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hypoproliferative anemia II

Terms in this set (33)

Anemia of Chronic Disease
AKA--anemia of chronic inflammation, anemia of inflammation, hypoferremia of inflammation

Seen in wide variety of conditions

Characterized by reduced marrow RBC production (and likely reduced survival of RBCs)
-Trapping of iron in macrophages (i.e. Fe is not in available form)
-Inability to increase erythropoiesis in response to anemia (EPO not elevated enough, EPO precursors die prematurely?)
-Increased erythrophagocytosis

"Acute" variant
Anemia of Chronic Disease: Pathogenesis - cytokines
Likely key role of IL-1, IL-6, and TNF
-Triggered by inflammation or neoplasm
-Reduce EPO production
Anemia of Chronic Disease: Pathogenesis - Hepcidin
Acute phase protein critical in iron metabolism
Stimulated by cytokines
Inhibit release of iron from storage pool
Anemia of Chronic Disease: Clinical Findings
Widely variable presentation
-Usually normocytic (close to microcytic) anemia 10-12 g/dL
-Retics usually lower

Markers of inflammation may be present (CRP, fibrinogen, ferritin, ESR)

Serum iron and transferrin low
-Saturation normal or low (unlike iron deficiency)
-Soluble transferrin receptor normal (high in iron deficiency)
Anemia of Chronic Disease: DDX
Critical to distinguish from:
-Iron Deficiency
-Renal Insufficiency
-Thalassemia
-Multiple disorders (esp ACD and iron deficiency)

Generally not required, but a bone marrow biopsy may be helpful
Anemia of Chronic Disease: Treatment
Control/treat underlying disease or inflammation

Symptom driven management
-Transfusion
-Symptomatic therapies

EPO - may be helpful but remains controversial

Iron trial (esp if iron deficiency not excluded)
Aplastic Anemia
Key: diminished or absent hematopoietic precursors in bone marrow

"Anemia" is misnomer as it is pancytopenia (although profound anemia)

Classic findings:
-Pancytopenia
-Marrow aplasia

Recall the presence and significance of hematopoietic stem cells (suppression or disappearance of myeloid stem cells in AA)

Unlike other marrow failure syndromes that cause pancytopenia due to other causes (malignant stem cells...) (autoimmune or intrinsic abnl'y)
Aplastic Anemia: Etiology
May be congenital (i.e. Fanconi anemia; rare auto recessive d/o of DNA repair) or acquired (more common)

Direct stem cell destruction
-Radiation
-Drugs

Viral Infection (Parvovirus B19, HIV, hepatitis)

Immune hypothesis
-? Autoimmune, role of IFN-gamma, natural killer cell depletion

Clonal disorder - relationship with paroxysmal nocturnal hemoglobinuria (PNH)
Causes of Aplastic Anemia
Idiopathic
Cytotoxic Drugs and Radiation
-Anticipated effect in cancer treatment

Idiosyncratic drug reaction
-Chloramphenicol
-Gold
-NSAID - phenylbutazone,indomethacin
-Sulfonamides
-Antiepileptic drugs - felbamate
-Arsenicals

Toxic chemicals
-Benzene
-Lindane
-Glue vapors

Viral infections
-Parvovirus B19
-Non-A, non-B, non-C hepatitis
-HIV infection
-Epstein-Barr virus

Immune disorders
-Eosinophilic fasciitis
-Systemic lupus erythematosus
-Graft versus host disease

Miscellaneous
-Paroxysmal nocturnal hemoglobinuria
-Thymoma
-Thymic carcinoma
-Pregnancy
Aplastic Anemia: Clinical Features
Symptoms/Signs of Pancytopenia
-Hb: fatigue, weakness, angina
-WBC: recurrent infections
-Plt: bruising, bleeding
-Physical: no diagnostic feature (no HSM)

Labs
-Pancytopenia
-Low reticulocytes

Bone marrow
-Profoundly hypocellular
-No malignant cells
-Residual production normal (no megaloblastic features)

Other:
-Findings not consistent with PNH (flow cytometry),
-No hemophagocytosis,
-No cytogenetics consistent with MDS
Aplastic Anemia: Classification Moderate AA
Bone marrow cellularity <30%
Absence of sever pancytopenia
Depression of at least 2 out 3 lines
Aplastic Anemia: Classification Severe AA
Bone marrow biopsy <25% normal cellularity
<50% cellularity in which fewer than 30% are hematopoietic and at least 2 present: retics <40,000, ANC <500/ul, plts <20 K/ul
Aplastic Anemia: Classification very severe AA
Severe AA findings with ANC <200/ul
Aplastic Anemia: Treatment
Treatment of AA includes:
-Withdrawal of potentially offending agents
-Supportive care (e.g. transfusion, antibiotics)
Definitive therapy
hematopoietic cell transplantation (HCT)
immunosuppressive regimens

Note: blood and platelet transfusions should be used selectively in patients who are candidates for HCT in order to avoid sensitization
Sideroblastic Anemia
Indolent and progressive anemia
Congenital and acquired forms
Iron overload due to increased iron absorption associated with ineffective erythropoiesis
Iron overload in liver indistiguishable from hereditary hemochromatosis

Key organs:
-Pancreas: diabetes
-Cardiac: arrhythmias, congestive heart failure
-Children: growth impairment
Classification of Sideroblastic Anemia - heredity
X-linked
X-linked with ataxia
Sporadic congenital
Assoc. w/thiamine-responsive megaloblastic anemia (Rogers syndrome)
Associated with mitochondrial cytopathy (Pearson Syndrome)
Associated with mitochondrial myopathy and lactic acidosis
Classification of Sideroblastic Anemia - acquired idiopathic
Pure sideroblastic anemia
Refractory anemia with ring sideroblasts (RARS)
Classification of Sideroblastic Anemia - reversible
Alcoholism
Drugs (isoniazid, chloramphenicol)
Copper deficiency (zinc toxicity)
Hypothermia
Sideroblastic Anemia: Diagnosis - CBC
Mild anemia
Other cell lines normal (except with hypersplenism)
Microcytosis, low MCH (mean corpuscular hemoglobin)
nemia: Diagnosis - iron
Increased % saturation, low transferrin, increased ferritin
Marrow reticuloendothelial iron increased
May be seen on MRI, but may require liver biopsy
nemia: Diagnosis - Free erythrocyte protoporphyrin
elevated in anemia due to failure of iron incorporation into heme (low in X-linked)
nemia: Diagnosis - bone marrow
ringed sideroblasts
nemia: Diagnosis - molecular studies
mutations
Sideroblastic Anemia: Management
Key: prevention of iron overload

Acquired forms have predisposition to leukemia

Anemia
-X-linked may respond to pyridoxine
-Transfuse if necessary

Iron Overload
-Therapeutic phlebotomy - induction then maintenance
-Chelation - IV or new oral agents
Acquired Sideroblastic Anemia
Middle aged to older individuals

Two forms:
Pure sideroblastic anemia (only erythroid line)
MDS-form: refractory anemia with ringed sideroblasts (RARS)

Diagnosis: normocytic or macrocytic anemia, RBCs with basophilic stippling, ringed sideroblasts

Free erythrocyte protoporphyrin - elevated (often very high)

Iron studies consistent with iron overload

Marrow: erythroid hyperplasia, increased macrophage iron content, ringed sideroblasts

Management - as with inherited, although pyridoxine not likely to help
-Consider stem cell transplant in young individuals
-Possible use of G-CSF and EPO
-Do NOT remove spleen
Sideroblastic Anemia: Marrow Findings
Upper panel: bone marrow
aspirate stained with Prussian blue
to show red cell precursors with
numerous iron- positive granules
surrounding the nucleus, in some
cases forming a complete ring
(arrows).

Lower panel: Electron micrograph
of a single erythroblast with iron
laden (electron dense deposits)
mitochondia (red arrows) clustered
around its nucleus.
Reversible Sideroblastic Anemia
Anemia is corrected upon removal of precipitating cause

Associated conditions:
-Alcohol
-Drug Induced (isoniazid, chloramphenicol)
-Copper deficiency
Lead Poisoning
Controversy over inclusion as a sideroblastic anemia

But included in ddx of hypochromic-microcytic anemia (with or without basophilic stippling)

Cause: inhaled fumes, paint (esp children), lead particles in firing range, beverages from lead lined containers
Lead Poisoning: Manifestations
Usually chronic course

Autonomic neuropathy
-Abdominal pain and ileus
-Motor neuopathy

Lead line on gums

Renal dysfunction

Musculoskeletal and neuropsychiatric symptoms
Lead Poisoning: Diagnosis
Anemia may be later manifestation
Morphology: basophilic stippling and hypochromia (not ringed sideroblasts)
Elevated lead levels - blood or urine
Neurodevelopmental issues in children
lead poisoning tx
Remove offending source
Give EDTA by slow IV infusion
Alternative is dimercaptosuccinic acid (DMSA) (chelation)
Conclusions - Lecture 2
Anemia of chronic disease is a complex but common cause of anemia
Aplastic anemia is characterized by marrow aplasia and must be investigated for associated conditions
Sideroblastic anemias are not common but must be considered in hypochromic anemia
Lead poisoning is a dangerous condition that is easily treatable
Overall Conclusions
Anemia is more complex than most think
Remember that the blood can be a window to the body (bone marrow)
Don't forget the numbers game
Learn the key tests: CBC, MCV, RDW, blood smear morphology, serum studies
Watch for signs of marrow insufficiency
Think about occult malignancy in unexplained blood loss
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