1/7

A STRUCTURED APPROACH TO NORMOCYTIC ANEMIA

A practical, population, and molecular look at how we reason through normocytic hypoproliferative anemia at the bedside.

(Full TBP tutorial linked below ⬇️) 2/7

1️⃣ The ABC Spine – A Bedside Framework

A: substrate supply (nutritional)
B: regulatory signaling (inflammatory)
C: organ dysfunction (kidney, liver, endocrine, marrow)

We focus here on the hypoproliferative end of the spectrum, where the marrow is not keeping up.

IV IRON AND FERRITIN

1/8

I recently posted a question about the spike in serum ferritin after IV iron.

It can shoot from <10 to >1000, yet transferrin saturation (TSAT) only rises to normal — it barely moves.

What’s going on?

This is macrophage physiology in action 👇 2/8

Step 1 – Uptake

IV iron–carbohydrate complexes (e.g., iron dextran) are endocytosed by macrophages in the liver, spleen, and marrow.

Inside, the iron is released and floods the labile Fe²⁺ pool, the cell’s internal “iron bank.”

1/4

Patients with SLE can present with a staggering array of hematologic abnormalities. Virtually no component of the blood is spared. Everything is fair game:

1. Blood cells - cytopenia and cytoses
2. Hemostasis - thrombosis, TMA
3. Lymphadenopathy/splenomegaly
4. Lymphoma 2/4

Diagnostic criteria for SLE include the following hematological parameters:

1. Hemolytic anemia
2, Leukopenia
3. Lymphopenia
4. Thrombocytopenia
5. Anti phospholipid antibodies

1/4

The Plasma Exchange Paradox

Have you ever wondered why plasma exchange saves lives in TTP but does nothing in ITP? Both are IgG-mediated. So why the difference? 2/4

In ITP, antibodies opsonize platelets. Even if you remove some by exchange, IgG quickly re-equilibrates from the extravascular pool and continues to be produced. With no missing factor to replace, there’s no lasting benefit.

1/5

SPLENOMEGALY/HYPERSPLENISM

Mechanisms of splenomegaly:
• Congestive
• Work hypertrophy
• Infiltrative

What enlarges?
• Red pulp: macrophages, sinusoids, blood
• White pulp: lymphocytes, plasma cells
• Infiltrative: tumor, storage cells, granulomas, amyloid

#MedEd 2/5

SPLENOMEGALY/HYPERSPLENISM

Red pulp = ~75% of spleen, the “filter & reservoir.”

Site of pooling, culling & destruction → main driver of splenomegaly + hypersplenism.

Open circulation = quality control: normal cells pass, rigid ones get removed.

1/7

I posted the graphic below earlier in the week and asked what was missing.

Before addressing the question, let's flesh out the various diagnostic containers.

1. HEMOLYSIS:

Immune hemolysis:
Autoimmune
Warm, Cold, Mixed
Alloimmune
ATR, DTR 2/7

Non-immune hemolysis
Intracapsular
Hemoglobinopathies
Membrane disorders
Hbopathies

Extracorpuscular
Infection (babesiosis, malaria, clostridial)
Liver (spur cell anemia, Zieve syndrome)
TMA

1/6

LYMPHOCYTOPENIA

1. Definition 2/6

2. Causes - Part 1

1/4

SPLENOMEGALY

1. Definition 2/4

2. Differential diagnosis

1/7

PSEUDOTHROMBOCYTOPENIA

I tweeted a poll asking for the next step in a patient with thrombocytopenia and a platelet clumping on a peripheral smear. 62% of you answered correctly, namely to repeat the CBC in a green top (heparin-containing) tube. 2/7

Key points:

1) Pseudothrombocytopenia is mediated by EDTA-dependent antibodies that react with platelets in blood that is anticoagulated with EDTA (chelates calcium, necessary for clotting reactions), causing platelet clumping and falsely low platelet counts.

1/6

LYMPHOCYTOPENIA (aka lymphopenia)

A) Definition

Absolute L count < 1,000/microliter or 1.0 x 10^9/L 2/6

B) Causes

1/7

RELATIONSHIPS BETWEEN RBC INDICES

RBC count

a. Used to calculate the Hct (Hct = MCV x RBC count)
b. Used by some to predict iron deficiency vs. thalassemia (e.g., Meltzer index)
b. Largely ignored because it says nothing about the size/Hbization of RBCs 2/7

... you could have LOTS of SMALL RBCs or FEWER LARGE RBCs amounting to the same Hct (viscosity) and Hb (oxygen carrying capacity)!

1/4

APPROACH TO NORMOCYTIC ANEMIA

This is the most common type of anemia, and its differential diagnosis can sometimes feel overwhelming, and 'all over the place'.

The following is organizational scheme with simple diagnostic buckets that covers virtually all causes: 2/4

BUCKET LIST 1:

Appropriate vs. inappropriate retic response (appropriate defined by absolute retic count > 120 x 10^9/L or 0.12 x 10^12/L)?

BUCKET LIST 2:

If appropriate retic response, is there bleeding or hemolysis?

1/5

COAGULATION IN VITRO/IN VIVO

In vitro (test tube):

1. The clotting cascade in plasma is activated by the addition of a negative charge, which activates the intrinsic pathway (aPTT) or tissue factor, which activates the extrinsic pathway (PT) in presence of Ca2+ and PL. 2/5

2. Once the ingredients are added together, the "stop watch" is started and time to clot formation at 37C is measured (the assays do not discriminate between crosslinked and uncrosslinked fibrin).

1/6

NORMOCYTIC, NORMOCHROMIC IRON DEFICIENCY ANEMIA (IDA)

We tend to think of IDA as being microcytic (more consistently than hypochromic). However, there are certain situations in which the MCV is normal in IDA. 2/6

Examples include:

1. A patient with high-normal baseline MCV whose MCV falls within the normal range in IDA (see first graphic for an example).

2. A patient with baseline macrocytosis, for example from concomitant liver disease, B12 deficiency, MDS or hydroxyurea use.

1/7

ANISOCHROMIA

We are used to considering variation in RBC size (increased variation = anisocytosis) by examining a blood smear or evaluating the RDW.

What about variation in RBC Hb concentration ([Hb]) (anisochromia)? 2/7

We can often identify cell-to-cell differences in central pallor on a blood smear.

While we may make mental note of such differences, we rarely incorporate the finding in a summary of the smear. And there is no lab equivalent to the RDW for Hb concentration or "chromia".

1/6

TRANSFUSION AS IRON THERAPY

Yesterday I posted a poll showing CBC data from a patient with severe iron deficiency anemia and asked: assuming she receives 4 units pRBCs (which of course would be excessive here), does she need iron therapy on top of that?

70% answered YES. 2/6

Each unit of RBC contains about 250 mg Fe. So she will have received about 1000 mg of Fe, not far off from her total needs. However, such is iron is bound up in Hb inside the donor RBCs and is not readily accessible for erythropoiesis.

1/4

CORTICOSTEROIDS IN ITP

I tweeted a poll asking whether you would treat a patient with newly diagnosed ITP with high-dose dexamethasone (HD-DXM) or prednisone (PRED).

57% chose HD-DXM. 2/4

I have done a deep dive into this question, and found that compared with PDN, HD-DXM:

1. Achieves higher and faster initial response
2. Is associated with less bleeding
3. Has fewer adverse effects
4. Has comparable response at 6 months

1/4

IGNORE THE MCH!

I don't know about you, but our institution provides the mean corpuscular hemoglobin (MCH) with the CBC.

Not only is it a virtually useless (and redundant) parameter, but it often gets confused with the much more meaningful MCHC. 2/4

The MCH is the ave weight of the RBC in Hb (reported in pg). In contrast to the MCHC, it has no place in diagnostic algorithms for anemia.

MCH tracks with the MCV and MCHC (MCH = MCV x MCHC; MCV has the largest effect because % deviation is far greater than with the MCHC).

1/4

DEFINITION OF ANEMIA

Yesterday, I posted a poll showing Hb 10.4 and Hct 41 and asked whether or not the patient had anemia.

About 62% of respondents answered YES.

That is the CORRECT answer. 2/4

Anemia is best defined by the Hb because patients with anemia have a deficit in oxygen carrying capacity. Hb binds and carries oxygen. The Hct, by contrast, is a function of cell size (MCV) and RBC count. It is impervious to the contents of the RBC.

1/12

PERNCIOUS ANEMIA AND ENDOSCOPY

I posted a poll yesterday asking whether you would refer a patient with pernicous anemia (PA) to a gastroenterologist for consideration of upper endoscopy.

Most of you answered YES. 2/12

There is no evidence that initial or surveillance endoscopy affects the outcome of patients with PA.

That being said, most GI practice guidelines recommend endoscopy, whereas the sole hematology guideline (BSH) does not.

1/7

CASE

Yesterday, I posted a time series of CBCs and reticulocyte counts and asked a series of questions.

Let's address each question in turn. 2/7

Q1. Describe the CBC on 2/11.
A1. Leukocytosis (WBC > 11 x 10^9/L) with normocytic, normochromic anemia (Hb < 12-13 g/dL, MCV 80-100 fL, MCHC 32-36 g/dL), anisocytosis (RDW-SD > 46 fL) and thrombocytosis (PLT > 400 x 10^9/L).