#444 Macrocytosis, Hemolytic Anemia, Myelodysplastic Syndrome

June 17, 2024 | By Matthew Watto, MD

Audio

Video

Transcript available via YouTube

Recorded LIVE! At Johns Hopkins Internal Medicine Grand Rounds

Step up your anemia game as we explore the causes and diagnostic approach for macrocytic anemia, what to do with a reticulocyte count, the differential diagnosis for hemolytic anemia, the significance of the direct antiglobulin test, and diagnosis and management pearls for autoimmune hemolytic anemia (AIHA) and myelodysplastic syndrome (MDS). Plus, common questions and concerns regarding folate supplementation and the use of bone marrow biopsies. We’re joined by hematologist and pun enthusiast Dr. Rakhi Naik MD, MHS, @redcell_doc @hopkinsheme. 

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Show Segments

• 00:00 Intro and Guest intro
• 05:53 Case 1: Elise – Macrocytic Anemia
• 14:59 Case 2: Jane – Hemolytic Anemia
• 23:24 Testing for Underlying Causes of Autoimmune Hemolytic Anemia
• 24:40 Association of Autoimmune Hemolytic Anemia with Lymphomas
• 25:10 Autoimmune Hemolytic Anemia: Diagnosis and Treatment
• 26:06 Management Approach for Autoimmune Hemolytic Anemia
• 27:30 Considerations for Outpatient Treatment of Autoimmune Hemolytic Anemia
• 28:18 Clotting Risk in Autoimmune Hemolytic Anemia
• 29:20 Treatment Options for Autoimmune Hemolytic Anemia
• 30:42 Long-Term Prognosis and Recurrence of Autoimmune Hemolytic Anemia
• 33:32 Diagnostic Challenges in Myelodysplastic Syndrome
• 35:00 Considerations for Folate Supplementation
• 36:24 Factors to Consider in the Management of Myelodysplastic Syndrome
• 39:30 When to Perform a Bone Marrow Biopsy in Myelodysplastic Syndrome
• 41:25 Shared Decision-Making in the Treatment of Myelodysplastic Syndrome

Macrocytic Anemia Pearls

1. Macrocytosis has two major mechanisms 1) lots of young, normal cells due to reticulocytosis (“big, juicy, young cells”) and 2) abnormal cells caused by abnormalities in lipid metabolism or  red cell membranes (e.g. liver disease, alcohol use) or  DNA synthesis with impaired cell division (e.g. B12 deficiency).
2. The differential diagnosis (DDx) for macrocytosis includes reticulocytosis, medications (e.g., antivirals, antimetabolites, antineoplastic agents), B12/folate deficiency, liver disease, chronic alcohol use, myelodysplastic syndrome (MDS), and VEXAS!
3. Elevated bilirubin is not sensitive for hemolytic anemia, so check LDH, haptoglobin, and a reticulocyte count (Dr. Naik prefers to send a reticulocyte count with every CBC). 
4. The DDx for hemolytic anemia includes immune mediated (autoimmune disease, hemoglobinurias, transfusion reactions), trauma (e.g., marching, cardiac valves), microangiopathic (e.g., MAHA, DIC), drugs, hemoglobinopathies (e.g., sickle cell), G6PD, hereditary spherocytosis, infections (e.g., malaria), and lymphomas (esp. CLL).
5. A positive direct antiglobulin test (DAT) confirms a diagnosis of autoimmune hemolytic anemia.
6. Refer to Hematology for suspected MDS when patients have numerous immature cells on a CBC with differential, progressive cytopenias (trajectory) and/or younger age.
7. Send B12 and methylmalonic acid together if high suspicion for B12 deficiency to prevent a delay in diagnosis (expert opinion).

Macrocytosis

Dr. Naik says macrocytosis occurs by two major mechanisms. 

1. Lots of young, normal cells from reticulocytosis (“big, juicy, young cells”)
2. Abnormal cells due to either abnormal lipid metabolism with abnormal red cell membranes (e.g. liver disease, alcohol use) or abnormal DNA synthesis with impaired cell division (e.g. B12 deficiency)

She reminds us that medications that effect DNA synthesis, repair, or polymerization can cause macrocytosis (e.g. methotrexate, HIV drugs, chemotherapy). 

Differential Diagnosis for Macrocytosis

1. Reticulocytosis 
2. *Medications (especially antivirals, antimetabolities, antineoplastic agents) 
3. B12/folate deficiency, 
4. Liver disease/**alcohol use disorder
5. Myelodysplastic syndrome (MDS) 
6. VEXAS (acquired bone marrow mutations lead to DNA damage and macrocytosis) (Grayson 2021)

*Allopurinol and metformin are common primary care medications that you might forget cause macrocytosis (Kaferle, 2009).

**Chronic alcohol use (even a few drinks per day) can cause macrocytosis (Hoffbrand, 1997)). It hits all the mechanisms because it can cause lipid problems, DNA damage, and liver disease. 

Basic Workup for Macrocytosis

The [Paul] Williams’ Principle involves repeating the labs until you like the results (see Curbsiders #167 CBC Abnormalities).

(Khoury, 2024)

• Check CBC with reticulocyte count
• Check comprehensive metabolic panel (CMP), which includes liver tests
• Vitamin B12 +/- folate (alcohol use disorder or food insecurity)
• TSH
• +/- copper (prior gastric bypass surgery) —Barcellin, 2024
• +/- peripheral smear
• Review the medication list 
• Look for evidence of liver disease
• Ask about alcohol use

Hemolytic Anemia (HA)

Dr. Naik recommends checking a reticulocyte count with every CBC! The reticulocyte count is low when macrocytosis is from a DNA problem and high when it’s caused by bleeding or hemolysis (Khoury, 2024). She tells us to look at the absolute reticulocyte count rather than the reticulocyte percentage to determine whether it is low, normal, or high, and then categorize the reticulocyte count as appropriate or inappropriate. 

Diagnosis of hemolytic anemia

First Round Testing

(Hill, 2018)

• Same workup as macrocytosis (see above)
• LDH (high in HA)
• Haptoglobin (low in HA)
• Urine (for hemosiderin)
• Peripheral smear
• Per Dr. Naik, indirect bilirubin has poor sensitivity so don’t use it to rule out HA
• Direct antiglobulin test (DAT) aka direct Coombs test, which identifies autoimmune hemolytic anemia (AIHA)

Further Testing (usually guided by hematology consult)

(Hill, 2018)

• Viral testing: HIV, Hep B, Hep C
• Serum electropheresis with immunofixation to detect monoclonal protein 
• ANA, anti-dsDNA if lupus suspected
• CT chest/abdomen/pelvis if lymphoma suspected
• BM biopsy in select cases

Hematology should be consulted for most (if not all) patients with hemolytic anemia (expert opinion)!

DAT looks for bound IgG and complement (Hill, 2018). DAT positivity is part of the diagnostic criteria fo Lupus (Aringer, 2019)!

Fun fact: Dr. Naik reminds us that spherocytes occur in autoimmune hemolytic anemia because the red cell is coated by immunoglobulins (IgG), the spleen eats the IgG membrane complex, and then the red cell “reseals” itself, going from a biconcave disc to a spherocyte!

Differential Diagnosis for Hemolytic Anemia

(Hill, 2018, Brodsky, 2023)

• Immune mediated: Autoimmune disease, hemoglobinurias, transfusion reactions
• Trauma (*marching, marathon running, bongo drums, cardiac valves)
• Microangiopathic (MAHA) or disseminated intravascular coagulation (DIC)
• Drugs (Barcellini, 2024)
• Hemoglobinopathies (e.g., Sickle cell anemia, thalassemia)
• G6PD
• Membrane abnormalities (e.g., hereditary spherocytosis)
• Infections (e.g., malaria, Babesiosis, C. perfringens)
• Lymphomas (esp. CLL)

*March hemolysis involves mechanical destruction of red cells in people marching in band or running marathons!

Treatment of autoimmune hemolytic anemia

Let’s be clear. Hematology should be consulted to guide management.

In AIHA, Dr. Naik determines the need for hospitalization by a patient’s symptoms and the trajectory of their anemia. A blood transfusion may be necessary, but is complicated by trouble finding a cross-match compatible unit. Typical therapy includes systemic steroids 1mg/kg/day.  It typically takes 1-2 weeks to see a response to therapy (Hill, 2018). Rituximab is typically a second line therapy (Hill, 2018).  

Kashlak Pearl: Watch out for clots! Dr. Naik explains that hemolysis can lead to an increased risk of clotting because cell membrane abnormalities (e.g. externalized lipids that are normally found inside the cell) can trigger the coagulation cascade. 

About 80% of patients initally respond to steroids, but the majority of patients with AIHA relapse when steroids are tapered. Rituximab has about a 60% initial response rate (Salama, 2015). Some patients ultimately require splenectomy. 

Myelodysplastic syndrome (MDS)

Male sex and a prior history of radiation or chemotherapy are associated with an increased risk for MDS (Garcia-Monero, 2023). MDS is caused by abnormal maturation of the myeloid stem cells. Dr. Naik tells us to think about myelodysplastic syndrome (MDS) when a patient has smouldering cytopenias of one or more cell lines. MDS varies in its cytopenias, symptoms (fatigue, infections, bruising/bleeding (Aster, 2023)), progression, and may transform to acute myelogenous leukemia (Garcia-Monero, 2023). Multiple scoring systems exist based on the number of cell lines affected, the severity of cytopenias, and mutation analysis (Garcia-Monero, 2023).

Dr. Naik recommends that we refer to Hematology for suspected MDS when patients have numerous immature cells on a CBC with differential, progressive cytopenias (trajectory) and/or younger age because younger patients have more time to progress and develop complications. 

Workup for MDS

(Garcia-Monero, 2023, Aster, 2023)

• CBC with differential
• Peripheral blood smear
• *Bone marrow biopsy (to evaluate for dysplasia and % blasts)
• Cytogenetic testing

*Dr. Naik does not pursue bone marrow biopsy for all patients, especially if it won’t change the treatment plan. She waits to perform a bone marrow biopsy until there is a reason to treat because the cells will be overtly dysplastic at that point and a false negative test is less likely (expert opinion).

MDS therapies

Therapy will directed by hematology and may include

• Erythropoeitin 
• Chemotherapy
• Bone marrow transplant

Dr. Naik tailors the conversation to the degree of MDS and engages in shared decision-making. 

Audience Questions

What is your approach to folate supplementation?

True folate deficiency is uncommon. It can occur in patients with malnourishment (e.g. alcohol use disorder (Khoury, 2024) or in hemolytic anemia when rapid turnover and red cell destruction depletes stores (Zhang, 2020). 

Will bone marrow biopsies go away?

Dr. Naik responds that abnormal cells can often be found in the peripheral blood with next-generation sequencing, but some mutations “stay in the marrow” because the cells don’t mature enough to leave the marrow. 

Kashlak Pearl: Send B12 and methylmalonic acid together in cases of high suspicion to prevent a delay in diagnosis. 

Links

Goal

Listeners will build on their knowledge of how to approach to the abnormal CBC

Learning objectives

After listening to this episode listeners will…

1. Develop a standardized approach to macrocytic anemia
2. Diagnose autoimmune hemolytic anemia
3. Recognize myelodysplastic syndrome

Disclosures

Dr. Naik no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Watto MF, Naik R, Syed F, Williams PN, Watto MF. “#444 Macrocytosis, Hemolytic Anemia, Myelodysplastic Syndrome”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date June 17, 2024.