Case

History and Presentation

Suzanne is a 68-year-old woman who is

obese and has a history of hypertension
that is well controlled with calcium
channel blocker therapy. She was
admitted to the hospital after presenting
to the emergency department with fever,
cough productive of yellow sputum (no
blood), and increasing shortness of
breath during the past 10 days. For 2
days, she has experienced a sharp pain
on the right side of her chest when she
takes a deep breath. Walking up stairs
has become increasingly difficult due to
shortness of breath and fatigue.
Suzanne has never smoked and is up to
date on cancer screening (negative
colonoscopy 2 years ago, normal
mammogram 6 months ago, and
negative Pap smear 1 year ago). She
had no complaints of respiratory distress
prior to the past 10 days and reports no
weight loss or abdominal discomfort.
Suzanne takes a baby aspirin almost
every day, which was not recommended
by her healthcare provider.
Physical Examination
Blood pressure: 130/80 mm Hg
Heart rate: 100 bpm
Temperature: 101.8F
Body mass index: 28 kg/m2
Lungs: decreased breath sounds over
right mid- and lower-lung field
Abdomen: normal bowel sounds, no
tenderness or organomegaly
Heart: tachycardia, regular rhythm, no
murmurs
Extremities: trace bilateral ankle
edema
Head, eyes, ears, nose, throat
(HEENT): dry mucous membranes,
otherwise normal
Skin: no rashes or ecchymosis
According to the 2008 American
College of Chest Physicians (ACCP)
Guidelines for VTE Prevention, how
should Suzannes level of
thromboembolism risk be classified?
A. Minimal risk
B. Low risk
C. Moderate risk
D. High risk

Answer: C
Is Suzanne a candidate for
anticoagulation therapy for
thromboprophylaxis according to the
ACCP guidelines?
Yes
No
Need more information to decide

Correct answer A

Thromboprophylaxis is recommended
for patients in the moderate- and high-
risk groups. For patients at high risk for
bleeding, only early ambulation and
mechanical thromboprophylaxis are
recommended. Mechanical prophylaxis
strategies include graduated
compression stockings, intermittent
pneumatic compression devices, and
the venous foot pump. These methods
do reduce VTE risk, but have not been
studied in randomized trials in medical
patients and are not as efficacious as
anticoagulant-based prophylaxis

Which anticoagulant should be

prescribed for Suzannes VTE
prophylaxis?
A. LMWH
B. Low dose UFH
C. Fondaparinux
D. Warfarin
Correct. According to the ACCP
guidelines, LMWH is a level 1A
recommendation (strong
recommendation based on randomized
trials or exceptionally strong
observational data) for VTE prophylaxis
in patients at moderate or high
risk. Enoxaparin and dalteparin are
LMWHs and the only pharmacologic
agents approved by the US Food and
Drug Administration for VTE prophylaxis
in medically ill patients. In the
Prophylaxis in Medical Patients With
Enoxaparin (MEDENOX) trial,
hospitalized medical patients at risk for
VTE were randomized to receive
subcutaneous enoxaparin 20 mg or 40
mg daily or placebo. A statistically
significant risk reduction of 63% for the
development of VTE was observed in
the enoxaparin 40-mg group versus
placebo (Table 3). The incidence of
major bleeding events was 1.7% for
patients receiving enoxaparin 40 mg
compared with 1.1% for those receiving
placebo. In the Prevention of Recurrent
Venous Thromboembolism (PREVENT)
trial, hospitalized medical patients at risk
for VTE were randomized to dalteparin
5000 IU daily or placebo. A statistically
significant risk reduction of 45% for the
development of VTE was reported in the
dalteparin group. The incidence of major
bleeding was low overall, but higher in
the dalteparin group (0.49% vs 0.16%).

B. Correct. Low-dose unfractionated

heparin (UFH) 2 or 3 times daily is an
AACP guideline level 1A
recommendation for VTE prophylaxis in
patients at moderate risk. Three
randomized trials of low-dose UFH
versus placebo or no prophylaxis
showed significant reductions in the
incidence of DVT in medical patients.
Two of these trials used 3-times-daily
dosing and 1 trial used twice-daily
dosing. A meta-analysis evaluating 12
trials of twice-daily or 3-times-daily
dosing of 5000 IU UFH versus placebo
or control drug (N = 7978) showed that
3-times- daily dosing decreased the rate
of VTE but increased the rate of
bleeding. In a separate meta-analysis,
LMWH compared with UFH was
associated with a relative risk of 0.68 for
the development of VTE. However, the
mortality rate did not differ between the
groups. UFH remains an efficacious
option for VTE prophylaxis.

C. Correct. The ACCP guidelines

include fondaparinux, a factor Xa
inhibitor, as a level 1A recommendation
for VTE prophylaxis in the medical
patient. In the Ambrisentan in Early
Idiopathic Pulmonary Fibrosis
(ARTEMIS) trial, a randomized study of
fondaparinux versus placebo in
hospitalized medical patients, there was
a significant risk reduction of 47% in the
fondaparinux arm (Table 3). One patient
in each group (0.2%) had major
bleeding. Eleven patients (2.6%) in the
fondaparinux group and 4 (1.0%) in the
placebo group had minor bleeding
episodes.

D. Incorrect. Oral vitamin K antagonists

such as warfarin are not recommended
for VTE prophylaxis in medical
patients.They are, however, an option
for high-risk patients such as those
undergoing major orthopedic surgery
and those with major trauma.

Case (contd)
Once-daily subcutaneous LMWH is
initiated for VTE prophylaxis. On day 2,
Suzanne had 2 episodes of blood-tinged
sputum, but this did not recur and she
was afebrile by day 4 of hospitalization.
Her condition had stabilized enough for
discharge from the hospital, but she still
had shortness of breath that limited
ambulation. The cough had somewhat
improved.

How long should anticoagulation

continue for VTE prophylaxis?
A. Stop anticoagulation on
discharge
B. Continue anticoagulation for 14
days
 C. Continue anticoagulation for 1
month
D. Continue anticoagulation
indefinitely

Selection Rationale
A. Possible. Optimal duration of
thromboprophylaxis in the medical
patient is not clear. In the MEDENOX
trial of enoxaparin versus placebo and
the ARTEMIS trial of fondaparinux
versus placebo, prophylaxis was given
for 6 to 14 days. In the PREVENT trial of
dalteparin versus placebo, prophylaxis
was given for 14 days. However, these
trials do not define the optimal duration
of anticoagulation. High-risk general
surgery patients, such as those
undergoing cancer surgery and those
with a history of VTE, may be
considered for prophylaxis after
discharge for up to 28 days; patients
undergoing hip or knee replacement or
hip fracture surgery should receive
prophylaxis for at least 10 days and up
to 35 days. However, the ACCP
guidelines do not include specific
recommendations for duration of
anticoagulation in medical patients.
B. Possible. After discharge, medical
patients remain at risk for VTE. In a
large retrospective study, 37% of 1399
patients who had DVT as outpatients
were hospitalized within 3 months
before being diagnosed with DVT.20 Half
were medical patients who had not had
a surgical procedure during
hospitalization. Within 1 month of
discharge, 67% of patients were
diagnosed with DVT and half of those
patients were admitted for 4 days or
fewer. Although medical patients remain
at risk after hospitalization, the optimal
duration of VTE prophylaxis is not clear.
If bleeding is not a concern, it is
reasonable to continue prophylaxis for
14 days; this was the maximum duration
in the MEDENOX, ARTEMIS, and
PREVENT randomized trials.

C. Possible. In the Extended Clinical

Prophylaxis in Acutely Ill Medical
Patients (EXCLAIM) study, 5105
medical patients with reduced mobility
initially were treated with 6 to 14 days of
enoxaparin for VTE prophylaxis. After
this initial treatment, patients were
randomized to receive placebo or to
continue enoxaparin for 24 to 32
days. The incidence of VTE was
decreased significantly among those
given extended prophylaxis versus
those given placebo (2.8% vs 4.9%).
However, bleeding also was increased
in the extended group (Table 5).
Because Suzanne has decreased
mobility, is obese, and has no excess
risk for bleeding, extended prophylaxis
may be considered if the risk-benefit
ratio is favorable. However, without
ongoing severely decreased mobility or
another significant VTE risk factor such
as a cancer or thrombophilia, most
clinicians probably would not give
anticoagulation beyond 14 days based
on the available data.

D. Incorrect. In a patient with only

transient risk factors for VTE secondary
to hospitalization, indefinite
anticoagulation is not a consideration.
However, indefinite anticoagulation for
secondary VTE prophylaxis may be
recommended in some patients after the
initial diagnosis of DVT, such as those
with cancer, unprovoked DVT, or
thrombophilia. Indefinite anticoagulation
also may be considered for patients in
long-term care facilities who have
decreased mobility.

Case Conclusion
Suzanne was discharged home on oral
antibiotics and prescribed LMWH for 14
days, including the days she received it
in the hospital. Before discharge, she
was taught how to administer
subcutaneous medication. She also was
directed to look for and report
immediately any signs of bleeding such
as blood in the sputum or spontaneous
bruising. She was not to resume taking
aspirin until she discussed it with her
primary care provider at the 2-week
follow-up postdischarge. She had no
bleeding and was largely asymptomatic
at the follow-up visit except for lingering
fatigue.

Chief Complaint
Im having pain in my leg.

HPI
Robert Roberts is a 54-year-old man who
presented to his primary care physician
because of pain in his right leg. He states
that he awoke with the pain 3 days ago and
that it has been continuous, although it hurts
more when he walks. The patient denies
chest pain, shortness of breath, fever,
headache, and leg trauma. The patient
started ezetimibe 10 mg daily for treatment
of hyperlipidemia approximately 3 weeks
prior to this visit. He stopped the ezetimibe
3 days ago because he thought it might be
causing his leg pain, but the pain has
continued. Physical examination reveals a
tight, warm, right calf with mild tenderness.
Lower extremity pulses and sensation are
normal bilaterally. The physicians
differential diagnosis includes deep vein
thrombosis and rhabdomyolysis, and the
patient is referred to the emergency
department for further evaluation. The
emergency department history includes
persistent pain in the right calf that is
exacerbated by walking, with no remitting
factors. The patient rates the pain intensity
as 3/10 at this time.

PMH
Graves disease with thyroid ablation
Gout
Hyperlipidemia
Left ankle fracture 9 years ago that required
a cast but no surgery
Remote history of depression
PSH
Left herniorrhaphy about 10 years ago
Pilonidal cyst excision in remote past

FH
Father died at age 81 of liver failure.
Mother, one brother, and son all alive and
well. No family history of venous
thromboembolism or clotting disorders.

SH
Married, one adult child. Drinks one to two
alcoholic beverages daily. Smokes one cigar
per month, no cigarettes. Denies illicit drug
use.

Meds
Allopurinol 300 mg po daily
Levothyroxine 150 mcg po daily
Ezetimibe 10 mg po daily (discontinued 3
days ago)

All
NKDA

ROS
Constitutional: No chills, no fatigue
Eyes: No eye pain or changes in vision
ENT: No sore throat
Skin: No pigmentation changes, no nail
changes
Cardiovascular: No chest pain, palpitations,
or syncope
Respiratory: No cough, SOB, wheezing, or
stridor
GI: No abdominal pain, nausea, diarrhea, or
vomiting
Musculoskeletal: No neck pain, back pain,
or injury
Neurologic: No dizziness, headache, or focal
weakness
Psychiatric/Behavioral: No depression
Physical Examination
Gen
Somewhat obese, Caucasian man who
appears comfortable. Cooperative, A & O
~ 3, normal affect.

VS
BP 106/78, P 75 regular, R 16, T 98.3F,
O2 sat 97/ra; Wt 245 lb, Ht 6'0''

Skin
Warm, dry, normal color. No rash or
induration.

HEENT
Pupils equal and reactive to light. EOM
intact. Mucous membranes moist and pink.

Neck
Normal range of motion with no meningeal
signs

Lungs/Thorax
Breath sounds normal, no respiratory
distress

CV
RRR, no rubs, murmurs, or gallops
Abd
Non tender, no masses, no distension, no
peritoneal signs
MS/Ext
Upper extremities: normal by inspection, no
CCE, normal

ROM.
Lower extremities: no CCE, normal ROM.
Right calf tender with mild swelling. No
obvious compartment syndrome.

Neuro
Glasgow coma scale of 15, no focal motor
deficits, no focal sensory deficits

Labs
Lower extremity venous duplex
ultrasonography: acute DVT of right distal
superficial femoral, popliteal, and peroneal
veins. No compression or flow in these
vessels.

Assessment
Acute DVT in right superficial femoral,
popliteal, and peroneal veins

Na 140 mEq/L WBC 5.9 ~ 103/L

K 3.9 mEq/L RBC 4.28 ~ 106/L
Cl 103 mEq/L Hgb 13.5 g/dL
CO2 27 mEq/L Hct 39.3%
BUN 10 mg/dL MCV 92.0 fL
SCr 0.84 mg/dL MCHC 34.4 g/dL
Glucose 88 mg/dL RBC dist 14.3
Uric acid 5.0 mg/dL Platelets 118 ~
103/L
CK 117 U/L Mean platelet volume 7.2 fL
Granulocytes, electronic 51.0%
Lymphocytes, electronic 38.2%
Monocytes, electronic 8.4%
Eosinophils, electronic 1.9%
Basophils, electronic 0.5%
ESR, Westergren 9 mm/h
Lower extremity venous duplex
ultrasonography: acute DVT of right distal
superficial femoral, popliteal, and peroneal
veins. No compression or flow in these
vessels.

Follow-Up Question
1. Identify the patientfs anticoagulation
therapy-related drug therapy problem(s) and
design treatment and monitoring plans for
managing each problem you identify.
CLINICAL COURSE
Mr. Roberts presents to his primary care
physicianfs office approximately 3 months
after his acute DVT episode. He reports that
he experienced an episode of very dark
brown, gcolah-colored urine 2 days
before this visit. He has had no recurrences.
The patient denies dysuria, back or groin
pain, and blood in his bowel movements.
His current dose of warfarin is 5 mg on
Monday, Wednesday, Friday, and Saturday
and 7.5 mg on Tuesday, Thursday, and
Sunday.
Physical examination reveals no CVA
tenderness.
Follow-Up Question
1. Identify the patientfs anticoagulation
therapy-related drug therapy problem(s) and
design treatment and monitoring plans for
managing each problem you identify.

CLINICAL COURSE
Five months after his initial presentation,
you see Mr. Roberts in the new
anticoagulation clinic at his primary care
physicians office. He is currently taking
warfarin 5 mg on Monday, Wednesday,
Friday, and Saturday and 7.5 mg on
Tuesday, Thursday, and Sunday. His INR is
3.3. The patients INR 2 weeks ago was 2.1
on the same dose.

Mr. Roberts has not experienced any

symptoms suggesting DVT recurrence or PE
occurrence. He states that he has not had any
problem with bleeding, has not missed doses
or taken extra doses of warfarin in the past
month, and has not changed his diet. His
medications have been unchanged, except
for the addition of rosuvastatin 5 mg every
other day for the treatment of his
hyperlipidemia approximately 23
weeks ago. You note that the following
thrombophilia tests were completed prior to
the initiation of anticoagulation therapy:

The laboratory summarizes the above results

as consistent with the presence of lupus
anticoagulants. Even though
anticoagulants are present, many patients
with this condition experience thrombotic
events.

My chest hurts and I feel like I cant get

enough air.

HPI
Michael Veder is a 52-year-old man who
was transferred to the hospitals skilled
nursing unit to complete IV antibiotic
therapy for a gangrenous chronic wound
infection on his left ankle secondary to
poorly controlled diabetes. The patient is
S/P BKA left leg (postop day #11) and has
completed 11/14 days of the IV antibiotic
regimen. He has tolerated the antibiotics
well and his pain is improving daily,
although he often refuses physical therapy in
the skilled nursing unit. Early this morning,
the patient complained of sharp chest pain
and shortness of breath. The pain does not
radiate.
He denies nausea, vomiting, and dizziness.
The patient is anxious.
He has a non-productive cough and he
claims that he has been having trouble with
deep inspiration since yesterday.

PMH
HTN 12 years
Type 2 DM 10 years; uncontrolled due to
noncompliance with diet and medications at
home
Diabetic nephropathy (baseline creatinine
1.4 mg/dL)
Obesity
Chronic wound infection left ankle
(previously failed 2 courses of IV
antibiotics)
S/P BKA left leg (post-op day #11)

FH
Father has Type 2 DM

SH
The patient performs with a local rock band
and leads an unhealthy lifestyle (poor diet,
no exercise). Significant for tobacco abuse
(20 pack-year history). Denies illicit drug
use. Drinks alcohol socially on the
weekends.

Meds
Home medications:
Novolin 70/30 40 units Q AM and 30 units
Q PM
Lisinopril 10 mg po once daily
Additional medications started in the skilled
nursing unit:
Unfractionated heparin 5,000 units
subcutaneously every 8 hours
Nicotine transdermal patch 21 mg/day
Cefepime 2 g IV every 24 hours
Vancomycin 2 g IV every 24 hours
Meperidine 50 mg po every 46 hours PRN
pain
Metformin 500 mg po twice daily
Regular insulin sliding scale subcutaneous
coverage AC and HS:
Glucose 150 to 199 mg/dL2 units
Glucose 200 to 249 mg/dL4 units
Glucose 250 to 299 mg/dL6 units
Glucose 300 to 349 mg/dL8 units
Glucose greater than or equal to 350
mg/dLcall physician for orders
All
NKDA

ROS
The patient denies headache, fever, chills.
Positive for shortness of breath, non-
productive cough. Positive for chest pain.
No palpitations.
No abdominal pain. No nausea, vomiting, or
diarrhea.

Physical Examination
Gen
The patient is alert and oriented 3;
moderate respiratory distress
VS
BP 132/66, P 88, RR 21, T 36.5C; Wt 102
kg, Ht 5'10'', O2 sat 96% on room air

Skin
Warm and dry
HEENT
Head: Atraumatic; PERRLA; EOMI
Neck/Lymph Nodes
No carotid bruits; no lymphadenopathy
Lungs/Thorax
Clear to auscultation bilaterally; no
wheezing or crackles

CV
RRR; normal heart sounds; no murmurs,
rubs, or gallops

Abd
Soft; NT/ND; good bowel sounds

Genit/Rect
Patient refused at this time

MS/Ext
S/P BKA left leg; range of motion within
normal limits; no swelling or redness; no
cyanosis
Neuro
No focal deficits noted; cranial nerves intact

ECG
Normal sinus rhythm at 88 bpm. No Q
waves or ST changes present. No ectopy.
Normal QRS axis, normal QRS
morphology.

Assessment
1. Chest pain, SOBmost likely non-
cardiac, R/O PE, R/O pneumonia
2. ThrombocytopeniaR/O heparin-
induced thrombocytopenia (HIT)
3. Chronic wound infection, S/P BKA
continue current antibiotic regimen to
complete 14 days, continue wound care and
pain management
4. Diabetes mellitusblood glucose well
controlled on current medications and
hospital no-added sugar diet
5. HTNstable on current regimen
Clinical Course
The patient was transferred to a monitored
unit within the hospital for further work-up.
A chest x-ray and spiral CT of the chest
were ordered.

The spiral CT was later canceled due to the

patients elevated creatinine and the risk of
contrast nephropathy. A V/Q scan was
ordered. A platelet count history was
obtained from the skilled nursing unit.
QUESTIONS
Problem Identification
1.a. What subjective and objective
information is consistent with a diagnosis of
PE in this patient?
1.b. What risk factors for PE are present for
this patient?
1.c. Calculate this patients pre-test
probability score for HIT
1.d. Develop a list of the potential drug
therapy problems related to
this patients increased serum creatinine.

Desired Outcome
2.a. What are the goals of therapy for the
treatment of PE?
2.b. What additional goals of therapy exist
for this patient with HIT?

Therapeutic Alternatives
3.a. Which agents are available to initiate
anticoagulation for the treatment of PE in
this patient?
3.b. What non-anticoagulant alternatives
(pharmacologic and nonpharmacologic) are
available? Is this patient an appropriate
candidate for any of these alternatives?

Optimal Plan
4.a. Choose an appropriate anticoagulant to
initiate therapy and calculate the dose for
this patient.
4.b. When can warfarin be started for long-
term management of PE in this patient?
Design a pharmacotherapeutic plan for the
transition to warfarin.

CLINICAL COURSE
The patient was started on an IV infusion of
lepirudin at 10:00 AM. A heparin-induced
platelet antibody ELISA (enzyme-linked
immunosorbent assay) was drawn and sent
to an outside laboratory for confirmation of
HIT. An order was written to avoid all
heparin (including catheter flushes). Prior to
initiating lepirudin, a baseline aPTT (27.3
sec; reference: 23.834.6 sec), PT (11.1 sec;
reference:
9.812.3 sec), and INR (1.0) were obtained
to assist with anticoagulation dosing.

Outcome Evaluation
5.a. Determine the therapeutic aPTT range
for the direct thrombin inhibitor
administered to this patient.
5.c. What clinical and laboratory parameters
will you use to monitor
the efficacy and safety of anticoagulation in
this patient?

Patient Education
6.a. Prior to discharge, what information
should be provided to this patient about
warfarin therapy to enhance compliance and
ensure efficacy and safety?
6.b. Discuss the information that you will
provide to this patient concerning the future
use of heparin and low molecular weight
heparin therapy.

SELF-STUDY ASSIGNMENTS
1. Compare the risk of the development of
HIT with unfractionated heparin and low
molecular weight heparin. List other risk
factors that influence the development of
HIT.
2. Investigate the sensitivity and specificity
of the various activation and antigen assays
available to confirm the diagnosis of HIT.
3. Considering the potential for combined
effects on the INR, list the steps necessary to
transition a patient receiving argatroban to
warfarin therapy.
Review the literature for available options to
reverse the effects of the direct thrombin
inhibitors if excessive anticoagulation
occurs.
CLINICAL PEARL
Heparin-associated thrombocytopenia (HIT
Type 1), which is more common than
heparin-induced thrombocytopenia (HIT
Type 2), is a nonimmunogenic mild
decrease in platelet count (nadir greater than
100 103/mm3) that occurs within 1 to 3
days after the initiation of heparin and does
not increase the patients risk of thrombosis
or require heparin discontinuation.