Hemat Flashcards
? ml blood has 1 mg iron
2ml blood = 1mg iron
Daily requirement = 1-2mg
Iron chelation drugs
- Deferoxamine (IV/SC)
- Deferiprone
- Deferasirox
Deferoxamine (aka Desferrioxamine)
- Deferoxamine
- IV/SC
- Prefer: Slow SC infusion over 8-12h
- SE: Local skin reactions, infection (Yersinia, Klebsiella), Growth retardation, skeletal abnormalities in children, hearing, visual problems
Deferiprone
- Deferiprone
- Oral
- 75mg/kg/day given tds
- Better cardiac function than Desferoxamine
- SE: Agranulocytosis (0.2/100 in 1y; CBC weekly at least in first 3 months), Arthropathy
- 1st line in thal major (but not in other transfusion dependent patient)
- Switch to Deferasirox if agranulocytosis
Deferasirox
- Deferasirox
- Oral, long half-life
- Once daily 20-30mg/kg
- SE: GI disturbance, reversible rise in creatinine
- CI in renal failure
Mx of thal major
- Confirm Dx with Hb pattern and thalassemia genotype; Screen family members
- Extend RBC Ag typing before transfusion to safeguard development of alloautoAb in future
- Check HBV, HCV, HIV before transfusion
- Give Rh C, c, E, e, Kell Ag compatible blood to minimize alloimmunization
- Aim pre-transfusional Hb at 9, Usual transufsion interval 3-4 wk
- Give WBC reduced, fresh packed cells
- Perform full pre-transfusion compatibility test and Ab screening before each transfusion
- Splenectomy only if Sx of splenomegaly or transfusion requirement >200ml/kg/yr as result of hypersplenism
Monitor iron overload
- Serum ferritin
- Monitor ferritin every 3m
- Iron chelation to keep ferritin <2500mg/L (preferably 1000)
- Persistent >2500 –> increased cardiac risk, mortality
- Ferritin monitoring often underestimates degree of iron overload in Thal intermediate
Tumor lysis syndrome
Hyper
-uric acid, K, phosphate, LDH
Hypo
-Ca
Tx
- Aggressive hydration (beware of fluid overload)
- Alkalinzation of urine (may worsen RFT due to Ca phosphate deposition)
- Allopurinol, Febuxostat (Xanthine oxidase inhibitor)
- Rasburicase (Recombinant urate oxidase in Aspergillus flavus, avoid in G6PD deficiency)
- Renal replacement therapy
- Monitor WBC, tumor size, fluid intake, urine output, body weight, electrolytes, RFT, LDH, pH, PT/APTT
LDH
A Lie
Lactate dehydrogenase
- Located in inner surface of cell membrane
- Converts lactate to pyruvate
- Anaerobic reaction
Bite cells
G6PD
aka Degmacyte
>=1 semicircular portions removed from the cell margin
Bites: due to removal of denatured Hb by MQ in the spleen
G6PD: uncontrolled oxidative stress causes Hb to denature and form Heinz bodies
Schistocyte
Fragmented part of RBC
In DIC, TTP, artificial heart halves
Hypersplenism 4 cardinal features
- Pancytopenia
- Hyperplastic BM
- Corrected by splenectomy
- Splenomegaly
Lab features of Hemolytic anemia
- Anemia - usu mild macrocytic, with reticulocytosis
- ↑Unconjugated bilirubin, LDH, methemalbumin
- ↓Serum haptoglobin
- Blood film
- Polychromasia
- Spherocytes (hereditary spherocytosis, immune hemolytic anemia)
- RBC fragmentation (microangiopathic hemolysis)
- RBC agglutination (cold agglutinin disease) - Direct antiglobulin test (Direct Coomb’s test) – positive in immune hemolytic anemia
AI hemolytic anemia
Warm (IgG), Cold (IgM)
- Both can be due to secondary cause
- Warm: Drug (e.g. Methyldopa), SLE, CLL
- Cold: infection e.g. Mycoplasma, IM, lymphoproliferative disorders
Tx of AIHA
- Transfusion if needed
- Folate supplement
- Decrease further hemolysis: steroid, avoid certain drugs, keep warm for cold hemagglutinin disease, splenectomy
- Treat underlying causes e.g. lymphoproliferative disorders
Dx of AIHA
- ↑Reticulocytes
- Blood film showing microspherocytes
- ↑Unconjugated bilirubin, LDH, methemalbumin
- ↓Haptoglobin
- Specific tests: Direct antiglobulin test (aka Direct Coombs’ test)
Aplastic anemia, clinical features
- Pancytopenia resulting from BM hypoplasia or aplasia
- Can be Congenital/Acquired (Acquired: Idiopathic/Secondary)
- Can be pure red cell aplasia, e.g. Diamond-Blackfan syndrome, or asso w/ large granular lymphocytosis
Clinical features
- Symptoms of pancytopenia
- No lymphadenopathy
- No hepatosplenomegaly
- Look for congenital physical abnormalities in young patients (inherited BM failure syndromes)
Etiology of Aplastic anemia
Idiopathic (70-80%)
- Pathogenesis (for idiopathic)
- Immune mediated T cell destruction of BM stem cells (IL-17 CD4, TH-17)
- Over-expression of HLA-DR2
- Polymorphism in perforin gene / TNF-alpha gene
- ∴Tx is by immunosuppressant
Congenital: Fanconi anemia, Shwachman-Diamond syndrome, Dyskeratosis congenita
Drugs: Gold, alcohol, diclofenac acid, indomethacin, chloramphenicol, anti-convulsants
Infection: Non-A/B/C hepatitis (Seronegative hepatitis)
Environmental: Benzene, pesticide
Tx of Aplastic anemia
- Supportive
- Cyclosporin A
- Anti-thymocyte globulin + Cyclosporin
- 1st line = Allogeneic HSCT (for young patients with matched sibling donors)
- Eltrombopag (high dose) – for relapse/refractory cases
Ix of Aplastic anemia
- CBC: Pancytopenia, macrocytic anemia (not as big as blasts), low reticulocyte
2, Blood film - AI markers
- Vit B12 and folate levels
- BM: Trephine biopsy to assess cellularity
- Specialized tests
- Ham tests/flow cytometry to rule out PNH (Paroxysmal Nocturnal Hemoglobinuria)
- Chromosome breakage with diepoxybutane (to screen for Fanconi anemia)
Hereditary spherocytosis, clinical features
- Presence of Spherocytes
- Hemolytic anemia
- AD inheritance
- 60% due to a defect in ankyrin-spectrin complex or vertical interaction
Features
- Jaundice
- Splenomegaly
- Gallstones
- Aplastic crisis (Primary parovovirus B19 infection – more prone + because of the reduced RBC half-life, more likely to have severe anemia)
- Extravascular hemolysis
- Blood film showing Spherocytes
- MCHC often raised
Specific test for Hereditary spherocyotsis
- Osmotic fragility test
2. Eosin-5-maleimide binding (↓binding in HS)
Tx for Hereditary spherocytosis
- Folic acid supplement
- If compensated hemolysis – no specific tx
- Cholecystectomy if symptomatic gallstone
- Splenectomy if severe hemolysis
Anticoagulation scheme for DVT
- 1st week: Heparin (overlaps Warfarin @ Day 3-7)
- 3rd day to 3-6 months: Warfarin
- Reason for not starting Warfarin at once: Protein C and S is also vitamin K dependent
G6PD
- X-linked recessive
- HK: 4.5% in M; 0.5 in F
- Type B refers to wild type
- 4 classes; Class 1 most severe
- Intravascular hemolysis with hemoglobinuria – acute/chronic (not common)
- Precipitated by infection or acute medical illness. drugs, Fava beans
- Drugs: Sulphonamide, Anti-malarial
- Blood film: Polychromasia, ghost / hemi-ghost cells
- G6PD assay maybe normal during acute phase as young RBC and reticulocytes may have normal G6PD levels
Tx
- Supportive
- Blood transfusion
- Folic acid
- Stop and avoid offending agents
R-CHOP
Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisolone
Cx of Iron overload
- Cardiomyopathy (HF is 1st cause of death)
- Hormonal deficiency: Hypogonadism, DM, HypoT, HypoPTH, GH deficiency, etc
* Untreated Thal Major can lead to Slow Growth and Puberty delay too - Liver Fibrosis and Cirrhosis (Uncommonly Severe enough to cause Cirrhosis)
- Hyperpigmented due to deposition on skin
Ix for Leukemia
- CBC w/ D
- PBS
- BM exam
- Morphology (Auer rods in AML)
- Cytochemistry (Myeloperoxidase in Myeloid lineage)
- Immunophenotyping
- Genetic tests
- Cytogenetics (Chromo)
- FISH (genes)
- PCR (genes, mRNA)
Induction for AML
Cytarabine x7d
Daunorubicin x3d
Induction for ALL
Cyclophosphamide Daunoubicin Vincristine Prednisolone L-asparaginase ?Dexamethasone ?MTX ?Cytarabine ?Doxorubicin
CNS prophylaxis for ALL
Intrathecal MTX
+
Cranial irradiation
Consolidation
2-6m, about 1 course/month
Indication for HSCT in AML
- 2nd complete remission for HLA identical donors, or MUD available
- 1st complete remission for intermediate/high risk AML for suitable donor available
Tx for APML
All-trans retinoic acid
Arsenic trioxide
Chemo: Cytarabine, Daunorubicin
Translocation for ALL
t(9;22)
Can add TKI (Imatinib, Dasatinib)
International prognostic index (IPI) for NHL
- Tumor stage (Ann-Arbor system)
- Serum LDH (represents tumor bulk)
- No. of extranodal disease stage
- Performance status (Ambulatory > Bed-ridden)
- Age
Principle of Mx of Lymphoma
- Chemo = main tx
- Anti-CD20 Ab for B cell lymphoma on top of chemo
- RT – for consolidation, relieve of obstruction, palliative tx
- Also used for Low-grade lymphomas, but always recur (chemo not given), RT to prevent local recurrence
- Consolidation tx for >10cm, i.e. bulky, high risk of local recurrence
- Relief obs - SVCO, brain obs
- Good palliative tx for chemo refractory cases
- Surgery – for tumor bleeding and obs; localized and indolent lymphoma (e.g. eyelid lymphoma)
- Symptomatic tx and psychosocial support
Ann Arbor system for Hodgkin lymphoma
- Stage 1: 1 group of LN
- Stage 2: 2 groups of LN on same side of diaphragm (i.e. either above or below)
- Stage 3s: Across diaphragm (either top to below or below to top; s means spleen)
- Stage 4: Involves non-lymphatic organ
Each stage can be categorized into A (Asymptomatic) or B (Constitutional symptoms)
*Difficult to apply in Non-Hodgkin lymphomas (NHL), but still used because no better classification
Lymphoma - other considerations
- Cx that require urgent attention
- Bleeding (ulcerative lymphoma in stomach –> GIB)
- Infection
- Obstruction (SVCO can be fatal) - Hepatitis status
- HBV occult carriers may have flare-ups if given intensive chemo, causing reactivation
- HCV: always find out underlying reason for HCV infection (transfusion, IV drug addicts) - HIV
- HIV test is routine for patients with lymphoma
- Need HIV tx tgt with lymphoma tx because need CD4 to work - Ig pattern / Serum protein immuno-electrophoresis
- Positive monoclonal band as marker to monitor progress - CVS function
- Anthracycline (e.g. Doxorubicin) leads to cardiac toxicity - Lung function
- Methotrexate, Bleomycin lead to lung toxicity - LRFT
- For baseline
Reed-Sternberg cells
- Hodgkin’s lymphoma
- Owl’s eye appearance (symmetric mirror image bilobed nucleus)
Histological exam for Lymphoma
- Morphology
- Follicles: Enlargement vs Effacement抹消
- Diffuse large B-cell lymphoma shows no follicles, effaced, replaced by sheets of large cells
- Follicular lymphoma shows enlarged follicles - Immunostaining
- Determine B or T cell *CD-20 for B cell - Clonality study
B cells (lymphoma vs reactive)
- Neoplasm = Clonal, arise from 1 type of lymphoid cell only
- B cell lymphoma: from same B cell lineage / 1 single clone, express only lamba OR kappa chain but not both
- Reactive: Some cells lambda, some kappa
T cells
- T cell receptor gene rearrangement
- PCR to see if cells belong to same clone
- Sharp band (gene rearrangement) instead of smearing/shadow = more suggestive of T cell lymphoma
Ix for Lymphoma
- CBC
- BM examination
- BM aspiration or trephine biopsy for histological Dx - Imaging
- CXR – may present w/ SOB, shows mediastinal LN involvement
- CT: Gold standard
- PET/CT: see if aggressive –> look for anatomical imaging + metabolic activity of lesion (high grade shows high metabolic activity; low shows low)
- MRI: when CT is not clear - Excisional biopsy of LN for histological examination
CML does not present with lymphadenopathy!
> _>
B cell lymphoma grades
High grade
- Diffuse large B cell lymphoma
- Burkitt lymphoma
- -> Dangerous, may die in short, but highly curable if early tx by intensive chemotherapy
Low grade
- Follicular lymphoma
- MALT lymphoma (indolent, no need to rush)
- -> Safe, can be untreated for months, but not curable (always recur), requires less aggressive tx
*MALT: Mucosa associated lymphoid tissue
Clinical manifestations of Lymphoma
- Enlargement of LN (Nodal) / extranodal organs (Extranodal)
- Systemic symptoms: fever, night sweats, weight loss (>10% in 6 months)
CML
- Cytogenic analysis - t(9;22); philadelphia chromosome
- Molecular analysis (BCR-ABL1 fusion gene)
> _>
JAK2 mutation in other Myeloproliferative disorders
Esp Polycythemia vera
> _>
Triphasic for CML
Chronic phase
Accelerated phase
Blast phase
Specific tx for CML
Cytotoxic chemotherapy
- Hydroxyurea, Busulphan, Thioguanine
Biological agent
- Interferon-alpha (now rarely used)
Signal transduction (Tyrosine kinase) inhibitors
- 1st gen: Imatinib, 2nd gen: Dasatinib, Nilotinib
- 1st line tx = 2nd gen TKI
- Target level = IS (international scale) ratio of <0.1% (from BCR-ABL/ABL ratio, PCR)
Allogeneic HSCT
- For failed TKI
Complications of HSCT
- Infection
- Hemorrhage
- Veno-occlusive disease of liver (VOD)
- Graft-versus-host disease (GVHD) (allo HSCT)
- Graft rejection (i.e. host-versus-graft) (allo HSCT)
- Cataract (mainly due to total body irradiation (TBI))
- Immunodeficiency
- Endocrine dysfunction & infertility
- Secondary malignancy
- Relapse of disease
2nd gen TKI for CML / ph+ ALL
Dasatinib
Nilotinib
TTP pentad
Fever Changes in mental status Thrombocytopenia Abnormal RFT Microangiopathic hemolytic anemia
