Interpreting an Abnormal Complete Blood Cell Count in Adults
Variables to focus on when examining the CBC:
Hgb (as general indicator of anemia or polycythemia)
MCV (useful in classifying anemias) (Normal 86-98) (MCH 28-35)
RBC distribution width (helpful in differential diagnosis of anemia)
Calculated from the MCV and the RBC count
Quantitative measure of anisocytosis (RBCs unequal in size)
May become abnormal before the anemia occurs
RBC count (an increased RBC count associated with anemia is characteristic in thalassemia trait)
Platelet count (to detect either thrombocytopenia or thrombocythemia)
WBC count with differential (usually gives important clues for diagnosis of acute leukemia and chronic lymphoid or myeloid diseases as well as for the presence of leucopenia and neutropenia)
NOTE: In patients with an abnormal WBC count, immediately ask which WBC type is affected: neutrophils, lymphocytes, monocytes, eosinophils, or basophils
What is “abnormal?”
Interpret an “abnormal” CBC within the context of an individual’s baseline value
Up to 5% of the general population without disease may display laboratory values outside the statistically assigned “normal” reference range
Always review old medical records before initiating a costly work-up of an “abnormal” CBC.
An individual may display a substantial change from his or her baseline (personal normal) and still fall within the “normal” reference range
Consider differences in the CBC based on race and sex
RBC-associated measurements are lower and platelet counts are higher in women than men
Persons of African ancestry display significantly lower Hgb, WBC, neutrophil, and platelet counts than white persons
History & Physical
Patient history: age, sex, race, diet, infection, inheritance, diarrhea (suspect small bowel disease with malabsorption of folate or B12, suspect blood loss)
Family history: anemia, jaundice, splenomegaly, bleeding tendencies, drug/toxin exposures, bone marrow failure, chronic disease
Patient’s nutritional history:
Dietary intake of iron sources, vitamins, milk, meat, vegetables
24 hour dietary recall
History of pica (an eating disorder typically defined as the persistent eating of nonnutritive substances for a period of at least 1 month at an age in which this behavior is developmentally inappropriate (e.g., > 18-24 mo). The substances include such things as clay, dirt, sand, stones, pebbles, hair, lead, plastic, ice, paper, paint chips, coal, chalk, wood, and plaster.)
Review of systems: jaundice, extremity pain, abdominal pain, blood loss, weight loss, recent infections, drug exposures, travel, behavioral changes, pallor, petechiae, ecchymoses, adenopathy, GI/GU disorders, changes in stool indicating GI bleeding
both iron and vitamin B12/folate deficiencies are possible causes of normocytic anemia (“average out”)
anemia of renal insufficiency (normal RDW)
can check serum creatinine
anemia of chronic disease/inflammation
concomitant low MCV and high MCV conditions
hemolysis (normal or elevated RDW, thrombocytosis)
always consider possibility of drug-induced hemolysis
Macrocytic Anemia (=Large cells)
First consideration: use of certain drugs (hydroxyurea, zidovudine), alcohol abuse
Rule out nutritional causes (B12 or folate deficiency)
Check homocysteine and B12 levels
If both are normal: B12 or folate deficiency unlikely
If MCV 100-110
Consider myelodysplastic syndrome as well as liver disease, alcohol consumption, hypothyroidism, and marked reticulocytosis from hemolysis
If MCV > 110
Consider myelodysplastic syndrome or other primary bone marrow disorder
Marked macrocytosis that is not secondary to either nutritional deficiency or drug effect almost always is associated with a primary bone marrow disease (e.g. myelodysplastic syndrome, aplastic anemia, pure red cell aplasia, or large granular lymphocyte disease). If a specific hematologic diagnosis will affect management decisions, obtain bone marrow biopsy.
(CBC = complete blood count; RBC = red blood cell; MCV = mean corpuscular volume; TIBC = total iron-binding capacity; MMA = methylmalonic acid)
Algorithm for evaluation of anemia in the elderly
(Reference: Smith, D.L. (Oct 1, 2000). Anemia in the elderly.Am Fam Physician, 62(7), 1565-1572.)
Iron Deficiency Anemia
Prominent in age groups experiencing rates of rapid growth: toddlers, adolescents, and pregnant and lactating women
Blood donation > 2 units/year in women and 3 units/year in men
Low socioeconomic status and postpartum status
Mexican ethnicity living in the US
Child and adolescent obesity
Decreased absorption due to gastric surgery or heavy antacid use
Fatigue caused by anemia in only 1 out of 52 patients in primary care
Pallor, spoon nails, glossitis, pale tachycardia, mild systolic ejection murmur
Testing: in addition to labs, remember colonoscopy!
Consider transfusion for patients of any age c/o symptoms such as fatigue or DOE, and for asymptomatic cardiac patients with hemoglobin < 10.
One month trial of oral iron: ferrous sulfate 325 mg tid until Hgb returns to normal, the 3-6 months of bid dosing to replenish ferritin stores.
Initiating with once-a-day dosing and gradually titrating upward may help minimize GI intolerance
Adding vitamin C potentiates iron absorption
Liquid iron stains teeth unless brushed right away; use straw
An increase in the Hgb level of 1 g should occur every 2-3 weeks on iron therapy; however, it may take up to 4 months for the iron stores to return to normal after the hemoglobin has corrected.
Reassess Hgb after 3-4 weeks to document improvement
Therapy should continue with bid dosing
Abnormal Hgb produced excessive RBC destruction; small cells (↓ MCV)
Pernicious anemia = a chronic, progressive, macrocytic anemia caused by a deficiency in intrinsic factor (substance necessary for B12 absorption in the GI tract; autoimmune disease most common in women age 35-60 of Northern or Eastern European ancestry
Cardiovascular: possible increased risk of MI and stroke
Treatment: Vitamin B12 replacement therapy (Note: Although the majority of dietary vitamin B12 is absorbed in the terminal ileum through a complex with intrinsic factor, evidence for an alternate transport system is mounting.)
Oral: Initial dose: 1,000-2,000 mcg/day for 1-2 weeks; Maintenance dose: 1,000 mcg/day for life
IM: Initial dose: 100-1,000 mcg every day or every other day for 1-2 weeks; Maintenance dose: 100-1,000 mcg every 1-3 months
Sublingual: 2,000 mcg/d
Intranasal: 500 mcg weekly
May need to supplement folate and iron stores as well (concomitant deficiencies)
First few days of treatment: The older adult is at risk for heart failure and hypokalemia. Why?
At high risk
Persons with poor dietary intake
Persons with rapid growth such as adolescents and pregnant women
More common in alcoholic and chronically malnourished persons
Low levels of folate can disrupt transmethylation reaction, leading to an accumulation of homocysteine
Medications which can interfere with folate utilization: anticonvulsants, metformin, methotrexate, sulfasalazine, triamterene, oral contraceptives
Clinical manifestations: glossitis, angular cheilitis, anorexia, diarrhea, pale or icteric skin, fine brittle hair, pica
Treatment: Replace with folic acid 1 mg/d p.o.
Recheck folate levels in 2 months to determine if correct amount of folate is being used
Encourage dietary intake
Spinach, liver, yeast, asparagus, and Brussels sprouts are among the foods with the highest levels of folate.
Other sources: vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, dairy products, poultry and meat, eggs, seafood, and grains
B12 should always be assessed in presence of folate deficiency
Folate replacement will mask hematologic findings but not prevent neurological sequelae caused by coexistent B12 deficiency
Anemia in the Elderly
Read: “Anemia in Older Persons” at http://www.aafp.org/afp/2010/0901/p480.pdf
Associated with poor clinical outcomes and increased mortality
Negative outcomes include: falls, fatigue, frailty, functional decline, decreased cognition, impaired mobility, MI, restricted mobility, increased hospitalizations, and impaired quality of life.
Hypoxia from anemia increases peripheral arterial vasodilation, myocardial dysfunction, and activation of the sympathetic and rennin-angiotensin system to maintain BP; these changes could result in the onset or progression of heart and renal failure.
Patients with heart failure whose hemoglobin measurements are in the lowest quartile have more symptoms, poorer hemodynamics, and greater mortality than those with higher hemoglobin levels.
Prevalence of > 10% (higher prevalence in long-term care 30-50%)
Causes of anemia in the elderly
Nutritional anemia (1/3 of anemia cases)
Iron deficiency, including chronic blood loss
Folate deficiency (related to excessive alcohol use and malnutrition)
Vitamin B12 deficiency (primarily related to atrophic gastritis)
Anemia of renal insufficiency or chronic inflammation
Primary disorder of hematopoiesis
Median age of onset = seventh decade of life
Fatigue, headache, dyspnea, dizziness, syncope, depression, decreased thought processes, tachycardia, palpitations, cold intolerance, edema, systolic ejection murmur, orthostasis, anorexia, impotence, pale skin, mucous membranes and conjunctiva
Disorders of RBC production (NOTE: if all 3 [RBC, WBC, Platelets] are low, think leukemia)
Anemia secondary to malignancies and/or chronic disease
Disorders of RBC maturation
Lead poisoning (especially in homes built before 1960s, occupations with lead)
Disorders of RBC destruction
Sickle cell anemia
Pyruvate kinase deficiency
Myelodysplastic syndromes (MDSs)
Definition: a group of bone marrow disorders that lead to underproduction of normal blood cells. Multilineage cytopenia (low RBC, WBC, and platelets) is not simply a normal consequence of aging; it warrants referral to a hematologist-oncologist.
Diagnosis of MDS implies a risk of developing acute myelogenous leukemia (AML) that is much greater than the expected rate for a healthy, age-matched control population.
20-30% of patients with MDS develop AML
AML arising in the setting of MDS is almost always lethal
MDS subtypes often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML
Lower-risk MDS survive a median of 3-7 years
Higher-risk types either develop AML or die of complications of MDS, on average within 1.5 years.
Other fatal complications of MDS-associated cytopenias
Infections due to neutropenia are leading cause of death due to MDS, killing 40-65% of affected patients
Life-threatening bleeding due to thrombocytopenia
Incidence rate increased from 3.28 per 100,00 per year in 2001 to 3.56 per 100,000 per year in 2004
Translate to 10,000-15,000 new cases per year
Increase attributed to enhanced awareness of the disease and to the aging of the population
Most MDS patients are older (median age at diagnosis is 71, with 72% of patients age 70 or older; prevalence increases with age
In East Asia, occurs almost 2 decades younger than in the rest of the world.
More common in men than women; in whites than blacks
Cause of primary MDS is not known
Smoking increases the risk of MDS.
Genetic and environmental factors probably both play a role
Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS
Assess for responsiveness of bone marrow to anemia via a reticulocyte count and/or an erythropoietin level (done before any blood transfusion)
Screen for relevant infections, including IV, hepatitis, or in rare cases, parvovirus
Screen for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake
Multilineage cytopenia (low RBC, WBC, and platelets) is not simply a normal consequence of aging; it warrants referral to a hematologist-oncologist, especially if above tests are negative.
Transfusions: almost all MDS patients need RBCs; fewer need platelets
Iron chelation: can get iron overload from multiple transfusions; this intervention should be reserved for patients with lower-risk disease who are expected to survive > 1 year and who have received > 25 units of packed RBCs.
Antibiotics for those with neutropenia and fever > 100.4o F: need to be hospitalized and given broad-spectrum antibiotics
For lower-risk disease: These patients can continue follow-up with their primary care provider once treatment goals and plans are established.
Treatment: erythropoiesis-stimulating agents (ESAs) such as Procrit and Arnaesp. About 40% of patients ultimately respond to an ESA, but those who respond eventually develop resistance to the agent.
The recommended threshold hemoglobin level for starting an ESA is< 10 g/dL.
The agent should be stopped once the hemoglobin level reaches 12 g/dL
If ESA treatment is ineffective, immunosuppressive therapy may be used.
For higher-risk disease: should be followed by a hematologist or medical oncologist; can try chemotherapy
Hematopoietic stem cell transplantation is the only curative treatment for MDS. However it is performed in fewer than 5% of patients, usually younger patients with few comorbidities, because the rate of transplant-related death is high.
Definition: too much iron in the body (iron overload); over time this extra iron may accumulate in various organs, including the liver, pancreas, and heart, causing tissue damage and dysfunction.
Primary: genetic disorder; absorb too much iron through the GI tract (normal= 10%, with this type of hemochromatosis = 30% absorption)
NOTE: the manifestations and complications of this form are fully preventable if the disease is recognized early enough and adequately treated. But, by the time a patient presents with symptoms or is referred for care, the disease phenotype may be well-established.
Secondary: acquired; due to:
other blood-related disorders such as thalassemia or certain anemias
Transferrin saturation measures the amount of iron bound to protein (transferring) that carries iron in the blood (> 45% is too high)
Phlebotomy: ½ L/week until iron is within normal limits
If untreated: liver damage (cirrhosis, liver failure, cancer). Can also build up in thyroid, testicles, pancreas, pituitary, heart, joints.
Multiple Myeloma (MM)
Definition: a progressive hematologic disease characterized by an excessive number of abnormal plasma cells in the bone marrow and by the overproduction of monoclonal immunoglobulins or Bence-Jones protein
Incidence: accounts for 1% of all cancers and causes 2% of all cancer deaths, median age of onset is 70 year; somewhat more prevalent in men; more than twice as many cases in African Americans as white Americans.
Precise cause is unknown.
Clinical manifestations result from the infiltration of plasma cells into the bone marrow and the secretion of MM protein into the blood and urine
New-onset bone pain secondary to severe osteopenia or multiple spinal compression fractures, fatigue, recurrent infections, anemia, hypercalcemia, or renal insufficiency.
70% present with persistent, unexplained bone pain in the lower back, chest, arms, or legs (describe the back pain as aggravated by movement or by lying in a supine position or as a band-like distribution around the body
60% has normocytic, normochromic anemia
Criteria for diagnosis:
Presence of at least 10% abnormal plasma cells in the bone marrow
Monoclonal protein present in the serum or urine
MM-related organ dysfunction (anemia, hypercalcemia, bone lesions or renal insufficiency)
What should the NP do
Complete H & P
CBC, CMP, serum protein electrophoresis and immunofixation, 24-hour urine collection for protein, electrophoresis, and immunofixation
Plain skeletal radiography of the spine, pelvis, skull, humeri, and femurs
Refer to hematologist for bone marrow biopsy, etc.
Prognosis: survival can vary from months to years
Autologous stem cell transplant
Healthy women may experience mild to moderate thrombocytopenia (75,000-150,000) during pregnancy
Step 1: make sure not caused by EDTA-induced platelet clumping
Do not miss HIT (heparin-induced thrombocytopenia)
Requires immediate cessation of heparin, including heparin flushes
For other rare causes (such as post-transfusion purpura), obtain hematology consultation.
Neutropenia: increased risk of infection
Most frequent cause: drug therapy (anticonvulsants, thyroid inhibitors, antibiotics, antipsychotics, antidysrhythmics, antirheumatics, NSAIDS)
Lymphopenia: due to immunosuppressive drugs, including corticosteroids; viral infections including AIDS
Bleeding and Bruising
Read: Ballas, M., & Kaut, E.H. (April 15, 2008) Bleeding and bruising: A diagnostic work-up. American Family Physician, 77(8), 1117-1124 at http://www.aafp.org/afp/2008/0415/p1117.pdf
Factors that accelerate clot formation: Factor V and VIII accelerate conversion of X --> Xa
Factors that inhibit clot formation: Protein C, Protein S, and Thrombomodulin. These form a complete that inactivates VIII and V This complex is activated by thrombin (IIa).
Antithrombin blocks XI, IX, X, and II (Prothombin).
• increased by estrogen, birth control pills, and smoking
• Alternatives for female smokers:Norplant,Depo-Provera, progestin
Left side (extrinsic pathway) is initiated by damage outside the blood vessel (in the tissue)
* factor VII is: - dependent on Vitamin K
- inhibited by warfarin (Coumadin)
- measured by PT/INR
Major increase in intake of Vitamin K-containing foods (green, leafy vegetables) can effect PT/INR (What would be the expected effect?)
INR (International Normalized Ratio)
• standardizes tests among hospitals, labs, and offices
• normal is 2-3 when on Coumadin
• Exceptions: normal needs to be higher for those with artificial heart valves (2.5-3.5)
Coumadin is very sensitive to drugs (Epocrates lists >300 interactions with prescription, herbal, and over-the-counter medications!):
These are due to interactions through the cytochrome P450 system (enzyme induction and enzyme inhibition) and reduced plasma protein binding.
Right side of cascade (intrinsic pathway) is initiated by damage within the blood vessel
Factor XII named after Dr. John Hageman
Factor IX (Christmas factor) named after patient (deficiency causes Christmas disease, or Hemophilia type B)
Factor VIII (AHF, or antihemophilia factor) (deficiency causes Hemophilia type A)
made in endothelial cells living the blood vessels
It takes 200-2,000 donors to make 1 vial of cryoprecipitate. Prior to heat treatment of cryoprecipitate, there was HIGH risk of HIV.
Heparin blocks the intrinsic cascade
- monitor with PTT/aPTT
When an individual develops a thrombosis, a hypercoagulation panel may be checked. The individual tests included in the panel vary, but at minimum include Factor V Leiden, Prothrombin, Protein C and S, Antithrombin, and homocysteine.
Hereditary Risk Factor
Prevalence in Caucasian Population
Prevalence in Patients with DVT
Factor V Leiden
According to the “second hit” theory for initiation of thrombosis, the presence of more than one risk factor is needed to manifest thrombosis in most patients. For example, 1 hereditary risk factor plus 1 acquired risk factor results in thrombosis. A patient with the factor V Leiden mutation (1st hit) who uses oral contraceptives (2nd hit) greatly increases their risk of thrombosis by combining the 2 risk factors.
(Source of above table: http://www.clinlabnavigator.com/hypercoagulable-panel.html)
Hyperhomocysteinemia combined with Factor V Leiden, heterozygous
*The terms heterozygous (hetero-different) and homozygous (homo-same) are terms used in genetics. The human genome contains to copies of the information. If the copies are the same, they are homozygous; if the copies are different, they are heterozygous. For example, take a protein called A. The normal genome would code for the protein as AA. This is homozygous for the normal protein. If there is a variation of the protein called a, there are two possible ways to get the a. The genome could be Aa, which is called heterozygous or the genome could be aa, which is called homozygous.
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Bauman, W.A., Shaw, S., Jayatilleke, E., Spungen, A.M., & Herbert, V. (September 2000). Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23:1227-1231.
Dharmarajan, TS,Adiga, GU, & Norkus, EP (March 2003). Vitamin B12 deficiency: Recognizing subtle symptoms in older adults. Geriatrics, 58(3), 30-38.
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Smith, D.L. (Oct 1, 2000). Anemia in the elderly.Am Fam Physician, 62(7), 1565-1572.
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