Haemotolgy Flashcards
Vincristine
Inhibits formation of microtubules, mitotsis inhibitor (M stage of cell cycle)
AE - Peripheral neuropathy (reversible)
Cisplatin
Causes Cross-linking in DNA
AE Ototoxicity, peripheral neuropathy,
hypomagnesemia
Bleomycin
Degrades preformed DNA
AE Lung fibrosis
Doxorubicin
stabilizes DNA-topoisomerase II complex. Inhibits DNA & RNA synthesis
Cardiomyopathy
Methotrexate
Inhibits dihydrofolate reductase and thymidylate synthesis
Myelosuppression, mucositis
Cyclophosphamide
Alkylating agent - causes Cross-linking in DNA
hemorrhagic cystitis (incidence ↓ by the use of hydration and mesna), myelosuppression, transitional cell carcinoma
Docetaxel
revents microtubule depolymerisation & disassembly, decreasing free tubulin
Neutropaenia + peripheral neuropathy
Imatinib*
inhibitor of the tyrosine kinase associated with the BCR-ABL defect →CML
Edema, nausea, rash and musculoskeletal pain are common but mild. Severe congestive cardiac failure is an uncommon but recognized side effect
Extravasation of chemotherapy:
extravasation should be suspected if a patient complains of pain, burning, swelling or redness at the site of the infusion cannula.
Immediate management would consist of stopping the infusion, immobilizing the arm and attempting to aspirate any accessible drug from the cannula and extravasation site before removal of the cannula.
* Agent specific antidotes can be given after receiving specialist advice. Cold compresses are generally applied except in the case of vinca alkaloids in which case a heat compress should be applied.
* Doxorubicin or daunorubicin extravasation injuries are particularly prone to causing ulceration, particularly on the back of the hand and hence a plastic surgery consultation is likely to be needed, Use topical corticosteroids to treat the site of inflammation.Consider reporting to the National Extravasation Information Service
Blood transfusions - * Bacterial contamination
Bacterial contamination is very rare with red cell transfusions and more common with platelet transfusions (which are stored at room temperature).
Blood transfusions - IgG antibodies cause
delayed extravascular hemolytic transfusion reactions much more commonly than acute intravascular reactions.
Blood transfusions - IgM anti-A and anti-B antibodies cause
acute hemolytic transfusion reactions. As little as 4 mm of transfused ABO incompatible blood can be fatal.
Delayed Transfusion Reactions:
occur 5-10 days post transfusion due to the development of red cell alloantibodies:
* Clinical features: usually minimal but can include unexplained pyrexia, jaundice or unexplained drop in hemoglobin.
* Diagnosis: Urinalysis shows urobilinogenuria and a blood shows fragile ballooned spherocytes, diagnosis is confirmed by Coombs test which is done by adding antihuman globulin (AHG) (anti-Ig G and anticomplement) to the patient’s washed RBCs. A positive test results in red cell agglutination.
Intravascular hemolysis
Causes:
* Mismatched blood transfusion
* G6PD deficiency
* Red cell fragmentation: heart valves, TTP, DIC, HUS
* Paroxysmal nocturnal hemoglobinuria
* Cold autoimmune hemolytic anemia
Extravascular hemolysis
- Hereditary spherocytosis
- Hemolytic disease of newborn
- Warm autoimmune hemolytic anemia
Cold Autoimmune hemolytic anemia (AIHA)
IgM
hemolysis best at 4°C
mediated by complement and is more commonly intravascular
Causes of cold AIHA
* Neoplasia: e.g. lymphoma
* Infections: e.g. mycoplasma, EBV
Warm AIHA
the antibody (usually IgG) causes hemolysis best at body temperature and hemolysis tends to occur in extravascular sites, for example the spleen. Management options include steroids, immunosuppression and splenectomy.
Causes of warm AIHA
* Autoimmune disease: e.g. Systemic lupus erythematosus*
* Neoplasia: e.g. Lymphoma, CLL
* Drugs: e.g. Methyldopa
Direct Coombs Test
used to detect these antibodies or complement proteins that are bound to RBCs; a blood sample is taken and the RBCs are washed (removing plasma) and then incubated with antihuman globulin (Coombs reagent). If this produces agglutination of RBCs, the test is positive, an indication that antibodies (and/or complement proteins) are bound to the surface of RBCs.
Indirect Coombs Test
used in prenatal testing of pregnant women, and prior to blood transfusion. It detects antibodies against RBCs that are present unbound in the serum. In this case, serum is extracted from the blood, and the serum is incubated with RBCs of known antigenicity. If agglutination occurs, the test is positive.
Hereditary spherocytosis
ost common hereditary hemolytic anemia in northern Europeans
* Autosomal Dominant defect of RBC cytoskeleton
* Biconcave disc → spherocyte
* Red cell survival ↓, destroyed by spleen
Sequestration crises
Sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
* Acute chest syndrome: dyspnea, chest pain, pulmonary infiltrates, low PO2 - the most common cause of death in adults (Hydroxyurea ↓ the incidence of acute chest syndrome)
* The most common cause of death in childhood: infraction and infection (Pneumococcus, Chlamydia, Mycoplasm)
Sickle Cell Disease
characterized by periods of good health with intervening crises. It is inherited as Autosomal Recessive. It s caused by mutation in β-globin chain of hemoglobin, causing hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the 6th position. The β-globin gene is found on the short arm of chromosome 11. The association of two wild- type α-globin subunits with two mutant β-globin subunits forms hemoglobin S (HbS).
Thrombotic crises
Also known as painful crises or vaso-occlusive crises
* Precipitated by infection, dehydration, deoxygenation
* Infarcts occur in various organs including the bones (e.g. avascular necrosis of hip), hand-foot
syndrome in children, lungs, spleen and brain.
Pernicious Anemia: Investigation
Anti gastric parietal cell antibodies in 90% (but low specificity)
* Anti intrinsic factor antibodies in 50% (specific for pernicious anemia)
* Macrocytic anemia
* Low WBC and platelets
* LDH may be raised due to ineffective erythropoiesis
* Also low serum B12, hypersegmented polymorphs on film, megaloblasts in marrow
* Schilling test
Sideroblastic anemia
where red cells fail to completely form heme, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired
Sideroblastic anemia causes
Congenital cause:
* Delta-aminolevulinate synthase-2 deficiency
Acquired causes
* Myelodysplasia
* Alcohol
* Lead
* Chloramphenicol and Anti-TB medications (INH + Pyrazinamide)
Sideroblastic treatment
Investigations
* Hypochromic microcytic anemia (more so in congenital)
* Bone marrow: sideroblasts and ↑ iron stores
Management
* Supportive
* Treat any underlying cause
* Pyridoxine may help
Pure red cell aplasia:
diagnosed when there is unexplained anaemia and reticulocytopenia, with a complete absence of red cell precursors in the bone marrow, but with preservation of other cell lines.
Pure red cell aplasia: Assciation:
- Either spontaneously or associated with
- Thymoma
- Autoimmune
- Lymphoproliferative disorder
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
commonest red cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in an X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad (fava) beans
Glucose-6-phosphate dehydrogenase (G6PD) deficiency features
Features
* Neonatal jaundice is often seen
* Intravascular hemolysis
* Heinz bodies on blood films
Glucose-6-phosphate dehydrogenase (G6PD) deficiency - drugs causing hemolysis
rugs causing hemolysis
* Anti-malarials: primaquine
* Ciprofloxacin
* Sulfonamides
* Co-trimoxazole (because it contains sulfa)
Paroxysmal nocturnal hemoglobinuria (PNH)
is an acquired disorder leading to hemolysis (mainly intravascular) of hematological cells. It is thought to be caused by ↑ sensitivity of cell membranes to complement (see below) due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
Paroxysmal nocturnal hemoglobinuria (PNH)
pathophysiology
- GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
- Complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly
bound to the cell membrane due a lack of GPI - Thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to
platelet aggregation
Paroxysmal nocturnal hemoglobinuria (PNH) Diagnosis and management
Diagnosis
* Flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test as the gold standard investigation in PNH
* Ham’s test: acid-induced hemolysis (normal red cells would not)
Management
* Blood product replacement
* Anticoagulation
* Eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being
trialled and is showing promise in reducing intravascular hemolysis
* Stem cell transplantation
Polycythaemia causes
Relative causes
* Dehydration
* Stress: Gaisbock
syndrome
Primauy * Polycythaemia Rubra Vera
2ndary COPD
* Altitude
* Obstructive sleep apnoea
* Excessive erythropoietin: cerebellar
hemangioma, hypernephroma, hepatoma, uterine fibroids*
Polycythemia Rubra Vera (PRV)
Myeloproliferative disorder c
aused by clonal proliferation of a marrow stem cell leading to ↑ RBCs, often accompanied by ↑ WBC (neutrophils) and ↑ platelets.
mutation in JAK2 is present in approximately 95% of patients with PRV
Polycythemia Rubra Vera (PRV) features
Features
* Hyperviscosity (headaches, tinnitus, visual disturbance, cyanosis, joint pain)
* Pruritus, typically after a hot bath
* Splenomegaly ± Hepatomegaly
* Hemorrhage (secondary to abnormal platelet function not number)
- Plethoric appearance
- Low ESR
- Hypertension in a third of patients
Polycythemia Rubra Vera (PRV) investigation
- ↑ Hemoglobin and hematocrit
- ↑ Leucocyte alkaline phosphatase (LAP)
- Additional:
o ±↑WBCand↑PLT o ±↑Plasmavolume o ↑ Vitamin B12
o ↑ Red cell mass
o ↓ Erythropoietin level
Polycythemia Rubra Vera (PRV) management
Management
* Venesection - first line treatment
* Hydroxyurea -slight ↑ risk of secondary leukemia
* Allopurinol & Phosphorus-32 therapy
Prognosis
* Thrombotic events are a significant cause of morbidity and mortality
* 30% of patients progress to myelofibrosis
* 5-15% of patients progress to acute leukemia
JAK2-positive PRV diagnosis criteria
A1 High hematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
A2 Mutation in JAK2
JAK2-negative PRV diagnosis criteria
diagnosis requires A1 + A2 + A3 + either another A or two B criteria
A1 Raised red cell mass (>25% above predicted) OR hematocrit >0.60 in men, >0.56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the hematopoietic cells B1 Thrombocytosis (platelet count >450 * 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers) B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin
Neutropenia:
Neutropenia is defined as an absolute peripheral blood neutrophil count of <2.0 × 109/l. There is a racial variation: black and Middle Eastern people may have neutrophil counts of <1.5 × 109/l normally.
Neutropenia: causes
Congenital neutropenia:
* Kostmann’s syndrome
* Chediak–Higashi
* Schwachmann–Diamond syndrome
* Cyclical neutropenia
Acquired neutropenia:
* Infection: viral e.g. influenza, HIV, hepatitis, bacterial sepsis.
* Drugs: anticonvulsants (phenytoin) – anti-thyroid (carbimazole) – phenothiazines
(chlorpromazine) – antibacterial agents (cotrimoxazole) – ACE-inhibitors (ramipril)
* Immune-mediated: SLE, Felty’s syndrome (Rheumatoid Arthritis + Neutropenia + Splenomegaly)
* Bone marrow failure: leukaemia, lymphoma, Hematinic deficiency
* Splenomegaly: any cause
Neutropenia Investigations:
Investigations:
* Blood film
* Hematinics: factors that ↑Hb (Iron, TIBC, Vit B12, Folic Acid, Vit D)
* Autoimmune profile bone marrow aspirate/trephine are indicated if there are severe or
prolonged neutropenia or features suggestive of marrow failure
Leukemoid reaction
- High leukocyte alkaline phosphatase score
- Toxic granulation (Dohle bodies) in the
white cells - ‘Left shift’ of neutrophils i.e. ↑neutrophils
or ≤ 3 segments of the nucleus
Myelofibrosis
Thought to be caused by hyperplasia of abnormal megakaryocytes [bone marrow cell
responsible for the production of blood thrombocytes (platelets)]
* The resultant release of platelet derived growth factor is thought to stimulate fibroblasts
* Hematopoiesis develops in the liver and spleen
Myelofibrosis features
Features
* E.g. Elderly person with symptoms of anemia e.g. Fatigue (the most common presenting symptom)
* Massive splenomegaly
* Hypermetabolic symptoms: weight loss, night sweats etc
Myelofibrosis lab findings
Laboratory findings
* Anemia
* High WBC and platelet count early in the disease
* ‘Tear-drop’ poikilocytes on blood film
* Unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
* High urate and LDH (reflect ↑ cell turnover)
Myelodysplasia Presentation:
Presentation:
* Anaemia }
* Infection
* Bleeding
Due to pancytopenia
Myelodysplasia
investigations:
* Serial blood counts show evidence of increasing bone marrow failure
* Bone marrow shows increased cellularity.
Management:
* < 5% blasts in the bone marrow → manage conservatively.
* ↑ WBC → gentle chemotherapy.
* < 60 years old → Intensive chemotherapy
Chronic Myeloid Leukemia genetics
The Philadelphia chromosome is present in more than 95% of patients with CML
. It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34:q11).
This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
Chronic Myeloid Leukemia Presentation
Presentation (40-50 years)
* Middle-age
* Anemia, weight loss
* Splenomegaly may be marked (lethargy, anorexia, abdominal discomfort – 75% palpable spleen)
* Hepatomegaly and lymphadenopathy are uncommon
* Spectrum of myeloid cells seen in peripheral blood
* ↓ neutrophil alkaline phosphatase
* May undergo blast transformation (AML in 80%, ALL in 20%)
Chronic Myeloid Leukemia Diagnosis:
Diagnosis:
* Philadelphia is confirmatory
* Peripheral blood film: (leukocytosis in all stages of differentiation within the myeloid linage)
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* Basophilia is important diagnostic marker especially when Philadelphia is absent
* Monocytopenia
* Bone-marrow hypercellularity with ↑ myloid-erythroid ratio
Chronic Myeloid Leukemia Management
Management
* Hydroxyurea (also used in PRV, painful attacks in sicklers and as antiretroviral in HIV)
* Interferon- α
* Imatinib (inhibitor of tyrosine kinase)
* Allogenic bone marrow transplant (optimum management)
Acute Myeloid Leukemia
s the most common form of acute leukemia in adults. It may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder (e.g CML, myelofibrosis). > 30% blasts are almost diagnostic of AML.
AML presentation
Presentation:
* Early signs are vague and non-specific (influenza-like)
* Persistent or frequent infections (due to ↓ WBC)
* Bruising and petechiae (due to ↓ PLT)
* Splenomegaly may occur but typically mild and asymptomatic. Lymph node swelling is rare.
AML Management:
hemotherapy: divided into two phases:
1. Induction: All types except M3 are given induction with cytarabine (ara-C) and an
anthracycline (such as daunorubicin or idarubicin).This regimen is known as “7+3”, because the ara-C is given as a continuous IVI for 7 days while the anthracycline is given for 3 consecutive days as an IV push.
2. Consolidation: even after complete remission, very few leukemic cells likely to remain undetected with current diagnostic techniques. If no further post-remission therapy is given, almost all patients will eventually relapse. Therefore, more therapy is necessary to eliminate non-detectable disease and prevent relapse — that is, to achieve a cure. The specific type of postremission therapy is individualized based on prognostic factors and general health:
For good-prognosis leukemias [t(8;21), and t(15;17)], patients will typically undergo an additional 3–5 courses of intensive chemotherapy
For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related AML), allogeneic stem cell transplantation is usually recommended
AML lassification - French-American-British (FAB)
MO - Undifferentiated
* M1 - Without maturation
* M2 - With granulocytic maturation
* M3 - Acute promyelocytic
* M4 - Granulocytic and monocytic maturation
* M5 - Monocytic
* M6 - Erythroleukemia
* M7 – Megakaryoblastic
aml Poor prognostic features
> 60 years
* > 20% blasts after first course of chemo
* Cytogenics: deletions of chromosome 5 or 7
Acute Promyelocytic Leukemia (APL) M3
Associated with t(15:17)
* Fusion of PML and RAR-α genes
* Presents younger than other types of AML (average = 25 years old) *
* Good prognosis (curable with well-documented treatment protocols)
* Treated with the ATRA in addition to induction chemotherapy. Care must be taken to prevent
DIC, complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation. APL is eminently.
Chronic Lymphocytic Leukemia (CLL)
is caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%)
CLL features
Features
* Often none
* Constitutional: anorexia, weight loss
* Bleeding, infections
* Lymphadenopathy more marked than CML
CLL Complications
Complications
* Hypogammaglobulinemia leading to recurrent infections → most common cause of death
* Warm autoimmune hemolytic anemia in 10-15% of patients
* Transformation to high-grade lymphoma (Richter’s transformation)
CLL Indications for treatment
- Progressive marrow failure: the development or worsening of anemia and/or thrombocytopenia
- Massive (>10 cm) or progressive lymphadenopathy
- Massive (>6 cm) or progressive splenomegaly
- Progressive lymphocytosis: > 50% ↑ over 2 months or lymphocyte doubling time < 6 months
- Systemic symptoms: weight loss > 10% in previous 6 months, fever >38oc for > 2 weeks, extreme fatigue, night sweats
- Autoimmune cytopenias e.g. ITP
CLL Immunophenotyping
Immunophenotyping will demonstrate the cells to be B-cells (CD19 positive). CD5 and CD23 are also characteristically positive in CLL
CLL management
None early on (when to start Rx is mentioned above)
* Chlorambucil to ↓ lymphocyte count
* Other options include fludarabine
CLL
Poor prognostic factors (median survival 3-5 years)
♂Sex
* Age > 70 years
* Lymphocyte count > 50
* Prolymphocytes comprising > 10% of blood lymphocytes
* Lymphocyte doubling time < 12 months
* Raised LDH
* CD38 expression positive
Veno-Occlusive Disease (VOD)
Hepatic veno-occlusive disease. It is a complication of high-dose chemotherapy given before a bone marrow transplant (BMT). The name sinusoidal obstruction syndrome is now preferred if VOD happens as a result of chemotherapy or bone marrow transplantation. Treatment is primarily supportive.
Veno-Occlusive Disease features
Features:
* Fluid retention (weight gain, generalized edema, pleural effusion)
* Hepatomegaly
* ↑ Bilirubin (Jaundice)
* Usually complicated by multi-organ failure
Veno-Occlusive Disease
U/S abdomen helps in diagnosis
* Liver biopsy shows centrolobar necrosis
Hairy Cell Leukemia
rare malignant proliferation disorder of B cells lymphocytes. It is more common in ♂s (4:1) and is usually classified as a sub-type of chronic lymphoid leukemia. Hairy cells are abnormal WBCs with hair-like projections of cytoplasm.
Hairy Cell Leukemia features
Features
* Pancytopenia (Monocytopenia is classical)
* Splenomegaly
* Skin vasculitis in 1/3 patients
* ‘Dry tap’ despite bone marrow hypercellularity (also seen in myelofibrrosis)
* Bone marrow biopsy migh show “fried egg appearance”
* Tartrate resistant acid phosphotase (TRAP) stain positive
Hairy Cell Leukemia Management
Management
* Chemotherapy is first-line: cladribine, pentostatin
* Immunotherapy is second-line: rituximab, interferon-α
* Splenectomy sometimes required
Acute Lymphoblastic Leukaemia:
causes damage and death by crowding out normal cells in the bone marrow, and by metastasizing.
ALL is most common in childhood with a peak incidence at 2-5 years of age, and another peak in old age.
The overall cure rate in children is ≈80%, and ≈45%-60% of adults have long-term disease-free survival. Acute → relatively short course of the disease (being fatal in as little as a few weeks if untreated)
Acute Lymphoblastic Leukaemia presentation
Presentation:
* Generalized weakness and fatigue
* Anemia
* Frequent or unexplained fever and infections
* Weight loss and/or loss of appetite
* Excessive and unexplained bruising
* Bone pain, arthralgia.
* Dyspnea due to lung infiltration.
* Lymphandeopathy, hepatosplenomegaly.
* Pitting edema in the lower limbs and/or abdomen
* Petechiae due to thrombocytopenia
ALL diagnosis
Diagnosis:
* Leukocytosis.
* Blast cells are seen on blood smear in 90% of cases
* Bone marrow biopsy is conclusive proof of ALL
* LP to detect CNS involvement.
* CXR: to look for mediastinal mass (common in ALL).
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* U&E to look for Tumor Lysis Syndrome.
* Immunophenotyping, establish whether the “blast” cells origin is B or T lymphocytes
* DNA testing; different mutations reflect prognosis.
Good prognostic factors ALL
Common ALL
* Pre-B phenotype
* Low initial WBC
* FAB L1 type
Poor prognostic factors ALL
- FAB L3 type
- T or B cell surface markers
- Philadelphia translocation, t(9;22)
- Age < 2 years or > 10 years
- ♂Sex.
- CNS involvement
- High initial WBC (e.g. > 100 * 109/l)
- Non-Caucasian
Leukoerythroblastic Anemia
left-shifted granulocytic series and nucleated red blood cells) with pancytopaenia. Also defined when there are immature cells (e.g myelocytes, and nucleated red blood cells) seen on the peripheral blood film.
Leukoerythroblastic Anemia Association:
↑ Bone marrow turnover e.g. in severe hemolytic anemia (in which case the reticulocyte count would be high).
- Myelofibrosis and Chronic Myeloid Leukaemia (where there would be splenomegaly, and the white cell and platelet count would usually be raised).
- Bone marrow invasion. Often in bone marrow invasion the invading malignancy will already have been diagnosed previously.
- Myeloma
- Polycythaemia Rubra Vera
- Osteopetrosis
- Tuberculous infiltration of the bone marrow
- Sarcoidosis
Hodgkin’s Lymphoma
is a malignant proliferation of lymphocytes characterized by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades. Hosgkin’s lymphoma is associated with EBV. 25% of patients have a constitutional upset, (night sweats, weight loss, fever, pruritus and lethargy)
Hodgkin’s Lymphoma Ann-Arbor
Ann-Arbor staging of Hodgkin’s lymphoma
* I: single lymph node
* II: 2 or more lymph nodes/regions on same side of diaphragm
* III: nodes on both sides of diaphragm
* IV: spread beyond lymph nodes
Hodgkin’s Lymphoma Other factors associated with a poor prognosis
Age = 45 years
* Stage IV disease
* Hemoglobin < 10.5 g/dl
* Lymphocyte count < 600/μl or < 8% *♂
* Albumin < 40 g/l
* White blood count = 15,000/μ
Classical Hodgkin’s lymphoma - Nodular sclerosing
MOST COMMON
composed of large tumor nodules showing scattered lacunar classical RS cells
background of
- reactive lymphocytes
- eosinophils and plasma cells with varying degress of collagen fibrosis/sclerosis.
Hodgkins lymphoma -
Mixed- cellularity subtype
common subtype
is composed of
- numerous classic RS cells
- numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells.
Without sclerosis. This type is most often associated with EBV infection and may be confused with the early, so-called ‘cellular’ phase of nodular sclerosing CHL. Good
Hodgkins lymphoma
Lymphocyte rich
s a rare subtype, show many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell Non-Hodgkin’s (B-NHL).
Best prognosis
Hodgkins lymphoma
Lymphocyte depleted
Rare + worse prognosis
composed of large numbers of often pleomorphic RS cells with only few reactive lymphocytes which may easily be confused with diffuse large cell lymphoma. Many cases previously classified within this category would now be reclassified under anaplastic large cell lymphoma
Hodgkins lymphoma
Diagnosis
Hodgkin results in patchy bone marrow infiltration, an isolated bone marrow biopsy may yield non-specific results.
* Bone marrow biopsy is more useful for staging of advanced disease.
* Lymph node biopsy would be more likely to be positive, Reed-Sternberg cell is evident on
microscopy
Hodkings lymphoma Management:
The choice of treatment depends on the age, sex, bulk and the histological subtype of the disease.
* Later disease (III, IVA, or IVB) are treated with combination chemotherapy alone.
* Large mass in the chest (regardless of stage) are usually treated with combined chemotherapy and radiation therap. Chemo includes: Doxorubicin, Bleomycin, Vincristine,
Cyclophosphamide and other cytotoxic drugs.
Non-Hodgkin’s Lymphomas:
are a diverse group of lymphomas that include any kind of lymphoma except Hodgkin’s lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive. Low-grade lymphoma is predominantly a disease of older people. Most non-Hodgkin’s lymphomas are of B cell phenotype, though T cell tumours are increasingly being recognized.
Non-Hodgkin’s Lymphomas Presentation:
- Most present with advanced disease, bone marrow infiltration being almost invariable.
- Burkitt’s lymphoma is a high-grade lymphoma, which was first described in children in West Africa who presented with a jaw tumour, extra-nodal abdominal involvement and ovarian
tumours. - Extra-nodal presentation is more common than Hodgkin’s disease.
- Renal impairment in non-Hodgkin’s lymphomas usually occurs as a consequence of ureteric
obstruction secondary to intra-abdominal or pelvic lymph node enlargement. - Anaemia, an elevated white cell count and/or thrombocytopaenia are suggestive of bone
marrow infiltration.
Non-Hodgkin’s Lymphomas Management:
Management:
* Lymph node biopsy is sufficient for a definitive diagnosis.
* It is essential for modern classification to submit the lymphoid tissue for immuno-phenotyping
and cytogenetic/molecular analysis.
* High-grade lymphomas are responsive to chemotherapy and potentially curable,
* Low-grade lymphomas are incurable with conventional therapy.
* Chemotherapy is the mainstay of treatment in most cases.
Burkitt’s Lymphoma
high-grade B- cell neoplasm (NHL). There are two major forms:
* Endemic (African) form: typically
involves maxilla or mandible
* Sporadic form: abdominal (ileo-caecal)
tumors are the most common form. More common in patients with HIV
Burkitt’s lymphoma gene
c-myc gene translocation, usually t(8:14). The Epstein- Barr virus (EBV) is strongly implicated in the development of the African form but the link to sporadic Burkitt’s is less clear
Tumor Lysis Syndrome association
This occurs after the initiation of a chemotherapeutic. TLS tends to occur in patients with bulky, rapidly proliferating, treatment-responsive tumors
Association:
* Acute leukemia
* High-grade non-Hodgkin’ s lymphomas.
* Pre-treatment ↑ LDH (levels of LDH correspond with tumor bulk)
Tumor Lysis Syndrome presentation
Manifestation: rapid development (48-72 hours after initiation) of
* ↑ kalemia (1st life-threatening abnormality)
* ↑ uricemia
* ↑ phosphatemia
* ↓ calcemia
* Acute renal failure.
Tumor Lysis Syndrome management
Management:
* Prevention is with good hydration before starting chemotherapy.
* ↑ uricemia → urine alkalinisation and allopurinol
* Osmotic diuretics are NOT first line therapy and may contribute to the precipitation
of uric acid in the renal tubules.
* Dietary modifications include restricting dietary potassium. *
t(9;22) Philadelphia chromosome
Present in > 95% of patients with CML
* This results in part of the Abelson (ABL) proto-oncogene being moved to the BCR
gene on chromosome 22
* The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase
activity in excess of normal
* Poor prognostic indicator in ALL and AML
t(15;17)
- Seen in acute promyelocytic leukemia (M3)
- Fusion of PML and RAR-α genes
t(8;14)
- Seen in Burkitt’s lymphoma
- MYC oncogene is translocated to an immunoglobulin gene
t(11;14)
Mantle cell lymphoma
* Deregulation of the cyclin D1 (BCL-1) gene
Hematological Malignancies: Infections
EBV:
Hodgkin’s and Burkitt’s lymphoma, nasopharyngeal carcinoma
Hematological Malignancies: Infections
HTLV-1 (Human T-lymphotropic virus Type I):
Adult T-cell leukemia/lymphoma
Hematological Malignancies: Infections
- HIV-1:
Hematological Malignancies infection
Helicobacter pylori:
gastric lymphoma (MALT)
Hematological Malignancies infection
Protozoa
Burkitt’s lymphoma
Irradiated blood
required in patients receiving a bone marrow transplant, patients with previous purine analogue exposure and a diagnosis of Hodgkin’s disease.
cytomegalovirus (CMV)-negative blood
should be used in patients who may need a bone marrow transplant in the future (since carriage of CMV increases transplant mortality).
Causes of Eosinophilia Pulmonary causes
Pulmonary causes
* Asthma
* Allergic bronchopulmonary
aspergillosis
* Churg-strauss syndrome
* Loffler’s syndrome
* Tropical pulmonary
eosinophilia
* Eosinophilic pneumonia
* Hypereosinophilic syndrome
Causes of Eosinophilia - infective
Schistosomiasis
* Nematodes: Toxocara,
Ascaris, Strongyloides * Cestodes: Echinococcus
Causes of Eosinophilia - drugs
Drugs: sulfasalazine, nitrofurantoin
* Psoriasis/eczema
* Eosinophilic leukemia (very
rare)
Hyper Eesinophilic syndrome:
are unknown cause disease, occurring most commonly in ♂ in the 30-40-year-age group with persistent and markedly raised peripheral blood eosinophil count.
Association:
* Lung involvement may occur
* Cardiovascular involvement with fibrosis and restrictive cardiomyopathy, which may lead to
mural thrombus formation and considerable morbidity and mortality.
* Angioedema or urticaria.
Hyper Eesinophilic syndrome treatment
is with high dose corticosteroids (e.g. prednisolone 50mg which leads to a response in around 50% of cases). Steroid sparing agents such as cyclophosphamide or azathioprine may also be of some value.
Factor VII deficiency
very rare, is inherited in an autosomal recessive fashion, and tends to cause a mild/moderate bleeding disorder, although the phenotype does vary. Treatment is by factor replacement with plasma-derived products or using recombinant activated factor VII
Vit. K deficiency APPT
Prothrombin time - prolonged
Partial thromboplastin time - prolonged
Bleeding time - unaffected
DIC APPT
Prothrombin time - prolonged
Partial thromboplastin time - prolonged
Bleeding time - Prolonged
Hemophilia APPT
Prothrombin time - unaffected
Partial thromboplastin time - prolonged
Bleeding time - unaffected
Acquired Factor VIII Deficiency association
Association:
* Malignancy
* Psoriasis
* Pemphigus
* Drugs: cephalosporins, penicillins
Acquired Factor VIII Deficiency diagnosis
Diagnosis:
* Bleeding tendencies
* APTT: is prolonged (intrinsic pathway).
* APTT doesn’t correct/will only correct slightly with the adding of normal plasma.
* Bethesda titre can quantify the inhibitor. There is a 20% mortality rate from acquired factor VIII
deficiency.
Activated protein C resistance
most common inherited thrombophilia
It is due to a mutation in the Factor V Leiden gene. Heterozygotes have a 5-fold risk of venous thrombosis whilst homozygotes have a 50-fold ↑ risk. Any white pt aged <45 with thrombotic event should make you think of factor V Leiden mutation.
most common inherited bleeding disorder
Von Willebrand’s
Hemophilia A
X-linked genetic disorder involving a lack of functional clotting Factor VIII and represents 90% of Hemophilia cases
Hemophilia B
X-linked genetic disorder involving a lack of functional clotting Factor IX (Christmas disease) It is more severe but less common than Hemophilia A
Hemophilia C
Autosomal genetic (not X-linked) lack of functional clotting Factor XI. It is not completely recessive: heterozygous individuals also show ↑ bleeding
Acquired Hemophilia Association:
Association:
* Autoimmune diseases: (Rheumatoid Arthritis or IBD)
* Drugs such as phenytoin.
Acquired Hemophilia Management:
Management:
* Where there are ↓ anti-factor VIII antibodies, factor VIII replacement may be all that is required.
* Where bleeding is a serious problem then immunosupression with corticosteroids +/- steroid sparing agents such as cyclosporine may be required.
Thrombophilia inherited causes
- Activated protein C resistance (factor V Leiden) * Antithrombin III deficiency
- Protein C deficiency
- Protein S deficiency
Thrombophilia: causes Acquired
- Antiphospholipid syndrome * The Pill (COCP)
Heparin works by
binding to antithrombin III, enhancing its anticoagulant effect by inhibiting
the formation of thrombin and other clotting factors. Patients with antithrombin III deficiency
may therefore by resistant to heparin treatment
Antithrombin III Deficiency
an inherited cause of thrombophilia occurring in approximately 1:2,000 of the population. Inheritance is autosomal dominant
Antithrombin III inhibits several clotting factors, primarily thrombin, factor X and factor IX. It mediates the effects of heparin
Antithrombin III deficiency comprises a heterogeneous group of disorders, with some patients having a deficiency of normal antithrombin III whilst others produce abnormal antithrombin III
Antithrombin III Deficiency Features
Features
* Recurrent venous thromboses
* Arterial thromboses do occur but is uncommon
Management
* Thromboembolic events are treated with lifelong warfarinisation
* Heparinisation during pregnancy*
* Antithrombin III concentrates (often using during surgery or childbirth)
*as patients with antithrombin III deficiency have a degree of resistance to heparin anti-Xa levels should be monitored carefully to ensure adequate anticoagulation
Antithrombin III Deficiency
Management
* Thromboembolic events are treated with lifelong warfarinisation
* Heparinisation during pregnancy*
* Antithrombin III concentrates (often using during surgery or childbirth)
*as patients with antithrombin III deficiency have a degree of resistance to heparin anti-Xa levels should be monitored carefully to ensure adequate anticoagulation
Von Willebrand’s disease
most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst hemoarthroses and muscle hematomas are rare.
Role of von Willebrand factor
* Large glycoprotein which forms massive multimers up to 1,000,000 Da in size
* Promotes platelet adhesion to damaged endothelium
* Carrier molecule for factor VIII
VwB
* types
:Type1 partial reduction in vWF (80% of patients)
* type 2: abnormal form of vWF
* type 3: total lack of vWF (autosomal
recessive) most sev
von Willebrand’s disease presentation
Presentation:
* Petechial skin
* Slightly elevated APTT
* ↓ factor VIII activity
von Willebrand’s disease investigation
Investigation
* Prolonged bleeding time
* APTT may be prolonged
* Factor VIII levels may be moderately ↓
* Defective platelet aggregation with ristocetin
von Willebrand’s disease management
Management
* Tranexamic acid for mild bleeding
* Desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade
bodies in endothelial cells. Used as prohyplaxis prior to procedures.
* Factor VIII concentrate
Thrombocytopenia
causes of severe thrombocytopenia
Causes of severe thrombocytopenia
* ITP
* TTP
* DIC
* Hematological malignancy
Thrombocytopenia
Causes of moderate thrombocytopenia
Causes of moderate thrombocytopenia
* Heparin induced thrombocytopenia (HIT)
* Drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)
* Alcohol and Vitamin B12 deficiency
* Liver disease
* Hypersplenism
* Viral infection (EBV, HIV, hepatitis)
* Pregnancy
* SLE/antiphospholipid syndrome
Idiopathic thrombocytopenic purpura (ITP)
immune mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb-IIIa or Ib complex. ♀:♂=2.6:1. Common cause of death is bleeding (mainly intracranial).
Idiopathic thrombocytopenic purpura (ITP) Investigations
Investigations
* Antiplatelet autoantibodies (usually IgG)
* Bone marrow aspiration shows megakaryocytes in the marrow. This should be carried out prior
to the commencement of steroids in order to rule out leukemia
Idiopathic thrombocytopenic purpura management
Management
* Oral prednisolone (80% of patients respond)
* Splenectomy if platelets < 30 after 3 months of steroid therapy
* IV immunoglobulins
* Immunosuppressive drugs e.g. Cyclophosphamide
Acute ITP
More commonly seen in children
o Equal sex incidence
o May follow an infection or vaccination
o Usually runs a self-limiting course over 1-2 weeks
Chronic ITP
More common in young/middle-aged women o Tends to run a relapsing-remitting course
Evan’s syndrome
ITP in association with autoimmune hemolytic anemia (AIHA)
Livedo reticularis
not commonly seen in TTP. It occurs more commonly in conditions such as
antiphospholipid syndrome and cholesterol embolism
HUS or TTP?
Neuro signs and purpura point towards TTP
Thrombotic thrombocytopenic purpura
Pathogenesis
Pathogenesis of thrombotic thrombocytopenic purpura (TTP)
* Abnormally large and sticky multimers of vWF cause platelets to clump within vessels
* In TTP there is a deficiency of caspase which breakdowns large multimers of vWF.
* Overlaps with hemolytic uraemic syndrome (HUS)
Thrombotic thrombocytopenic purpura
Features
Features
* Rare, typically adult ♀
* Fever
* Fluctuating neuro signs (microemboli)
* Microangiopathic hemolytic anemia
* Thrombocytopenia
* Renal failure
Thrombotic thrombocytopenic purpura
causes
Causes
* Post-infection e.g. Urinary, gastrointestinal
* Pregnancy
* Drugs: cyclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
* Tumors
* SLE
* HIV
Thrombotic thrombocytopenic purpura
management
anagement
* No antibiotics - may worsen outcome
* Plasma exchange is the treatment of choice
* Steroids, immunosuppressants
* Vincristine
Drug causes of pancytopenia
Cytotoxics
* Antibiotics: trimethoprim, chloramphenicol
* Anti-rheumatoid: gold, penicillamine
* Carbimazole*
* Anti-epileptics: carbamazepine
* Sulphonylureas: tolbutamide
Heparin Induced Thrombocytopenia (HIT):
severe immune-mediated drug reaction that can occur in patients receiving unfractionated heparin (at full therapeutic doses and low prophylactic doses, including the minute amounts in heparin flushes and on heparin-coated catheters) and those receiving low-molecular weight heparin (LMWH).
Antibodies usually develop after a patient has been on heparin for five or more days, but may develop sooner if there has been previous heparin exposure.
Heparin Induced Thrombocytopenia (HIT): Presentation:
HIT is strongly associated with thrombosis. Thromboembolic complications can be venous, arterial, or both, and include:
* DVT
* Pulmonary embolism
* Myocardial infarction
* Thrombotic stroke
* Occlusion of limb arteries.
Types:
*Heparin Induced Thrombocytopenia (HIT):
- Type I: usually occurs 48 to 72 hours post commensing heparing and PLT rarely < 100. PLT
returns to normal over 4 days and there is no ↑ risk of thromboembolism - Type II: much rarer and usually occurs 5 to 10 days after starting heparin, PLT usually <100, patients are at ↑ risk of thromboembolic events. Heparin products should be stopped and the
patient commenced on alternative medication
Management Heparin Induced Thrombocytopenia (HIT):
Stop all forms of Heparin
* Start alternative anticoagulant which do not cross-react with HIT antibodies, such as:
o Danaparoid o Lepirudin o Argatroban.
* Oral anticoagulation with warfarin should NOT be initiated for longer-term protection from further events until substantial platelet count recovery has occurred. HIT patients who are switched to warfarin alone after the discontinuation of heparin may paradoxically have worsening thrombosis and develop venous limb gangrene and skin necrosis.
Blood film - Hyposplenism
Target cells
* Howell-Jolly bodies
* Cabot’s rings
* Siderotic granules
* Acanthocytes
* Schizocytes
Blood film Iron-deficiency anemia
- Target cells
- ‘Pencil’ poikilocytes
- If combined with B12/folate deficiency a ‘dimorphic’ film
occurs with mixed microcytic and macrocytic cells
Blood film G6PD Deficiency
Heinz bodies
Blood film - myelofibrosis
- ‘Tear-drop’ poikilocytes
Blood film intravascular hemolysis
- Schistocytes
Megaloblastic anemia Blood film
- Hypersegmented neutrophils
Smudge or smear cells
CLL
Lymphocytes with polar villi
Splenic lymphoma with villous lymphocytes
Lymphocytes (mature) with cleaved nucle
Follicular lymphoma
Lymphocytes (immature) with prominent nuclei
ALL
Tartrate-Resistant Acid Phosphatase TRAP
Always +ve in hairy cell leukaemia
Sudan black B stain and myeloperoxidase
acute myeloblastic leukaemia
Terminal Deoxynucleotidyl Transferase Stain (TDT)
acute lymphoblastic leukaemia
Leukocyte Alkaline Phosphatase (LAP
↑ in polycythemia RV and myelofibrosis ↓ in chronic myeloid leukaemia
Hereditary Hemorrhagic Telangiectasia
Also known as Osler-Weber-Rendu syndrome, hereditary hemorrhagic telangiectasia is an autosomal dominant condition characterized by (as the name suggests) multiple telangiectasia over the skin and mucous membranes. 20 % of cases occur spontaneously without prior family history.
Features Hereditary Hemorrhagic Telangiectasia
Epistaxis
* Telangiectasia develop ob skin, mucous membranes and internal organs
* Associated with pulmonary and other AV malformations in 10%
* May present as iron-deficiency anemia secondary to bleeding in the GI
tract or nasal mucosa
Waldenstrom’s Macroglobulinemia features
Features:
* Monoclonal IgM paraproteinemia
* Systemic upset: weight loss, lethargy
* Hyperviscosity syndrome e.g. Visual disturbance
* Hepatosplenomegaly
* Lymphadenopathy
* Cryoglobulinemia e.g. Raynaud’s
* ↑ESR
Waldenstrom’s Macroglobulinemia managment
anagement:
* Alkylating agents
* Young patient may benefit from doxorubicin.
* Treatment includes the monoclonal antibody rituximab, sometimes in combination with
chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or Vincristine or with
thalidomide.
* Corticosteroids, such as Prednisone, may also be used in combination.
* Plasmapheresis can be used to treat the hyperviscosity (it does not address the underlying disease)
Monoclonal Gammopathy of Undetermined Significance vs myeloma
One of the key differentiating features between (MGUS) and myeloma is the absence ofcomplications such as immune paresis, hypercalcemia and bone pain
Differentiating features from myeloma
* Normal immune function
* Normal β-2 microglobulin levels
* Lower level of paraproteinemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)
* Stable level of paraproteinemia
* No clinical features of myeloma (e.g. Lytic lesions on x-rays or renal disease)
Monoclonal Gammopathy of Undetermined Significance Diagnostic Criteria:
Serum paraprotein <30 g/L AND
* Clonal plasma cells <10% on bone marrow biopsy AND
* NO myeloma-related organ or tissue impairment
Methemoglobinemia
Methemoglobinemia = oxidation of Fe2+ in hemoglobin to Fe3+
Hemoglobin which has been oxidised from Fe++ (Ferrous) to +++
Fe . This is normally regulated by NADH methemoglobin reductase, which transfers electrons from NADH to methemoglobin resulting in the reduction of methemoglobin to hemoglobin. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the left
Methemoglobinemia causes
Congenital causes
* Hemoglobin chain variants: HbM, HbH
* NADH methemoglobin reductase deficiency
cquired causes
* Drugs: sulphonamides, nitrates, dapsone, sodium nitroprusside, primaquine
* Chemicals: aniline dyes
Methemoglobinemia features
Features
* ‘Chocolate’ cyanosis
* Dyspnea, anxiety, headache
* Severe: acidosis, arrhythmias, seizures, coma
* Normal PO2 but ↓ oxygen saturation
Methemoglobinemia manaement
Management
* NADH - methemoglobinemia reductase deficiency: ascorbic acid
* IV methylene blue if acquired
Fanconi’s Anemia:
Autosomal recessive
* Aplastic anemia
* ↑ risk of AML
* Neurological manifestation
* Skeletal abnormalities
* Skin pigmentation (café-au-lait spots)
Screening for hemochromatosis
General population: transferrin saturation > ferritin
* Family members: HFE genetic testi
Hemochromatosis
is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. The British Committee for Standards in Hematology (BCSH) published guidelines for the investigation and management of hemochromatosis in 2000
Hemochromatosis Diagnostic tests
Molecular genetic testing for the C282Y and H63D mutations
* Liver biopsy: Perl’s stain
hemochromatosis
Presenting features
Early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)
* ‘Bronze’ skin pigmentation
* Diabetes Mellitus
* Liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition.
* Cardiac failure (2nd to dilated cardiomyopathy)
* Hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)
* Arthritis (especially of the hands)
hemochromatosis Reversible complications
Reversible complications
Cardiomyopathy * Skin pigmentation
hemochromatosis irreversible complications
- Liver cirrhosis**
- Diabetes mellitus
- Hypogonadotrophic hypogonadism * Arthropathy
Splenectomy:
Vaccs +abx
Vaccination
* If elective, should be done 2 weeks prior to operation
* Pneumococcal, HIB, meningitis A & C and annual influenza vaccination
Antibiotic prophylaxis
* Penicillin V: unfortunately clear guidelines do not exist of how long antibiotic prophylaxis should be continued. It is generally accepted though that penicillin should be continued for at least 2 years and at least until the patient is 16 years of age, although the majority of patients are usually put on antibiotic prophylaxis for life
Hyposplenism
Causes
Causes
* Splenectomy
* Sickle-cell
* Coeliac disease, dermatitis herpetiformis (HLA DR3)
* Graves’ disease
* SLE
* Amyloid
Aplastic Anemia: manamgent
Supportive
* Blood products
* Prevention and treatment of infection
Anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG)
* Prepared in animals (e.g. Rabbits or horses) by injecting human lymphocytes
* Is highly allergenic and may cause serum sickness (fever, rash, arthralgia), therefore steroid
cover usually given
* Immunosuppression using agents such as Cyclosporin may also be given
Stem cell transplantation
* Allogeneic transplants have a success rate of up to 80%
Macrocytic anemia
Megaloblastic causes:
Megaloblastic causes:
* Vitamin B12 deficiency
* Folate deficiency
* Cytotoxics e.g. Hydroxyurea
Macrocytic anemia
Normoblastic causes:
Normoblastic causes:
* Alcohol
* Liver disease
* Hypothyroidism
* Pregnancy
* Reticulocytosis e.g. Hemolysis * Aplastic anemia
* Myelodysplasia
* Drugs: cytotoxics
Thalassemia:
hemoglobinopathy resulting from defective synthesis of globin chains required for hemoglobin synthesis. Each copy of chromosome 16 has two genes for the alpha globin subunit (four in total), and each copy of chromosome 11 has one gene for the beta subunit (two in total). Adult hemoglobin HbA(α2β2), second adult hemoglobin HbA2(α2δ2), fetal hemoglobin HbF(α2γ2).
(α) Thalassemia
due to a deficiency of α chain in hemoglobin
* 2 separate α-globulin genes are located on each chromosome 16
* Clinical severity depends on the number of α chains present
* If 1 or 2 α chains are absent then the blood picture would be hypochromic and microcytic, but
the Hb level would be typically normal
* Loss of 3 α chains results in a hypochromic microcytic anemia with splenomegaly. This is
known as HbH disease
* If all 4 α chains absent (i.e. homozygote) then death in utero (hydrops fetalis, Bart’s hydrops)
o 1 gene deletion: silent carrier
o 2 gene deletion: α-thalassaemia trait (microcytosis, +/- anemia, decreased HbA2) o 3 gene deletion: hemoglobin H disease (β4)-moderate anemia, splenomegaly
o 4 gene deletion: Bart’s hemoglobin(γ4) - hydrops fetalis
(β) Thalassemias
HbB gene on chromosome 11,
autosomal-recessive fashion.
1 gene deletion: β-thalassaemia minor (mild anaemia, microcytosis, elevated HbA2)
o 2 gene deletion: β -thalassaemia major (anaemia when HbF tries to convert to HbA during
first year of life, extramedullary hemopoiesis with hepatosplenomegaly and bone marrow expansion, ‘hair on end’ appearance of bone).
Delta (δ) Thalassemia
As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which affect the ability of this gene to produce delta chains.
halassemia can co-exist with other hemoglobinopathies
Hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically
similar to β thalassemia major or thalassemia intermedia.
* Hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically
similar to sickle cell anemia, with the additional feature of splenomegaly
* Hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin
C/β+ thalassemia produce a milder disease.
