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
