Table of contents
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Approach to Pancytopenia
- A - Aplasia
- I - Infiltration
- Malignant
- Primary - Malignancy
- Secondary - Metastasis
- Non-Malignant
- TB
- Malignant
- D - Dysplastic
- Primary - MDS
- Secondary - Alcohol, HIV
- S - Substrate
- B12, folate, low calorie intake
- S - Spleen
Aplastic Anemia
- Pathobiology:
- Abnormal suppressor T-cell line that suppresses bone marrow.
- Suppresses all 3 cell lines.
- Treatments target suppressor T-cells
- Classification:
- ANC (Absolute Neutrophil Count = [% of Neutrophils+ % Bands] * WBC)
- Normal ANC 4000
-
Severity ANC Very Severe <200 Severe 200-500 (Plts + Retics Low) Moderate 500-1000
- ANC (Absolute Neutrophil Count = [% of Neutrophils+ % Bands] * WBC)
- Causes:
- Congenital
- Must rule out secondary causes:
- Infectious: HIV, Hepatitis ABC
- Nutritional: Vitamin B12, Folate
- Drugs: Chloramphenicol, Sulfa Drugs, Gold
- Others: Toxins, Radiation Exposure
- Congenital: 20% inherited, most common Fanconi (see below)
- Idiopathic (Majority)
- Fanconi Anemia:
- Autosomal recessive (X-linked disorder) characterized by skin defects, short stature, hypogonadism, microcephaly, urogenital abnormalities, and marrow suppression.
- Many mutations/abnormalities in DNA... bone marrow failure.
- Diagnosed by chromosomal breakpoint analysis (fragile DNA)
- Presentation:
- Anemia: Fatigue, dyspnea, worsening angina
- Thrombocytopenia: Bleeding, Bruising
- Neutropenia: infection (sx rare)
- Diagnosis/Workup:
- Suspect in pts with pancytopenia without a particular cause.
- **Bone Marrow Biopsy** (essential)
- Note: Cellularity = 100-Age (i.e. 5yo has 95% cellularity)
- Acellular with increased fat space.
- **Bone Marrow Aspirate** (essential)
- Lack of stem cells and immature cells.
- Cytogenetics
- Further define the disorder (chromosomal abnormalities: MDS)
- Flow Cytometry (FLAER)
- To exclude PNH (aplasia predates hemolysis)
- Treatment:
- <40yo and healthy with HLA matched sibling
- Allogenetic hematopoietic stem cell transplant (Definitive Treatment)
- As get older, GVH disease risk increases (BM transplant less likely to work)
- Still 5-10% risk of MDS or AML
- If cannot transplant:
- Cyclosporine + Antithymocyte Globulin (equine or rabbit, horse one works better)
- Can result in long-term remission (50%), relapses occur during tapering of cyclosporin, may need chronic low-dose cyclosporine to maintain counts.
- Cyclosporine + Antithymocyte Globulin (equine or rabbit, horse one works better)
- Supportive Care:
- Prophylactic abx, antivirals (herpes), antifungals
- Need transfusions or RBC and platlets (<10,000 if not bleeding)
- Must minimize alloimmunization by leukodepletion (at collection and leukoreduction filter) (also decreases tfsn-associated fever).
- Give CMV negative products if CMV status unknown.
- Irradiated blood products (T-cells in blood can cause GVH disease)
- Annual screening for PNH clone is recommended. (aplasia predates classic hemolytic presentation of PNH)
- NOTE: Growth factor therapy are ineffective b/c don't have growth factor stem cells.
- <40yo and healthy with HLA matched sibling
- Source:
- MKSAP Lecture Series (audio)
Paroxysmal Noctural Hemoglobinuria
- Acquired Stem Cell Disorder due to dysfunction of the GPI linker protein.
- Pathophysiology:
- Mutations in PIG-A gene lead to reduction or absence of glycosylphosphatidylinositol (GPI) (erythrocyte anchoring protein).
- Lose GPI linker, as well as GPI-linked proteins
- Unable to anchor CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis)
- Absense of them on RBC surface leads to sensitivity to complement --> complement mediated destruction.
- Eventually PNH clone can infiltrate bone marrow.
- Mutations in PIG-A gene lead to reduction or absence of glycosylphosphatidylinositol (GPI) (erythrocyte anchoring protein).
- Characterized by triad:
- 1. Chronic hemolytic anemia (acquired)
- Iron deficiency (Urinary loss of Hb)
- 2. Venous Thrombosis
- unusual places: i.e. mesenteric and cerebral circulation.
- Unclear why (unclear why, perhaps through GPI-linked urokinase receptor or platelet activation from ADP released from hemolyzed cells)
- 3. Pancytopenia (predates hemolysis)
- GPI linker proteins on all cells
- 1. Chronic hemolytic anemia (acquired)
- Must exclude this in patients with marrow aplasia
- Diagnosis:
- Flow cytometry: look for CD55, CD59 (absent due to absence of linker protein)
- FLAER:
- Fluorescent linkled GPI linked molecule
- This typically detects a "PNH clone"
- FLAER:
- Flow cytometry: look for CD55, CD59 (absent due to absence of linker protein)
- Treatment
- In absence of hemolysis, typically not treated.
- Anticoagulation w/ warfarin:
- Indications:
- Active clot
- if >50% are CD55 and CD59 negative, addition of warfarin markedly decreases thrombosis. (Prophylaxis)
- (Source: MKSAP16, http://www.onlinecjc.ca/article/S082...10)00031-0/pdf)
- Indications:
- Eculizumab
- NEW! (2006-2014) RCT of eculizumab (humanized monoclonal ab against C5 terminal complement).
- Decreased transfusion requirements, improved QOL, decrease thrombosis.
- Higher risk of neisserial infection (MUST VACCINATE for meningococcus) due to complement inhibition.
- If Severe! (refractory hemolysis, or bone marrow failure)
- Treat similar to aplastic anemia (immunosuppressives or allogeneic BM transplant).
- NEW! (2006-2014) RCT of eculizumab (humanized monoclonal ab against C5 terminal complement).
- Corticosteroids:
- Reduce complement activation, improves Hb.
- Survival: 10-15y Median, often death from thrombosis
Pure Red Cell Aplasia
- Symptoms of anemia.
- Isolated normocytic anemia, only red cell lineage affected.
- Causes:
- Primary (Idiopathic)
- Secondary:
- Infection:
- Parvovirus B19 (rare, need concurrent hemolytic anemia, sickle cell, b/c red cells last >120 days), HIV
- Malignancy:
- Thymomas
- Lymphoproliferative Disorders (i.e. CLL)
- Large Granular Lymphocytosis (Granular lymphocytes, ++cytoplasm, blueish granules on smear), often few of these cells, if overproduced => LGL
- CD57 positive, and clonal if rearrangement studies, big spleen, rheumatoid condition (i.e. arthritis)
- Collagen Vascular and Autoimmune Disease
- Drugs (Phenytoin, Chloramphenicol)
- Pregnancy
- ABO incompatible transfusion
- Previous EPO treatment (anti-EPO antibodies)
- Infection:
- Evaluation:
- Virus testing (serologic, Parvovirus B19, HIV, Hepatitis)
- Chest Xray for thymoma.
- Management:
- Treat Cause (drugs, anti-infectives, chemotherapy, surgical resection to thymoma.)
- Prednisone, Anti-Thymocyte Globulin, Cyclosporine
- Can also use cyclophosphamide.
- (Historically keep transfusing until patient passes away).
- IVIG if Parvovirus B19 - but most often resolves by itself.
- Many resolve without therapy
- REF: MKSAP audio
Neutropenia
- Infection risk increases greatly when absolute neutrophil count if ANC < 500, and greatest in ANC < 200.
- Causes:
- Mild chronic congenital asymptomatic neutropenia (ANC 1000-1500) -> no risk of infection.
- Severe Congenital Neutropenia (varied inheritance/pathogenesis). Present early in life.
- Acquired:
- Drugs (MOST COMMON!, always ask old/new drugs)
- Chemotherapy (Antimetabolites, alkylating therapies - often given GCSF)
- Anticonvulsants: (Carbamazepine, Phenytoin)
- Antibiotics (cefalosporins, septra)
- Antiarrhythmics (Procainamide, Amiodarone)
- Antiinflammatories (NSAIDs, Gold salts)
- Vitamin Deficiencies: B12, Folic Acid
- Autoimmune Disorders (SLE, often mild neutropenia)
- Viral Syndromes (HIV, EBV, CMV, ricketsial infections, sepsis with S. pneumoniae, M. meningitidis)
- Malignancies (I.e. LGL)
- Drugs (MOST COMMON!, always ask old/new drugs)
- Cyclic neutropenia
- Abnormality in gene for neutrophil elastase.
- Fall in 21-day cycle (Collie dogs also have short-cycle neutropenias)
- Dampening problem (i.e. such as drunk person walk.. overcompensate both ways)
- Non-autoimmune Chronic Neutropenia
- Dx of exclusion
- NOTE: "Felty Syndrome"
- Rheumatoid Arthritis, Splenomegaly, Neutropenia
- Easy to remember "Feel the spleen".
- Workup
- If severe, new onset, excluded drugs
- Bone Marrow Evaluation
- Cytogenetic workup to ensure no myelodysplasia
- If severe, new onset, excluded drugs
- Treatments:
- Often self-limited, stop drugs (may take some time to resolve), replace vitamins.
- GCSF
- Effective in increasing neutrophil counts, decreasing infectious risks, improve aphthous ulcers.
- High risk for myelodysplasia, and AML.
- Effective in nadirs of cyclic neutropenia.
- Ref: MKSAP audio
Thrombocytopenia
- Isolated thrombocytopenia is not due to bone marrow syndromes!
- Causes
- Vitamin B12, Folate deficiencies (often causes pancytopenia)
PLATELETS --> See Platelet Disorders Section (Click here)
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