Clinical Guidance for Common Hematology Questions

Condition:  Microcytic anemia

Definition:

• Hb <130g/L in males and <120g/L in females, with mean corpuscular volume (MCV) < 80 fL

Common causes:

• Iron deficiency (serum ferritin ≤ 30 µg/L)
• Anemia of inflammation (serum ferritin ≥ 100 µg/L with transferrin saturation < 20%)
• Hemoglobinopathy

First line investigations and management:

• CBC, reticulocyte count, ferritin, transferrin saturation
• Hemoglobin electrophoresis (check after confirming serum ferritin ≥ 30 µg/L)

When to consult a hematologist:

• Serum ferritin < 30 µg/L (or serum ferritin ≤ 100 µg/L combined with transferrin saturation < 20%) despite 3 months of oral iron supplementation
  In the absence of clear cause (ie., chronic blood loss, menorrhagia, or low-iron diet), most patients with iron deficiency should also be referred to a gastroenterologist
• Confirmed hemoglobinopathy
  Patients with beta-thalassemia trait (ie., Hgb ≥ 100 g/L with Hgb A2 ≥ 3.5%) do not require hematology follow-up but should have their partners screened for the same condition if considering having children
• Otherwise unexplained microcytic anemia
  Patients with anemia of chronic inflammation of unknown etiology do not require hematology consultation but should have additional laboratory and imaging studies ordered on the basis of individual history and physical exam findings

When to seek out urgent medical attention:

• Anemia associated with severe fatigue, chest discomfort, or impaired cognition
• New onset hemoglobin < 80 g/L

Additional resources:

• Zeller MP, Verhovsek M. Five things to know about treating iron deficiency anemia. CMAJ 2017;189:E409
• Lopez A, Cacoub P, Macdougall IC, et al. Iron deficiency anaemia. Lancet 2016;387:907-16

Condition:  Macrocytic anemia

Definition:

• Hb <130g/L in males and <120g/L in females, with mean corpuscular volume (MCV) > 100 fL

Common causes:

• B12 deficiency
• Folate deficiency
• Hypothyroidism
• Liver disease
• Elevated reticulocyte count
• Myelodysplastic syndrome
• Medication effect (eg., hydroxyurea, methotrexate, zidovudine, azathioprine, antiretroviral agents, valproic acid, phenytoin)

First line investigations and management:

• CBC, reticulocyte count, serum B12, serum or RBC folate level, TSH, AST, ALT, ALP, bilirubin, serum protein electrophoresis
• Abdominal ultrasound

When to consult a hematologist:

• Elevated reticulocyte count without history of bleeding
• Macrocytic anemia with normal B12, folate, and TSH, no evidence by laboratory testing or imaging of liver disease, and no concurrent use of medications known to cause macrocytosis
  • In the absence of clear cause (ie., vegan diet), most patients with B12 deficiency should be referred to gastroenterology for endoscopic assessment for gastritis

When to seek out urgent medical attention:

• Anemia associated with severe fatigue, chest discomfort, or impaired cognition
• New onset hemoglobin < 80 g/L
• Presence of blasts on peripheral blood film

Additional resources:

Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults.  Mayo Clin Proc. 2005 Jul;80(7):923-36

Condition:  Normocytic anemia

Definition:

• Hb <130g/L in males and <120g/L in females, with mean corpuscular volume (MCV) 80-100 fL

Common causes:

• Artefact due to dilution
• Anemia of inflammation (serum ferritin ≥ 100 µg/L with transferrin saturation < 20%)
• Anemia of renal failure (increased serum creatinine combined with low/normal reticulocyte count)
• Hypersplenism (enlarged spleen combined with anemia, thrombocytopenia and high reticulocyte count)
• Myelosuppressive medications (eg., chemotherapy, anticonvulsants, antibiotics)
• Hemoglobinopathy
• Hypothyroidism
• Primary marrow failure syndrome

Investigations and management:

• CBC, reticulocytes, ferritin, B12, transferrin saturation, creatinine, TSH, AST, ALT, ALP, total bilirubin, serum protein electrophoresis, serum free light chain, abdominal ultrasound, hemoglobin electrophoresis, LDH, indirect bilirubin, haptoglobin

When to consult a hematologist:

• Any anemia not due to nutritional deficiency, inflammation, hypothyroidism, renal failure or hypersplenism, or if etiology not clear despite the above investigations

Note: in absence of obvious cause, nutritional anemias require endoscopic evaluation

When to seek out urgent medical attention (eg., refer to emergency department):

• Anemia associated with severe fatigue, chest discomfort, or impaired cognition
• New onset hemoglobin < 80 g/L
• Presence of blasts on peripheral blood film

Additional resources:

Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults.  Mayo Clin Proc. 2005 Jul;80(7):923-36

Condition:  Thrombocytopenia

Definition:

• Platelet count < 150 x 10⁹/L

Common causes:

• Myelosuppressive medication (especially if initiation or dose change in preceding 2 weeks)
• Hypersplenism (eg, enlarged spleen accompanied by anemia, thrombocytopenia and normal-high reticulocyte count)
• Primary marrow failure syndrome
• Autoimmune (immune thrombocytopenia)

First line investigations and management:

• Review duration: if new onset and platelet count > 100 x 10⁹/L in otherwise well patient, consider repeating in two weeks to confirm

• Consider holding or reducing dose of suspected medication
• Hemolytic markers (reticulocyte count, bilirubin, LDH, haptoglobin), coagulation tests (aPTT, INR, fibrinogen), creatinine
• Abdominal ultrasound

When to consult a hematologist:

• New onset thrombocytopenia > 2 weeks duration not attributable to medication or hypersplenism

When to seek out urgent medical attention (eg., refer to emergency department):

• Presence of blasts, teardrop cells or schistocytes on peripheral blood film
• Thrombocytopenia accompanied by signs of hemolysis, coagulopathy or acute renal injury
• Fall in platelet count > 50% from baseline within 5-10 days of new heparin exposure
• Platelet count < 10 x 10⁹/L or accompanied by bleeding, petechiae or bruising

Additional resources:

• Swain F, Bird R. How I approach new onset thrombocytopenia. Platelets. 2020;31(3):285-290

Condition:  Leukopenia

Definition:

• A decrease of either the total white blood cell count (eg., < 3 x 10⁹/L) or a specific type of leukocyte below normal range

Common causes:

• Myelosuppressive medication (especially if initiation or dose change in preceding 2 weeks)
• B12 deficiency
• Hypothyroidism
• Hypersplenism (eg, enlarged spleen accompanied by anemia, thrombocytopenia and normal-high reticulocyte count)
• Viral infection (lymphopenia)
• Congenital (neutropenia).  Note that individuals of African ethnicity often have absolute neutrophil counts in range of 1.0 to 1.5 x 10⁹/L
• Autoimmune
• Primary marrow failure syndrome

First line investigations and management:

• Review duration: if new onset of mild abnormalities in otherwise well patient, consider repeating in two weeks to confirm
• Consider holding or reducing dose of suspected medication
• B12, TSH, reticulocyte count, ALT, bilirubin, abdominal ultrasound
• HBsAg, HCV and HIV antibodies in high-risk individuals

When to consult a hematologist:

• New onset leukopenia > 2 weeks duration not attributable to medication, B12 deficiency, hypothyroidism or hypersplenism

When to seek out urgent medical attention (eg., refer to emergency department):

• Presence of blasts or teardrop cells on peripheral blood film
• Absolute neutrophil count < 0.5, or < 1.0 x 10⁹/L and accompanied by fever

Additional resources:

• Onuoha C, Arshad J, Astle J, Xu M, Halene S. Novel Developments in Leukopenia and Pancytopenia. Prim Care. 2016 Dec;43(4):559-573

Condition:  Erythrocytosis

Definition:

• Men: hemoglobin >165 g/L or Hct > 49%
• Women: hemoglobin >160 g/L or Hct > 48%

Common causes:

• Dehydration
• Chronic hypoxemia (eg., hypoventilation, chronic lung disease, smoking)
• Renal artery stenosis
• Myeloproliferative disorders
• Medication-induced (erythropoietin-receptor agonists, testosterone)
• Congenital

First line investigations and management:

• Review duration: if new onset of mild abnormalities in otherwise well patient, consider repeating in two weeks to confirm, ensuring patient is euvolemic
• Pulse oximetry and/or arterial blood gas, serum ferritin, AST, ALT, bilirubin, creatinine, erythropoietin level, hemoglobin electrophoresis, molecular studies of peripheral blood for JAK2 mutations
• Pulmonary function test, chest x-ray, abdominal ultrasound with renal doppler study, echocardiogram with bubble study, sleep study

When to consult a hematologist:

• Erythrocytosis associated clonal population (as per molecular studies) or high-oxygen affinity hemoglobin variant (as per hemoglobin electrophoresis)
• Erythrocytosis > 3 months without apparent cause (all other investigations normal)

When to seek out urgent medical attention (eg., refer to emergency department):

• Presence of blasts or teardrop cells on peripheral blood film
• Erythrocytosis accompanied by venous or arterial thrombosis

Additional resources:

• Mithoowani S, Laureano M, Crowther MA, Hillis CM. Investigation and management of erythrocytosis. CMAJ. 2020 Aug 10;192(32):E913-E918

Condition:  Thrombocytosis

Definition:

• Platelet count > 450 x 10⁹/L

Common causes:

• Infection
• Inflammation
• Iron deficiency
• Post-splenectomy
• Myeloproliferative disorder

First line investigations and management:

• Assess patient for signs and symptoms of infection and inflammation; consider chest x-ray and abdominal ultrasound
• C-reactive protein, serum ferritin
• Review duration: if new onset of mild abnormalities in otherwise well patient, consider repeating in two weeks to confirm
• If no other clear cause, molecular studies of peripheral blood (JAK2, CALR or MPL mutations)

When to consult a hematologist:

• Thrombocytosis associated with a clonal population (as per molecular studies) or hepatosplenomegaly
• Thrombocytosis > 3 months without apparent cause (all other investigations normal)

When to seek out urgent medical attention (eg., refer to emergency department):

• Presence of blasts or teardrop cells on peripheral blood film
• Thrombocytosis with accompanying venous or arterial thrombosis

Additional resources:

• Mora B, Passamonti F. Developments in diagnosis and treatment of essential thrombocythemia. Expert Rev Hematol. 2019 Mar;12(3):159-171

Condition:  Leukocytosis

Definition:

• An elevation of either the total white blood cell count or a specific type of leukocyte above normal range

Common causes:

• Infection
• Inflammation
• Allergic reaction
• Post-splenectomy
• Steroid effect
• Bone marrow infiltration/expansion
• Hematologic malignancy

First line investigations and management:

• Assess patient for signs and symptoms of above; consider chest x-ray and abdominal ultrasound
• Review duration: if new onset of mild abnormalities in otherwise well patient, consider repeating in two weeks to confirm
• Microbiologic studies in symptomatic patients (eg., blood cultures for suspected bacteremia, Monospot test for suspected EBV)
• If no other apparent cause, peripheral blood for flow cytometry (for chronic lymphocytosis) or molecular studies (BCR-ABL for neutrophilia/monocytosis, FIP1L1-PDGFRA for eosinophilia)

When to consult a hematologist:

• Leukocytosis associated with a clonal population (as per flow cytometry or molecular studies), splenomegaly, lymphadenopathy, other cytopenias, or accompanied by constitutional symptoms
• Chronic leukocytosis > 3 months without apparent cause (all other investigations normal)

When to seek out urgent medical attention (eg., refer to emergency department):

• Presence of blasts or teardrop cells on peripheral blood film
• Leukocytosis associated with constitutional symptoms (eg., fever, weight loss, night sweats)

Additional resources:

• Riley, Lyrad K., MD ; Rupert, Jedda, MD, “Evaluation of Patients with Leukocytosis”, American Family Physician, 2015, Vol.92 (11), p.1004-1011

Condition:  Elevated ferritin

Definition:

• Ferritin > 300 µg/L

Common causes:

• Iron overload (accompanied by transferrin saturation ≥ 45%)
• Inflammation (accompanied by transferrin saturation < 45%)

First line investigations and management:

• History and physical: recent illness; transfusion history; family history of hemochromatosis
• Laboratory: ferritin, transferrin saturation, AST, ALT, bilirubin
• Imaging: abdominal ultrasound to assess for both potential complications of iron overload (ie. cirrhosis) and inflammatory conditions that might increase serum ferritin

When to consult a hematologist:

• Iron overload not due to iron supplements
• Iron overload accompanied by signs of liver injury

Note: common causes of elevated serum ferritin in the absence of iron overload include infections, autoimmune disease and metabolic syndrome.  Additional investigations should be informed by history and physical exam. 

When to seek out urgent medical attention (eg., refer to emergency department):

• Serum ferritin > 10 000 µg/L

Additional resources:

Knovich MA, Storey JA, Coffman LG, et al, Ferritin for the clinician. Blood Reviews, 2009;23:95–104

Condition:  Monoclonal protein

Definition:

• A monoclonal protein (“M-spike”) detected by serum protein electrophoresis, or by analysis of either plasma or urine for free-light chains

Common causes:

• Benign Monoclonal Gammopathy (Monoclonal protein of unknown significance/MGUS)
• Lymphoproliferative disorder (eg., multiple myeloma, lymphoma)
• Amyloidosis

First line investigations and management:

• Assess patient for symptoms of bone pain, generalized weakness, neuropathy (ie., muscle weakness or atrophy, pain, numbness), enlarged lymph nodes and pathologic bone fracture
• CBC, calcium, phosphate, creatinine, albumin, LDH
• Serum protein electrophoresis (including immunoglobulin quantitation and immunofixation), urine protein electrophoresis (with immunofixation for Bence-Jones proteins)
  • Serum free light chains should be ordered in patients with positive urinary Bence-Jones proteins, and can be considered as an alternative first-line test, but may incur cost to patient

When to consult a hematologist: 

• Monoclonal protein accompanied by any of the following
  • Neuropathy, lymphadenopathy, bone pain (unless there is a clear alternative explanation)
  • Anemia, leukopenia, thrombocytopenia, lymphocytosis, elevated LDH or increased creatinine (unless there is a clear alternative explanation)
  • M-protein > 15 g/L
  • IgA paraprotein
  • Serum free light chain ratio outside of the following ranges:
    •  0.26 to 1.65 for eGFR > 60
    • 0.46 to 2.62 for eGFR 45 to 59
    • 0.48 to 3.38 for eGFR 30 to 44
    • 0.54 to 3.30 for eGFR < 30
• In the absence of any of the above, investigations may be repeated in 6 months and if stable every 2-3 years or following the onset of symptoms

When to seek out urgent medical attention (eg., refer to emergency department):

• Bone fracture, osteolytic lesions, or hypercalcemia
• New onset hemoglobin < 80 g/L, platelets < 30 x 10⁹/L or serum creatinine > 50% above baseline

Additional resources:

• Mouhieddine TH, Weeks LD, Ghobrial IM. Monoclonal gammopathy of undetermined significance. Blood. 2019 Jun 6;133(23):2484-2494
• Long TE, Indridason OS, Palsson R, et al.  Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study. Blood Cancer J. 2022 Sep 14;12(9):133