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Leukoerythroblastic blood picture

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Dr.Mohamed Hanafy

on 22 March 2015

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Transcript of Leukoerythroblastic blood picture

Diagnosis by patterns
A pattern, which is formed by a gathering of relevant findings, serves as an intermediate hypothesis in diagnostic reasoning.
Each pattern encompasses a set of differen­tial diagnoses, and an experienced hematologist uses the predominant pattern as a guide in determining which additional information needs to be gathered to render a final diagnosis.

Diagnosis by patterns reflects the
problem solving methods applied daily in the diagnostic evaluation of hematological disorders.

The goal of the pattern approach is to arrive at a single predominant pattern that indicates a list of differential diagnoses based on common features. Therefore, a hierarchical clas­sification of the patterns must be established. This hierarchical classification is based on two principles: (1) if WBC abnormalities are present, associated RBC and platelet abnormalities tend to be secondary to the WBC disease; and (2) the predominant pattern is that pattern which suggests a more specific (i.e. shorter) list of differential diagnoses.


and examination of the peripheral blood film are the first steps in the work-up of most hematological disorders, both benign and malignant. The preparation of good quality films
(i.e. well spread and properly stained)
is crucial to the proper interpretation of the peripheral blood findings.

Leukoerythroblastic blood picture
Two major mechanisms, acting alone or in concert, have been proposed to account for the peripheral blood changes characteristic of a leukoerythroblastic reaction:

Altered marrow—blood barrier

(i.e. disrupted marrow sinusoids) due to bone marrow infiltration.
Bone marrow infiltrative disorders include :
hematological malignancies, metastatic carcinomas and

non-neoplastic conditions such as : granulornata and storage disorders (e.g. Gaucher's disease).

Noninfiltrative marrow fibrosis can also occur as the result of injury to the bone marrow microenvironment (e.g. radiation therapy).
Any of these disorders can elicit a variable degree of reticulin fibrosis that may progress to collagen fibrosis and new bone formation. This evolution is typically encountered in Primary myelofibrosis (PMF)

Qualitative abnormalities in erythroid precursors

• Binucleation, multinucleation, nuclear lobulation.
• Nuclear fragmentation (karyorrhexis).
• Nuclear/cytoplasmic asynchrony.
• Ragged cytoplasm or hypochromia, indicating defective hemoglobinization.
• Basophilic stippling.
• An increase in the number of siderotic granules (more than four per cell) as seen on a Prussian blue (iron) stain. When visible on routine Romanovsky stains, this finding is termed 'Pappenheimer bodies'.

Macrocytes and ovalocytes/elliptocytes

Are relatively nonspecific changes reflecting disturbed erythropoiesis in both benign conditions (e.g. B12/folate deficiency) and malignant diseases .
DD Of Peripheral Blood Film & BM Features
Part 1 : Peripheral Blood Film

Lecture 2 (Leukoerythroblastic blood picture)
Dr. Mohamed Hanafy, MD
Clinical Pathology (Hematology)

Basophilic stippling:
Represents aggregates of ribosomes and/or RNA granules. It is found in dyserythropoiesis (e.g. B12/folate deficiency or myelodysplastic syndromes) and abnormal Hgb formation (e.g. thalassemias, unstable Hgb and heavy metal poisoning) .

Polychromatophilic RBCs:
Which correspond to young reticulocytes with a high RNA content. The younger the cell, the more basophilic the appearance. Late reticulocytes are indistinguishable from mature RBCs on Romanovsky films, except by virtue of their larger size. Supravital staining with methylene blue allows better visualization of reticulocytes at various stages.
Polychromatophilic RBCs may have the teardrop deformity and can be abnormally large, indicating dyserythropoiesis .

Microcytosis and/or hypochromia:
which when present in a leukoerythroblastic pattern strongly suggests thalassemia intermedia or thalassemia major. If sickle cells are also present, consideration must be given to S-B-thalassemia, or, less commonly, Hgb S with superimposed iron deficiency .

Other RBC abnormalities,

for example spherocytes, often indicate the specific cause of the leukoerythroblastic pattern. Giant platelets, megakaryocyte fragments and circulating micromegakaryocvtes may be encountered in a leukoerythroblastic pattern.

A leukoerythroblastic picture may be accompanied by qualitative abnormalities in granulocytes such as hypogranulation, hyposegmentation, and/or giant forms . These may, but do not necessarily, indicate that the underlying pathology is a stem cell disorder (MDS, leukemia or an MPD). Marked hyper-granulation is a key feature of G-CSF therapy .

The following situations, which occur mainly in the early stage of PMF, can raise diagnostic difficulties:
Peripheral blood findings
Similar to other MPDs, the peripheral blood findings in CIMF are often more informative than the bone marrow morphology, especially since many patients present late in the course of the disease. In most instances, the peripheral blood demonstrates
a mild normochromic, normocytic (NCNC) anemia
that is due to a combination of ineffective erythropoiesis and shortened RBC survival secondary to splenomegaly.

If basophilia and circulating blasts are not present, other processes including recovery from chemotherapy, inflammation/sepsis and carcinomatosis need to be considered.

In general, there is a higher proportion of NRBCs to circulating intermediate myeloid precursors in chronic, congenital hemolytic anemias. The reverse is usually true in MPDs. Since there is considerable overlap in WBC counts between these two groups, the degree of leukocytosis is less helpful as a differentiating feature.

Teardrop cells (Dacrocyte):

are an acquired abnormality caused by one of two mechanisms:
(1) Normal RBCs may be damaged in transit through marrow sinuses that are distorted by fibrosis; or
(2) Erythrocytes with hemoglobin precipitates become too rigid to pass through the microvasculature.
The precipitates may be secondary to denatured hemoglobin (e.g. Heinz bodies, unstable Hgb) or can arise from an excess of globin chains (as seen in thalassemia).
Some times may be due to preparation ARTIFACT ! !
Circulating NRBCs are abnormal finding in PB except in the neonatal period. A few NRBCs may be observed in the peripheral blood of term, healthy newborns up to 5 days of age.
In premature infants
or those with hypoxic stress, the number of NRBCs is higher.
Intermediate myeloid precursors include:
promyelocytes, myelocytes and metamyelocytes.
Myelocytes and metamyelocytes are usually present in higher numbers than promyelocytes.
The promyelocyte
has nuclear features that resemble those of a blast (high nuclear/cytoplasmic ratio, fine chromatin, and conspicuous nucleoli) along with basophilic cytoplasm that contains an appreciable number of azurophilic (primary) granules.
The myelocyte,
the last myeloid precursor capable of cell division, acquires secondary (specific) granules that eventually out number the primary granules as the cell matures. Specific granules can barely be seen by light microscopy. The nucleus, which is located off-center next to a prominent pale Golgi hof, appears flattened on one side.

PMN Lucocytosis
Abnormal mononuclear cell
Absolute lymphocytosis

The leukoerythroblastic blood picture is characterized by presence of circulating NRBCs and immature myeloid precursors, often with RBC anisopoikilocytosis.
The WBC count can be normal or high. In most cases, this pattern is associated with anemia. A high RDW and analyzer flags for NRBCs and immature granulocytes are often present.

Recommended work-up for a leukoerythroblastic pattern

Normochromic, normocytic anemia
Anemia with anisocytosis
Leukemoid Reaction
Nonspecific pattern

Leucomoid Reaction

Mechanisms of LER
2.Extramedullary hematopoiesis :
as a compensatory response to either due to :
Bone marrow infiltration/fibrosis or
Bone marrow stress caused by severe chronic hemolytic anemias.

- Look for HB Level
Morphologic findings in the leukoerythroblastic pattern :
- Abnormal RBCs morphology
- Immature Myeloid Precursor
- Feature of PMF
Approach to diagnosis
Neucleated RBCs
Bone marrow infiltration in carcinoma, lymphoma (Hodgkin
lymphoma, non‐Hodgkin lymphoma), chronic lymphocytic
leukaemia, multiple myeloma, acute lymphoblastic leukaemia or
other malignant disease
Myeloproliferative neoplasms, particularly primary myelofibrosis and
chronic myelogenous leukaemia
Acute myeloid leukaemia and the myelodysplastic syndromes

Bone marrow granulomas, e.g. in miliary tuberculosis
Storage diseases, e.g. Gaucher disease
Acute haemolysis (including erythroblastosis fetalis)
Shock, e.g. due to severe haemorrhage
Severe infection
Rebound following bone marrow failure or suppression
Crises of sickle cell anaemia

Thalassaemia major
Severe megaloblastic anaemia
Systemic lupus erythematosus

The extent of anisopoikilocytosis in leukoerythroblastic reactions depends on the underlying pathology. Marked poikilocytosis with many teardrop cells usually indicates bone marrow infiltration. If the underlying etiology is stressed hematopoiesis (e.g. severe hemolysis, hemorrhage or severe infection), poikilocytosis is often less severe, except in thalassemia major or sickle cell anemia.
The following RBC changes are frequently observed in the leukoerythroblastic pattern:
Schistocytes (i.e. fragmented erythrocytes):
Are acquired when RBCs squeeze through fibrin strands (as in microangiopathic anemia) or an altered (rigidified) bone marrow (or splenic) microvasculature damaged by infiltration with accompanying fibrosis.
• A marked leukocytosis in the leukemoid range, similar to that associated with CML. The differential diagnosis can best be resolved by testing for BCR-ABL rearrangements.

• Increased hemoglobin or a marked thrombocytosis, with a minimal or absent leukoerythroblastic reaction, simulating PRV and ET, respectively. Laboratory investigations for PRV (such as the determination of RBC mass) can facilitate the distinction between early PMF and PRV .

A history of malignant neoplasm, exposure to radiation, chemotherapy (including G-CSF), sepsis, severe thermal injury, severe bleeding, or congenital/hereditary hemolytic anemia may indicate the cause of a leukoerythroblastic pattern.

• Supravital stains for Heinz bodies and/or a search for Hgb H inclusions.
• Hemoglobin electrophoresis with quantitation of globin chain synthesis.
• An osmotic fragility test and/or a direct Coombs test if spherocytes are present.
• Heat denaturation or isopropanol precipitation tests, if RBC abnormalities are minimal or bite cells are seen.
• Enzyme screening.
• Determination of plasma or urine Hgb.

If the peripheral blood findings and clinical history do not clearly indicate a benign etiology for the leukoerythroblastosis,

A bone marrow aspirate and biopsy are usually indicated. it is important that enough bone marrow is obtained for FCM immunophenotyping, cytogenetics , since these studies may be necessary to confirm the diagnosis.
Bone marrow barrier
 The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow.
Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium. Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.
In leukoerythroblastic reactions :
of circulating NRBCs varies depending on the severity of the underlying pathology. All of the different stages of erythroid maturation may be represented and NRBCs may exhibit qualitative abnormalities reflecting dyserythropoiesis , In the enumeration of circulating NRBCs, it is not necessary to separate the large early erythroid precursors (proerythroblasts and basophilic erythroblasts) from the late precursors (polychromatophilic and orthochromatic erythroblasts). Early erythroid precursors have deeply basophilic cytoplasm . The late precursors are smaller, with increased nuclear condensation and gray-blue to gray-brown cytoplasm indicating an accumulation of hemoglobin.
Neucleated RBCs
Myeloid Precursors
Peripheral blood findings suggestive of PMF
If the peripheral blood findings, or the clinical and laboratory data, suggest an underlying hemolytic anemia, the following additional studies may be helpful:

Features suggestive of Primary Myelofibrosis (PMF)

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