Haematology Flashcards by Nabeel Salim

Describe the importance of the bone marrow microenvironment in haemopoiesis

The bone marrow microenvironment (stroma) supports developing haematopoietic stem cells

It provides a rich environment for growth and development of stem cells

Stromal cells are supported by an extracellular matrix

Stromal cells include; Macrophages, Fibroblasts, Endothelial Cells, Fat Cells, Reticulum Cells

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Describe the major myeloproliferative disorders

Clonal blood disorder characterised by over effective haemopoiesis

JAK2 mutation is highly prevalent

Too many platelets = Essential Thrombocytosis

Too many RBCs = Polycythaemia Rubra Vera

Too much fibrous tissue = Myelofibrosis

ET & PRV
- Good outcome
- Risk of vascular events (managed with aspirin)
- Managed by cytoreduction (hydroxycarbamide, venesection or interferon)
- 5-10% risk of progression to AML
- 10% progress to myelofibrosis
MF
- Splenomegaly + Systemic Symptoms
- Blood counts may be high or low
- Incurable other than with SCT
- New drug class - JAK2 inhibitors

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Describe myelodysplastic syndrome

Clonal blood disorder characterised by failure of effective haemopoiesis (low blood count)

More common in the elderly

Dysplastic blood and marrow appearance

Approx. 25% rate of progression to AML

(Blast cell % cut off for MDS vs AML is 20%)

Symptoms characterised by consequences of marrow failure

Incurable other than with SCT for those <65yrs

Consider supportive care and drug therapy (e.g. azacitidine)

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State the requirements for normal RBC production

Erythropoietin (Drive for Erythropoiesis)

Genes (Recipe for Erythropoiesis)

Iron, B12, Folate and Minerals (Ingredients for Erythropoiesis)

Functioning Bone Marrow

No Increased Loss or Destruction of RBCs

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Describe the physiology of B12 metabolism

Essential for DNA synthesis and nuclear maturation

Required for all dividing cells

B12 (Cobalamin) necessary for methionine production and methylmalonyl-CoA isomerisation

Found in meats (esp. liver and kidney)

Require 1ug/day

Absorbed with Intrinsic Factor in the ileum

Stores in the body for 3-4 years

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Describe the physiology of Folate metabolism

Essential for DNA synthesis and nuclear maturation

Required for all dividing cells

Found in green veg (but destroyed by cooking)

Absorbed in the small intestine (no carrier molecule required)

Only a few days store in the body but quickly used up if there is increased demand (i.e. increased cell turnover)

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Describe the effects of B12/Folate deficiency

Affects all tissues with rapidly growing, DNA synthesising cells (bone marrow, epithelia etc.)

Blood (B12 and Folate) - Megaloblastic Anaemia

Neurological (B12) - Bilateral Peripheral Neuropathy, Demyelination of the Posterior and Pyramidal Tracts of the Spinal Cord

Growing Foetus (Folate) - Neural Tube Defects in first 12 Weeks

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State causes of B12 and Folate deficiency

B12 - Dietary, Pernicious Anaemia, Gastrectomy, Achlorhydria, Crohn’s, Ileal Resection

Folate - Dietary, Coeliac, Severe Crohn’s, Haemolysis, Severe Skin Disorders, Pregnancy

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Define haemoglobinopathies

‘a group of inherited conditions characterised by a relative lack of normal globin chains due to absent genes (thalassaemias) or abnormal globin chains (e.g. sickle cell disease)’

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Describe Alpha-Thalassaemia

Relative lack of alpha globin chains

Alpha globin chains are duplicated on each chromosome for a total of 4 genes

Prevalent in Meditteranean countries, Africa, South East Asia and the Indian subcontinent

If missing 4 Genes - Incompatible with Life

If Missing 3 Genes - HbH Disease (significant anaemia and abnormally shaped RBCs)

If Missing 1/2 Genes - Alpha Thalassaemia Trait (mild anaemia, microcytosis, reduced MCV and MCH but increased RBC count)

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Describe Beta-Thalassaemia

Deficiency in beta globin genes (should normally two)

Prevalent amongst Greek Cypriots, Turks, Asians and Africans

Beta Thalassaemia Major - Missing Both Genes - Autosomal Recessive - Severe anaemia due to ineffective erythropoiesis and haemolysis renders patient transfusion dependent from early life with iron overload being the major problem

Thalassaemia Intermedia

Beta Thalassaemia Trait - May be a mild microcytic anaemia, is often confused for IDA

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Describe Sickle Cell Disease

Arises due to abnormal HbS which occurs following a single amino acid substitution in the beta-globin gene

RBCs undergo sickling

Results in reduced RBC survival due to haemolysis and vaso-occlusive crises leading to tissue hypoxia and infarction

Complications include Stroke, Moya Moya, Acute Chest Syndrome, Retinopathy, Osteonecrosis

Crisis Prevention - Hydration, Analgesia, Vaccination, Antibiotics and Folic Acid

Cris Management - Oxygen, Fluids, Analgesia, Antibiotics, Transfusion

Can be cured with Bone Marrow Transplantation

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Describe the Direct and Indirect Coombs Test

The Coombs test detects autoantibodies against antigens on the RBC membrane

The direct test detects antibodies on the RBC surface and is positive in Haemolytic Disease of the Newborn and Acquired Immunohaemolytic Anaemia

The indirect test detects antibodies in the plasma and is used in prenatal screening of Rh antibodies

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Describe an approach to the investigation of a patient with anaemia

Is it new?
- Congenital or Acquired?
History
- Blood Loss
- Diet
- Chronic Disease
- Family History
- Medication
Examination
- Angular Stomatitis
- Splenomegaly
- Lymphadenopathy
- Abdominal Masses
Haematology
- Size of RBCs
- Are WBCs/Platelets affected?
- Is marrow able to mount a reticulocyte response?
- What are the haematinic results?
- What does the blood film look like?

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Define Lymphoma and describe a basic classification system

‘a group of malignancies of lymphoid tissue with accumulation of B/T-Lymphocytes’

Broadly divided into Hodgkin and Non-Hodgkin Lymphomas

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Describe the pathology of Hodgkin Lymphoma

The malignant cells (Reed-Sternberg and Hodgkin’s cells) comprise a minority of the tumour, with the remainder comprised of lymphocytes, granulocytes, fibroblasts and plasma cells

Reed-Sternberg cells are bi/multi-nucleated giant cells of B-Lymphocyte origin

Up to 40% of HL cases are associated with EBV

Describe the clinical presentation of Hodgkin Lymphoma

Bimodal Age Incidence (20s-30s and >50s)

Painless Lymphadenopathy (Cervical or CXR Mass)

Spread from one nodal group to adjacent

Later there may be haematogenous spread to liver or lungs

May have B symptoms (fever, drenching night sweats or weight loss)

Managed by Chemo and Radiotherapy

Describe the clinical presentation of high-grade Non-Hodgkin’s Lymphomas such as Diffuse Large B-Cell Lymphomas

Most common subtype of NHL

Increasing incidence with age

Aggressive

Often presents with localised or generalised painless lymphadenopathy

40% present extra-nodally with abdominal pain, anaemia, CNS disease or on the skin

May also present with Pyrexia of Unknown Origin

Managed by R-CHOP Chemotherapy +/- Radiotherapy

Describe the pathology of low-grade/indolent Non-Hodgkin’s Lymphomas such as Follicular Lymphoma

B-Cell Lymphoma

90% of follicular lymphomas are characterised by the t(14;19) translocation where the BCL2 gene on chromosome 18 is moved to the immunoglobulin heavy chain

This leads to excessive expression of BCL2, an oncogene known to inhibit apoptosis

it is likely that further change (e.g. activation of a proto-oncogene or an antigenic stimulus) produces the clonal malignancy

Describe the clinical presentation of low-grade/indolent Non-Hodgkin’s Lymphomas such as Follicular Lymphoma

Increasing incidence with age

Median presentation between 60-65 years

Often presents with late-stage disease due to its indolent course

Local disease may be managed with radiotherapy but most cases require a rituximab-containing regime (e.g. R-CVP or R-CHOP)

Average survival of 15-20 years

Responsive to treatment but tendency to relapse or transform to DLBCL

Describe the staging of Lymphoma

Ann-Arbor Staging System

I - Single Lymph Node Group

II - More than one LN group on the SAME side of the diaphragm

III - LN groups on BOTH sides of the diaphragm

IV - Extranodal involvement (e.g. liver, bone marrow)

A or B is added to signify absence or presence of B symptoms (fever, night sweats, weight loss)

Early Stage = 1 or 2A

Advanced Stage = 2B or 3 or 4

Describe the diagnosis of Lymphoma

Excision or Core Biopsy of Lymph Node, Other Tissue or Bone Marrow

CT Neck, Chest, Abdomen and Pelvis

PET-CT

Define Multiple Myeloma

‘a clonal malignancy characterised by uncontrolled proliferation of plasma cells in the bone marrow and production of monoclonal immunoglobulin’

Describe the pathophysiology of Multiple Myeloma

MM is preceded by a clinical syndrome known as Monoclonal Gammopathy of Undetermined Significance

Plasma cells in the bone marrow secrete paraprotein (monoclonal immunoglobulin or immunoglobulin fragments)

Most produce IgG or IgA or light chains only

Occasionally myelomas may be non-secretory

Myeloma Triad = Increased Plasma Cells in the Bone Marrow + Clonal Immunoglobulin/Paraprotein + Lytic Bone Lesions

Describe the clinical presentation of Multiple Myeloma

Back Pain Rib Pain Pathological Fractures Vertebral Collapse Anaemia Thrombocytopenia Frequent Infection Hypercalcaemia Renal Failure

Describe the main differences between Hodgkin's (HL) and Non-Hodgkin's (NHL) Lymphoma

NHL is a monoclonal proliferation of B/T-Lymphocytes and HL is a lymph malignancy of proliferating germinal centres EBV is associated with both HL has a bimodal age distribution HL is characterised by presence of Reed-Sternberg Cells Both present with painless lymphadenopathy and possibly B symptoms and HL may also present with pruritis Contiguous LN spread in HL, Non-Contiguous LN spread in NHL Radiation and Chemotherapy for both

State techniques used to diagnose Lymphoma

Morphology Immunohistochemistry Flow Cytometry Karyotyping Fluorescence in situ Hybridisation PCR Clonality Assays Gene Sequencing/Array Based Technologies

Describe lymphocyte development

B-Cells are produced in bone marrow from a committed stem cell progenitor Mature B-Cells circulate in peripheral blood and populate lymphoid and other organs T-Cells originate in bone marrow from committed stem cell progenitor Precursor T-Cells migrate to thymus where they develop into mature T-Cells Mature T-Cells circulate in peripheral blood and populate lymphoid and other organs

Describe the physiological processes involved in the coagulation system

* Blood Vessel Damage * Endothelial Disruption * Exposure of Tissue Factor and Collagen * Primary Haemostasis * Recruitment of Platelets * Secondary Haemostasis * Activation of Coagulation Factors * Cascade: * Initiation - Extrinsic Pathway * Propagation - Intrinsic Pathway * Thrombin Generation * Fibrin Production (The Clot) * Each step in the cascade requires phospholipids from the platelet surface and calcium

State the laboratory tests used to assess the coagulation system

* Assessment of Primary Haemostasis * In Vivo - Bleeding Time * Ex Vivo - FBC, Platelet Count, Platelet Function * Assessment of Secondary Haemostasis * Prothrombin Time (PT) * Activated Partial Thromboplastin Time (APTT) * Thrombin Clotting Time (TCT) * Individual Coagulation Factor Assays

Describe the use of Prothrombin Time (PT) to assess the coagulation system

Simulates activation via the extrinsic pathway Add patient's plasma and thromboplastin, warm to 37C, add calcium and time taken to form clot Normal range is 10-13 seconds Ratio is the patient's PT/average of 20 normal PTs (normal ratio is 1 - 1.2) PT depends on factors in the extrinsic and common pathways (Factors VII, X, V, II and Fibrinogen)

Describe the use of International Normalised Ratio (INR) to assess the coagulation system

The standardised form of prothrombin time Used in the monitoring of oral coumarins such as Warfarin A patient's INR is identical in any laboratory Patient's PT/Average of 20 Normal PTs Result factored by the International Sensitivity Index (ISI) Every thromboplastin preparation has its own ISI

Describe the use of Activated Partial Thromboplastin Time (APTT) to assess the coagulation system

Stimulates activation via the intrinsic pathway Add the patient's plasma, contact factor and phospholipid Warm to 37C and add calcium and time the taken to form a clot Normal range is 26-38 seconds Ratio of Patient/Average of 20 Normals APTT depends on factors in the intrinsic and common pathways (Factors VIII, IX, XI, XII, X, V, II and Fibrinogen)

Describe the use of Thrombin Clotting Time (TCT) to assess the coagulation system

Measures conversion of fibrinogen to fibrin clot At 37C, add the patient's plasma and bovine thrombin Less calcium or phospholipid-dependent Measure the time taken to clot Normal range is 10-16 seconds Depends on how much fibrinogen is present in the plasma and how well it functions Will also be prolonged by inhibitors of thrombin (heparin, dabigatran), FDPs or inhibitors of fibrin polymerisation (paraprotein)

State and briefly describe the three classes of anti-thrombotics

Anti-Coagulants (inhibit one or several components of the coagulation cascade) Fibrinolytic Agents (enhance lysis of the fibrin clot) Anti-Platelet (inhibit platelet activation or aggregation)

Describe some of the acquired disorders of the coagulation system

* Disseminated Intravascular Coagulation * Acquired, consumptive process with activation of the coagulation cascade (resulting in microthrombi) and subsequent exhaustion of the coagulation cascade (resulting in bleeding) * Caused by sepsis, malignancy, massive haemorrhage, severe trauma or complications in pregnancy * Treat the underlying cause and give FFP +/- platelets if bleeding or at high risk * Warfarin-Induced Bleeding * If INR is too high, stop warfarin or reduce dose, give Vitamin K or give coagulation factors * Coagulopathy in Liver Disease * Poor coagulation factor synthesis due to liver damage

Describe some of the inherited disorders of the coagulation system

* Haemophilia A * Classical Haemophilia * Factor VIII Deficiency * Prolonged APTT * X-Linked Inheritance * Replacement with Recombinant Produced Factor Concentrate * Von Willebrand Disease * VW Factor facilitates platelet adhesion and aggregation in primary haemostasis * Binds Factor VIII and prolongs its half-life in the plasma * Thrombophilia * Deficiencies of natural anticoagulants such as antithrombin, Protein C or Protein S * May be due to specific gene mutations such as Factor V Leiden (resistance to APC) or the prothrombin gene (which results in increased prothrombin)