HEMATOLOGY FAQ

There are many reasons for an increased hemoglobin/hematocrit in isolation including dehydration, hypoxia, smoking, carbon monoxide exposure and/or drug effects. Relative polycythemia is a result of dehydration including use of diuretics. Causes of hypoxia include chronic pulmonary conditions, obstructive sleep apnea and congenital heart disease. Excess carbon monoxide can be attained via chronic tobacco use and environmental exposures. Exogenous use of testosterone and anabolic steroids raise erythropoietin levels, which leads to elevated Hgb/Hct. Rarely, endogenous extra-renal erythropoietin production can result from intra-abdominal/pelvic or intra-cerebral masses.

We advise the patient to repeat the CBC with differential (non-fasting), and that if this abnormality persists you review the patient’s history and screening for the above causes as appropriate. This possibly may include: a chest x-ray, arterial blood gases, overnight oximetry, and/or an abdominal/pelvic ultrasound, if indicated. On a 6-12 month basis, it would be reasonable to re-order a CBC with differential.

If other CBC with differential abnormalities emerge such as persistent leukocytosis or thrombocytosis, a hemoglobin reaches 200g/L (males) / 180 g/L (females) or alternatively, the patient develops thrombo-embolic disease please refer the patient to hematology for review.

Causes of macrocytosis include alcohol intake, vitamin B12 and folate deficiency, chemotherapy and other drugs, hemolysis or bleeding, liver dysfunction and hypothyroidism. It is recommended that the patient undergo laboratory assessment for possible causes of macrocytosis as indicated based on clinical history.

While myelodysplastic syndrome can be associated with macrocytosis, this is highly unlikely in the absence of cytopenias (anemia, thrombocytopenia or neutropenia). No formal hematology consultation is necessary at this time.

The patient should be re-referred to hematology if the patient develops macrocytic anemia (hemoglobin less than 100 (g/L)), MCV >110 FL, or if additional cytopenias are present (e.g., platelets less than 70 (10E9/L)) and/or neutrophils less than 1.0 (10E9/L))

a)    During the work-up of microcytic anemia with normal iron stores, you may have performed a hemoglobinopathy screen (requisition: Hematology Specialty Requisition CH-0312 (albertahealthservices.ca) and identified an alpha thalassemia trait, or alpha thalassemia silent carrier.

Individuals who have alpha thalassemia trait (2 missing alpha globin genes --/aa or -a/-a) or are alpha thalassemia silent carriers (1 missing alpha globin gene -a/aa) will not have associated health problems and they will not develop symptomatic anemia related to these mutations.

Patients with alpha thalassemia trait do not require iron supplementation for their microcytic anemia unless iron deficiency is identified based on a low ferritin.

It is important for patients of reproductive age to have their partners screened prior to family planning. Patients with affected partners (i.e., With alpha thalassemia trait or alpha thalassemia carriers) need genetic counselling regarding the risk of having an affected child with Hemoglobin H disease (moderate/severe anemia) or hydrops fetalis (severe anemia in utero). You may wish to refer your patients with affected partners to the Prenatal Genetics Clinic (Ph: 403-943-8375, Fax: 403-943-8376) for preconception counselling.

Please refer to the attached resource for further information. In addition, you may wish to share these hand-outs with your alpha thalassemia trait patients (attached):

https://www.stjude.org/content/dam/en_US/shared/www/patient-support/hematology-literature/alpha-thalassemia-trait.pdf.

a)    During the work-up of microcytic anemia with normal iron stores, you may have performed a hemoglobinopathy screen (requisition: Hematology Specialty Requisition CH-0312 (albertahealthservices.ca) and identified a beta thalassemia trait. People who have beta thalassemia trait (1 missing beta globin) will not have associated health problems. They will have a mild microcytic anemia and will not develop symptomatic anemia related to the single beta globin gene mutation. Patients with beta thalassemia trait do not require iron supplementation for their microcytic anemia unless iron deficiency is identified based on a low ferritin.

It is important for patients of reproductive age to have their partners screened prior to family planning. If the patient’s partner is also affected, genetic counselling is needed regarding the risk of having an effected child with beta thalassemia major. You may wish to refer your patients with affected partners to the Prenatal Genetics Clinic (Ph: 403-943-8375, Fax: 403-943-8376) for preconception counselling.

Please refer to the attached resource for further information. In addition, you may wish to share this hand-out with your beta thalassemia trait patients (attached):

https://www.stjude.org/content/dam/en_US/shared/www/patient-support/hematology-literature/fact-sheet-beta-thalassemia-trait.pdf

a)    Based on family history, ethnicity, and/or the need for genetic counseling, you may have performed a hemoglobinopathy screen (requisition: Hematology Specialty Requisition CH-0312 (albertahealthservices.ca) and identified i) a sickle cell trait (heterozygosity for the Hg S gene), ii) a Hg C trait (heterozygosity for the Hg C gene), or iii) a Hg E trait (heterozygosity for the Hg E gene). Heterozygosity (having one mutation) for any of these 3 mutations is not associated with disease. Please do note that compound heterozygosity (when Hg S, C or E is combined with a second beta globin mutation such at beta thalassemia or Hg S, C or E) is associated with disease. If you require help with interpretation of the hemoglobinopathy screen, please consider using specialist link or sending in a referral requesting a phone consultation.

i)                 Most people who have sickle cell trait (SCT) will not have associated health problems and they will not develop sickle cell disease. In rare cases, carriers may experience some health issues such as hematuria, proteinuria or chronic renal disease.

People who carry SCT may also experience exertional health illness associated with extreme strenuous activities or during periods of significant dehydration and therefore those situations should be avoided. Most importantly, patients with sickle cell trait need genetic counselling regarding the risk of having an effected child.

With the recent introduction of newborn screening for sickle cell disease, Toward Optimized Practice (TOP) has created resources for primary care to aid in the education and counselling of patients with SCT. It has been attached here and the url is: SCT-Practice-Guide.pdf (albertadoctors.org)  

In addition, you may wish to share these hand-outs with your SCT patients (attached):

SCT-FAQs.pdf (albertadoctors.org)

https://www.cdc.gov/ncbddd/sicklecell/documents/factsheet_sickle_cell_trait.pdf

ii and iii) People who have Hb C or E trait (mutation in one beta globin gene) will not have associated health problems. They will have a mild microcytosis and will not develop symptomatic anemia related to the single beta globin gene mutation. These individuals do not require iron supplementation for their microcytosis unless iron deficiency is identified based on a low ferritin.

It is important for patients of reproductive age to have their partners screened prior to family planning. If the patient’s partner is also affected, genetic counselling is needed regarding the risk of having an effected child with beta thalassemia major or sickle cell disease. You may wish to refer your patients with affected partners to the Prenatal Genetics Clinic (Ph: 403-943-8375, Fax: 403-943-8376) for preconception counselling.

Most people with mild isolated thrombocytopenia (platelet count 100-150 (10E9/L) will be asymptomatic and are not at increased risk of bleeding even with major surgery.

Often, the cause of mild thrombocytopenia is unknown and may be related to low grade immune-mediated clearance or acute infection (especially viral). An underlying bone marrow problem is highly unlikely in the absence of additional cytopenias (i.e., persistent anemia or neutropenia).

It is recommended that other potentially reversible or treatable causes of thrombocytopenia be ruled out including clinical and/or laboratory assessment for autoimmune disease, occult infection, alcohol consumption, liver disease, viral hepatitis, HIV, and vitamin B12/folate deficiencies. Otherwise, no further hematologic investigations or consultation is necessary.

The patient should be referred to hematology if the platelet count persistently falls below 100 (10E9/L), or if additional cytopenias are present in addition to thrombocytopenia (e.g., hemoglobin less than 100 (g/L) and/or neutrophils less than 1.0 (10E9/L))

Low leucopenia (low WBC value) is not clinically significant if the neutrophils are within normal range.

Mild neutropenia is defined as neutrophilis as low as 1.0x10^9. Without other cytopenias (anemia and thrombocytopenia), a serious bone marrow disease is unlikely to be the cause.  Likewise, a neutrophil count greater than 1.0 x 10 9 affords normal immunity and is not associated with an increased risk of infection. 

There are many causes of a low neutrophil count in adults that include but are not limited to:

1. Medications: please review the patient’s current medications and their documented association with neutropenia (consider switching to an alternate therapy if appropriate)

2. Autoimmune and connective tissue diseases: rheumatoid arthritis and SLE

3. B12 and folate deficiency

4. Infections: both viruses and bacteria can cause transient leukopenia

5. Autoimmune neutropenia: no therapy is required unless the patient has serious, recurrent infections or develops severe neutropenia

6. Benign Ethnic neutropenia: seen frequently in patients of African ancestry where a neutrophil count as low as 1.0 x 10 9 is considered normal (may be seen also in other ethnic groups, such as those of Middle Eastern and West Indian descent)

7. Chronic benign neutropenia: long standing neutropenia without an obvious cause and without serious recurrent infections

We would advise reviewing the patient’s history and screening for causes as appropriate. On a yearly basis, it would be reasonable to order a CBC. If other cytopenias emerge, or if the patient experiences serious recurrent infections, please refer the patient to hematology for review.

Mild lymphocytosis can either be because of a clonal process or a reactive/infectious process.

Clonal lymphocytosis at a low level does not meet criteria for a diagnosis of lymphoma and is considered a pre-malignant condition known as monoclonal B cell lymphocytosis. The chances of becoming malignant and requiring treatment is less than 1% per year. Management for this condition is expectant, and therefore we do not advise ordering flow cytometry for a lymphocytosis of less than 5 x10^9. CBCs can be reviewed every 6 months (for newer or rapidly changing lymphocytosis) or annually (for lymphocytosis that has not significantly changed over a few years).

If the lymphocyte count is consistently above than 5 x10^9 (over 6 months, more than 3 times), proceed with ordering flow cytometry (FLOW CYTOMETRY requisition, Flow Cytometry Requisition FC3200 (albertahealthservices.ca)) – On the requisition, please indicate: Peripheral Blood, HEMEFLOW). Flow cytometry is a very sensitive test for identifying clonal lymphocytes. Lymphoma/leukemia will often demonstrate clonal lymphocytes, and a negative flow cytometry is in keeping with a reactive cause or infectious cause of mild lymphocytosis, NOT a lymphoproliferative disorder. If flow cytometry identifies a monoclonal population of lymphocytes, please refer to hematology for further guidance.

Infectious causes include but are not limited to: mononucleosis (EBV), whooping cough, HIV, influenza, and other viral upper respiratory pathogens. Parasites and other bacterial infections can also lead to lymphocytosis. We would advise reviewing the patient’s history and screening for infections as appropriate.

Reactive causes include smoking, autoimmune disease, medical stress (for example, recent trauma, cardiac emergency, or seizure), and asplenic state. Certain medications, including anti-depressants, can also rarely cause lymphocytosis. Non-hematologic malignancy can be associated with a reactive lymphocytosis as well. We would advise reviewing the patient’s history and physical examination for such an etiology.

Chronic, non-progressive and non-clonal lymphocytosis (<10 x 10^9) can be a normal variant and requires no additional investigations. Routine CBCs to follow this condition are not required. Please follow as otherwise indicated based on clinical status and co-morbidities.

Acquired lymphopenia in an adult or child is usually related to a decrease in circulating T-cells secondary to infection (usually viral), inflammation, advanced age, or medications (e.g., steroids). B-cell lymphopenia may be related to autoimmune diseases (e.g., rheumatoid arthritis, SLE, IBD, sarcoidosis) particularly if receiving biologic treatments (i.e., B-cell depleting agents, rituximab or other anti-CD20 antibodies). Lymphopenia may also be idiopathic in nature. Lymphopenia is not considered clinically significant unless the patient experiences serious recurrent infections.

We would advise reviewing the patient’s history and screening for causes as appropriate. We advise that you screen for HIV if clinically indicated based on relevant risk factors. On a yearly basis, it would be reasonable to order a CBC. If other cytopenias emerge, of if the patient experiences serious recurrent infections, please refer the patient back to hematology for review.

A high ferritin should be re-assessed with repeated testing and the addition of fasting iron studies (serum iron, TIBC, and iron saturation). (N.B. When serum iron and TIBC is ordered, the iron saturation is calculated. Iron saturation and transferrin saturation are the same thing). Common causes for elevated ferritin include it being an acute phase reactant, infection, inflammation, malignancy, or fatty liver. A C-reactive protein may also be ordered to assess for these concerns. Fatty liver is a common cause of elevated ferritin. In this case, a shear wave elastography (SWE) of the liver may be helpful: NAFLDPathway_CalgaryZone (specialistlink.ca). An isolated high ferritin (with a normal iron saturation) does not need referral to hematology or genetic testing for hereditary hemochromatosis (HFE). We would advise reviewing the patient’s history and physical examination for inflammatory/infectious causes and referral to hepatology or internal medicine as appropriate.

A patient with consistently elevated ferritin and iron saturation (>45%), regardless of sex, should have genetic HFE testing performed (after appropriate counseling and consent, Molecular Genetics Laboratory General Requisition (albertahealthservices.ca) and would be appropriate for non-urgent referral to hematology.

The normal range for sFLC are 3.3-19.4 mg/L for kappa, and 5.7-26.3 mg/L for lambda. sFLC can be elevated as a result of infection, inflammation, or due to decreased clearance in the setting of reduced renal function. In these cases, the light chains produced are polyclonal and both kappa and lambda will be elevated in similar proportions such that the ratio between the two usually does not change. The normal k:l ratio is from 0.26 to 1.65.  In myeloma and related disorders, light chain production will be monoclonal. Either kappa or lambda is produced in excess, and the ratio can be abnormal. It is also important to note that a normal FLC values or ratio does not exclude myeloma if other clinical or chemical findings support the diagnosis.

A serum protein electrophoresis is an analysis of serum protein by agarose gel electrophoresis that allows the proteins in serum to be separated by charge and/or size and quantified using densitometry. It is used clinically to identify monoclonal immunoglobulins that can be seen in myeloma and related disorders. Immunoglobulins are found in the gamma and when a peak is seen – meaning the proteins are the same size/charge, it suggests that that protein is a mono-clonal protein, also known as an M-protein. The M-protein can be further identified (e.g., IgG or IgM/kappa vs lambda) by immunofixation and will be reported or summarized in the comments. Increases in the other proteins that are found in the blood, such as in the alpha or beta regions, or non-specific increases in the gamma region (i.e. Not a peak or not clonal) can be non-specific finding and associated with infection, inflammation, malignancy, drugs or dyslipidemia.

In a patient with a normal free light chain ratio, normal SPEP and 24h UPEP and no clinical or chemical features to suggest myeloma, lymphoma, or related disorders, a serious bone marrow disease is unlikely to be the cause. It is prudent to consider repeating the sFLC studies in 3 months time to ensure stability if there are no other clinical explanation for the abnormal values.