2–3 ˜1–4 weeks depending on patient status and
Treatment of first VTE with transient risk
First episode of unprovoked VTE 2–3 3 months
Consider extended treatment if first
episode of VTE is PE or proximal DVT
Second episode of unprovoked VTE 2–3 Long term
VTE and cancer 2–3 Indefinitely or until cancer resolved
VTE prophylaxis after hip or knee
arthroplasty, hip fracture surgery
2–3 Up to 35 days after surgery
Atrial fibrillation (persistent or
Acute MI: high risk (large anterior MI,
significant heart failure, intracardiac
thrombus visible on ECHO, AF, previous
Post-UA/NSTEMI (with or without stent
placement): with AF requiring dual
antiplatelet therapy and warfarin therapy
Bileaflet mechanical valve or tilting disc
valve in aortic position in sinus rhythm
Bileaflet mechanical valve or tilting disc
Caged-ball or caged-disc valve 2.5–3.5 Long term
Mechanical aortic heart valves with
additional risk factors (AF, previous VTE,
LV dysfunction, hypercoagulable
Bioprosthetic valve in aortic position
c N/A Aspirin 81 mg daily alone
Bioprosthetic valve in mitral position 2–3 3 to 6 months
Followed by aspirin 81 mg daily
Bioprosthetic valves with additional risk
factors (AF, previous VTE, LV dysfunction,
aLow-molecular-weight heparin preferred for patients with VTE and cancer.
bHigher goal INR recommended by the AHA/ACC. INR 2–3 recommended by ACCP.
cWarfarin (goal INR 2–3) for 3 to 6 months is also recommended by the AHA/ACC.
VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; CHADS2
myocardial infarction; ECHO, echocardiogram; AF, atrial fibrillation; EF, ejection fraction.
Source: Nishimura RA et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the
management of patients with valvular heart disease. Circulation. 2017; 70(2):252–289.
Patients with DVT typically present with unilateral leg swelling that often is
accompanied by warmth and local tenderness or pain.
caused by venous obstruction can sometimes be palpated in the affected area. J.T.
presented with the sudden onset of swelling along with soreness, but without
evidence of a cord. Discoloration of the affected limb, including pallor from arterial
spasm, cyanosis from venous obstruction, or a reddish color from perivascular
inflammation, may also occur. The presence or absence of a positive Homans sign
(pain behind the knee or calf on dorsiflexion of the foot) is rarely helpful in making
the diagnosis because it is present in only about 30% of patients with DVT. Many
patients (>50%) can present with asymptomatic disease, but even asymptomatic
patients can have long-term complications such as recurrent DVT or post-thrombotic
syndrome. Because symptoms of DVT are nonspecific, the diagnosis must be
confirmed by objective testing.
CASE 11-1, QUESTION 2: What risk factors does J.T. exhibit that are associated with DVT?
The diagnosis of DVT depends not only on the presenting signs and symptoms but
also on the presence of risk factors (Fig. 11-1). J.T. has presented with obesity and
immobilization (i.e., prolonged bed rest), two important risk factors for
thromboembolism, as well as an acute medical illness. It is common for more than
one risk factor to be present in patients who exhibit DVT, and these factors are
CASE 11-1, QUESTION 3: How should the final diagnosis of DVT be made in J.T.?
After evaluation of the signs and symptoms of DVT and consideration of risk
factors for the development of thrombus, a definitive diagnosis should be made.
Diagnostic strategies should include an assessment of pretest clinical probability
(clinical suspicion), D-dimer assay (an evaluation of the presence of fibrin
degradation products, indicative of clot formation; see Chapter 2, Interpretation of
Clinical Laboratory Tests), and noninvasive imaging tests.
Despite its limitations as a single diagnostic tool, clinical assessment can improve
the diagnostic accuracy of noninvasive testing. A clinical prediction rule, such as the
Wells criteria, takes into account signs, symptoms, and risk factors to categorize
patients as being at low, intermediate, or high probability of having DVT (Table 11-
13 The D-dimer test can be used in conjunction with clinical evaluation or a
clinical prediction rule to help “rule out” DVT in patients with a low clinical
suspicion and thus decrease the need for imaging tests in these patients.
clinical suspicion of DVT is high, diagnostic imaging is indicated, and if the imaging
is negative, the D-dimer is helpful to rule out the diagnosis.
The most common noninvasive test is duplex scanning, which combines B-mode
imaging or color flow imaging with Doppler ultrasonography to visualize veins and
thrombi while investigating flow patterns. Other noninvasive testing options include
I-fibrinogen leg scanning (injection of radiolabeled fibrinogen followed by
scanning to detect areas of accumulation corresponding to thrombosis), impedance
plethysmography (use of pneumatic cuffs to detect leg blood volume changes
associated with thrombosis), and Doppler ultrasonography alone (use of a transducer
to audibly detect venous flow changes indicative of thrombosis). Each option differs
with respect to sensitivity, specificity, and cost. Venography (radiographic
visualization of the involved vessels with injection of radiocontrast material), an
invasive diagnostic test, is the most sensitive and specific method for diagnosis of
DVT, but exposes patients to the risks associated with contrast material, and is not
readily available in many hospitals.
Clinical Model for Evaluating the Pretest Probability of Deep Vein Thrombosis
Active cancer (cancer treatment within previous 6 months, or currently on palliative
Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden for ≥3 days, or major surgery within the previous 12 weeks requiring
general or regional anesthesia
Localized tenderness along the distribution of the deep venous system 1
Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm
Pitting edema confined to the symptomatic leg 1
Collateralsuperficial veins (nonvaricose) 1
Previously documented deep vein thrombosis 1
Alternative diagnosis at least as likely as deep vein thrombosis −2
Clinical probability of deep vein thrombosis: low, <0; moderate, 1–2; high, >3.
In patients with symptoms in both legs, the more symptomatic leg is used.
Source: Wells PS et al. Does this patient have deep vein thrombosis? JAMA. 2006;295(2):199–207.
CASE 11-1, QUESTION 4: What additional baseline data should be obtained before administering
In addition to assessing the integrity of the clotting process with platelet count,
Hgb/Hct, PT, and aPTT, the patient’s baseline renal function should also be
evaluated and documented because some anticoagulants are renally eliminated.
Baseline values are used for comparison with the parameters that will be used in
monitoring both therapeutic and adverse effects of anticoagulant therapy.
Prompt and optimal anticoagulant therapy is indicated to minimize thrombus
extension and its vascular complications, as well as to prevent PE. Acute
anticoagulation treatment options include injectable IV UFH initiated with a loading
dose followed by a continuous infusion, adjusted-dose SC UFH, SC LMWH, or SC
15 Alternatively, initial treatment with oral rivaroxaban or apixaban can
be selected, without any initial parenteral anticoagulation. LMWH or UFH may be
continued as monotherapy or transitioned to treatment with a VKA, dabigatran or
edoxaban. Because J.T. is currently hospitalized and may need further surgical
procedures, IV UFH is selected for initial treatment of his DVT.
A loading dose of heparin is required for several reasons. Based on
pharmacokinetic principles, a therapeutic serum level will be achieved more quickly;
thus, pharmacodynamic and therapeutic responses to help prevent progression of the
clot will occur rapidly. Second, a relative resistance to anticoagulation exists during
the active clotting process. Therefore, a larger initial dose generally is necessary to
Although standardized doses of heparin for initiation of therapy (i.e., 5,000 units
loading dose; 1,000-units/hour maintenance dose) were used historically, this
approach can result in significant
delays in reaching a therapeutic intensity of anticoagulation. Body weight
represents the most reliable predictor of heparin dosing requirement. For patients
who do not have extremes of body weight (i.e., <165 kg), the use of the actual body
weight (ABW) has been recommended to calculate the initial UFH dose.
patients more than 165 kg, the use of the ABW is controversial, and the use of an
adjusted-dosing weight is recommended by some experts.
different “dosing weight” calculations:
Compared with standardized dosing, weight-based dosing (80 units/kg loading
dose; 18 units/kg/hour initial infusion rate) increases the frequency of therapeutic
aPTT at 6 hours and at 24 hours, and decreases the risk of recurrent VTE.
Initial heparin loading doses of 60 to 100 units/kg followed by an infusion rate of
13 to 25 units/kg/hour are commonly recommended.
21 Selection of the lower or upper
dosage range is guided by the severity of the patient’s symptoms and his or her
potential sensitivity to adverse effects. For this 92-kg patient, a midrange loading
dose of 7,400 units (92 kg × 80 units/kg), followed by a continuous infusion of 1,700
units/hour (92 kg × 18 units/kg/hour), is recommended. Loading doses are typically
rounded to the nearest 500 units and maintenance infusion rates to the nearest 100
units for convenience of administration.
Time aPTT (seconds) Heparin Dosage Order
0800 31 (baseline) 7,400 units bolus
1500 40 Rebolus with 2,400 units,
Although the aPTT drawn 1 hour after the initiation of the maintenance infusion (9
AM) demonstrates excessive prolongation of the aPTT (130 seconds), this value is
most likely explained by inappropriate timing of the test. When aPTT values are
drawn too soon after a heparin bolus dose (i.e., before the maintenance infusion has
achieved a steady state concentration in serum), they are predictably very high, but
are not associated with a bleeding risk and do not accurately reflect the anticipated
level of anticoagulation in the patient. To ensure accuracy, the clinician should obtain
aPTT values no sooner than 6 hours after a bolus dose or any change in the infusion
rate. Even results obtained at 6 hours may be excessively prolonged in some patients
because of the dose-dependent pharmacokinetic characteristics of heparin.
J.T.’s heparin dose was decreased at 0900 based on this prolonged, yet
inappropriately timed, value. A repeat aPTT at 3 PM was only 40 seconds. The
decrease in the dosage to 1,500 units/hour and the repeat aPTT of 40 seconds reflect
near steady state conditions because 6 hours has elapsed since the dosage change.
Because the aPTT was subtherapeutic at 3 PM (40 seconds), administration of a
smaller repeat bolus dose (2,000 units) and an increase in the maintenance infusion to
1,700 units/hour was the correct course of action. Subsequent aPTT values reflected
Dosing nomograms or protocols have been recommended for adjustment of heparin
3,16 Nomogram-based dosing reduces the time to reach
therapeutic range compared with empiric dosing.
22 Attaining a therapeutic aPTT in
<24 hours has been shown to lower in-hospital and 30-day mortality rates.
initiation based on patient weight, dosing adjustments may also be weight-based or
may simply be made in international units per hour. A sample heparin dosing
nomogram specific for a reagent with a therapeutic aPTT range of 60 to 100 seconds
(and used in the adjustment of heparin doses for J.T.) is illustrated in Table 11-11.
Responses to changes in infusion rates of heparin are not always linear, and to
some extent, heparin doses are adjusted by trial and error. As the patient’s condition
improves after several days and endothelialization of the clot occurs, heparin dosing
CASE 11-1, QUESTION 8: How should J.T.’s heparin therapy be monitored?
Once baseline clotting parameters have been established and a loading dose of
heparin has been administered, the aPTT should be measured routinely to guide
subsequent dosing adjustments. The aPTT should be evaluated no sooner than 6 hours
after the loading dose or after any changes in infusion rate, as noted previously. If
dosing is stable, the aPTT should be evaluated once daily (Table 11-11).
Additional monitoring parameters for heparin therapy include evaluation for
potential adverse reactions and possible therapeutic failure. The Hgb and/or Hct and
a platelet count should be checked every 1 to 2 days. J.T. should be examined for
signs of bleeding, as well as for signs and symptoms associated with thrombus
extension and PE. Finally, if unusual or unexpected aPTT results are reported, the
clinician should consider the possible influence of solution preparation errors (see
Chapter 2, Interpretation of Clinical Laboratory Tests), infusion pump failure,
infusion interruption, and administration or charting errors in the assessment of J.T.’s
CASE 11-1, QUESTION 9: How long should heparin therapy be continued in J.T. if the patient starts
Adherence of a thrombus to the vessel wall and subsequent endothelialization
usually takes 7 to 10 days. However, anticoagulation therapy must generally continue
for 3 months to prevent recurrent thrombosis.
15 For many years, warfarin was
preferred for this long-term anticoagulation because it can be administered orally,
and it is generally initiated on the same day as heparin. The long elimination half-life
of warfarin and the long elimination half-lives of clotting factors II and X necessitate
a prolonged period of overlap between warfarin and heparin. Therefore, if warfarin
is initiated, heparin is continued for a minimum of 5 days and until the INR is greater
than 2.0 for 24 hours. If the INR exceeds the therapeutic range (i.e., INR > 3.0)
prematurely, it is acceptable to stop parenteral therapy before the patient has
Sample Heparin Dosing Nomogram
Treatment of DVT/PE: 80 units/kg (rounded to nearest 500 units)
Prevention, including cardiovascular indications: 70 units/kg (rounded to nearest 500 units)
Treatment of DVT/PE: 18 units/kg/hour (rounded to nearest 100 units)
Prevention, including cardiovascular indications: 15 units/kg/hour (rounded to nearest 100 units)
First aPTT check: 6 hours after initiating therapy
Dosing adjustments: per this chart (rounded to nearest 100 units)
Time Infusion Rate Adjustment Next aPTT
<50 4,000 units 0 Increase by 200 units/hour In 6 hours
50–59 2,000 units 0 Increase by 100 units/hour In 6 hours
101–110 0 0 Decrease by 100 units/hour In 6 hours
111–120 0 0 Decrease by 200 units/hour In 6 hours
121–150 0 30 minutes Decrease by 200 units/hour In 6 hours
151–199 0 60 minutes Decrease by 200 units/hour In 6 hours
>200 0 PRN Hold until aPTT < 100 Every hour until
concentration of 0.3–0.7 units/mL determined by anti-factor Xa activity.
CASE 11-1, QUESTION 10: On day 2 of heparin therapy, J.T.’s complete blood count reveals a platelet
thrombocytopenia and how should it be managed?
Thrombocytopenia induced by heparin has two distinct presentations.
5 Heparinassociated thrombocytopenia (HAT) occurs as a direct effect of heparin on platelet
function, causing transient platelet sequestration and clumping with reductions in
platelet count, but usually remaining greater than 100,000/μL. This reversible form of
thrombocytopenia occurs within the first several days of heparin therapy. Patients
remain asymptomatic, and platelet counts return to normal even when heparin therapy
is continued. J.T.’s reduction in platelet count is somewhat modest and likely
represents HAT. His platelet count should be monitored daily, and heparin therapy
Reductions in platelet count of greater than 50% from baseline suggest the
heparin therapy. In contrast, “rapid-onset” HIT can occur rapidly (within 24 hours of
UFH initiation) and is strongly associated with recent heparin exposure. And
“delayed-onset” HIT is associated with an onset of thrombocytopenia that begins
several days after heparin has been stopped.
Heparin use leads to the formation of immunoglobulin G (IgG) antibodies that
recognize multimolecular complexes of a platelet protein called platelet factor 4
(PF4) and heparin that form on the surface of platelets.
PF4/heparin complexes are responsible for the prothrombotic nature of HIT due to
their capability to induce platelet activation by cross-linking platelet Fcc receptor IIa
25 and release procoagulant, platelet-derived microparticles, resulting in a
large generation of thrombin and the formation of venous and arterial thromboses.
The diagnosis of immune-mediated HIT is made based on clinical findings
5,26 The 4-T score is the most common pretest probability test
that can be used to estimate the likelihood of HIT based on extent and timing of
platelet count reduction, the presence of thrombus, and the possibility of other causes
of thrombocytopenia (Table 11-12).
The overall incidence of HIT is less than 3% after 5 days of UFH use, but the
cumulative incidence can be as high as 6% after 14 days of continuous heparin use.
Despite its low incidence, HIT is a life-threatening condition with a reported
mortality rate of 5% to 10%. Venous thrombosis is the most common complication
secondary to HIT, with rates reported at 2.4 to 1 more common than arterial
thrombosis (limb artery thrombosis, thrombotic stroke, and myocardial infarction).
Limb gangrene has been reported at 5% to 10%, with a resulting risk of amputation.
In patients who develop HIT, heparin therapy should be stopped immediately, and
treatment with an alternative anticoagulant should be initiated.
with a lower risk of HIT (<1%) than UFH, LMWH products are contraindicated in
patients with HIT because of a high incidence of immunologic cross-reactivity with
5 The future use of heparin in patients with HIT, especially in the first 3
months after the diagnosis, should be avoided. Treatment options include the direct
thrombin inhibitors argatroban and bivalirudin, although only argatroban is approved
for this indication by the FDA. The dose of argatroban is administered as an IV
infusion due to its short half-life and should be titrated based on aPTT testing.
Bivalirudin also appears to be a promising alternative for the treatment of HIT due to
its short-half life, low immunogenicity, minimal effect on INR, and enzymatic
metabolism. Various patient-related factors (such as the presence of renal or hepatic
dysfunction; drug availability, cost, and institutional preference) should be used to
select the most appropriate agent
The 4T Score: Pretest Probability of Heparin-Induced Thrombocytopenia
Category 2 Points 1 Point 0 Points
Thrombocytopenia Platelet count fall >50%
None apparent Possible Definite
thrombocytopenia in two clinicalsettings. J Thromb Haemost. 2006;4:759.
CASE 11-1, QUESTION 11: On day 3 of heparin therapy, J.T.’s Hct has dropped from a baseline of 37.5%
Bleeding is the most common adverse effect associated with heparin. A summary of
eight studies reporting heparin-associated bleeding found the absolute frequency of
fatal, major, and all (major or minor) bleeding to be 0.4%, 6%, and 16%,
31 The corresponding average daily frequencies were 0.05% for fatal
bleeding, 0.8% for major bleeding, and 2% for major or minor bleeding; cumulative
pharynx. The use of different criteria to define major versus minor bleeding accounts
for much of the variability in reported frequency of bleeding among studies.
In addition to length of therapy, many factors influence the risk of bleeding during
heparinization, including advanced age, serious comorbid illnesses (heart disease,
renal insufficiency, hepatic dysfunction, cerebrovascular disease, malignancy, and
severe anemia), and concomitant antithrombotic therapy.
(2%–4%) with therapeutic doses given via IV infusion. Soft tissue bleeding
commonly occurs at sites of recent surgery or trauma. Previously undiagnosed
abnormalities, including malignancy and infection, may be identified in some patients
with GI or urinary tract bleeding associated with heparin therapy.
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