Transcript 301.

Lab Tests—what to do with a patient with
neutropenia, thrombocytopenia, and/or
erythropenia
Barb Bancroft
RN, MSN, PNPenia
Oh, GROW UP!!
• The process of maturation and differentiation
• Everything starts with a pleuripotential stem cell—to 2
cell lines
1) Myeloid stem cells—erythrocytes (RBCs),
eosinophils*, neutrophils*, basophils*,
monocyte/macrophages,
megakaryocytes/thrombocytes/platelets
*collectively called the “granulocytes” because they have
granules in their cytoplasm—for staining purposes
(red/eosin/acid; white/neutral; blue/basic
1) Lymphoid stem cell—T lymphocytes, NK cells, plasma
cells/B lymphocytes
Some normal numbers
Platelets (thrombocytes)—150,000-450,000—
less than 100,000 is considered
thrombocytopenia
Erythrocytes (RBCs)--4.5 million to 6 million
• Gender differences
• Women with less blood volume and more fat
tissue than men with more muscle mass
• Women closer to the 4.5 million; men up
around the 6 million
Some normal numbers…
• Neutrophils /segs (57-63%) of the total white
count; acute inflammation, bacteria, acute
necrosis (1.51-7.07)
• NOTE: the precursor to the neutrophil is the band
neutrophil; Bands (0-4%) (0.00-.51)—it’s almost
mature and can perform many of the functions of
the mature neutrophil ; In fact, when a band is
released from the bone marrow it only takes 2
hours to mature into a neutrophil
• Eosinophils? 3% of total WBC
• Basophils? <1% of total WBC
Cell growth—Too much? Too little?
• Too much? Thrombocytosis
• Too little? Thrombocytopenia
• Too much? Neutrophillia, eosinophillia, basophillia (CML, PV)
• Too little? Life-threatening neutropenia
(There is no such thing as life-threatening eosinopenia or basopenia)
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OUR FOCUS TODAY? What happens when you don’t have enough?
Too little? Thrombocytopenia
Too little? Life-threatening neutropenia
Too little? Erythropenia?  Anemia
First question in the work-up of a
patient with a “penia”…
• Is this an isolated “penia”?
• Normal platelets, RBCs, but just neutropenia?
• Thrombocytopenia, but with normal # of
platelets, and normal # of neutrophils?
• OR more importantly, is this pancytopenia?
EVERYTHING is “penic”—more ominous but
even isolated “penias” require diagnostic
acumen
The neutrophil
• Neutrophils—(phagocytic)—only job in
the world is to EAT until it dies
• Cell of acute inflammation
• First responder to bacterial invasion
• Loves acute necrotic tissue
Drugs and neutropenia
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Chemotherapy (all patients)
Cimetidine (Tagamet), ranitidine (Zantac)
Captopril (Capoten), enalapril (Vasotec), amiodarone, quinidine
Zidovudine (Retrovir), vidarabine (Vira-A),
Flucytosine (Ancoban)
ASA, acetaminophen
Anti-convulsants-- Carbamazepine (Tegretol); Phenytoin (Dilantin)
Antibiotics including metronidazole (Flagyl),gentamicin,
clindamycin, vancomycin, imipenem, PCNs, tetracyclines, TMP-SMX
• Azothiaprine (Imuran)
• PTU and methimazole
Other causes of neutropenia
• Bone marrow replacement—tumor infiltration,
leukemia, myelofibrosis
• Immunologic—autoimmune (antineutrophil
antibodies—SLE, newborns from maternal IgG)
• Metabolic—hyperglycemia (other rare causes of
metabolic disorders)
• Nutritional—anorexia nervosa, B12/folate
deficiency, copper deficiency
• Sequestration—hypersplenism
Transient neutropenia
• The most common cause is viral infection—
influenza, adenovirus, coxsackie virus, RSV,
hepatitis A and B, measles, rubella, EBV, CMV,
and varicella.
• The neutropenia usually develops in the first 2
days of the illness and may persist for up to one
week
• Redistribution of neutrophils (margination pool),
sequestration in lymph nodes and BM, marrow
suppression)
• low risk for serious infectious complications
The neutrophil in the world of ONCOLOGY
• Fastest dividing cell in the body as an adult
• Chemotherapy and radiation therapy kill cells
that are rapidly dividing causing life-threatening
neutropenia
• ANC—absolute neutrophil count
• Neutrophils (60%) + bands (4%) = ANC = 64% of
the total WBC
• If the total WBC is 10,000/ml³, the ANC is 64% or
6,400
The Absolute Neutrophil Count (ANC)
• Neutropenia is defined as an absolute neutrophil
count (ANC) <500/mm3 or an ANC of
<1,000/mm3 with an expected decline.
• Serious bacterial infection risk increases directly
with the following: (1) severity of neutropenia
(ANC < 100 cells/mm3 imposes a greater risk than
ANC < 500 cells/mm3), (2) rate of ANC decline
(rapidly falling rate imposes a greater risk than
chronic neutropenia or aplastic anemia), and (3)
duration of neutropenia
The Absolute Neutrophil Count
• When the ANC falls below 500, control of
endogenous microbial flora (mouth, gut) is
impaired
• When the ANC falls below 200, the
inflammatory process is absent.
The oncology patient with neutropenia
• Patient with a total WBC of 2,000/ml³ is
LEUKOPENIC. But, is she NEUTROPENIC? Her
neutrophils are 30%, bands are 2%; what’s 32% of
2,000? 640/ml³
• Patient with a total WBC of 2,000/ml³ is
LEUKOPENIC. But, is she NEUTROPENIC? Her
neutrophils are 50%, bands are 4%; what’s 54% of
2,000? 1080/ml³
• [Neupogen (1991) (filgrastim) and Neulasta
(2002)(pegfilgrastim)
Febrile neutropenia
• The most serious immediate consequence of
chemotherapy is febrile neutropenia—defined as an
absolute neutrophil count of less than 500 cells per cubic
millimeter and a temperature of more than 38.5° C.
• Most standard dose chemotherapy regimens are associated
with 6 to 8 days of neutropenia
• Neutropenia blunts the inflammatory response to
infections, allowing bacterial multiplication and invasion
• Predisposes patients to serious infections and death if
severe neutropenia persists for longer than 10-14 days
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(N Engl J Med 2013 Mar 21;368:12)
Neutropenia
• Acute neutropenia, such as that caused by
cancer chemotherapy, is more likely to be
associated with increased risk of infection
than neutropenia of long duration (months to
years)
• Rare—usually may manifest in early childhood
as a profound constant neutropenia or
agranulocytosis
Approach to the patient with
thrombocytopenia
• Is this a healthy young adult with
thrombocytopenia or an elderly hospitalized ill
patient receiving multiple medications?
• Limited differential in the young patient
Approach to the patient with
thrombocytopenia
• Myelodysplasia can present in patients presenting with
isolated thrombocytopenia who are greater than 60
years of age
• FH (inherited thrombocytopenia is rare)
• PE: spleen (mild to moderate splenomegaly is easier to
pick up with abdominal ultrasound); enlarged liver,
extremities (a platelet count of 5,000 to 10,000 is
required to maintain vascular integrity in the
microcirculation. With markedly decreased platelets,
petechiae first appear in areas of increased venous
pressure, the ankles and feet in an ambulatory patient
Clinical signs of thrombocytopenia
• Petechiae are pinpoint, non-blanching
hemorrhages and are usually a sign of decreased
platelet number and not platelet dysfunction
• Wet purpura, blood blisters that form on the oral
mucosa, are thought to denote an increased risk
of life-threatening hemorrhage in the
thrombocytopenic patient
• Excessive bruising is seen in disorders of both
platelet number and function
Manifestations of platelet deficiency
or platelet dysfunction
• Superficial bleeding is the rule with platelet
dysfunction or deficiency
• Mucous membrane bleeding—easy bruising,
nose bleeds (most common cause?), gum
bleeds, blood in the urine (hematuria), blood
in the stool (occult blood) –
Causes of thrombocytopenia
• Decreased production—bone marrow depression,
marrow infiltration, congenital
• Excessive pooling—hypersplenism
• Infection: HIV, EBV, HCV
• Coagulopathies—HELLP syndrome, DIC
(meningococcal septicemia)
• Increased destruction—Immunologic destruction
with
autoimmune disease, Henoch-Schonlein purpura,
thrombotic thrombocytopenic purpura (TTP); severe
hemorrhage,
Immune thrombocytopenia (ITP)
• Acquired disorder leading to immune-mediated
destruction of platelets and possibly inhibition of
platelet release from the megakaryocyte
• Kids? Usually an acute disease following a viral
infection
• Adults? More chronic and usually secondary –
associated with an underlying disorder
• Autoimmune, especially lupus (SLE)
• Infections: HIV, HCV, EBV, Helicobacter pylori
Lab tests
• Test for HIV, hepatitis C, EBV and other
infections depending on the patient, of course
• Coomb’s test if anemia is present (to rule out
combined autoimmune hemolytic anemia)
• Is this a 27-year-old female with anemia and
thrombocytopenia?
• Is this a 27-year-old male with anemia and
thrombocytopenia?
Drugs definitely reported to cause
isolated thrombocytopenia
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Abciximab (Reopro)
Acetaminophen
Acyclovir
Aminosalicylic acid
Amiodarone
Amphotericin B
Ampicillin
Carbamazepine
Chlorpropamide
Danazol
Diclofenac
Digoxin
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Eptifibatide
HCTZ
Ibuprofen
Levamisole
Octreotoide
Phenytoin
Quinine
Rifampin
Tamoxifen
Tirofiban
TMP/SMX
vancomycin
Other drugs that decrease platelets or
cause platelet dysfunction
• Prescription drugs and platelets: SSRIs
(fluoxetine/Prozac; paroxetine/Paxil/Pexeva;
sertraline/Zoloft; citalopram/Celexa;
escitalopram/Lexapro)—increased risk of
bleeding
• Valproic acid – keep eye on platelet counts—
more problems…
Heparin-induced thrombocytopenia
• Thrombocytopenia due to heparin differs from
that seen with other drugs in two major ways
1) The thrombocytopenia is not usually severe
(not less than 20,000)
2) HIT is not associated with bleeding and, in
fact, markedly increases the risk of
thrombosis due to antibody formation to a
complex that activates platelets
Causes of platelet bleeding
• Don’t forget ETOH abuse also causes
thrombocytopenia
Causes of platelet dysfunction
• Ask about OTC and complementary and
alternative therapies; over-the-counter such
as NSAIDS (24 hours for ibuprofen)*, ASA (7
days);
*Don’t have to stop Celebrex before surgery
• the G’s—gingko, ginseng, glucosamine, garlic,
ginger; omega-3s, vitamin E
Platelets
• Just a reminder…some patients can have
plenty of platelets but the platelets don’t work
• Qualitative Platelet dysfunction
• How well do they “plug a hole”? OLD:
Measure the bleeding time (3-6 minutes)
• NEW: PFA – Platelet Function Assay
One last point about platelets…
• Can you hemorrhage with low platelets?…yes
• The rate of the fall is more important than the
total number of platelets in most instances
• However, very low platelets, less than 10,000
increase the risk of hemorrhage no matter
how fast the platelets fell
Erythropenia () and anemias
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What do you need to make happy, healthy RBCs?
Good parents (good genes)--hemoglobinopathies
Healthy thyroid (metabolism and production of RBCs)
Healthy kidney (the hormone erythropoietin to stimulate
the production of RBCs in response to hypoxia)
• Iron (dietary deficiency in growing kids and pregnant
moms; celiac disease—poor absorption in distal
duodenum; —the major source of iron in adults is recycled
RBC—not dietary; hence—loss of blood increases risk)
• B12 –animal protein, stomach IF, ileum for absorption,
vegetarians, drugs such as metformin, PPIs, Crohn’s, aging
• Folic acid (B9)—fruits and veggies
So what can go wrong?
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Lousy genes
Hypothyroidism
Renal failure
Iron deficiency
B12 deficiency
Folic acid deficiency
Anemia
• The skin and mucous membranes may be pale if
the hemoglobin is less than 80 – 100 g/L (8-10
g/dL)
• Focus on the areas where vessels are close to the
surface such as the mucous membranes, nail
beds, and palmar creases
• If the palmar creases are lighter in color than the
surrounding skin when the hand is
hyperextended, the hemoglobin level is usually
less than 80 g/L (8 g/dL)
Get the most bang for your buck with
3 tests
• Hemoglobin
• MCV (mean cell volume)—what is the SIZE of the
RBC? Are they too small? microcytic anemia; are
they too big? Macrocytic anemia; are they
normal size but just too few of them? Normocytic
anemia
• Reticulocyte count—is this patient “reticking”—is
the bone marrow producing RBCs? 0.5-2% of
total RBC count; takes 7-12 days to make and
release a “retic” from the bone marrow
Some other numbers…
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Hemoglobin
adult females (12-16 g/dl) (120-160 g/L)
males (14-18)(140-180g/L
What is anemia defined as?
Hemoglobin under 12 g/dl (120 g/LL) for females and under
14 g/dL (130 g/L for males)
3 tests for anemia that are most
important
• MCV (mean cell volume)—what is the SIZE of
the red blood cell? Too small (microcytic)? 9
out of 10 cases are caused by iron deficiency
anemia; to BIG (macrocytic)? 7 out of 10 are
due to either a B12 deficiency or a folic acid
deficiency; normal size (normocytic)? Check
the thyroid and the kidneys!
Microcytic anemia
• MCV 65 (normal 83-97 fl)
• 9/10 with iron deficiency anemia
• Adults Where’s the bleed? Female? Male? Exercise?
NSAIDS?
• Are you pregnant?
• Growing kid? Lousy diet
• Not growing? Celiac disease from malabsorption
of iron in the duodenum
• Tea drinking?
• Two other causes of microcytic anemia—lead poisoning,
Thalassemia
Iron and RBCs
• How do we get iron?
• Food—especially as children for vertical growth
• Food—not so much in adults as we are not growing
vertically and we usually get plenty of iron from our
diet (only need 1 mg from diet of the 20 mg used per
day—the other 19 mg is recycled through the
senescence of old RBCs)
• Pregnancy -- need extra iron to grow a baby
How do we become deficient in iron?
• Bleeding—anywhere; women have 20% less
blood than men, hence, lower iron stores and
a greater risk of iron deficiency anemia; also
have periods premenopausally which
increases risk of iron deficiency due to RBC
depletion (and depends on type of period)
• Bleeding—ALWAYS THINK GI, GI, GI
Macrocytic anemia
• MCV greater than 100 fL
• MCV between 100 and 120—think booze
• MCV greater than 120—think B12 or Folic acid
deficiency (also known as megaloblastic
anemia)
Drugs that cause megaloblastic
anemia
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Acyclovir (anti-herpes drug)
ASA
Anticonvulsants
Azathioprine (Imuran)
Colchicine (gout)
INH (TB)
Metformin (Glucophage, Glumetza, Fortamet)—type
2 diabetes, PCOS)
• MTX (methotrexate)
• Proton Pump inhibitors (more in a minute)
B12 … a few more notes
• Normal B12 range is 200-800 pg/mL
• 2,000 to 5,000 mcg of B12 is stored in the liver for 5-7 years;
• Use about 2.4 mcg per day for making RBCs, keeping the
myelin in our central and peripheral nervous system healthy,
and making serotonin in our “happy” centers
• Takes 5-7 years of no B12 intake to deplete
Clinical conditions associated with B12
deficiency
• Big, immature RBCs—called megaloblastic
anemia (MCV is greater than 100 fl)
• Cognitive dysfunction—#1 cause of nutritional
dementia
• Peripheral neuropathy (one of three top causes in
elderly)
• Depression (B12 is a co-factor in the production
of serotonin)
• So you have NO energy, you’re demented, can’t
feel your feet and depressed…JEEZZZZ…how
important is B12?
High-risk patients for B12 deficiency
• Over 55
• Lack of intrinsic factor (IF); autoimmune gastritis;
gastrectomy patients
• No animal protein in the diet; vegetarians; Tea and
Toasters; alcoholics
• Liver failure
• Malabsorption—Crohn’s disease, celiac disease; gastric
by-pass surgery
• Metformin (glucophage)
• Proton Pump Inhibitors—inhibit the pump that pumps
HCL acid AND Intrinsic factor; Intrinsic factor binds B12
and moves it to the ileum for absorption
• (Am J Clini Nutr (2007);86:1384)
B12 supplements?
• The 4 S’s
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Swallow it
Suck it
Snort it
Shoot it…
• Don’t overdose…
You need Folic acid (B9) to make happy,
healthy RBCs
• Dr. George Herbert
• 40 days and 40 nights to deplete bone marrow
stores
• Maintenance of healthy RBCs--anemia
• Maturation of the neural tube (first 28 days)-NTDs
• Take folic acid 400 mcg (0.4 mg) BEFORE you
get pregnant + eat
• Green leafys and citrus fruits
Drugs that block folic acid synthesis that are
taken longer than 40 days and 40 nights…
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TMP/SFX (Bactrim, Septra)
Rheumatrex (Methotrexate)
Phenytoin (Dilantin)
Oral contraceptives
• Supplement with folic acid
Normocytic anemia
• RBCs 3,000,000
• MCV normal
• The anemia of chronic disease—CKD,
hypothyroidism, chronic inflammation),
cancer (unless a bleed is involved)
3 tests for anemia that are most
important
• Reticulocyte count—how well is the bone marrow making
RBCs?
• Is this patient “reticking”?
• Is the retic count HIGH? Hemolytic anemia
• FYI: Corrected retic count for patients with anemia (NEXT
time)—there is a formula
• High retic count means that the bone marrow is making
RBCs, but something is destroying them rapidly—either in
peripheral blood or bone marrow (hemolytic)
• Consider drug-induced hemolytic anemia
• Drugs? Penicillin, cephalosporin, procainamide, quinidine,
quinine, sulfonamide—drug-induced hemolytic anemias
Diseases with hemolytic anemias and
high retic counts
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Sickle cell? Genetic hemoglobinopathy
Thalassemia? (as above)
G6PD deficiency?(as above)
Autoimmune hemolytic anemia (lupus, drugs)
Hemolytic uremic syndrome (drugs, Shiga
toxin producing E.coli)
Coomb’s test
• Coomb’s test—what is it used for? If +, it
means an autoimmune process with
antibodies against RBCs (drugs, lupus)
Thank you…
• Barb Bancroft, RN, MSN, PNP
• Chicago, IL
• www.barbbancroft.com
Selected Bibliography
• Bakerman’s ABC of Interpretive Laboratory
Data 3rd Printing
• Harrison’s Hematology and Oncology. 2010.
McGraw Hill.
• Kee JL. Laboratory and Diagnostic Tests. 2014.
Pearson.
• Lam JR, et al. Proton pump inhibitors and H2
receptor antagonist use and vitamin B12
deficiency. JAMA 2013:310(22):2435-2442
Bibliography
• DeJager J, Kooy A, Lehert P, et al. Long-term
treatment with metformin in patients with
type2 diabetes mellitus and risk of vitamin
B12 deficiency: randomized placebo
controlled trial. BMJ 2010;340:c2181). Sando
KR, Barbora J, Willis C et al. Recent diabetes
issues affecting the primary care clinician.
Southern Med J 2011;104(6):456-61)