3. Heparins
Antithrombin 3 is a naturally occuring slow inhibitor of clotting
pathway. Heparin binds to AT-3 and converts it from slow
to rapid inhibitor by forming a ternary complex with AT-3
and thrombin
Unfractionated Heparin : Unfractionated heparin is a
heterogeneous mixture of polysaccharide chains with a
mean molecular weight of 15,000 Daltons. Given I.V.
Requires Inpatient Rx. Higher incidence of Throbocytopenia
and osteopenia. Monitored by measuring APTT
LMWH: Derived from heparin. Molecular weight-5000 D.
Can be given twice daily doses on OP basis. Less incidence
of throbocytopenia and osteopenia. LMWHs have more anti
factor X a activity than UF heparin. LMWH activity is
monitored by factor Xa activity.
Heparins can cause Hyperkalemia
4.
5. Heparin Induced Skin Necrosis
Affects middle age women with history of thrombotic
disease
Characterized by the formation of one or more painful red
plaques or necrotic skin lesions.
5 days or more after starting heparin treatment. Earlier in
those treated previously with heparin.
Some patients develop thrombocytopenia when lesion first
appears, often with paradoxical thrombosis.(HIT) Is not
always associated with thrombocytopenia
A rare complication of heparin characterized by immune
complex formation and thrombosis.
HIT Should be suspected if the patient develop skin
necrosis in areas of SQ injection or IV site.
Rx – stop Heparin + start Direct thrombin inhibitors or
heparinoids ( Leupiridin or Argatroban ) ( i.e; treat like
HIT)
6. Warfarin
Mechanism of action
Antagonist
Skin necrosis
Uses
INR monitoring
Dealing with Supratherapeutic INR on case by case
basis
Dealing with Sub therapeutic INR ( APLA, OBESITY,
WARFARIN RESISTANCE, INTERACTIONS, NONCOMPLIANCE)
7. WARFARIN: MECHANISM OF ACTION
Vitamin K epoxide
WARFARIN
Vitamin K reduced
Inactive factors II,
VII, IX, and X
Proteins S and C
Active factors II,
VII, IX, and X
Proteins S and C
Prevents the reduction of vitamin K, which is essential for
activation of certain factors
Has no effect on previously formed thrombus
8. PLASMA HALF-LIVES OF VITAMIN KDEPENDENT PROTEINS
Factor II
Factor VII
72h
6h
Factor IX
24h
Factor X
36h
Peak anticoagulant effect may be delayed by 72 to 96 hours
PROTEIN S HALF LIFE : shorter than above
9. Coumadin Skin Necrosis
•
•
•
Warfarin Procoagulant Effect in
first few hours can cause
warfarin skin necrosis due to
thrombosis.
Concomitant heparin use can
decrease the incidence
Patients developing coumadin
skin necrosis should be
evaluated for Protein C
deficiency
13.
Warfarin has a narrow therapeutic index
Therapeutic INR typically targeted at 2-3.
The risk of bleeding increases significantly when the INR >
4-6. However, the absolute risk is still low at 5.5 bleeding
events per 1000 per day
Therefore, patients with an INR < 9 and no significant
bleeding Manage by omitting subsequent doses of
warfarin, more frequent monitoring of the INR, and
resumption of therapy at a lower dose when the INR is
therapeutic.
When rapid reversal of the INR is needed, fresh frozen
plasma, prothrombin complex, or recombinant factor VIIa
can be administered.
Administration of coagulation factors provides only a
temporary solution due to the short half-life of the provided
clotting factors (3-4 hours for Factor VII), compared with a
duration of action of 2 to 5 days for warfarin, as well as
relative instability of clotting factors upon administration.
Administration of either fresh frozen plasma or factor
concentrates will decrease the PT/INR for 4 to 6 hours
So, complete return to a therapeutic INR will require
supplementation with vitamin K
14. Rxng Supratherapeutic INR
Treatment of a supra therapeutic INR requires a
balance between reducing the risk for hemorrhage
while minimizing the risk of thrombembolism.
Treatment approaches are based on the current
INR, presence of bleeding, and the time frame in
which reversal is required.
Vitamin K1 CAN BE GIVEN to reverse the
anticoagulation effect of warfarin.
The most appropriate dose of vitamin K1 is
the one that lowers the INR to a safe level without
resulting in a subtherapeutic INR.
High doses of vitamin K1 are effective but may
lead to warfarin resistance for a week or more,
resulting in an increased risk for
thromboembolism. In such cases, heparin should
be given until the effects of the vitamin K1 are
complete. ( note this point)
15. Forms of Vitamin K
Available in subcutaneous, IV and oral forms
Subcutaneous route delayed onset and is less
predictable.
If rapid reversal is desired, the IV route should be utilized,
as this route has the fastest onset of action. ( Historically,
intravenous vitamin K1 has been associated with an increased risk of anaphylaxis. A
retrospective review of anaphylactic reactions associated with IV vitamin K1 from the
Mayo Clinic revealed that the risk of anaphylaxis with vitamin K1 was 3 per 10,000
doses—a rate comparable to all forms of penicillin and less than that of IV iron
dextran. If is administered by the IV route, lower doses and slower infusion rates are
recommended)
Unless rapid reversal of the INR is critical, oral vitamin K1
is the preferred route of administration.
In the United States, oral vitamin K1 is only available as a
5 mg tablet (Mephyton®). Therefore, oral doses prescribed
should reflect even divisions of 5 mg (e.g., 2.5 mg).
16. Forms of Vitamin K
Route
Advantages
Disadvantages
IV
•
Fastest Onset of
Action
•
Subcutaneous
•
Lower risk of
anaphylaxis
•
Oral
•
Safest route
•Low risk of
anaphylaxis
•No IV site needed
•
Must be given by slow
IV infusion
•Warfarin resistance
Delayed onset
•Unpredictable
response
•Least desired route
Slower onset of action
•Warfarin resistance
17. Management of Elevated INR in Patients Receiving Vitamin K Antagonists
INR
Bleeding Present
Rapid Reduction Required
Management*
<5
No
No
Lower dose by 10% or
omit dose; resume at
lower dose when INR is
therapeutic i.e; 2 TO 3
5-9
No
No
Omit one or two doses,
resume at lower dose by
10%.
No
Yes — high risk
May give vitamin K 2.5 mg
orally if at increased risk
for bleeding.
No
Yes—surgery
2-4 mg oral vitamin K1 for
reduction of INR in 24
hours; if INR still high, can
repeat with 1-2 mg orally.
≥9
No
No
Hold dose and give
vitamin K1 10 mg orally to
reduce INR in 24 hours;
may repeat vitamin K1as
necessary. Resume at
lower dose when
therapeutic.
Any
Yes—Serious Bleeding
Yes
Hold dose, give vitamin K1
10 mg by slow IV infusion,
along with fresh frozen
plasma, prothrombin
complex, or recombinant
factor VIIa; vitamin K1 may
be repeated every 12
hours.
Any
Yes—Life Threatening
Yes
Hold dose, give
prothrombin complex
along with vitamin K1 10
mg by slow IV infusion;
repeat if necessary
depending on INR.
18.
When the INR is elevated in a patient who
has been on a consistent dose of warfarin
for past few weeks Always, consider
why it is elevated
Antibiotics can potentate by causing
Vitamin k deficiency.
If drug interaction is considered stop
the other drug if possible. If stopping the
interacting drug is feasible and if INR < 5,
no need to reduce the warfarin dose
20. Sub-Therapeutic INR
INR< 1.5 – Increase the dose by 10 to
20%, consider extra dose and repeat
INR in 4 to 8 days.
1.5 to 2.4 – Increase dose by 5 to
10%. Repeat INR in one to two weeks
2.5 to 3.5 – No change in dose.
Repeat INR is the # of consecutive inrange INRs (For example, if a patient
has had three consecutive in-range
INR values, recheck in 3 weeks.
Maximum repeatable period not
longer than 4 weeks )
21. Foods that can cause
sub-therapeutic INR
Foods with very high vitamin K content
(more than 200 mcg) — Brussel sprouts,
chickpeas, collard greens, coriander,
endive, kale, liver, parsley, red leaf
lettuce, spinach, Swiss chard, black or
green teas, turnip greens, watercress.
Foods with high vitamin K content
(100-200 mcg) include basil, broccoli,
butterhead lettuce, canola oil, chives,
coleslaw, cucumbers (with peel), green
onions, mustard greens, soybean oil.
26. Economy class syndrome
Economy-class syndrome is a name used
by the media to describe Venous
Thrombo-Embolism that can occur in
anyone - but has been of particular worry
in air travellers.
Incidence of DVT & PE increases with the
flight distance
Prevention tips : Drink fluids, avoid
caffeine and alcohol, keep moving legs
and wear graduated support stockings
designed for travel.
28. Proximal vs. Distal DVT
Thrombosis confined to deep calf veins is Distal
DVT where as thrombosis at or above popliteal
veins is Proximal DVT.
A distal DVT becomes clinically important when it
extends proximally
Risk of PE is much higher with proximal DVT.
Silent PE occurs in about 50% of pts with
proximal DVT.
All patients with Proximal DVT are at increased
long term risk for chronic venous insufficiency.
Compression ultrasound is more sensitive to
proximal DVT when compared to distal DVT.
29. Idiopathic DVT
A case of DVT where no evidence of
underlying obvious cause such as
surgery, trauma or known
malignancy is present.
Search for a hypercoagulable state in
such conditions
Hypercoagulable states : inherited or
acquired
32. Hypercoagulabilty – Whom to test?
DVT occurring in a pt < 50 yrs of age
Positive Family Hx of Venous
thromboembolism
Recurrent episodes of unexplained Venous
thromboembolism
Don’t forget to include Homocysteine When homocysteine levels are elevated in
the presence of factor V Leiden or the
prothrombin gene G20210A mutation, risk
of recurrent thrombosis appears to be
increased beyond the risk associated with
any one defect alone
33. Hypercoagulabilty – When to test?
Heparin
• Controversial AT-III (heparin vs acute event)
• Most coagulation based test for APLA
Hexagonal phospholipid not affected
Warfarin
• Protein C and protein S
• Need to wait 3 weeks before testing protein S
• Most coagulation based APLA tests
34. Hypercoagulable states
Inherited
-“ The big five”
• Factor V Leiden
• Prothrombin gene mutation
• Protein S deficiency
• Protein C deficiency
• Antithrombin III deficiency
35. Factor V Leiden
Most common inherited risk factor
Often associated with other risk
factors e.g: homocysteine
Dramatic increase in risk with
estrogens ( OC Pills)
36. Hypercoagulability states
Acquired
Cancer
Antiphospholipid antibody syndrome
Nephrotic syndrome
Inflammatory bowel disease. Etiology:
inflammatory cytokines, low protein s
Homocysteine
Clues to Acquired state : older age at the
time of onset, refractory to Warfarin , both
venous and arterial thromboembolism.
37. DVT and Cancer
Clues –
Bilateral DVTs, Arterial and venous
thrombosis and Warfarin refractory
thrombosis
40. INVESTIGATIONS
Venogram : Gold standard. Rarely performed due
to accuracy of non invasive testing. Risks:
phlebitis, hypersensitivity, nephrotoxicity,
cardiotoxicity
Venous duplex ultrasound : non invasive,
accurate, first line study in moderate to high risk
DVT. Specificity : 95%. Sensitivity 97% for
proximal DVT and only 73% for distal DVT. Can
identify other pathology e.g.: calf haematoma,
bakers cyst, abscesses
MRI : 90% sensitive and specific for acute
Proximal DVT.
41. D-Dimer assays
D-Dimer should not be used as a screening test.
Can be used as a first line test in pts with low
pretest probability for DVT.
The utility of D-Dimer is mainly to reduce the
number of ultrasound testings.
The negative predictive value of a d-dimer assay
falls as the pretest probability for DVT increases.
An assay with a sensitivity of 80% has a negative
predictive value (NPV) of 97.6% in a low-risk
patient. However, the NPV of the same assay is
only 33% in high-risk patients with a pretest
probability of 90% for DVT.
42. CLINICAL ( PRETEST) PROBABILITY OF
DVT
WELLS DVT SCORE SYSTEM ( most popular )
Clinical Parameter
Score
Active cancer (treatment ongoing, or within
6 months or palliative)
Paralysis or recent plaster immobilization
of the lower extremities
Recently bedridden for >3 d or major
surgery <4 wk
Localized tenderness along the distribution
of the deep venous system
Entire leg swelling
Calf swelling >3 cm compared to the asympto
- matic leg
Pitting edema (greater in the symptomatic leg)
Previous DVT documented
Collateral superficial veins (non varicose)
Alternative diagnosis (as likely or > that of DVT )
+1
+1
+1
+1
+1
+1
+1
+1
+1
- 2
43. Wells DVT Clinical Score ( contd )
Score of Zero – low probability ( 0 to
13%)
Score 1 – 2
probability)
- moderate probability
( 13 to 30%
Score > or = 3 - high probability
( 49 to
81%probability)
44. Complications - DVT
Pulmonary Embolism
Post obstructive syndrome : pain and
edema in the affected limb without
new clot formation
Chronic venous insufficiency
Rarely, thrombosis is massive,
causing vascular compromise of the
leg due to high venous pressure
(i.e., phlegmasia cerulea dolens).
47. OPTIMIZING WARFARIN THERAPY
Dosage to be individualized according to patient’s
INR response. Target INR -2-3
Use of large loading dose may lead to
hemorrhage and other complications.
Initial dose: 2-5 mg once daily
Maintenance dose: 2-10 mg once daily
Start heparin on day 1 and warfarin in the
evening of Day1 or on Day2. Heparin is usually
discontinued after 4-5 days. Before discontinuing,
ensure INR is in therapeutic range for 2 consecutive
days
Monitor daily until INR is in therapeutic range,
then 3 times weekly for 1-2 weeks, then less
often (every 4 to 6 weeks)
48. CONTARINDICATIONS AND
PRECAUTIONS - WARFARIN
Hypersensitivity to warfarin
Condition with risk of hemorrhage
Hemorrhagic tendency
Protein C & S deficiency
Vitamin K deficiency
50. Uncomplicated DVT - OP management
Any reason for Hospitalization ?
potential probm with home Rx
No probm with Home Rx
Hospitalize
Give BID S.C LMWH + Warfarin
Ongoing Evaluation
Give 1st dose S.C LMWH Stat
Begin Warfarin in Doses 5mg QD
Assign a visiting nurse for twice
daily injs ( until the pt or family
member can inject ) Daily PT and
CBC with platelet count.
After atleast 5 days twice daily
injs of LMWH, a therapeutic INR
for 2 consecutive days – d/c LMWH
and follow warfarin carefully as per
routine for DVT.
Repeat physician evaluation by 5-7,
if no problem, repeat 1 wk later and
as per routine for DVT.
51. Reasons for hospitalization in DVT
Signs and symptoms of PE
Co-existing medical illness – anemia, lung
disease, previous bleeding, high risk of
bleeding or clotting
Depression or any other mental illness
that restricts pt’s co-operation and
compliance with the home Rx.
Insurance problem or other logistic
difficulty that limits pt’s access to home
Rx, nursing care, monitoring, food &
shelter
53. Duration depends on risk factor for
DVT
Risk of recurrence depends on type of risk factor.
If 1st DVT occurred after a major risk factor,
recurrence is 3% where as if it occurred after
minor risk factor recurrence is 10% So, stratify
pts based on risk factor and then decide duration
Major transient risk factors : Major surgery,
major medical illness and leg casting.
Minor transient risk factors : OC Pills, HRT
High risk thrombophilias : Homzygos Prothrombin
gene mutation, Homozygos Factor v leiden,
antithrombin, protein c and protein s deficiencies
and APLA Syndrome
Low risk thrombophilias : Heterozygosity for
prothrobin gene mutation and Factor V leiden
54. Recommendations – Duration of Anticoagulant Rx in pts with DVT
Patient
Risk of recurrence
Duration of
characteristics
(%)
Therapy
- In the year after
discontinuation
Major transient risk
factor
b.Minor risk factor, no
thrombophilia
a.
Idiopathic event, no
or low risk
thrombophilia
d.Idiopathic event,
high risk
thrombophilia
e.More than one
idiopathic event
f.Cancer, other
ongoing risk factor
Ref: NEJM, 2004, 351
3%
<10% if risk factor
avoided. >10% if
persistent
c.
<10%
>10%
>10%
>10%
3 months
6 months
Until factor resolves
6 months
Indefinite
Indefinite
Indefinite. Consider
long term Rx with
LMWH in pts with
cancer
55. Contraindications - Anticoagulant
RX
Absolute contraindications:
Active bleeding
Severe bleeding diatheses or platelet count< 20,000/mm3
Neurosurgery, ocular surgery or intracranial bleeding in
past 10 days
Relative contraindications:
Mild/moderate bleeding diatheses or thrombocytopenia
Recent major trauma
Major abdominal surgery in past 2 days
Brain metastases
Gastro/genitourinary bleeding in past 2wks
Endocarditis
Severe hypertension at presentation ( SBP>200 and
DBP>120)
56. Case Study
A 79-year-old man is admitted to the medical ward 3 days status
post subdural hematoma drainage, C3 cervical spine fracture, and
fixation of multiple extremity fractures sustained in a motor
vehicle accident. The patient is now awake and oriented to person,
place, and time, but is a lower cervical spine incomplete
quadriplegic. Physical examination reveals some minimal sensation
in the legs, but no ability to move the extremities. There is a Foley
catheter in place that is draining yellow colored urine. Doppler
ultrasonography demonstrates a thrombus in the left popliteal
vein. The most important next step in the management of this
patient is
A. daily Doppler ultrasonography of the lower extremities
B. inferior vena cava filter placement
C. subcutaneous heparin
D. tissue plasminogen activator thrombolysis
E. warfarin
F. weekly ventilation/perfusion scans for a pulmonary embolus
57. Case Study
A 49-year-old man comes to clinic for follow up and monitoring of
his oral anticoagulation levels. The patient is postoperative day 62
from a left total knee replacement. On postoperative day number 2
he suffered a pulmonary embolism. He was placed on intravenous
unfractionated heparin and then oral warfarin. He was discharged
home with follow-up instructions to return to the clinic for
monitoring of his prothrombin time/international normalized ratio
(INR) every 3 weeks. On return to the clinic today his PT/INR is
found to be 22.4/7.3. His physical examination is unremarkable.
The most appropriate management at this time is to
A. admit the patient to the hospital
B. instruct the patient to discontinue warfarin and return in 1
week
C. instruct the patient to discontinue warfarin week until his next
visit in 3 weeks
D. give protamine sulfate, intravenously
E. give vitamin K and follow up with the patient at his next visit
59. Preventing Thrombosis in
Pregnancy
Give prophylaxis with heparin during pregnancy and
continued heparin or warfarin for 6 weeks
postpartum in women with high risk of recurrent
thrombosis:
Recent thromboembolism (within the previous 6
months)
An indication for lifelong anticoagulation
Previous thrombosis with a thrombophilia
associated with a high risk of recurrent
thrombosis (homozygotes for factor V Leiden,
homozygotes for the prothrombin gene mutation,
or antiphospholipid antibodies
A history of recurrent thromboembolism
60.
Consider heparin prophylaxis antepartum
and intrapartum, and heparin or warfarin
prophylaxis postpartum in women with
one previous thromboembolic event even
without underlying thrombophilia, family
history, or other risk factors (such as
obesity, smoking, recent surgery,
immobilization, advanced age, and parity).
Advise pregnant women, especially those
with a history of thrombosis or
thrombophilia, to stop smoking
61. Rxng Thrombo-embolism in
Pregnancy
Avoid the use of warfarin during
pregnancy because it crosses the placenta
and is associated with teratogenesis and
increased fetal morbidity and mortality.
Treat with LMWH @ therapeutic doses.
Continue long-term prophylaxis against
recurrent venous thromboembolism after
the postpartum period and completion of
therapy using warfarin, aiming for a target
INR of 2 to 3 ( usually 6 mos if no other
hx of thrombophilia is present)
63. Anemias
Look At MCV Microcytic, Macrocytic & Normocytic
Iron deficiency – Colon ca scenarios, Fibroids, malabsorption
syndromes (Celiac sprue), Gastric bypass surgery (Iron is
mainly absorbed in the duodenum and jejunum)
B12, Folic acid deficiency
B12 deficiency in the elderly
Sideroblastic Anemia
Thalassemias
Autoimmune Hemolytic Anemias – initial rx sterods, then
IVIG, if unresponsive splenectomy
Hereditary Spherocytosis
G6PD Deficiency – sulfa, dapsone, primaquine
Sickle Cell Anemia – Crisis, Aplastic crisis, Acute chest
syndrome, Avascular necrosis, osteomyelitis,
autospenectomy, Folate supplement importance
Aplastic Anemia
Anemia of Renal Disease – Give EPO if Hgb < 10 and
supplement iron if Tsat < 20%
Anemia of Chronic Disease
Bone marrow biopsy – indications in Anemia
64. Microcytic Anemias
Importance of RDW
Peripheral smear – increase in
central pallor
Iron studies – IRON/TIBC, Ferritin
Differentiate from AOCD – in AOCD,
ferritin normal/ high, iron low, tibc
low
65. Rx – Iron Deficiency
Correct underlying cause – Menorrhagia,
Malabsorption
Recommend Hysterectomy for fibroids
with menorrhagia in a patient who has
completed her family.
Oral Iron Supplements – preferred
Side effects oral iron – nausea,
constipation
If too many side effects and severe Fe
deficiency – consider Iron dextran IV
66.
67. Hereditary Spherocytosis
Lack of central pallor
Osmotic Fragility test
Rx : blood transfusions, splenectomy
Watch secondary hemochromatosis –
use Desferrioxamine
68.
A 32-year-old man of Italian descent is evaluated for a routine preemployment physical examination. He has always been healthy, and his
physical examination is normal.
Laboratory Studies
Hematocrit 35%
Mean corpuscular volume 63 fL
Leukocyte count 6800/μL
Reticulocyte count 40,000/μL (0.7% of erythrocytes)
Platelet count 270,000/μL
Results of fecal occult blood testing are negative. Peripheral blood smear
shows microcytosis and many target cells.
Which of the following is the best diagnostic test to evaluate the
cause of the anemia and microcytosis?
( A ) Coombs' direct antiglobulin test
( B ) Measurement of hemoglobin A2 level
( C ) Glucose-6-phosphate dehydrogenase screen
( D ) Measurement of serum iron, total iron-binding capacity, and ferritin
levels
69.
A 22-year-old female college student of Greek descent is evaluated
because she tires easily and has had palpitations
when playing tennis for the past 3 months. She reports no night sweats or
weight loss, and her family history is negative for anemia. She has two
healthy siblings.Physical examination is unremarkable. A complete blood
count shows a hemoglobin of 9.0 g/dL with a hematocrit of 28% and an
erythrocyte count of 3.7 million/μL. Erythrocyte distribution width is
elevated at 17% (normal range 10.5% to 14.5%). The neutrophil,
lymphocyte, and platelet counts are normal.
Which of the following is the most appropriate initial step in the
management of this patient?
( A ) Perform hemoglobin electrophoresis for hemoglobin A2 and F.
( B ) Perform complete blood counts for siblings.
( C ) Measure serum ferritin.
( D ) Perform ultrasonography of the spleen.
( E ) Perform Southern blot analysis
70. Key Points
An elevated erythrocyte distribution width is
consistent with iron-deficiency anemia.
Measurement of serum ferritin can differentiate
iron-deficiency anemia from the anemia of
thalassemia trait.
71.
72. Macrocytic Anemias
Vitamin B12 def
Folic acid def
Alcohol/ Zidovudine
Hypothyroidism
Subtle clues for Vit b12 def ataxia,
neurological symps, psychosis, dementia
Pernicious anemia – screen all B12 def pts
with anti-parietal cell abs. ( Rx is IM b12
for life )
73. Hemolytic Anemias
Labs that suggest Hemolysis Indirect
bilirubin, LDH, Reticulocyte count,
Haptoglobin
Peripheral smear help to r/o
microangiopathic hemolysis
(Schistocytosis), increased reticulocytes
Urine Hemosiderin elevated only in
uintravascular hemolysis
Direct coomb +ve Autoimmune
Hemolysis.
Concomitant thrombocytopenia may
suggest TTP, DIC, EVANS syndrome
74.
75. Microangiopathic Hemolysis
Characterized by schistocytosis –
fragmented RBCs on peripheral
smear
Seen in TTP, DIC, HUS, HELLP
syndrome, CAPS, malignant
hypertension
Macroangiopathic hemolysis – also
can have schistocytes eg: prosthetic
valves.
76.
77. Autoimmune Hemolytic Anemias
Direct coombs +ve
Microspherocytes on peripheral smear
Urine hemosiderin –ve
LDH elevated, Hapto may be low
Retic count increased
Rx : Steroids, IVIG, Splenectomy
Recognize Autoimmune hemolysis in CLL
78.
A 63-year-old man with stage I chronic lymphocytic leukemia (CLL) is evaluated for
increasing dyspnea on exertion that has developed over the past 2 weeks. He
currently takes no medications. On physical examination, he has pale conjunctivae
and scattered axillary and inguinal lymphadenopathy that are unchanged from his
last examination 1 year ago. His is afebrile. Pulmonary examination is normal except
for tachypnea.
Laboratory Studies
Hematocrit 18%
Leukocyte count 12,000/μL (25% polymorphonuclear leukocytes, 75%lymphocytes)
Platelet count 285,000/μL
A peripheral blood smear shows spherocytes, a reticulocyte count of 10%,
polychromatophilia, smudge cells, and normal-appearing lymphocytes with no
schistocytes. Hematocrit 1 year ago was 46%.
Which of the following is the most likely cause of this new onset of anemia?
( A ) Conversion of CLL to acute lymphoblastic leukemia
( B ) Autoimmune hemolytic anemia
( C ) Disseminated intravascular coagulation
( D ) Marrow infiltration by CLL
( E ) Conversion to a large-cell lymphoma (Richter's syndrome)
79.
A 27-year-old black man is admitted to the hospital for treatment
of community-acquired pneumonia, for which he received
erythromycin. On the second hospital day, he is lethargic and has
easy fatigability, a temperature of 38.4 °C (101.1°F), and scleral
icterus. The patient had a similar episode during a childhood ear
infection. His two brothers have had similar problems, though his
sister has not. His hematocrit, which was 40% on admission, is
now 32%. His reticulocyte count is 140,000/μL (4% of
erythrocytes).Liver studies show a serum total bilirubin
concentration of 5.4 mg/dL and a direct bilirubin concentration of
1.4 mg/dL.
A peripheral blood smear is shown.
Which of the following is the most appropriate diagnostic
study at this time?
( A ) Sickling test
( B ) Glucose-6-phosphate dehydrogenase measurement
( C ) Hemoglobin electrophoresis
( D ) Erythrocyte pyruvate kinase activity measurement
( E ) No further testing
80. Key Point
Following an acute hemolytic event due to
glucose-6-phosphate dehydrogenase deficiency
(G6PD),G6PD levels will be normal. Testing
should be delayed for 3 to
4 weeks.
81. Anemias
A 19-year-old woman comes to the student health service
complaining that since the new semester has begun, she finds
herself unable to focus and concentrate as well as before. She
attributes this largely to feeling fatigued. She denies any other
symptoms such as sadness, sleeplessness, or loss of libido. She
has no other medical issues. Her medications are only oral
contraceptive pills. She has never been pregnant and denies
current pregnancy. She has a history of long menses, often lasting
8 days. Laboratory studies show:
Hct 31%
MCV 69um3
Ferritin 10mcg/L
The most appropriate next step is to
A. administer iron, intravenously
B. administer vitamin B12, intravenously
C. advise her to take folate tablets
D. change her oral contraceptive formulation to estrogen only
E. tell her to take oral iron tablets
82.
Anemias
A 5-year-old boy is brought to the clinic for a periodic health maintenance
examination. He is generally healthy, enjoys school, plays well with his
siblings and with other children his age. He and his family live in a housing
development down the street that was built 10 years ago. Since his mother
usually works until late in the evening, he tends to spend a lot of time at a
friend's apartment in an old, dilapidated housing development nearby. You
notice that he has unusually pale skin and mucus membranes and so you
inquire about related symptoms. The mother tells you that she has noticed
that he is significantly more tired than his siblings and he has been a "bit
irritable" lately but she "didn't think nothing of it." He is up-to-date on all of
his immunizations. There is no family history of blood disorders, however
several of his playmates "are anemic." You decide to order hemoglobin,
hematocrit, and a peripheral blood smear and schedule a follow-up visit in 1
week. He returns for his next appointment and you review the results of the
laboratory studies. His hemoglobin is 9.5 g/dL, hematocrit is 30%, and the
peripheral blood smear shows microcytic red blood cells with basophilic
stippling. The most appropriate next step is to
A. administer ferrous sulfate, orally
B. administer dimercaprol, orally
C. administer edetate disodium, orally
D. determine B12 levels
E. determine blood lead levels
F. obtain an abdominal radiograph
G. order hemoglobin electrophoresis
H. Check Erythrocyte Zinc Protoporphrin levels
83.
During a routine screening for mild dementia, a 78-year-old male resident of a
nursing home is found to have a low serum vitamin B12 level. He does not have
fatigue, dyspnea, chest pain, dizziness, unsteadiness, or paresthesias. His
medical history is significant for coronary artery disease, for which he underwent
coronary stent placement 5 years ago. His medications include metoprolol and
atorvastatin. Physical examination does not indicate any symptoms of vitamin B12
deficiency, such as glossitis or impaired sensation.
Laboratory Studies
Hematocrit 43%
Mean corpuscular volume 94 fL
Serum creatinine 1.4 mg/dL
Serum vitamin B12 level 200 pg/mL
Which of the following is the most appropriate next step in the management
of this patient?
( A ) Weekly vitamin B12 injections
( B ) Intrinsic factor antibody test
( C ) Serum methylmalonic acid level
( D ) Schilling test
84. Subclinical B12
Deficiency
- May not have any symps
- Elevation of MMA is a sensitive
marker of significant deficiency
- Treat it!
85. Sickle Cell Anemia
Sickle cell trait/ Sickle cell anemia
Sickling test : sickle cell screen
C/F:Sickle cell crises
Acute Chest syndrome
Infections
Dactylitis
Aplastic Crises : folic acid deficiency vs. Parvo virus
Avascular Necrosis hip get MRI
Labs : HGB electrophoresis, Peripheral smear – howell-jolley
bodies, stress lymphocytosis, increased retic count, anemia,
hemolysis, elevated indirect bilirubin
Management :
Acute pain crises manage with IV Fluids, analgesics, septic
w/u, electrolyte repletion, watch for substance abusers ( clues
are labs)
Recurrent Acute pain crises more than 3-4 episodes per
year, use Hydroxyurea. D/W pt benefits vs. toxicity of hydrea
Acute Chest Syndrome O2, analgesics, Exchange
Transfusion
86.
A 17-year-old male patient with homozygous sickle cell
anemia was admitted to the hospital for hydration and
analgesia of a painful crisis. On hospital day 3, his condition
deteriorated, with the onset of fever, new chest pain, and
dyspnea. On physical examination, he has a temperature of
38.9 °C (102 °F), pulse rate of 120/min, and respiration
rate of 32/min. He is using accessory muscles of inspiration
and has crackles bilaterally. Chest radiographs show new,
bilateral pulmonary infiltrates and a normal-sized heart.
Pulse oximetry shows an oxygen saturation rate of 80% on
room air. Which of the following is the most important
immediate therapeutic option?
( A ) Amoxicillin
( B ) Hydroxyurea
( C ) Diuretics and digoxin
( D ) Partial-exchange transfusion
( E ) Polyvalent pneumococcal vaccine
87. Key point
The acute chest syndrome is characterized by
chest pain, fever, diffuse pulmonary infiltrates,
and hypoxia in a patient with sickle cell anemia.
The most effective therapy for the acute chest
syndrome in sickle cell anemia is partialexchange transfusion to lower the hemoglobin
S.
88. Splenectomy
Prior to splenectomy Patients should
be immunized with pneumococcal,
HIB and meningococcal vaccines
Daily oral penicillin prophylaxis for
splenectomized patients.
89.
A 56-year-old man is evaluated for fatigue during a routine office visit. His history is
significant for diverticulosis,hypertension, and supraventricular tachycardia, for
which he takes aspirin, metoprolol, and ramipril. On physical examination, he is
afebrile, his blood pressure is 120/80 mm Hg, and pulse rate is 80/min. No
abdominal tenderness,splenomegaly, or lymphadenopathy is noted.
Laboratory Studies
Hemoglobin 8 g/dL
Mean corpuscular volume 76 fL
Leukocyte count 11,200/μL
Platelet count 847,000/μL
Which of the following is the most appropriate next diagnostic test for this
patient?
( A ) Fluorescence in situ hybridization analysis of blood for Philadelphia chromosome
( B ) Examination of bone marrow aspirate
( C ) Serum ferritin measurement and fecal occult blood testing
( D ) Repeated complete blood count in 2 weeks after discontinuation of all current
medications
( E ) Bleeding-time measuremen
90. Ans. Reactive Thrombocytosis
Iron deficiency
Malignancy
Major Surgery
Acute blood loss
Primary thrombocytosis can be caused by clonal disorders, such
as chronic myelogenous leukemia (CML), polycythemia vera, and
essential thrombocythemia. CML is characterized by the presence
of the Philadelphiachromosome in blood and marrow myeloid
cells. Patients with CML typically have a high leukocyte count,
high or normal platelet and erythrocyte counts, and
splenomegaly. The absence of leukocytosis and splenomegaly and
thepresence of severe microcytic anemia make CML unlikely
Essential thrombocythemia may be associated with thrombotic
and hemorrhagic complications. Patients with essential
thrombocythemia have a platelet count of greater than
600,000/μL without known causes for reactive thrombocytosis;
therefore, iron deficiency precludes this diagnosis.
92.
A 48-year-old female nurse is evaluated for hematuria. One week
ago, she experienced dysuria, for which cephalothin was
prescribed. Her history is remarkable only for an uneventful
tonsillectomy as a child and removal of a benign ovarian cyst at
age 36; there is no family history of bleeding. The patient does not
smoke or use alcohol or recreational drugs. She has a normal diet,
and her weight has been stable. She has a history of depression
that has been treated with numerous antidepressants, but she is
not taking any medications currently. On physical examination, she
has two ecchymoses on her lower extremities. Laboratory
evaluation includes a prothrombin time (PT) of 28.2 sec (INR 4.2),
activated partial thromboplastin time (PTT) of 45 sec (normal < 35
sec), normal thrombin time, negative D-dimer, and normal
complete blood count and platelet count. Liver enzymes are within
normal limits, and serum albumin is 4.1 g/dL. An inhibitor-screen
mixing study shows complete correction of the PT and PTT after
mixing of patient and control plasma at a 1:1 ratio. The factor VII
level is 6%, factor IX level is 10%, factor VIII level is 110%, and
factor V level is 95% (reference range 60% to 150%).
Which of the following is the most likely diagnosis?
( A ) Acquired factor VIII inhibitor
( B ) Lupus anticoagulant
( C ) Hemophilia B (Christmas disease)
( D ) Surreptitious warfarin ingestion
93. Key Point
In severe vitamin K deficiency, the prothrombin
time and the Partial thromboplastin time are
prolonged.
In mild vitamin K deficiency (including
therapeutic warfarin), only the prothrombin
time is prolonged
95. Screen for VWd
Screen for VWD in women with menorrhagia and no
gynecologic reason for heavy bleeding, in patients with
unexplained procedural bleeding, and in individuals with a
personal or family history or physical evidence of
mucocutaneous bleeding.
Remember VWd can be asymptomatic for a long time with
no hx at all and may just present with excess bleeding
during surgical procedures
Conduct a first-line coagulation screening work-up,
including PT, PTT, CBC/platelets, and thrombin time. If
PTT is prolonged and other initial test results are normal,
suspect VWD as a possible diagnosis ( BT is prolonged too.
BT is N in Hemophilia ) ( Remember d/d for isolated PTT
prolongation is also thrombotic condition APLA/ LA – This
manifests by thrombosis though, unlike VWd which is
bleeding)
Initial tests for the diagnosis or exclusion of VWD include
VWF function, VWF:Ag, and factor VIII activity and should
be done more than once.
96. Rx - VWd
In treatment of significant bleeding
events or for prevention of bleeding
during invasive procedures or
surgeries use Desmopressin
Remember Tachyphylaxis with
desmopressin ( in case of continued
bleeding after desmopressin , use
Cryoprecipitate/ VWF concentrate)
97. Uremic Bleeding
Bleeding time is the best predictor
for tendency to bleed.
Desmopressin – Rx of choice in
preventing bleeding for surgical
procedures or in Rx of Bleeding
Conjugated Estrogens
Blood transfusion to keep hct high
Recombinant Factor VIIa
98. Hemophilia
Screen for hemophilia A and B in individuals with:
A history of bleeding
Family members known to have hemophilia or be
hemophilia carriers
Unexplained aPTT prolongation ( BT normal)
DX : If APTT prolonged, do mixing study. Correction
suggests Factor deficiency.
Then obtain quantitative factor VIII/ IX levels and activity.
In patients with prolonged PTT and decreased factor VIII
activity who have no family hx of hemophilia a, obtain VWF
level to r/o VWd
Hemophilias can present with deep bleeding ( Hemarthrosis)
apart from superficial bleeding ( mucosal bleeding,
ecchymoses, bruises with minimal trauma)
RX: factor VIII/ IX concentrates ( A – Factor VIII def, B –
FACTOR ix DEF)
100. Thrombocytopenias
Drug Induced : HIT, GP IIb IIIA inhibitors
( abciximab, eptifibitide), Linezolid,
Clopidogrel
Always r/o Pseudothrombocytopenia – this
is our first step.
Congenital thrombocytopenia ( Some are
microthrombocytopenias)
Consumption Thrombocytopenias : TTP,
DIC, Massive Bleeding, Sepsis
ITP
ITP + AIHA ( Coombs +ve, Evans
syndrome)
101. Platelet transfusions - Indications
Platelets < 15k
Platelets<50k + ICH/Life threatening
hemorrhage
Platelets > 50k no platelets ( all we
need is 50k platelets for enough clotting.
So, no need of transfusions for
platelets>50k)
Avoid platelets in TTP/ DIC unless severe
bleeding which is unlikely manifestatuion
in these cases.
102. Idiopathic thrombocytopenic purpura
Previous CBC is a clue
Rule out other causes – drugs, liver disease, HIV, HEP-C, APLA, SLE
etc
HIV related ITP responds to HAART/ Zidovudine most studied.
Rx – mild ITP is often associated with a good prognosis.
Platelet counts >50 × 109 cells/L with no history of bleeding
careful observation with regular visits and platelet count
determinations
Prednisone f Plts < 30k If there is a response with a
normalization of the platelet count over 1 to 2 weeks, taper by 5 to
10 mg/week.
IVIG if immediate response is required i.e; before surgical
procedures, or in initial treatment for patients with severe bleeding
AND also, in patients who are refractory to treatment with
glucocorticoids. Remember, response short-lived.
Consider RhIG as outpatient therapy: In patients who are Rh(+)
and have not had a splenectomy , For patients in whom
splenectomy is not feasible and along with IVIG in patients in
whom steroids have failed
Splenectomy if no response to steroids (persistent platelet counts
<10 × 109 cells/L for 4 to 6 weeks and for patients who have had
ITP for 3 months with persistent severe thrombocytopenia
(platelet count <30 × 109 cells/L) despite treatment) or Relapse
after tapering Steroids
Can try immunosuppressants (AZA) or Rituximab if
splenectomy and Steroids are unsuccessful
103. HIT
Usually occurs with in 5-7 days after exposure to heparin.
Immediate HIT is possible if there was prior exposure in
past 3 months enabling circulating antibodies
Heparin induced Anti-platelet Abs screening test
Serotonin Release Assay confirmatory test
Base your decision most on clinical probability rather than
these tests.
Features deep vein thrombosis, PE, Arterial thrombosis
in a setting of acute thrombocytopenia after exposure to
heparin.
Rx Once HIT is suspected/ diagnosed , must be treated
Rx Argatroban, leperidin overlap with warfarin
Lepiridin difficult to monitor
Argatroban adds to INR. So, safely discontinued after
warfarin started and INR of 4.0 is reached. Repeat INR in 6
hrs after discontinuing Argatroban to confirm therapeutic
range INR ( 2 to 3)
104. Case Study
A 67 y/o man in previously good health is
hospitalized with 2 day hx of fever and decreased
consciousness. Temp is 103 F, HR 140, BP 88/50.
There is no bleeding. The hgb 12.1 gm%, wbc
29,000, platelets 20,000/ul. Which of the
following should be obtained next?
A) Bone marrow biopsy
B) Factor VIII level
C) Measurement of platelet associated IgG
D) Measurement of D-Dimer and fibrinogen
E) Bleeding time
105. Anemias
A 21-year-old man with no significant past medical history
presents to office with complaints of blood in his urine and
mucosal bleeding while brushing his teeth. He denies any drug or
alcohol use. He has no family history of bleeding disorders.
Petechiae are noted in the oral cavity, as is dried blood in the
nostrils. Laboratory studies show the following: Hematocrit 32%;
white blood cell count 8,000/mm3 with 60% neutrophils; platelet
count 13,000; PT 13 seconds; PTT 28 seconds; LDH 1,200 U/L;
elevated indirect bilirubin. Coombs' test is positive; abdominal
examination is normal; and the peripheral smear shows
spherocytes.
What is the most likely diagnosis?
(A) Gordon's syndrome
(B) Bernard-Soulier syndrome
(C) Felty's syndrome
(D) Thrombotic thrombocytopenic purpura
(E) Evans' syndrome
(F) Idiopathic thrombocytopenic purpura (ITP)
107. Polycythemia Vera
Measure RBC mass to r/o relative polycythemia
Differentiate from Secondary polycythemia – R/o
hypoxia which is the most common cause.
Presence of leucocytosis and thrombocytosis as
well as spelenomegaly are big clues that this
could be primary.
EPO level
JAK-2 mutation
Pruritis during shower often seen in primary
polycythemia due to histamine release from mast
cells
Bone marrow biopsy if EPO is low or normal in
presence of polycythemia
108. Secondary Polycythemia
R/o Relative Polycythemia secondary to
hemoconcentration/ dehydration repeat
CBC after Hydration
Chronic Hypoxia : COPD, high altitudes,
OSA, Obesity hypoventilation, intracardiac shunts, smoking EPO elevated/
normal
Neoplasms : RCC, Pheochromocytoma,
Cushings disease, cerebellar
hemangioblastoma, hepatoma
Endocrine : Cushings disease
109.
C/F and Rx
Pruritis in Polycythemia vera
Ruddish complexion, erythematous rashes on
abdomen, extremities, purpura.
Pts have increased risk of both thrombosis and
bleeding
Phlebotomy to keep hct < 45%
Patients with symptomatic polycythemia should
undergo immediate Phlebotomy
Headache, Dizziness, chestpain
Blurred vision, papilledema, hypertensive
emergencies are indication for immediate
Phlebotomy.
Begin cytoreductive therapy concomitantly with
phlebotomy in cases of P.Vera (Hydroxyurea).
110. Hematological Malignancies
Leukemias – ALL, AML, CML, CLL
Know when to treat CLL ( Anemia,
thrombocytopenia, Rx – Fludaribine,
Chlorambucil)
CML – Studies, Rx
AML Know M3, associations and Rx
Lymphomas Hodgkins, NHL
Secondary malignancies after radiotherapy
( Hodgkins survivors ) follow up
mammograms
113. Multiple Myeloma
D/D
MGUS
Solitary Plasmocytoma
POEMS syndrome (peripheral neuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, skin changes, as well as
other paraneoplastic features and osteosclerotic lesions)
Waldenström macroglobulinemia
114. MGUS
M-Protein < 3gm%
Bone Marrow plasma cells < 10%
Normal hgb, creatinine and serum calcium
Normal bone survey ( x-rays not bone
scan)
RX : may progress to MM. There’s no
evidence that chemotherapy reduces
progression – so don’t treat
Observation
115. Solitary plasmacytoma
Single lytic lesion in the bone
No evidence of anemia, renal
insufficiency or high calcium
M-protein may or may not be
elevated
75% progression to MM in 10 yrs
No chemotherapy is recommended
Rx is excision and Radiation
116. Smoldering Myeloma
Characteristics
• Serum M protein >3 g/dL and/or bone marrow
plasma cells ≥10%
• Absence of anemia, renal failure,
hypercalcemia, lytic bone lesions
Disease Management
• Observation with treatment beginning at
disease progression
• Bisphosphonates
• Supportive care
• Participation in clinical trial
117. Symptomatic MM
Patients with symptomatic myeloma
require immediate treatment.
Characteristics
•
•
•
Presence of serum/urine M protein > 3gm%
Bone marrow plasmacytosis (usually >30%)
SYMPTOMS+ Anemia, renal failure,
hypercalcemia, or lytic bone lesions
Treatment — Thalidomide + dexa,
lenalidomide, Melphalan
118. Waldenstroms Macroglobulinemia
Incidence and clinical features
Increased IgM. IgG may be decreased
1,500 cases/year in USA
Median age -, 63 yrs
Presenting symptoms
•
•
•
•
•
•
Weakness and fatigue
Hemorrhagic manifestations
Weight loss
Neurologic symptoms
Visual disturbances
Raynauds phenomenon
44%
44%
23%
11%
8%
3%
124. Case Study
A 43 y/o m with severe acquired aplastic anemia
has not responded to immunosuppressive agents.
He has a HLA identical brother who has been
cleared as a donor for his planned allogeneic
stem cell transplant. They are both CMV negative.
Which of the following will be prevented by using
irradiated cellular blood products to this patient?
A) Graft versus Host disease, Transfusion related
B) CMV disease
C) Alloimmunization
D) Hemolytic transfusion reaction
E) Febrile non hemolytic transfusion reaction
125.
A 57-year-old woman (gravida 5, para 5) was admitted to the
hospital with a bleeding duodenal ulcer for which she was given
three units of packed erythrocytes. A regimen of antacids and
cimetidine was initiated, and the patient was discharged after 3
days. Two days later, she returns to the hospital because of
weakness, increased malaise, and dark urine. Her hematocrit,
which was 37% at discharge, is now 26%. Liver studies show a
total serum bilirubin of 6.1 mg/dL, with a direct value of 2.3
mg/dL, and a lactate dehydrogenase concentration of 467 U/L.
Renal function is normal. Stools and a gastric lavage are negative
for blood. The peripheral blood smear shows numerous
microspherocytes.
Which of the following is the most appropriate next step in
the management of this patient?
( A ) Corticosteroid therapy
( B ) Blood typing re-evaluation and cross-match
( C ) Osmotic fragility test
( D ) High-dose immunoglobulin infusion
( E ) Emergency surgical consultation
126. Key points
1.
A delayed hemolytic transfusion reaction occurs
several dayS after transfusion and is characterized
by an elevated serum lactate dehydrogenase level
and a high indirect bilirubin level along with
decreasing hematocrit and the presence of
microspherocytes.
2. A repeated cross-match is likely to detect
antibodies missed on the original cross-match.
