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c. Familial: Autosomal dominant (5q 31–33)
d. Undefined: Ranges from benign to complex to episodic involvement May have
episodic angioedema
e. Overlap: Eosinophilia affects only one organ, such as chronic eosinophilic pneumonia
and eosinophilic gastrointestinal disease
f. Associated: Eosinophilia is due to a second disease such as ulcerative colitis, sarcoid, or
collagen vascular disease (2–5).
REFERENCES
1. Tefferi A. Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment. Mayo
Clin Pro 2005;80:75–83.
2. Roufosse F, Klion AD, Weller PF. Clinical manifestations, pathophysiology, and diagnosis of the
hypereosinophilic syndromes. Up To Date Topic 2211, version 8.0. January 25, 2012. 23 pages.
3. Weller, PF. Approach to the patient with eosinophilia. Up To Date Topic 7133, Version 13.0. April 27,
2011.
4. Simon HU, Rothenbeg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome.
J Allergy Clin Immunol 2010;126:45.
5. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization classification of tumours of
haematopoietic and lymphoid tissues. Lyon: IARC Press, 2008.
16.3
I. BACKGROUND. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are
currently the most widely used indicators of the acute-phase protein response used to detect
illnesses associated with acute and chronic infection, inflammation, trauma, tissue destruction,
infarction, and advanced neoplasm. The CRP test is a more sensitive and rapidly responding
indicator than the ESR, often showing an earlier and more intense increase than the ESR in
an acute inflammatory process. With recovery, the disappearance of the CRP precedes the
normalization of the ESR (1).
II. PATHOPHYSIOLOGY. The acute-phase response is a major pathophysiologic phenomenon
that accompanies inflammation and other disorders (2). Focus on this phenomenon first
occurred with the discovery of elevated serum concentrations of CRP during the acute phase
of pneumococcal pneumonia (3). The initial concept of an ESR dates back to 1918. The
Westergren method is still considered the gold standard for measuring the ESR (4).
III. EVALUATION
A. History and Physical Examination.
Acute-phase reactant measurements are useful in
conjunction with a thorough history and physical examination. Since the ESR and CRP
levels are influenced by multiple factors, the results should be interpreted in the light of the
clinical findings.
B. Testing
1. The ESR, which measures the distance in millimeters that erythrocytes fall during
1 hour, is a simple but nonspecific lab test ordered frequently in clinical practice. The
CRP is a nonspecific (3) acute-phase reactant protein used to diagnose infectious and
inflammatory disorders; it also serves as a cardiovascular disease (CVD) marker (5).
The ESR has the advantages of familiarity, simplicity, and extensive literature compiled
Erythrocyte
Sedimentation Rate
and C-Reactive Protein
Elisabeth L. Backer
348
over many decades (3). The CRP test is standardized, inexpensive, and widely available.
High-sensitivity CRP does not differ from CRP, but refers to the assay used, which is
capable of measuring very low levels of CRP.
2. Although elevations in multiple components of the acute-phase response commonly
occur together, not all happen uniformly in all patients, and discrepancies between ESR
and CRP are found fairly frequently (2) (e.g., an elevated ESR together with a normal
CRP may reflect a false-positive value for the ESR; in lupus, the CRP response, but not
the ESR, may be muted). Currently, the optimal use of acute-phase reactants may be to
obtain several measurements and interpret the results in light of the clinical context (3,5).
IV. DIAGNOSIS
A. Differential Diagnosis
1. CRP levels can be affected by lifestyle choices, concurrent disease, pharmacotherapy, age,
gender (female), and possibly ethnicity (e.g., African Americans).
a. Factors known to increase CRP values include smoking, elevated body mass index,
elevated blood pressure, dyslipidemia, metabolic syndrome, type 2 diabetes, hormone use,
chronic infections (bronchitis), and chronic inflammations (rheumatoid arthritis) (5).
b. Factors known to decrease CRP values include moderate alcohol consumption,
physical exercise, weight loss, and medications (statins, fibrates, thiazolidinediones,
anti-inflammatory agents, salicylates, and steroids) (5).
2. ESR levels can be affected by menstruation and pregnancy, hematologic disorders, medi-
cations, gender, age, ethnicity, and obesity (1,3). Conditions with an ESR > 100 mm/h
include abscess formation, subacute bacterial endocarditis, osteomyelitis, temporal arte-
ritis, collagen vascular disease, multiple myeloma, leukemia/lymphoma, neoplasms, and
drug hypersensitivity reactions.
a. Factors known to increase ESR values include chronic renal failure (nephritis,
nephrosis), macroglobulinemia, hyperfibrinogenemia, iron/B12 deficiency anemias,
medications (dextran, heparin, methyldopa, oral contraceptives, penicillamine, pro-
cainamide, theophylline, vitamin A), female gender, advanced age, African American
ethnicity, and hyperlipidemia (1).
b. Factors known to decrease ESR levels include sickle cell anemia, spherocytosis, hypo-
fibrinogenemia, polycythemia vera, medications (aspirin, cortisone, quinine), and
chronic heart failure (1).
B. Clinical Manifestations
1. Despite the lack of diagnostic specificity, measuring acute-phase protein levels is useful in
differentiating between inflammatory and non-inflammatory conditions and in evaluat-
ing the response to and need for therapeutic interventions. In general, the ESR increases
as the disease worsens and decreases as it improves. Whereas the ESR changes relatively
slowly, the CRP concentration does so more rapidly. The CRP may be useful when the
ESR is equivocal or inconsistent with the clinical impressions (1). Results should be
expressed as the average of two tests performed 2 weeks apart. Patients with levels above
10 mg/L should be examined for sources of inflammation before repeating the test (5).
Acute-phase reactants should not be ordered for screening purposes in asymptomatic
patients (1).
a. Normal ESR rates for men between the ages of 20 and 65 years can be empirically
calculated as age/2; for women, it would be (age plus 10)/2 (1). Most normal subjects
have a CRP level of <3 mg/L. Levels of 3-10 mg/L may indicate minor degrees of
inflammation or other influences, such as metabolic dysfunction, obesity, and insulin
resistance. Levels >10 mg/L suggest significant inflammation (3) or infections, espe-
cially of bacterial origin.
b. CRP testing is also recommended as an adjunct to traditional risk factor assessment
in CVD. It has been found to be the strongest marker for future CVD, de novo ath-
erosclerosis, and plaque rupture. Additionally, it has independent prognostic value for
future strokes and peripheral vascular disease (5). The relative risk category based on
CRP levels is shown in Table 16.3.1.
349
2. Specific applications of acute-phase reactant measurements include monitoring of
disease processes such as Crohn’s disease, rheumatoid arthritis (CRP superior to ESR),
polymyalgia rheumatica and giant cell arteritis (ESR often above 100 mm/h, but CRP
may be more sensitive for disease detection), and the noninvasive prognostic assessment
in patients with malignancy (3). Systemic lupus erythematosus represents an exception
in that CRP levels are often not elevated, except during bacterial infections (3).
REFERENCES
1. Pagana KD, Pagana TJ. Mosby’s manual of diagnostic and laboratory tests. St. Louis, MO: Mosby, 1998.
2. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982;389:39–48.
3. www.UpToDate.com. Accessed April 27, 2012.
4. Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med 1985;78(6 Pt 1):
1001–1009.
5. Brunton S. The value of C-reactive protein in the clinical assessment of cardiovascular disease risk.
Female Patient 2005;30:11–16.
TABLE 16.3.1 Risk of Cardiovascular
Disease Based on C-Reactive
Protein (CRP) Level
Risk CRP level (mg/L)
Low
<1
Average 1.0–3.0
High
>3.0
16.4
I. BACKGROUND. Neutropenia is defined as an absolute neutrophil count (ANC) of <1,500
cells/μL. Severe neutropenia is defined as an ANC of <500 cells/μL. The risk of infection
increases with levels <1,000 cells/μL and is dependent on the cause and length of the neutro-
penia. As the ANC only represents 3% of the body’s neutrophils, neutropenia in the presence of
preserved marrow function poses a decreased risk of infection. Infection in severe neutropenia
is most commonly caused by normal flora (1–3).
II. PATHOPHYSIOLOGY
A. Etiology.
Neutropenia may be congenital or acquired. Three basic processes leading to
acquired neutropenia include (a) decreased production, (b) enhanced peripheral destruc-
tion, and (c) pooling of neutrophils in the vascular endothelium or tissue. Infection most
commonly causes acquired neutropenia (2).
B. Epidemiology. ANC may vary by race and ethnicity. Blacks and some Jewish populations
may normally have ANCs as low as 1,500/μL and have no clinical manifestations (1,3).
III. EVALUATION
A. History.
A history of frequent or recurrent infections should be elicited, as well as symp-
toms of fevers, chills, night sweats, easy bleeding or bruising, and unintended weight loss.
Neutropenia
Anna Maruska
350
Race, ethnicity, prior and current medications, alcohol abuse, toxin exposure, and family
history should be sought (1).
B. Physical Examination. The oral cavity should be explored, as gingivitis and stomatitis
may be the first presenting symptoms of neutropenia. Splenomegaly and lymphadenopathy
may be present. In children, evidence of failure to thrive may indicate a congenital disorder.
Examine sinuses, ears, and the perirectal area for active infection (1,2).
C. Testing. A manual differential and peripheral blood smear confirm the diagnosis of neu-
tropenia. If pancytopenia exists, a bone marrow biopsy is required. If the patient has mild
neutropenia and an absence of infection, ANC measurements up to three times per week
may be performed to monitor for resolution or to diagnose cyclic neutropenia (2). If counts
normalize, surveillance for the next year should include a complete blood count at the first
sign of infection to look for recurrence. If neutropenia fails to resolve after 8 weeks, recurrent
infections develop, or lower ANC (<1,000/μL) counts are noted, further workup is needed.
Additional laboratory tests may include bone marrow biopsy (even if not pancytopenic),
antinuclear antibodies, complement levels, rheumatoid factor, antineutrophil antibodies,
reticulocyte count, lactate dehydrogenase, erythrocyte sedimentation rate, thyroid-stimulat-
ing hormone, immunoglobulins, human immunodeficiency virus serology, vitamin B12 and
folate levels, and bone marrow culture (1,2).
D. Genetics. Hereditary neutropenia is rare. Two main forms include cyclic neutropenia and
severe congenital neutropenia (Kostmann’s syndrome). ELA2 and HAX1 gene mutations
have been linked to these disorders (4).
IV. DIAGNOSIS
A. Differential Diagnosis. See Table 16.4.1.
TABLE 16.4.1 Differential Diagnosis of Neutropenia
Acquired Neutropenia Congenital Neutropenia
Infectious
EBV, HBV, CMV, parvo virus, varicella, measles, HIV, any
infection causing sepsis, TB, tularemia, ehrlichiosis, rickettsia
Ethnic neutropenia
Medication induced
Clozapine, sulfasalazine, thioamides Severe congenital neutropenia
Chronic idiopathic neutropenia Cyclic neutropenia
Primary immune
Antineutrophilic antibodies, seen in children Shwachman-Diamond
syndrome
Secondary Immune
RA, SLE, hyperthyroid, Felty syndrome, Wegener’s
granulomatosis
Fanconi anemia
Malignant
MDS, leukemia Chédiak-Higashi syndrome
Nutritional deficiency
B12, folate, copper Barth’s syndrome
Hypersplenism (sequestration) X-linked neutropenia
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HIV, human immunode-
ficiency virus; MDS, myelodysplastic syndrome; RA, rheumatoid arthritis; SLE, systemic lupus
erythematosus; TB, tuberculosis.
Information pooled from references 1–4.
351
B. Clinical Manifestations. Signs and symptoms are generally based on the underlying
etiology of neutropenia; however, moderate to severe neutropenia may present with recur-
rent infection. The inflammatory response is blunted, decreasing radiographic signs, peri-
toneal signs, pyuria, or pyrexia. As a result, the patient’s infection may go undetected until
late in the course (3).
V. TREATMENT
A. Initial Treatment.
Fever and neutropenia warrant immediate treatment with empiric
antibiotics (2,5).
B. Risk Assessment. Determination of patient risk will determine inpatient versus outpatient
and oral versus parenteral treatment. Patients with brief durations of neutropenia (<7 days)
and no comorbidities are generally considered low risk. Patients with longer durations of
neutropenia, comorbidities, ANCs <100 cells/μL, or neutropenia due to chemotherapy are
considered high risk (5).
C. Prophylaxis. Prophylactic fluoroquinolone administration is indicated in high-risk
patients (2,5).
D. Long-Term Therapy. Treatment with granulocyte colony-stimulating factor (G-CSF) is
indicated in severe congenital neutropenias and chemotherapy-induced neutropenia. Stem
cell transplants may offer curative treatment for those who respond poorly to G-CSF (2,4).
REFERENCES
1. Reagan JL, Castillo JJ. Why is my patient neutropenic? Hematol Oncol Clin North Am 2012;26(2):
253–266.
2. Bonilla MA. Neutropenia. In: Bope and Kellerman: Conn’s current therapy 2012. St. Louis, MO: W.B.
Saunders, 2012:825–827.
3. Berliner N. Leukocytosis and leukopenia. In: Goldman: Goldman’s Cecil medicine. St. Louis, MO: W.B.
Saunders, 2011:1101–1106.
4. Boztug K, Welte K, Zeidler C, Klein C. Congenital neutropenia syndromes. Immunol Allergy Clin
North Am 2008;28:259–275.
5. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobials in
neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin
Infect Dis 2011;52:56–93.
16.5
I. BACKGROUND. Polycythemia is defined as an increased number of red blood cells (RBCs)
in the blood. This condition is diagnosed when a man has a hemoglobin over 18.5 and a
hematocrit over 52% or a woman has a hemoglobin over 16.5 and a hematocrit over 48%.
This elevation in hemoglobin or hematocrit may be relative or absolute. Absolute polycythemia
occurs when there is a true increase in the RBC mass due to either primary or secondary causes.
Relative polycythemia occurs when a contraction in plasma volume causes an apparent increase
in RBC mass (1).
II. PATHOPHYSIOLOGY
A. Etiology
1. Primary polycythemia is due to genetic mutations. Polycythemia vera (PV) is related to a
genetic mutation in the JAK2 gene on the short arm of chromosome 9. Primary familial
and congenital polycythemia is due to a mutation in the EPOR gene. In both diseases,
there is an increased sensitivity in the bone marrow to epopoietin (EPO), resulting in
Polycythemia
Carol A. LaCroix
352
increased RBC production. In PV, there may also be increased production of white
blood cells or platelets (2–4).
2. Secondary polycythemia occurs in response to increased levels of circulating erythro-
poietin. This may occur with chronic hypoxia which causes low blood oxygen levels),
abnormal RBCs (which results in poor delivery of oxygen), or EPO-secreting tumors.
EPO is produced in the kidneys in response to hypoxia. The increase in cell mass
results in hyperviscosity of the blood. This causes most of the symptoms experienced by
the patient such as headaches, dizziness, pruritus especially after a shower, and stroke (2–4).
III. EVALUATION
A. History.
Since the most common cause of polycythemia is related to hypoxia, a thorough
evaluation of the respiratory status should be done. Patients should be asked if they have a
history of asthma or chronic obstructive pulmonary disease (COPD), shortness of breath,
dyspnea on exertion, or cyanosis. A thorough smoking history should be obtained, includ-
ing how much tobacco is smoked daily and how many years the patient has smoked. If the
person is no longer smoking, document how many years ago he/she stopped. Occupational
history is important because many jobs predispose patients to environmental exposures,
especially carbon monoxide (2,3,5).
B. Physical Examination. The physical examination in patients with polycythemia may
be notable for cyanosis of lips, earlobes, and extremities. Clubbing may also be evident. A
thorough abdominal examination for hepatosplenomegaly and a heart examination evaluat-
ing for murmurs or bruits should be performed (2,3,5).
C. Testing. The most important laboratory tests are hemoglobin, hematocrit, and RBC
count. These values should be adjusted for the sex and age of the patient. One should also
obtain a white blood cell count and platelet count. A urinalysis should be obtained, looking
for hematuria. Liver function tests should also be obtained. If the patient has significant his-
tory of carbon monoxide exposure, a serum carboxyhemoglobin should be obtained. Once
elevation of the RBC mass has been confirmed, the next two tests should be carboxyhemo-
globin and erythropoietin (2,3,5).
D. Imaging Studies. If cardiopulmonary disease is suspected, a chest X-ray may be helpful
to assess the patient for COPD or congestive heart failure. Ultrasound or CT scan of the
abdomen can be utilized to evaluate for EPO-secreting tumor (4,5).
IV. DIAGNOSIS
A. Differential Diagnosis
1. Elevated carboxyhemoglobin. If the occupational exposure can be stopped, the carboxy-
hemoglobin level should return to normal within 3 months.
2. Decreased (or normal) erythropoietin level, increased RBC mass, and presence of the
JAK2 mutation V617F are diagnostic of PV. There is a 10–25% chance that the person
will progress from this myeloproliferative neoplasm into myelofibrosis over the next
25 years.
3. If the person has COPD, congestive heart failure, pulmonary hypertension, or obstruc-
tive sleep apnea, the serum EPO is appropriately elevated in an effort to compensate for
chronic hypoxemia. No further evaluation is needed although management is important.
4. EPO-secreting tumors include renal cell carcinoma, hepatocellular carcinoma, adrenal
tumors, and uterine cancer (2–5).
REFERENCES
1. Rakel RE, Rakel DP. Textbook of family medicine, 8th ed. Philadelphia, PA: WB Saunders, 2011:887–888.
2.
Adamson JW, Longo DL. Chapter 57. Anemia and polycythemia. In: Longo DL, Fauci AS, Kasper
DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s principles of internal medicine, 18th ed. New
York, NY: McGraw-Hill, 2012, http://www.accessmedicine.com/content.aspx?aID=9113377.
3. Tefferi A. Diagnostic approach to the patient with polycythemia. UpToDate. Topic 7075, Version 8.0.
Jan 18, 2012.
4. Tefferi A. Overview of the myeloproliferative neoplasms. UpToDate. Topic 4511, Version 27.0, June 6,
2012.
5. Nabili ST. Polycythemia. WebMD. Feb 26, 2010. http://www.emedicinehealth.com.
353
16.6
I. BACKGROUND. Normal adults excrete less than 150 mg of protein per day with up to 20 mg
of albumin. The rate of albumin excretion is 4–7 mg/d in an young adult. It increases with age
and body weight. It is also higher in non-Hispanic blacks and Mexican Americans. Persistent
excretion of albumin between 30 and 300 mg/d (20–200 μg/min) is called microalbuminuria,
while values above 300 mg/d are called macroalbuminuria (1,2).
II. PATHOPHYSIOLOGY. There are three types of proteinuria: glomerular, tubular, and overflow.
Glomerular proteinuria involves increased permeability to plasma proteins, especially albumin,
across the glomerulo-capillary membrane and may range from the minimal to the nephrotic
range. Tubular proteinuria occurs when tubulointerstitial disease interferes with reabsorption
of small molecular weight proteins in the proximal tubule. Overflow proteinuria results from
an overproduction of immunoglobulins, particularly in multiple myeloma.
Proteinuria may be transient or persistent. Transient proteinuria can occur with exercise,
cold exposure, fever, and congestive heart failure. Persistent proteinuria is diagnosed when a
value of >300 mg/dL has been documented in three urine specimens (1,3).
III. EVALUATION
A. History.
Annual screening for proteinuria in healthy people below age 60 years is not
cost-effective (3). However, urinalysis is warranted if the person has a history of diabetes,
hypertension, polycystic kidney disease, or autoimmune disease.
B. Physical Examination. Check vital signs, especially blood pressure. Perform a funduscop-
ic examination, checking for diabetic retinopathy or vascular changes from hypertension.
Edema of the legs or face may be due to hypoalbuminemia. Check the abdomen for renal
artery bruits and masses such as polycystic kidneys.
Rheumatoid arthritis may be accompanied by amyloid deposition in the kidneys (3,5).
C. Testing
1. The standard urine dipstick identifies only albumin, and it does not detect microalbu-
minuria. It can be falsely negative when the urine is dilute (specific gravity <1.015) and
when the proteins are of low molecular weight. The dipstick can be falsely positive for
24 hours after a contrast dye study or with alkaline urine, gross hematuria, pus, semen,
vaginal secretions, and the presence of penicillin and sulfonamides. Proteinuria is graded
as 30 (1+), 100 (2+), 300 (3+), and 1,000 mg/dL (4+).
2. The gold standard has been to evaluate persistent proteinuria with a 24-hour urine col-
lection. However, two spot urine tests have been found to be generally as valid and much
easier to obtain. The albumin-to-creatinine ratio is used to screen for microalbuminuria.
The threshold for concern is 20 mg/24 h in women and 30 mg/24 h in men, due to the
difference in muscle mass. The protein-to-creatinine ratio is useful in monitoring disease
progression. A ratio less than 0.2 is normal, whereas a ratio over 3.0 is in the nephrotic
range (3,4).
3. If abnormal proteins are suspected but not detected on the standard dipstick, the sulfo-
salicylic acid test should be done. If a patient has acute renal failure, a benign urinalysis,
and only trace protein on dipstick, the person is likely to have light chain immunoglobu-
lins due to multiple myeloma (3).
4. Any adult or child with proteinuria or hematuria without a clear diagnosis should have
a nephrology consult. This is especially true if the proteinuria is >2 g/d, because the
person most likely has some type of glomerular disease. Most of these patients will need
a renal biopsy. One exception is patients with postinfectious glomerulonephritis, which
is usually self-limited (4).
Proteinuria
Carol A. LaCroix
354
IV. DIAGNOSIS
A. Differential Diagnosis
1. Dehydration, fever, intense physical activity, emotional stress, and seizures can cause
benign proteinuria. Transient proteinuria does not require further evaluation or moni-
toring.
2. Orthostatic proteinuria accounts for up to 60% of asymptomatic proteinuria in indi-
viduals 6–30 years of age. This is seen when the first-morning spot urine is negative but
a specimen later in the day after the person has been upright is dipstick positive (at least
1+). This condition appears to be benign.
3. Secondary glomerulonephropathy occurs with diabetes mellitus, hypertension, lupus,
amyloidosis, preeclampsia, recent streptococcal infections, endocarditis, human immu-
nodeficiency virus, and hepatitis B and C. Patients should be closely monitored for
proteinuria and hyperlipidemia.
4. If hematuria is present, further evaluation is needed. The most common causes are uri-
nary tract infection, stones in the kidney or bladder, nephritis, and tumor. Red cell casts
are seen in glomerulonephritis.
5. Tubular nephropathy may be due to hypertension, sickle cell disease, or urate stones.
6. Gold, penicillamine, lithium, and heroin can cause glomerulonephropathy. Nonsteroidal
anti-inflammatory drugs and heavy metals can damage both the glomeruli and the tubules.
7. Multiple myeloma causes proteinuria with light-chain immunoglobulins, which can
be detected with the sulfasalicylic acid test. Monocytic or myelocytic leukemia causes
increased production and excretion of lysozyme, which can be detected on the standard
dipstick (3,5).
REFERENCES
1. Rose BD, Post TW. Measurement of urinary protein excretion. UpToDate. Topic 3102, Version 10.0,
Oct 21, 2011.
2. Molitch MR, DeFrazo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care 2004;27(suppl
1):S79–S83.
3. Rose BD, Fletcher SW. Evaluation of isolated proteinuria in adults. UpToDate. Topic 3101, Version
6.0, Apr 15, 2011.
4. Hassan A. Proteinuria. Postgrad Med 1997;101(4):173–180.
5. Carroll MF, Temte JL. Proteinuria in adults. Am Fam Physician 2000;62(2):1333–1342.
16.7
I. BACKGROUND
A. Definition.
Thrombocytopenia is defined as a pathologic decrease in platelet count. It is
identified typically as a laboratory finding of a platelet count below 150,000 cells/μL (1),
but it is generally not detected clinically until platelets fall below 100,000/μL. Bleeding
tendencies may occur, but spontaneous bleeding generally does not occur until the platelet
count is below 20,000 cells/μL unless other preexisting conditions occur that would encour-
age bleeding risk (1–5).
II. PATHOPHYSIOLOGY
A. Etiology.
Thrombocytopenia occurs through one or more of the following mechanisms:
decreased platelet production by the bone marrow, increased platelet destruction, splenic
entrapment, dilutional effect, and laboratory error (2,3).
Thrombocytopenia
Mandeep Bajwa
355
III. EVALUATION
A. History.
A meticulous history must be obtained, with particular focus on the following:
1. Recent infection
2. A thorough review of all medications currently being taken and the date prescribed
3. Menstrual and pregnancy history
4. The presence of the following: epistaxis and bleeding gums, reddish or purplish discol-
oration of the skin, excessive bruising, hematuria, and melena or hematochezia
5. Dietary intake, alcohol use
6. Past personal medical history
7. Family history
B. Physical Examination. A thorough physical examination is warranted with special
emphasis on the following:
1. Skin examination looking for petechiae, purpura, and ecchymoses
2. Abdominal examination to assess for splenomegaly and hepatomegaly
3. Neurologic examination to ascertain if hemorrhage has occurred, although rare
C. Testing
1. Complete blood count with differential and peripheral smear
2. Bone marrow biopsy is beneficial in patients with splenomegaly and in those who follow
an uncharacteristic course
D. Imaging studies are rarely indicated (1,3–5).
IV. DIAGNOSIS
A. Differential Diagnosis
1. Decreased platelet production by the bone marrow
a. Viral infections
b. Chemotherapy/radiation
c. Congenital bone marrow abnormalities
d. Alcohol toxicity
e. Vitamin B12/folate deficiency
2. Increased platelet destruction
a. Idiopathic thrombocytopenic purpura (ITP)
ITP is a relatively common autoimmune thrombocytopenic disease that occurs
in the acute and chronic setting with a prevalence of 1 in 10,000 persons. Acute ITP
is seen solely in children 2–9 years of age, with a peak incidence at 3–5 years of age.
It affects boys and girls equally. Acute ITP typically follows an acute viral syndrome
and has a self-limiting course. In contrast, chronic ITP affects adults 20–50 years of
age, has a female predominance of 3:1, and rarely results in spontaneous remission.
b. Drug induced
Drug-induced thrombocytopenia may be caused by a plethora of medications.
The most frequent culprit, especially in hospitalized patients, is heparin. Although
drug-induced thrombocytopenia is also an antibody-mediated syndrome, it is tran-
sient, typically resolving when the offending agent is discontinued.
c. Alloimmune destruction
d. Disseminated intravascular coagulation
e. Thrombocytopenic purpura/hemolytic uremic syndrome
f. Antiphospholipid syndrome
g. Hemolysis, Elevated Liver enzymes, Low Platelets (HELLP) syndrome
h. Viral infections
i. Mechanical platelet destruction
3. Splenic entrapment: may occur in cirrhosis, myelofibrosis, Gaucher’s disease.
4. Dilutional effect: large blood replacement with too few platelets.
5. Laboratory error: clotted specimen, wrong patient, or technical/equipment errors (1–6).
356
REFERENCES
1. Rakel RE, Rakel DP Textbook of family medicine, 8th ed. Philadelphia, PA: WB Saunders, 2011:
892–895.
2. George JN. Evaluation and management of thrombocytopenia by primary care physicians. UpToDate.
Topic 6864, Version 6.0, July 10, 2012.
3. Landaw SA, George JN. Approach to the adult patient with thrombocytopenia. UpToDate. Topic 6680,
Version 14.0, May 30, 2012.
4. Thiagarajan P. Platelet disorders. Last updated March 29, 2011. http://emedicine.medscape.com/
article/201722-overview#aw2aab6b3
5. Kaplan JL, Porter RS, eds. 2011. Merck manual Of diagnosis and therapy, 19th ed. Whitehouse Station,
NJ: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. ISBN-10: 0-911910-19-0,
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