Hematology tips for primary care: Hemoglobin abnormalities

Author

Heather A. Leitch, MD, PhD, FRCPC (biography & disclosures)

Disclosures: Has received honoraria, advisory boards, research funding from AbbVie, Alexion, BeiGene, BMS, Celgene, Fibrogen, Forma, Janssen, Novartis, Taiho. Mitigating potential bias: I speak to all companies that make medications relevant to my patients. I recommend the treatment that is in the best interest of the patient at all times. Recommendations are consistent with current practice patterns.

What care gaps or frequently asked questions I have noticed

In medical school, we had two weeks of lectures to cover the breadth of malignant and benign hematology. A dedicated clinical rotation in hematology during training is only four weeks. Exposure to cases with blood conditions on the Clinical Teaching Unit (CTU) does occur, however, on the CTU there is a broad range of medical conditions and many distractions. This article aims to provide backup in anticipation of questions hematologists are commonly asked about hemoglobin disorders, using a case-based approach.

Although the complete blood count (CBC) and differential (D) include 14 parameters, in the majority of cases we pay most attention to: the white blood cell count (WBC), hemoglobin (Hb), mean corpuscular volume (MCV), platelet count and any abnormal counts on the WBC differential. Comments from the hematopathologist’s morphology review can be very helpful.

Using specific cases, I will review the following frequently asked questions:

1. 1. How does one replete iron?
   2. Do these patients require hematology referral?

Data that answers these questions or gaps

Case 1

A 63-year-old woman has a routine CBCD. The results are shown in Table 1. The hematopathologist’s comment is: Hypochromic microcytic anemia consistent with iron deficiency. Suggest ferritin level (see Figure 1A).^1,2 Ferritin level is 16µg/L (µg/L; <15 diagnostic; 15-30 probable; >30 unlikely; >100 normal stores, >600 consider testing for iron overload).

Table 1. Relevant laboratory parameters in Case 1.

Figure 1A shows a peripheral blood smear from a patient with iron deficiency anemia. In iron deficiency, red blood cells (RBCs) are typically smaller than the nucleus of a mature lymphocyte, indicating microcytosis. These cells are also hypochromic, as evidenced by the expanded area of central pallor. For comparison, Figure 1B shows an RBC from a normal blood smear.

Figure 1A. Peripheral blood smear on a patient with iron deficiency anemia.	Figure 1B. Normal peripheral blood smear.

Feedback: The etiology of iron deficiency is multifactorial, often requiring a thorough dietary history. With a Western diet, it is difficult to become iron-deficient through diet. Iron is absorbed primarily in the proximal duodenum and the condition affecting this part of the gastrointestinal (GI) tract, celiac disease, can reduce iron absorption due to villous atrophy. Identifying celiac disease is crucial because it increases the risk of GI T-cell non-Hodgkin’s lymphoma, a condition with suboptimal treatment outcomes. While the screening test for celiac disease is the tissue transglutaminase (tTG), a definitive diagnosis requires an upper GI endoscopy with biopsy. A more common cause of iron deficiency, however, is blood loss, particularly from GI sources like polyps. Identifying and treating these polyps is important to prevent progression to adenocarcinoma. Other common causes of blood loss include heavy menstrual bleeding and microscopic hematuria. Therefore, the question of iron repletion should be reframed as: What is the underlying cause of the iron deficiency?

Does this patient require hematology referral? No, they should be referred to the specialist best suited to address the underlying source of blood loss, typically a gastroenterologist.

Practice tip: The majority of patients with iron deficiency require evaluation of the GI tract, regardless of the results of FIT testing, as blood loss from polyps can be intermittent. Although the MCV is within the normal range and not flagged, it is at the low end of normal and should be considered when assessing potential causes of anemia. In iron deficiency, the platelet count may be elevated, possibly as an evolutionary response to compensate for blood loss. In cases of inflammation, ferritin levels may appear falsely normal, so a high index of suspicion for iron deficiency should be maintained. For detailed guidance, the British Columbia guidelines for iron deficiency can be found on the Guidelines and Protocols Advisory Committee (GPAC) website.³ Oral iron repletion can typically be managed by a family doctor or nurse practitioner. For patients requiring parenteral repletion, referral to an internist is recommended.

Case 2

A 23-year-old woman has a routine CBC, shown in Table 2. The hematopathologist’s comment is: Hypochromic microcytic anemia with target cells suggestive of thalassemia, suggest hemoglobin electrophoresis (see Figure 2).⁴ A Hb electrophoresis is consistent with beta-thalassemia trait.

Table 2. Relevant laboratory parameters in Case 2.

Figure 2. Peripheral blood smear on a patient with thalassemia trait. The RBCs are microcytic and hypochromic, and target cells are present (indicated by the arrow).

Feedback: Frequently, patients are given iron based on the assumption of iron deficiency due to microcytic anemia. However, thalassemia typically presents with a very low MCV, in contrast to the just-low or low-normal MCV seen in iron deficiency. While patients with thalassemia can also be iron deficient, they may become iron overloaded even without transfusions, due to increased GI iron absorption.⁵ If iron deficiency is confirmed, it is reasonable to replete iron until the ferritin level reaches 100, then stop, after completing appropriate GI investigations for patients in the relevant age group. Target cells form in thalassemia due to a relative excess of lipid membrane compared to cytoplasmic contents, as there is less hemoglobin present in the cells.

Does this patient require hematology referral? Yes, they should be referred for non-urgent counselling regarding the inheritance patterns of thalassemia genes.

Practice tip: Patients with thalassemia, even if not transfusion dependent, can become iron overloaded with supplementation. Iron repletion should be done with caution.

Case 3

A 40-year-old woman presents with fatigue and shortness of breath. Blood counts are done (see Table 3). The hematopathologist’s review says: anemia with spherocytes and reticulocytes, suggestive of immune-mediated hemolysis (see Figure 3).⁶

Table 3. Relevant laboratory parameters in Case 3.

Figure 3. Peripheral blood smear from a patient with autoimmune hemolytic anemia shows spherocytes (indicated by the arrow), which are smaller than normal RBCs and lack the typical central pallor. This occurs when red blood cells coated with antibodies lose membrane material as they pass through the spleen, where macrophages engulf the antibody-bound membrane.

Feedback: This patient requires a workup for autoimmune hemolytic anemia, including lactate dehydrogenase (LDH), bilirubin (bili) levels, and reticulocyte count, all of which are expected to be elevated. Additionally, a direct antiglobulin test (DAT) and haptoglobin level should be measured, which are expected to be positive and low respectively.

Does this patient require hematology referral? Yes, they should be referred either semi-urgently or urgently, depending on the severity of hemolysis and their symptoms. The triaging hematologist typically determines the urgency based on these factors.

Practice tip: Hemolytic anemia should be referred to a hematologist for further workup, including ruling out an underlying lymphoproliferative disorder, as well as for management.

Case 4

A routine CBC is done (see Table 4).

Table 4. Relevant laboratory parameters in Case 4.

Practice tip: Patients with bicytopenia, even if mild, should be referred to a hematologist unless there is an obvious non-hematologic cause, such as hepatic cirrhosis with portal hypertension.

Case 5

Blood work is done (see Table 5). The hematopathologist’s review says: teardrop cells present along with nucleated red blood cells, comprising a leucoerythroblastic picture (see Figure 4).⁷

Table 5. Relevant laboratory parameters in Case 5.

Figure 4. A leukoerythroblastic picture is seen in the peripheral blood, with teardrop cells (small arrow) and an immature red blood cell (large arrow) that has not yet extruded its nucleus, referred to as an erythroblast.

Feedback: A leukoerythroblastic picture can be seen in conditions of severe stress, such as sepsis; however, bone marrow infiltration should be ruled out. Teardrop cells are formed when red blood cells squeeze through packed marrow elements to be released into the circulation, resulting in deformation. In normal hematopoiesis, the red blood cell nucleus is extruded before the cells are released into the bloodstream.

Practice tip: A patient with a leukoerythroblastic picture is likely to require a bone marrow biopsy and should be referred for the procedure, unless there is an obvious source of marrow infiltration, such as widely metastatic adenocarcinoma.

Case 6

Blood counts are done on a 74-year-old man (see Table 6).  The hematopathologist’s review says: hypogranular and hypolobular neutrophils are seen, rule out myelodysplastic syndrome (see Figures 5A & 5B).^8,9

Table 6. Relevant laboratory parameters in Case 6.

Figure 5A. Dysplastic changes on the peripheral blood smear.	Figure 5B. Normal peripheral blood smear.

In Figure 5A, a hypogranular, hypolobular neutrophil is seen. Normal neutrophils are shown in Figure 5B for comparison.

Feedback: Myelodysplastic syndrome (MDS) is a condition characterized by the abnormal formation and morphology of blood cells. Because of their abnormal structure, these cells are often broken down in the bone marrow before they can enter the bloodstream, leading to cytopenias. Dysplastic changes may be absent in the peripheral blood and may only be evident in the bone marrow. MDS is associated with a shortened lifespan and carries a risk of progression to acute myeloid leukemia (AML). Patients with MDS require assessment and follow-up by a hematologist. Some patients may be eligible for newer therapies targeted at specific MDS subtypes, which can help alleviate cytopenias and extend survival. Somatic mutations play a crucial role in MDS prognosis, so if a bone marrow aspirate and biopsy are performed prior to hematology referral, the marrow should be sent to the nearest cytogenetics lab for karyotype analysis. Additionally, a myeloid panel should be sent to the BC Cancer Agency Cancer Genetics Lab. The CGL sample will be stored and can be activated if the morphology and cytogenetics support an MDS diagnosis.

Does this patient require hematology referral? Yes, for risk stratification and management of MDS.

Practice tip: As the field of MDS is complex and evolving rapidly, Canadian hematologists developed an online algorithm to support health care providers in the workup, diagnosis and management of MDS, termed the MDS ClearPath. An iPad/iPhone App is available for free download. After taking the user through the steps required to make an MDS diagnosis and determine prognostic score, the Treatment Wizard leads through a series of questions particular to the specific patient’s clinical status, leading to a treatment recommendation. Information on medications used in MDS, including dosing, monitoring, safety, efficacy and provincial reimbursement, is provided. All references are included within the algorithm, with links to PubMed abstracts. In areas where data are lacking, recommendations are based on expert opinion and consensus.¹⁰

Case 7

A 68-year-old man receiving testosterone supplementation has an increased Hb.

Feedback: Testosterone/anabolic steroids can raise the Hb level, as can hypoxemia and volume depletion.

Does this patient require hematology referral? No, the steroid should be discontinued, and the Hb should be retested to confirm if the hormone is the cause of the increased Hb level. If this is the case, the steroid can be resumed at a dose that maintains Hb and hematocrit (HCT) within the normal range. If not, phlebotomies can be considered to keep the HCT below 0.55. There is no information on the use of aspirin in secondary erythrocytosis. Most patients with elevated cell counts in the absence of hormones, hypoxemia or volume depletion should be referred for further evaluation or advice.

What I recommend (practice tip)

• For anemia, always check the MCV, even if it is not flagged.
• For a somewhat low MCV, with or without anemia, check ferritin levels.
• In cases of iron deficiency, investigate the underlying cause.
• Autoimmune hemolytic anemia requires referral to a hematologist.
• A leukoerythroblastic picture also warrants a hematology referral.
• Bicytopenia or pancytopenia generally requires referral.
• There is an online algorithm available to support HCP in the diagnosis, workup and management of MDS.¹⁰
• Secondary erythrocytosis, in the vast majority of cases, does not require a hematologist.

References

1. Uthman, E. Iron-deficiency anemia, peripheral blood smear. Wikimedia Commons. Published March 8, 2010. (View)
2. Central pallor of RBCs. Medical Labs. Published December 20, 2014. (View)
3. Government of British Columbia. Iron deficiency – diagnosis and management. Updated November 2, 2023. (View)
4. Kwon, G. Thalassemia – 9. MLS Collection, University of Alberta. Published May 22, 2018. (View)
5. Porter JB, Cappellini MD, Kattamis A, et al. Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions. Br J Haematol. 2017;176(2):288-299. doi:10.1111/bjh.14373 (View)
6. Palla AR, Kennedy D, Mosharraf H, Doll D. Autoimmune hemolytic anemia as a complication of nivolumab therapy. Case Rep Oncol. 2016;9(3):691-697. doi:10.1159/000452296 (View)
7. Leukoerythroblastic blood smear. MedSchool. March 4, 2023. (View)
8. Kwon, G. Myelodysplastic syndrome – 6. MLS Collection, University of Alberta. Published June 11, 2018. (View)
9. Walker, MI. Neutrophils in peripheral blood smear. Science Photo Library. (View)
10. Wells RA, Leitch HA, Olney HJ, Shamy A. Streamlining the continuum of care for MDS patients, from diagnosis and staging through to treatment. MDS Clear Path. March 2024. (View)

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