Non-Malignant Leukocyte Disorders Flashcards
Organization of bone marrow
Indications for performing a bone marrow examination
- Unexplained decrease or increase in blood cell counts beyond the normal range
- Presence of abnormal cells in the blood, such as immature leukocytes
Normal bone marrow aspirate
“Dry tap”
When you tap someone’s bone marrow but you don’t get anything.
Indicates bone marrow fibrosis.
Bone marrow aspirate vs bone marrow biopsy
Bone marrow aspirate: Great for cytology, but doesn’t give much information about organization or cellularity of marrow biopsy, and may come back dry.
Bone marrow biopsy: Gives an idea of cellularity and organization of marrow, but not nearly as useful for cytological purposes.
Normal bone marrow biopsy
Normal vs aplastic anemia bone marrow biopsy
Where does marrow aplasia come from?
Marrow aplasia is thought to arise from genetic alterations in hematopoietic stem cells, either spontaneous mutations or mutations induced by an extrinsic insult such as a drug, toxin, or viral infection.
May be due to impaired capacity for proliferation, or due to acquired neoantigen and subsequent attack by CD8 T cells.
The most frequent cause of marrow aplasia
Iatrogenesis
Due either to drugs or radiation therapy.
Chloramphenicol
An antibiotic
For whatever reason, can induce irreversible aplastic anemia in an idiosyncratic manner, affecting only an extremely small fraction of exposed individuals.
Evaulating a patient with aplastic anemia
Elicit a thorough history of exposure to toxic chemicals, particularly hydrocarbons and other industrial solvents.
The most frequent offender is benzene. Viral infections, particularly non-A, non-B, and non-C hepatitis, can occasionally cause severe, irreversible marrow aplasia.
Idiopathic aplastic anemia
Patients with marrow aplasia not due to drugs, toxins, or viral infection
Clinical presentation of aplastic anemia
- Progressive fatigue
- Pallor
- Acute infection symptoms (if associated neutropenia)
- Petechiae and ecchymoses (if associated thrombocytopenia)
- Lack of lymphadenopathy
- Severe anemia on CBC with high retic count and therefore high MCV
Pancytopenia CBC
- Low erythrocytes
- Low thrombocytes
- Low neutrophils
- Low monocytes
- Often higher lymphocytes due to higher lifespans
Normal vs aplastic marrow density (%s)
30-50% is normal
aplastic is usually <10%
Therapy for aplastic anemia
- Discontinue myelosuppressive drug or toxin exposure
- Transfusion if needed
- Hematopoietic stem cell transplant
- Immunosuppression if CD8-mediated autoimmune process
- If HSC transplant not possible in severe cases, calcineurin inhibitors (cyclosporine) and antithymocyte/antilymphocyte globulin
Pure red cell aplasia
Severe anemia but normal white cells and platelets.
May be immune mediated, as suggested by presence of thymoma (tumor of thymic epithelial cells), lymphoma, or autoimmune disorder.
May be due to acquired anti-EPO in patients on EPO supplementation.
May be due to parvovirus B19.
Myelophthisis
Crowding out of bone marrow, most often by metastatic cancer.
Some causes, such as metastatic cancer, will also cause fibrosis of surrounding marrow, worsening the anemia.
Smear indicative of myelophthisic anemia with myelofibrosis
Neutrophil storage pool
Mature neutrophils that reside in the bone marrow, waiting for infection before springing out.
Neutrophil circulating pool
Neutrophils outside of the bone marrow and in the bloodstream circulating at any given moment
Neutrophil marginal pool
Neutrophils sequestered on the walls of blood vessels at any given moment
Normally, ___ of the neutrophils in the body are in the circulating pool
Normally, <5% of the neutrophils in the body are in the circulating pool
Myelopoiesis
“Left shift”
Release of band cells into circulation
Leukemoid reaction
Extreme leukocytosis due to left shift that mimicks leukemia
Leukoerythroblastosis
Inflammatory process involving the marrow itself that produce marrow fibrosis and distortion, leading not only to the release of immature myeloid elements but also nucleated erythroid progenitors and misshapen tear-drop red cells
Hereditary neutrophilia
Rare form of chronic granulocytosis that usually exhibits an autosomal dominant pattern of inheritance.
Often gain-of-function mutations in the granulocyte colony-stimulating factor (G-CSF) receptor that lead to marrow hyperstimulation and increased neutrophil production.
Down syndrome myeloproliferative disorder
About 10% of infants with Down syndrome develop a transient myeloproliferative disorder characterized by granulocytosis, circulating immature myeloid precursors, and hepatosplenomegaly.
This disorder appears to be caused by acquired mutations in the transcription factor GATA-1 that result in deregulated growth of myeloid progenitors. Resolves spontaneously in 75% of patients, but 25% develop full-blown acute myeloid leukemia over a period of months to several years.
Leukocyte adhesion deficiency
Rare autosomal recessive disorder. Deleterious effects on the function of β2 integrin (LAD I) or the selectin ligand PSGL-1 (LAD II).
Elevated neutrophil counts, particularly in the face of infection, due to an inability of neutrophils to adhere to endothelium and migrate into infected tissues.
Secondary causes of granulocytosis
- Stress (catecholamines and glucocorticoids cause demargination)
- Infection
- Inflammation of noninfectious etiology
- Drug reactions
- Marrow hyperstimulation (like in megaloblastic anemia or ITP)
Döhle bodies and toxic granulations
Both seen in neutrophils in acute infection.
Toxic granulation: Persistence of neutrophil granules.
Döhle bodies: pale blue cytoplasmic aggregates of endoplasmic reticulum
The second most common form of leukocytosis is ___
The second most common form of leukocytosis is eosinophilia
Causes of eosinophilia
- Th2 reaction
- Worm infection
- SLE or vasculitis (rheumatic disease)
- Certain myeloproliferative neoplasms
- Reaction to Hodgkin’s lymphoma
Basophilia
- Uncommon, if found usually in association w/ eosinophilia
- Sometimes seen in asthma or atopy
- Occurs in some myeloid neoplasms like CML
Monocytosis
Occasionally seen in association with tuberculosis or myeloid neoplasms, particularly those myeloproliferative neoplasms in which the monocytes and their precursors are a component of the malignancy.
Lymphocytosis
- Most commonly due to gamma group Herpesvirus infection
- Bordetella pertussis releases a toxin that inhibits the migration of lymphocytes out of the blood into lymph nodes, causing lymphocytosis
Activated CD8 T cells
Characteristically have abundant cytoplasm containing a few azurophilic granules and are sticky, often adhering to surrounding red cells
Mononucleosis
Evaluating neutropenia
- Helpful to obtain serial neutrophil counts
- Careful history can determine whether the neutropenia is likely to be acute or chronic
- Examine oropharynx, lymph nodes, spleen, and perianal region for signs of infection
Treatment of neutropenia
Initial treatment: Manage complications!!! If the patient has a fever, give them broad spectrum antibiotics immediately, even if cultures are negative.
Long-term treatment: Restore neutrophil count. Stop nonessential drugs (resolves 7-10 days), G-CSF administration, HSC transplant. Autoimmune may be managed with glucocorticoids. LGL responds well to glucocorticoids and low-dose methotrexate,
Common causes of lymphopenia
- HIV
- Chronic corticosteroid treatment
- DiGeorge syndrome (thymic aplasia due to germline deletions involving chromosome 22q11)
- SCID (RAG1/RAG2 mutations)
Qualitative neutrophil dysfunction
- Lack of adhesion
- Lack of chemotaxis
- Lack of pathogen recognition and phagocytosis
- Lack of granule fusion machinery (inability to degranulate)
- Lack of pathogen-killing equipment (especially Phox)
Chédiak-Higashi syndrome
Disorder affecting neutrophil granules. Abnormal granules in this disorder result in impaired bacterial killing.
Hemophagocytic lymphohistiocytosis
Variety of settings and has a number of triggers. Common feature in all is the activation of macrophages throughout the body due to overstimulation by factors released by effector T cells. Activated macrophages phagocytose hematopoietic cells and release additional cytokines and chemokines, producing a systemic inflammatory state associated with cytopenias.
What’s wrong with this bone marrow aspirate?
Hemophagocytic histiocytosis
Treating HLH
- Primary: Responds to chemotherapy and immunosuppressive agents but inevitably recur unless hematopoietic stem cell transplantation is performed.
- Secondary: Treat with therapy for the underlying illness, but also require HLH management with chemotherapy and immunosuppressive agents. Etoposide particularly effective.
Etoposide
Topoisomerase II inhibitor, chemotherapeutic
Spicule
Mix of fat and bone bits. Come through on bone marrow aspirates. If you are looking at what you are told is a marrow aspirate and you don’t see this, you have been horribly deceived, this is not a bone marrow aspirate.
This may occur with “hemodilute” aspirates, i.e. aspirates that are really more blood than bone marrow.
Normocellular marrow
Equally cells and fat
Kids may have less fat, geriatrics may have more
Bone marrow biopsy or aspirate precursor lineages
Granulopoiesis summary
“Leukemoid reaction” is really two things together
Leukocytosis + left shift
Leukoerythroblastic response is really 3 things:
Left shift, leukocytosis, erythrocytosis
Overproduction and “left shift” of all lineages
___ antibiotics may trigger leukocytosis.
-cycline antibiotics may trigger leukocytosis.
Elevation of platelet count in leukemoid reaction is probably ___.
Elevation of platelet count in leukemoid reaction is probably a physiologic response.
Slgiht thrombocytopenia is often part of the acute phase response and is non-malignant.
You are only really worried about neutropenias that are under ___.
You are only really worried about neutropenias that are under 500 per unit vol.
Benign neutropenia of childhood
Presents in some infants (6-12 months)
Do get some prophylactic antibiotics, but almost always resolves by end of early childhood.
Neutropenia may result following ___ infection.
Neutropenia may result following viral infection.
Managing a patient with neutropenia
Preventive: Neutropenic precautions, isloation, + pressure
Supportive: Aggressive antibiotics during infection
Therapeutic:
- Immune etiology: steroids, IVIG
- Neutropenia of immunodeficiency: methotrexate
- Congenital neutropenias and drug-induced neutropenias: G-CSF
- Severe congenital neutropenias: HSC transplant
Lovitch Leukocytosis Flowchart
Lovitch Neutropenia Flowchart
Lovitch Pancytopenia Flowchart
One platelet on a 40x field is roughly ___ in circulation.
One platelet on a 40x field is roughly 10,000 per unit in circulation.
EDTA artifacts on smear
EDTA in blood preparation may result in some burr/spur cells as an artifact. This is not abnormal.
What are the major sources of G-CSF?
- Endothelial cells
- Fibroblasts
- Macrophages
Common causes of drug-induced leukocytosis
- Catecholamines (demargination)
- Beta adrenergics (demargination)
- Corticosteroids
General approach to leukopenia/leukocytosis
