1
Q
Describe the bone marrow micro-environment:
A
- Stroma is the bone marrow microenvironment that supports the developing haemopoietic cell
- Stromal cells supported by an ECM
- Stromal cells: macrophages, fibroblasts, endothelial cells, fat cells and reticulum cells
- ECM: fibronectin, haemonectin, collagen, proteoglycans and laminin
2
Q
What is a clonal disorder of haemopoietic stem cells (HSC)?
A
Haematological malignancies and pre-malignant conditions are termed “clonal” if they arise from a single ancestral cell
3
Q
What are myeloproliferative disorders?
A
Clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progeny
- variably associated with the JAK2 and calreticulin mutation
- have potential to transform into AML
4
Q
What are common myeloproliferative disorders?
A
- Polycythaemia rubra vera (PRV)
- Essential thrombocytosis
- Myelofibrosis
5
Q
Describe fanconi anaemia:
A
- 10-20% of aplastic anaemia cases
- Bone marrow failure may present from birth into adulthood
- Autosomal recessive inheritance
- Characteristics
- somatic abnormalities
- bone marrow failure
- short telomeres
- malignancy (very common)
- chromosome instability
- 7 genetic subtypes (A-G)
6
Q
How are abnormal blood cells produced?
A
- Secondary to previous chemotherapy or radiotherapy
- Often associated with acquired cytogenetic abnormalities
- Characterised by dysplasia and ineffective haemopoiesis in >1 of the myeloid series
7
Q
How is ET managed?
A
- Low risk (age <40 with no high risk features)
- Aspirin or anti-platelet agent
- Intermediate risk (age 40-60 with no high risk features)
- Aspirin +/- hydroxycarbamide
- High risk (aged >60, or other RFs (CVD, diabetes)
- First line therapy is same as intermediate risk, second line is anagrelide + aspirin
8
Q
What is hydroxycarbamide?
A
Ribonucleotide reductase inhibitor (“gentle chemotherapy”)
9
Q
How is iron transported in plasma, and what is the transporters iron saturation?
A
Transferrin (a glycoprotein synthesised in hepatocytes). 30% saturated with iron
10
Q
Where does iron absorption take place?
A
Predominantly in the duodenum (duodenal enterocytes)
11
Q
Is haem iron or non-haem more readily absorbed?
A
Primarily in the duodenum and upper jejunum
12
Q
How much iron is lost each day, and how is it lost?
A
1 mg of iron is lost each day through sloughing of cells from skin and mucosal surfaces, including the lining of the GI tract. Menstruation increased the average daily iron loss to about 2 mg per day in premenopausal female adults
13
Q
How does iron absorption occur?
A
At physiological pH, ferrous iron (Fe2+) is rapidly oxidised to the insoluble ferric (Fe3+) form. Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron. Absorption is enhanced by Vit C, citric acid and inhibited by phytates and tannins (tea)
14
Q
What are the requirements for normal red cell production?
A
EPO, correct genes to make haemoglobin, and iron, folate and B12 for erythropoiesis, as well as functioning blood marrow
15
Q
What is the pathophysiology of iron deficiency anaemia?
A
Lack of iron to make haemoglobin, so reduced oxygen saturation of RBCs
Caused by:
- Dietary (in premature neonates or adolescent females)
- Malabsorption (e.g. in coeliac)
- Blood loss (most common cause, assumed to be GI until proven otherwise)
16
Q
What is the pathophysiology of anaemia of chronic disease?
A
- Failure of iron utilisation as iron is trapped in RES
- Common
- Causes
- Infection
- Inflammation (RA, IBD)
- Neoplasia
- Anaemia of chronic renal failure = ACD + decreased EPO
17
Q
What diseases cause anaemia?
A
- Haematinic deficiencies
- ACD
- Globin disorders
- Haemolysis
18
Q
Describe the importance of B12/folate:
A
- Essential for DNA synthesis and nuclear maturation
- Required for all dividing cells, deficiency noted first in RBCs
- Deficiency results in megaloblastic anaemia initially, but will affect other organs
- B12 absorbed with intrinsic factor in the terminal ileum
19
Q
What is the general pathology of anaemia?
A
Caused by reduced production or increased destruction/loss of red blood cells
20
Q
What are thalassaemias?
A
Lack of globin genes (alpha and beta)
Alpha
- Missing one alpha: mild microcytosis
- Missing two alpha: microcytosis, increased red cell count, and (sometimes) asymptomatic anaemia
- Missing three alpha: signifiant anaemia and bizarre shaped small red cells (HbH disease- excess beta chains)
- Missing four alpha genes: incompatible with life
Beta
- Beta thalassaemia major: Autosomal recessive condition resulting in lack of both beta globin gene, pt unable to make adult haemoglobin and significant dyserythropoiesis is seen
21
Q
Describe sickle cell disease:
A
- Single chromosome AA (glutamine to valine = HbS) substitution on B globin gene
- Causes abnormal globin (2 alpha + 2 beta sickle chains), results in abnormal RBC structure which causes reduced red cell survival (haemolysis) and vaso-occlusion (causing tissue hypoxia and infarction)
- Multi-system disease (stroke, dactilytis/osteonecrosis, acute chest syndrome)
- Treated with early prevention of crises and prompt management of crises
- Life expectancy around 37
22
Q
What are the categories of haemolytic anaemia?
A
Congenital - Haemoglobinopathies - Abnormalities of RBC enzymes - Pyruvate kinase deficiency - Glucose 6 phosphate dehydrogenase deficiency Acquired - Autoimmune (warm and cold type) - Isoimmune (haemolytic disease of the newborn) - Non-immune (fragmentation haemolysis)
23
Q
How does cold AIHA occur?
A
- Usually triggered by mycoplasma infection
- Auto-antibody IgM (+ complement) to RBCs
- Antibodies form aggregates with RBCs: cold agglutinins
- Idiopathic
24
Q
How does warm AIHA occur?
A
Autoantibody IgG (+/- complement)
- Idiopathic 30%
- Other AI disease (lupus, RA, thyroid)
- Lymphoproliferative disorder
- Drug induced
- Hapten (usually mild haemolysis)
- Immune complex (innocent bystander): severe haemolysis
- RBCS appear spherocytic and polychromatic (due to reticulocytes in blood)
25
What is the difference between chronic and acute leukaemia?
Chronic leukaemia can be undetected and symptomless for a long time, eventually causes symptoms from accumulation of cells
Acute leukaemia requires immediate treatment and causes symptoms from marrow failure
26
What are the different types of leukaemia?
- Acute leukaemia can be split into acute myeloid (ALL) and acute lymphoid leukaemia (ALL)
- Chronic can be split into chronic myeloid leukaemia (CML) and chronic lymphoid leukaemia (CLL)
- Myelodisplastic syndrome and myeloproliferative disorder (MDS and MPD) can develop to acute leukaemia
- CLL can develop to high grade Non-Hodgkin lymphoma (NHL)
- CML can develop to AML/ALL
27
How are acute leukaemias managed?
AML
- 3 choices: intensive (+/- SCT, pts <60-65, 5yr SR ~50%) or low dose chemotherapy (pts >60-65, 5yr SR <10%) or supportive care only (old pts, major comorbidities, 3-6 month SR)
- Most young pts entered into clinical trials
ALL
- Managed in specialist units
- Chemotherapy: initially aggressive therapy, with CNS directed treatment, then oral maintenance for 1-2 years
- Supportive: blood transfusion for symptomatic patients, fresh frozen plasma (for coagulopathy/DIC), platelet transfusion (purport and bleeding, and during fever, sepsis, DIC), prophylactic antibiotics and granulocytes in refractory infections
Transplants in:
- relapsed patients
- refractory patients
- only when age less than 60 years/fit
- Allogenic transplants
- higher early mortality (GvHD/GvL)
- less risk of relapse
28
What is the difference between leukaemia and lymphoma?
Lymphoma and leukaemia are descriptive terms to indicate the usual distribution of a particular disease:
- Leukaemia: widespread involvement of bone marrow and peripheral blood, usually neoplasms of immature blood cells
- Lymphoma: discrete tissue masses, often neoplasms of mature T and B cells
29
How do typical leukaemias present?
```
AL:
Rapid onset of symptoms
- lethargy
- infection
- bleeding and bruising (purpuric rash)
- bone pain (common in children)
- gum swelling
- lymphadenopathy
CL
Not always seen; 1/3rd patients with CL never require treatment
- lethargy, night sweats (changing bed clothes), weight loss
- symptoms of anaemia
- lymphadenopathy
- infection
- abdominal discomfort and splenomegaly in CML
```
30
Describe acute leukaemia:
AML
- monocytic anaemia most common
- common in older patients
- rapid onset of symptoms (same for ALL)
- lethargy, infection, bleeding and bruising, bone pain
- diagnosis:
- bone marrow: blast cells >20%
- morphology important for treatment (M3 AML)
- flow cytometry
- cytogenetics (karyotype)
31
Describe acute leukaemia:
AML
- monocytic leukaemia most common type
- common in older patients
- rapid onset of symptoms (same for ALL)
- lethargy, infection, bleeding and bruising, bone pain
- diagnosis:
- bone marrow: blast cells >20%
- morphology important for treatment (M3 AML)
- flow cytometry
- cytogenetics (karyotype)
ALL
- common in younger patients/children
- diagnosis: bone marrow biopsy and standard cytogenetics
- philadelphia translocation occurs in 20% of ALL
- management is chemotherapy and supportive
- 5yr SR for children is 90%, 5yr SR for adults is 40%
32
Describe acute leukaemias:
AML
- monocytic leukaemia most common type
- common in older patients
- rapid onset of symptoms (same for ALL)
- lethargy, infection, bleeding and bruising, bone pain
- diagnosis:
- bone marrow: blast cells >20%
- morphology important for treatment (M3 AML)
- flow cytometry
- cytogenetics (karyotype)
ALL
- common in younger patients/children
- diagnosis: bone marrow biopsy and standard cytogenetics
- philadelphia translocation occurs in 20% of ALL
- management is chemotherapy and supportive
- 5yr SR for children is 90%, 5yr SR for adults is 40%
33
Describe chronic leukaemias:
CLL
- commonest leukaemia
- diagnosed by unique B cell immunophenotype
- co-expression of CD5, CD19 and CD23
- also diagnosed with cytogenetics: FISH
- variable disease behaviour
- immune complications
- AIHA
- AI thrombocytopenia
- infection (hypogammaglobulinaemia, T lymphopenia, neutropenia, defects in complement activation)
CML
- often exposure to ionising radiation
- always has Philadelphia translocation (BCR-ABL tyrosine kinase always on, activating downstream products, causing malignancy)
- diagnosed by blood film and clinical features, molecular test on blood (by PCR/FISH for BCR-ABL) and cytogenetic analysis
34
Describe management of chronic leukaemias:
CLL
- only managed when symptoms appear
- treatment triggers:
- symptoms: sweats, weight loss, symptomatic nodes
- bone marrow failure:
- anaemia, thrombocytopenia
- treated with chemoimmunotherapy (against B cells)
CML
- Treated with imatinib or other BCR-ABL inhibitors
35
How is lymphoma staged?
Staging: Ann Arbor Classification
- Stage 1: single lymph node group
- Stage 2: more than one lymph node group on the SAME side of the diaphragm
- Stage 3: lymph node groups BOTH sides of the diaphragm (includes spleen)
- Stage 4: Extranodal involvement e.g. liver or bone marrow
A or B added to signify presence or absence of B symptoms
- Early stage 1 or 2A, late stage is 2B, 3 or 4
- Most HL diagnosed at early stage, most NHL diagnosed at advanced stage
36
What is myeloma?
Neoplasm of mature plasma cells with varied clinical course
| - Neoplastic cells resemble normal plasma cells but show aberrant phenotype (CD19 negative, CD56 positive)
37
What are the presenting symptoms of different lymphomas?
- Lymphadenopathy
- painless
- rubbery
- Splenomegaly
- B symptoms
- night sweats
- weight loss
- unexplained fever
- Anaemia
- Itch is not a B symptom and can occur in NHL or HL
- Alcohol induced pain in lymph nodes is a rare feature of HL
38
What is the difference between high and low grade lymphoma?
Low Grade:
- Neoplastic cells mostly of small size
- Low rate of proliferation
- Low rate of apoptosis
- Cell cycle characteristics result in slow accumulation of neoplastic lymphocytes
- Widely disseminated at presentation, often involving bone marrow
- Indolent clinical course
- Incurable
High Grade:
- Neoplastic cells usually of large size with activated (blast-like) appearance
- High rate of cell division
- Variable rate of cell death
- Cell cycle characteristics result in rapid accumulation of neoplastic lymphocytes
- Tend to be localised at presentation
- Rapid growth and early death if untreated, but often curable
39
How are the commoner subtypes of lymphoma treated?
FL
- Treatment is aimed at alleviating symptoms
- Early stage: localised radiotherapy
- Advanced stage:
- Asymptomatic: watch and wait
- Symptomatic and/or organ compromise: treatment with immunohemotherapy (rituximab follows by maintenance rituximab)
- Very responsive to treatment
DLBCL
- Requires aggressive chemotherapy with intention to cure
- Early stage: R-CHOP x 3 plus radiotherapy
- Late stage: R-CHOP x 6
- Elderly/unfit patients: mini R-CHOP
BL
- Requires intensive chemotherapy with aim to cure: 70-70% long term survival
HL
- Early stage is chemotherapy followed by radiotherapy
- Advanced stage: chemotherapy
- ABVD regimen of chemotherapy
40
What typifies myeloma?
Classica triad:
1. Increased plasma cells in bone marrow
2. Clonal immunoglobulin or paraprotein
- abnormal production of monoclonal protein (M/paraprotein) either IgG, A, M, D or E
- sometimes only part go Ig molecule is produced: light chain myeloma
- rarely no Ig is produced: non-secretory myeloma
3. Lytic bone lesions
41
How is myeloma treated?
Not treated until symptoms appear (determined by CRAB criteria: hyperCalcaemia, Renal impairment, Anaemia, Bone lesions)
- All patients receive chemotherapy usually including a steroid and thalidomide
- Radiotherapy for patients with severe bone pain
- Supportive therapy
- Bisphosphonates
- Blood transfusion/EPO
- Surgery
- Interventional radiology
42
How is myeloma treated?
Not treated until symptoms appear (determined by CRAB criteria: hyperCalcaemia, Renal impairment, Anaemia, Bone lesions)
- All patients receive chemotherapy usually including a steroid and thalidomide
- Radiotherapy for patients with severe bone pain
- Supportive therapy
- Bisphosphonates
- reduce pain, pathological fractures, hypercalcaemia
- Blood transfusion/EPO
- Surgery
- Interventional radiology
43
What are the common subtypes of lymphoma?
- Follicular lymphoma
- Diffuse large B-cell lymphoma
- Burkitts
- Three epidemiological variants
- endemic BL (equatorial Africa + PNG)
- sporadic BL (UK and Europe)
- immunodeficiency associated BL (HIV, post transplant)
- Classic HL
44
Describe the main chemotherapy regimens:
```
R-CHOP
R=rituximab
C=cyclophosphamide
H=Adriamycin
O=Vincristine
P=Prednisolone
```
```
ABVD
A=adriamycin
B=bleomycin
V=vinblastine
D=dacarbazine
```
45
Describe the clotting cascade:
- When endothelium is disrupted platelets in blood are exposed to collagen, tissue factor (TF) and Von Willebrand factor (VWF)
- Platelets adhere to VWF and release granular contents attracting more platelets to aggregate
- This is the platelet plug
- Simultaneously, TF coming into contact with F7 activates F8, which activates F10. F10 and F5a activate F2 which activates F1 (becoming fibrin)
46
What are the basic lab tests that asses clotting function ?
```
PT
APPT
TCT
Fibrinogen
D-Dimer
```
47
Describe the clotting cascade:
- When endothelium is disrupted platelets in blood are exposed to collagen, tissue factor (TF) and Von Willebrand factor (VWF)
- Platelets adhere to VWF and release granular contents attracting more platelets to aggregate
- This is the platelet plug
- Simultaneously, the extrinsic pathway is activated: TF coming into contact with F7 activates F7, which activates F10. F10 and F5a activate F2 which activates F1 (becoming fibrin). F2a also activates F13 to from cross-linked fibrin
- Intrinsic pathway: F2a activates F11, activating F9 which, along with F8, the prothrombinase complex (F10a, F5a and F2)
- Requires calcium and phospholipid
48
What are the basic lab tests that asses clotting function?
PT:
- simulates activation via the extrinsic pathway
- depends on factors in the extrinsic (F7) and common pathways (F10, F5, F2 and F1)
- INR is the standardised form of prothrombin time
APPT:
- simulates activation via the intrinsic pathway
- depends on factors in the intrinsic (F12, 11, 9 and 8) and common pathways (F10, 5, 2 and 1)
TCT:
- measurement of conversion of fibrinogen to fibrin clot
- depends on how much fibrinogen is present in plasma and how well fibrinogen functions
- will also be prolonged by inhibitors of thrombin (heparin, dabigatran), FDPs and inhibitors of fibrin polymerisation
D-Dimer:
- tests for D-dimer platelet fragments
49
What are the inherited and acquired disorders of the clotting system?
Disseminated Intravascular Coagulation (DIC)
- Acquired consumptive process: activation of coagulation cascade and exhaustion of clotting factors
- Caused by numerous disease processes (sepsis, malignancy)
Warfarin induced bleeding (acquired)
- Treatment: stop warfarin, give IV vitamin K and IV clotting factor concentrate
Coagulopathy in liver disease (acquired)
- Difficult to account for one cause
- Poor coagulation factor synthesis in liver, vitamin K deficiency, poor clearance of activated clotting factors, DIC, hypersplenism for portal hypertension and reduced thrombopoietin synthesis (hence low platelets)
Haemophilia A
- F7 deficiency, can be severe, mild or moderate
- X-linked inheritance
- Prolonged APPT
Von Willebrand Disease
- AD inheritance
- Mucosal type bleeding pattern
- Types refer to qualitative and quantitative disorder
Inherited Platelet Disorders
- AR inheritance
- mucosal type bleeding pattern
- Glansmanns thrombasthenia
- Bernard Soulier syndrome
Thrombophilia
- deficiency of natural anticoagulant, or
- specific genetic mutations
- lupus anticoagulant (acquired)
- phospholipid dependent antibody which, if persistent, may be associated with prothrombotic state
- persistent lupus anticoagulant + thrombosis (or recurrent foetal loss) is antiphospholipid syndrome
Phase 3
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