Hereditary angioedema AD low plasma levels of the C1 inhibitor (C1-INH) protein (Multifunctional serine protease inhibitor . probable mechanism behind attacks is uncontrolled release of bradykinin & kallikrein resulting in oedema of tissues failure of C1-

esterase inhibitor upregulation of the complement system and membrane attack complex activation of the signalling protein kallikrein (directly on the vascular wall to increase permeability) and it cleaves high molecular weight kininogen to release bradykininpotent peripheral vasodilator

Type I deficiencies in factors C4 and C1-esterase inhibitor. Type II C1-esterase inhibitor levels are normal but the enzyme is dysfunctional and ↓↓ activity Type III Clinical features of angioedema but normal levels and activity of complement factors

Investigation C1-INH level is low during an attack low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool

Symptoms attacks may be proceeded by painful macular rash painless, non-pruritic swelling of subcutaneous/submucosal tissues) may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema) urticaria is not usually a feature DD. Anaphylaxis

Management Acute

IV C1-inhibitor concentrate Cinryze "1000 units" or Berinert "20 units/kg" slow IV infusions. Good clinical response is often even in HAE type III where C1-esterase levels are normal.  Icatibant "specific antagonist at B2 bradykinin receptors" in vascular smooth muscle 30mg may be repeated up to 3

times /Day rapid resolution of symptoms is often seen. Many patients with HAE are supplied with their own icatibant autoinjectors prehospital 

fresh frozen plasma (FFP) if this is not available Prophylaxis anabolic steroid Danazol may help

Anaphylaxis food (e.g. nuts) - the most common cause in children drugs

venom (e.g. wasp sting) Adrenaline is by far the most important drug. doses for adrenaline, hydrocortisone and chlorphenamine 

Adrenaline Hydrocortisone Chlorphenamine(Antihistamin)< 6 months 150 μg (0.15ml 1 in 1,000 ) 25 mg 250 μg /kg6 months - 6 years 150 μg (0.15ml 1 in 1,000) 50 mg 2.5 mg

6-12 years 300 μg (0.3ml 1 in 1,000) 100 mg 5 mg

> 12 years 500 μg (0.5ml 1 in 1,000) 200 mg 10 mg

Adrenaline can be repeated every   5 minutes  if necessary. The best site for IM injection is the anterolateral aspect of the middle third of the thigh.

Management following stabilisation: should be observed for   6–12 hours  from the onset of symptoms known that biphasic   reactions can occur in up to 20% of patients If difficult to diagnose true episode of anaphylaxis. Serum   tryptase   levels remain elevated for up to 12 hours following an

acute episode of anaphylaxis.

Blood product transfusion Blood products: FFP, cryoprecipitate and prothrombin complexFresh frozen plasma (FFP) 'clinically significant' but without 'major haemorrhage' in patients with a prothrombin time (PT) ratio or (APTT) ratio > 1.5 typically 150-220 mL can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding In contrast to red cells, the universal donor of FFP is AB blood because it lacks any anti-A or anti-B antibodies

Cryoprecipitate contains concentrated Factor VIII:C, von Willebrand factor, fibrinogen, Factor XIII and fibronectin, produced by further

processing of Fresh Frozen Plasma (FFP). Clinically it is most commonly used to replace fibrinogen much smaller volume than FFP, typically 15-20mL most suited for patients for 'clinically significant' but without 'major haemorrhage' who have a fibrinogen concentration < 1.5

g/L DIC, liver failure and hypofibrinogenaemia 2ry to massive transfusion. Emergency situation for haemophiliacs (when

specific factors not available) and in von Willebrand disease can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding where the

fibrinogen concentration < 1.0 g/L

Prothrombin complex concentrate used for the emergency reversal of anticoagulation in patients + severe bleeding or a head injury with suspected ICH can be used prophylactically in patients undergoing emergency surgery depending on the particular circumstance

Platelet transfusion1.Active bleeding

Patients with a platelet <30 x 10   9  + significant bleeding (WHO Bleeding grade 2 haematemesis, melaena, prolonged epistaxis)

Severe bleeding (WHO bleeding grades 3&4) OR bleeding at critical sites, such as the CNS maximum < 100 x 10 9) for patients with

Highest risk of bacterial contamination compared to other types of blood product.

2.Pre-invasive procedure (prophylactic) Platelet target > 50 ×109/L most patients 50-75 ×109/L high risk of bleeding >100 ×109/L surgery at critical site

3.If no active bleeding or planned invasive procedure A threshold of 10 x 109 except where platelet transfusion is contradindicated or there are alternative treatments for their

condition Do not perform platelet transfusion for any of the following conditions:

Chronic bone marrow failure Heparin-induced thrombocytopenia, or Autoimmune thrombocytopenia Thrombotic thrombocytopenic purpura.

ComplicationsAcute haemolytic transfusion reaction

(ABO) mismatch RBCs destruction by IgM-type antibodies massive intravascular haemolysis. minutes after the transfusion ( a fever, abdominal and chest pain, agitation and hypotension). immediate transfusion termination, generous fluid, informing the lab Complications DIC, and renal failure

Non-haemolytic febrile reactionFebrile reactions

due to WBCs HLA antibodies

often the result of sensitization by previous pregnancies or transfusions paracetamol may be given

Allergic/anaphylaxis reactionAllergic reactions caused by hypersensitivity reactions to components within the transfusion. Symptoms within minutes of starting ( range from urticaria to anaphylaxis hypotension, dyspnoea, wheezing, and stridor, or angioedema. Simple urticaria discontinuing the transfusion +   antihistamine . Once the symptoms resolve transfusion may be continued with no further workup. More severe allergic reaction or anaphylaxis should be treated urgently permanently discontinued, IM adrenaline  supportive care. Antihistamine, corticosteroids and bronchodilators should also be considered for these patients. 

post-transfusion purpuradelayed transfusion reaction High dose immunoglobulin is used to treat, which is a rare,

Transfusion-related acute lung injury (TRALI)A rare but potentially fatal Characterised by hypoxaemia / ARDS within 6 hours of transfusion. Features include:

hypoxia pulmonary infiltrates on chest x-ray fever hypotension

Transfusion-associated circulatory overload (TACO)A relatively common reaction due to fluid overload pulmonary oedema. patient may also by hypertensive, a key difference from patients with TRALI.

Infective1.Transmission of vCJD

although the absolute risk is very small, vCJD may be transmitted via blood transfusion a number of steps have been taken to minimise this risk, including: → from late 1999 onward, all donations have undergone removal of white cells (leucodepletion) in order to reduce any vCJD

infectivity present →from 1999, plasma derivatives have been fractionated from imported plasma rather than being sourced from UK donors. Fresh

Frozen Plasma (FFP) used for children and certain groups of adults needing frequent transfusions is also imported

→ from 2004 onward, recipients of blood components have been excluded from donating blood2.bacterial contamination

platelet concentrates are generally stored at room temperature they provide a more favourable environment for than other blood products.

Latex allergy type I hypersensitivity (anaphylaxis) type IV hypersensitivity (allergic contact dermatitis) irritant contact dermatitis more common in children with myelomeningocele spina bifida. Latex-fruit syndrome

Many people allergic to latex allergic to fruits,(banana/ pineapple/ avocado/ chestnut/ kiwi fruit/ mango/ passion fruit/ strawberry.

Allergy tests

Skin prick test

Most commonly used 1 st line easy to perform and inexpensive. Drops of diluted allergen are placed on the skin skin is pierced using a needle. A large number of allergen s can be tested in one session. Normally includes a histamine (positive) and sterile water (negative) control. A wheal will typically develop if a patient has an allergy interpreted after 15 minutes Useful for food allergies and also pollen

Radioallergosorbent test (RAST)

Determines the amount of specific IgE that reacts specifically with suspected or known allergens (IgE to egg protein.

Results are given in grades from 0 (negative) to 6 (strongly positive) Useful for food allergies, inhaled allergens (e.g. Pollen) and wasp/bee venom Blood tests may be used when skin prick tests are not suitable extensive eczema OR patient

is taking antihistaminesSkin patch testing Useful for contact dermatitis.

Around 30-40 Allergens & ((also Irritants may be tested)) are placed on the back. The patches are removed 48 hours later with the results being read by a dermatologist after a

further 48 hours

Primary immunodeficiency disorders

Classified according to which component of the immune system they affect.1.Neutrophils disorders

Disorder Underlying defect NotesChronic granulomatous disease

Lack of NADPH oxidase ↓↓ ability of phagocytes to produce reactive oxygen species

Recurrent pneumonias and abscesses Catalase-positive bacteria  (Staph.Aureus)  and fungi

(Aspergillus) -Ve Nitroblue-Tetrazolium test Abnormal dihydrorhodamine flow cytometry test 

Chediak-Higashi syndrome

Microtubule polymerization defect ↓↓ phagocytosis

Affected children have 'partial albinism' and peripheral neuropathy.

Recurrent bacterial infections are seen Giant granules in neutrophils and platelets

Leukocyte adhesion deficiency

Defect of LFA-1 integrin (CD18) protein on neutrophils

Recurrent bacterial infections.  Delay in umbilical cord sloughing may be seen Absence of neutrophils/pus at sites of infection

2.B-cell disordersDisorder Underlying defect NotesCommon variable immunodeficiency

Many varying causesCommonest clinically significantimmunodeficiency

Hypogammaglobulinemia ≥ 2 (low IgG > low IgM, IgA,), Recurrent sinopulmonary infections ↓↓ functional antibody responses

Absent Isohaemagglutinins   antibodies W bl. transfusion reactions)

Poor responses to protein ( diphtheria, tetanus ) OR Polysaccharide vaccines (S pneumoniae), or both.

May predispose to autoimmune disorders and lymphonaBruton's congenital Agammaglobulinaemia

Defect in Bruton's tyrosine kinase (BTK) gene severe block in B cell development

X-linked recessive. Recurrent bacterial infections Absence of B-cells with reduced immunoglogulins of all

classesSelective immunoglobulin A

Maturation defect in B cells Most common primary antibody deficiency(but Asymptomatic)

Disorder Underlying defect Notesdeficiency Recurrent Sinus and respiratory infections

Associated with Coeliac disease and may cause false -Ve antibody screen

Severe reactions to blood transfusions (IgA antibodies → analphylaxis)

3.T-cell disordersDisorder Underlying defect NotesDiGeorge syndrome22q11.2 deletion failure to develop 3rd

and 4th pharyngeal pouches Congenital heart disease (tetralogy of Fallot) learning difficulties ,  hypocalca emia, cleft palate Recurrent viral/fungal diseases 

4.Combined B- and T-cell disordersDisorder Underlying defect NotesSevere combined immunodeficiency

Many varying causes (↑↑ X-linked) 1. Defect in the common gamma chain

(protein receptors for IL-2 and other interleukins.

2.Adenosine deaminase deficiency

Recurrent infections viruses, bacteria and fungi. 

↓↓ T-cell receptor excision circles Stem cell transplantation may be successful

Ataxic telangiectasia Defect in DNA repair enzymes (Autosomal recessive)

Cerebellar ataxia Telangiectasia (spider angiomas) Recurrent chest infections 10% risk of malignancy (lymphoma or

leukaemia)Wiskott-Aldrich syndrome

Defect in WASP gene (X-linked recessive) Recurrent bacterial infections, ↓↓ IgM Eczema (Rash) Thrombocytopaeni a. ↑↑ risk of autoimmune disorders and

malignancyHyper IgM Syndromes Mutations in the CD40 gene Infection/Pneumocystispneumonia, hepatitis,

diarrhoea

Lung cancer: non-small cell3 main subtypes of non-small cell lung cancer:

Squamous cell cancer Adenocarcinoma Large cell lung carcinoma Typically central associated

1. parathyroid hormone-related protein (PTHrP) secretion → hypercalcaemia

2. Strongly associated with finger clubbing3. hypertrophic pulmonary

osteoarthropathy (HPOA)

Typically peripheral Most common type of lung cancer in

non-smokers. although the majority of patients who develop lung adenocarcinoma are smokers

Typically peripheral Anaplastic poorly

differentiated poor prognosis may secrete β-hCG

Haematological malignancies: infectionsViruses

EBV 1.Hodgkin's 2.Burkitt's lymphoma3.Nasopharyngeal carcinoma

HTLV-1 Adult T-cell leukaemia/lymphoma HIV-1 High-grade B-cell lymphoma

Bacteria H. pylori: gastric lymphoma (MALT) the antrum of the stomach +/- systemic features (fevers and night sweats)

Protozoa Malaria Burkitt's lymphoma

Haematological malignancies: geneticst(9;22) - Philadelphia chromosome

> 95% of patients with CML 25% of adult acute lymphoblastic leukaemia  this results in part of the Abelson 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 poor

prognostic indicator in ALL

t(12;15) Breast cancer, more specifically secretory breast carcinoma rare and the clinical outcome following is usually good.

t(15;17) Acute Promyelocytic leukaemia (M3) fusion of PML and RAR-alpha genes

t(8;14) Burkitt's lymphoma MYC oncogene is translocated to an immunoglobulin gene

t(14;18) Follicular lymphoma (Non- Hodgkin)  ↑↑ BCL-2 transcription

t(11;14)  Mantle cell lymphoma (Non- Hodgkin)  deregulation of Cyclin D1 (BCL-1) gene on Chromosome 11 Mantle cell is also CD5 positive

t(11;22) Ewing sarcoma malignant bone tumour < 15 years of age. The disease is known to be very aggressive and is associated with the development of early metastases .

Genetics and surgical diseasegenetic conditions occurring in surgical patients

Li-Fraumeni Syndrome AD Consists of germline mutations to p53 tumour suppressor gene High incidence of malignancies particularly sarcomas and leukaemias Diagnosed when:

1. Sarcoma < 45 years2. 1rst degree relative with any cancer < 45 years + another family member malignancy < 45 years OR sarcoma at any

age

BRCA 1 and 2 Chromosome 17 (BRCA 1) and 13 (BRCA 2) Linked to developing breast cancer (60%) risk. ovarian cancer (55% with BRCA 1 and 25% with BRCA 2). BRCA2 mutation is associated with prostate cancer in men

Lynch Syndrome AD Develop colonic cancer and endometrial cancer at young age 80% of affected individuals colonic and/ or endometrial cancer ↑↑ risk individuals may be identified using the Amsterdam criteria

Amsterdam criteria≥ 3 family members with a confirmed diagnosis of colorectal cancer, (1 is 1st degree + 2 other relatives)2 successive affected generations.≥ 1 colon cancers diagnosed < 50 years.0 Familial adenomatous polyposis (FAP) has been excluded.

Gardners syndrome AD familial colorectal polyposis + Extra colonic Mutation of APC gene located on chromosome 5 Multiple colonic polyps Extra colonic skull osteoma/ Hyroid cancer/ Epidermoid cysts Desmoid tumours are seen in 15% Due to colonic polyps most patients will undergo colectomy to reduce risk of colorectal cancer Now considered a variant of familial adenomatous polyposis coli

HRas is mainly associated with bladder cancer

The most common causes of cancer The most common causes of death from cancer

1. Breast 5 and 10% hereditary. Mutation (BRCA1& BRCA2) also increase the risk of ovarian cancer2. Lung3. Colorectal 5% (HNPCC) 4. Prostate5. Bladder6. Non-Hodgkin's lymphoma7. Melanoma8. Stomach9. Oesophagus10. Pancrease

1. Lung2. Colorectal3. Breast4. Prostate5. Pancreas6. Oesophagus7. Stomach8. Bladder9. Non-Hodgkin's lymphoma10. Ovarian

CarcinogensCarcinogen Cancer

Aflatoxin (produced by Aspergillus)

Liver - (hepatocellular carcinoma)

Aniline dyes Bladder (transitional cell carcinoma)Asbestos Mesothelioma

bronchial carcinomalaryngeal cancer and ovarian cancer↑↑ risk of benign diseases( pleural plaques, diffuse pleural thickeningand effusion

Nitrosamines Oesophageal and gastric cancer

Vinyl chloride Hepatic angiosarcoma arsenic is a risk factor for lung malignancy and liver angiosarcoma. Exposure to benzene is a risk factor for leukaemia.

Positron Emission Tomography (PET)

A form of nuclear imaging uses fluorodeoxyglucose (FDG) as the radiotracer. allows a 3D image of metabolic activity to be generated using glucose uptake as a proxy marker. The images obtained are then combined with a conventional imaging technique such as CT to decide whether lesions are metabolically active. Uses

1.evaluating primary and possible metastatic disease2.Cardiac PET: not used mainstream currently

Cervical cancer: human papilloma virus infectionis the most important risk factor for developing cervical cancer. Subtypes 16,18 & 33 are particularly carcinogenic produces oncoproteins inhibition of the tumor suppressor genes p53 and RB causing cervical carcinomaThe other most common subtypes (6 & 11) are non-carcinogenic and associated with genital warts.Infected endocervical cells may undergo changes resulting in the development of koilocytes. These have the following characteristics:

1. enlarged nucleus2. irregular nuclear membrane contour3. the nucleus stains darker than normal (hyperchromasia)4. a perinuclear halo may be seen

Tumour markers may be divided into: monoclonal antibodies against carbohydrate or glycoprotein tumour antigens Tumour antigens Enzymes (alkaline phosphatase, neurone specific enolase) Hormones (calcitonin, ADH)

Monoclonal antibodies Tumour marker Association

CA 125 Ovarian cancer, 1ry Peritoneal Cancer

CA 19-9 Pancreatic cancerCA 15-3 Breast cancer

Tumour antigens Tumour marker Association

Prostate specific antigen (PSA)Prostatic carcinomaAlpha-feto protein (AFP) Hepatocellular carcinoma, teratoma Testicular cancer

Tumour marker AssociationCarcinoembryonic antigen (CEA)Colorectal cancerS-100 Melanoma, schwannomasBombesin Small cell lung carcinoma, gastric cancer, neuroblastoma,

retinoblastomasB-HCG Testicular cancer

ThymomaThe most common tumour of the anterior mediastinum and is usually 6th and 7th decades of life. Associated with

1. Myasthenia gravis (30-40% of patients with thymoma)2. Red cell aplasia3. Dermatomyositis4. also : SLE, SIADH

Causes of death1. compression of airway2. cardiac tamponade

Waldenstrom's macroglobulinaemiaAn uncommon malignancy in older men lymphoplasmacytic lymphoma (lymphoplasmacytic infiltration in the bone marrow or lymphatic tissue)

Features1. Monoclonal IgM paraproteinaemia2. Systemic upset weight loss, lethargy3. Hyperviscosity syndrome (visual disturbance) (10-15%)

pentameric configuration of IgM increases serum viscosity 4. Immunoglobulin deposition  

Pancytopenia (Anaemia and thrombocytopenia) Organomegaly Hepatospleenomegaly Neuropathy Lymphadenopathy

5. Cryoglobulinaemia Raynaud's

6. Less likely to develop Bone paim DD. Multiple Myeloma Bone lesions & Hypercalcaemia. ( ↑↑ Ig A & ↑↑ IgG ), No organomegaly Lymphoma No thrombocytopenia Bence Jones protein Multiple Myeloma OR Waldenstrom's macroglobulinaemia OR chronic B cell lymphocytic leukaemia.

Acute myeloid leukaemia The more common form of acute leukemia in adults. 1ry disease or a 2ry transformation of a myeloproliferative disorder.

Features are largely related to bone marrow failure:1. neutropenia: ↑↑ WBCs + ↓↓↓ functioning neutrophil frequent infections etc2. Bone Marrow failure due to accumulation of abnormal WBCs Suppress hematobiotic cells ↓↓ WBC3. anaemia: pallor, lethargy, weakness4. thrombocytopenia: bleeding5. Blood film might show Aurer rod or bilobed cells6. Splenomegaly7. bone pain

Poor prognostic features > 60 years > 20% blasts after first course of chemo Cytogenetics chromosomal abnormalities detected by cytogenetics are the single most important prognostic factor.

deletions of chromosome 5 or 7

Acute promyelocytic leukaemia M3 Associated with translocation of (15;17) genes → causes fusion of PML and RAR-alpha genes good prognosis

younge r than other types of AML (average = 25 years old) Auer rods (seen with myeloperoxidase stain) DIC or thrombocytopenia often at presentation

Classification - French-American-British (FAB) MO - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - granulocytic and monocytic maturation

M5 - monocytic M6 - erythroleukaemia M7 – megakaryoblastic

Chronic myeloid leukaemia The   Philadelphia chromosome present in more than 95% (CML). ranslocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11). part of the ABL proto-oncogene from C 9 being fused with the BCR gene from C 22 BCR-ABL gene codes fusion protein ↑↑ tyrosine

kinase activity

Presentation (60-70 years) anaemia: lethargy weight loss and sweating are common splenomegaly  may be marked → abdo discomfort ↑↑ granulocytes at different stages of maturation (Basophil, Neutrophil, Lymphocyte, Monocytes) +/- Thrombocytosis ↓↓↓ leukocyte alkaline phosphatase may undergo blast transformation (AML in 80%, ALL in 20%)

Management Imatinib is now considered first-line treatment

inhibitor of the tyrosine kinase  associated with the BCR-ABL defect very high response rate in chronic phase CML

hydroxyurea interferon-alpha allogenic bone marrow transplant

Leukaemoid reactionpresence of immature cells ( Myeloblasts, Promyelocytes and Nucleated red cells) in the peripheral blood This is due to infiltration of the bone marrow immature cells to be 'pushed out' or sudden demand for new cells

Causes (↑↑↑↑Severe)1.severe infection2.severe haemolysis3.massive haemorrhage4.metastatic cancer with bone marrow infiltration

A relatively common clinical problem is differentiating leukaemoid reaction from chronic myeloid leukaemia.:1.↑↑ leucocyte ALP score (↓↓ in CML)

2.toxic granulation (Dohle bodies) in WBCs3.'left shift' of neutrophils three or fewer segments of the nucleus

Acute lymphoblastic leukaemia: prognostic featuresmalignancy of lymphoid progenitor cells affecting B or T cell arresting of lymphoid cell maturation and proliferation of immature blast (lymphoblast) cells that leads to bone marrow and tissue infiltration.

1. most common childhood cancer 80% of childhood leukaemia2. peak age = 2-5yrs

Good prognostic factors (Sensitive to Chemotherapy Poor prognostic factors1. French-American-British (FAB) L1 type2. common ALL3. Pre-B phenotype 4. del(9p)5. Hyperdipliody Trisomy 4, 10 and 17 6. t(12;21) translocation associated with a fusion

protein TEL-7. t(1:19) low levels of resistance to chemotherapy 8. low initial WBC

1.FAB L3 type2.T or B cell surface markers3.Philadelphia translocation,

t(9;22)4. Hypodiploidy5.age < 2 years or > 10 years6.male sex7.CNS involvement8.high initial WBC. > 100 * 109/l)9.non-Caucasian

Chronic lymphocytic leukaemia: management is caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%). It is the most common form of leukaemia seen in adults(old age)

often none constitutional: anorexia, weight loss bleeding, infections lymphadenopathy more marked than CML

Complications anaemia hypogammaglobulinaemia  leading to recurrent infections

warm autoimmune haemolytic anaemia in 10-15% of patients transformation to high-grade lymphoma (Richter's transformation)

Investigations CBC ↑↑ WBCs with marked lymphoctosis blood film: smudge cells (also known as smear cells) immunophenotyping ( investigation of choice) demonstrate the cells to be B-cells (CD19 positive). CD5 and CD23 are

also characteristically +Ve chronic lymphocytic leukaemia

Indications for treatment1. progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia2. massive (>10 cm) or progressive lymphadenopathy

3. massive (>6 cm) or progressive splenomegaly

4. progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months5. systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats6. autoimmune cytopaenias e.g. ITP

Management patients who have no indications for treatment are monitored with regular blood counts fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial treatment of choice for the majority

of patients ibrutinib may be used in patients who have failed a previous therapy

Poor prognostic factors (median survival 3-5 years)1. male sex2. age > 70 years3. Lymphocyte count > 50

4. Pro-lymphocytes comprising > 10% of blood lymphocytes5. lymphocyte doubling time < 12 months6. raised LDH7. CD38 expression positive8. TP53 mutation

Chromosomal changes deletion of the long arm of chromosome 13 (del 13q) is the most common abnormality, being seen in around 50% of

patients good prognosis deletions of part of the short arm of chromosome 17 (del 17p) are seen in around 5-10% of patients  poor prognosis

the strongest independent prognostic factor for CLL . The disease progresses more rapidly and tends to be refractory to many conventional treatments

Hairy cell leukaemiarare malignant proliferation disorder of B cells. It is ↑↑↑ males (4:1) Features

1.Pancytopenia2.Splenomegaly3.Skin vasculitis in 1/3 patients4.'Dry Tap' despite bone marrow hypercellularity5.Tartrate resistant acid phosphotase (TRAP) stain positive

Management chemotherapy is first-line cladribine, pentostatin immunotherapy is second-line rituximab, interferon-alpha

Non-Hodgkin's lymphoma

A malignant proliferation of lymphocytes accumulate in lymph nodes or other organs . 6th commonest cancer in the UK Lymphoma may be classified

1.Hodgkin's lymphoma (a specific type of lymphoma characterized by the presence of Reed-Sternberg cells) 2.Non-Hodgkin's lymphoma (every other type of lymphoma that is not Hodgkin's lymphoma).

May affect either B or T-cells Can be high grade or low grade.  Follicular lymphoma, mantle cell lymphoma

Epidemiology

1.Non-Hodgkin's lymphoma ↑↑common than Hodgkin's lymphoma2.Any age 1/3 >75 years of age3.28 for men and 20 for females /100,000

Risk factors1.Elderly2.Caucasians3.History of viral infection (EPV)4.Family history5.Chemical agents (Pesticides, Solvents)6.History of chemotherapy or radiotherapy7.Immunodeficiency (Transplant, HIV, D.M)8.Autoimmune disease (SLE, Sjogren's, coeliac disease)

Symptoms1.Painless lymphadenopathy (non-tender, rubbery, asymmetrical)2.Constitutional/B symptoms (fever, weight loss, night sweats, lethargy)3.Extranodal Disease

gastric (dyspepsia, dysphagia, weight loss, abdominal pain) bone marrow (Pancytopaenia, bone pain) CNS (nerve palsies)

DD. Non- Hodgkin's lymphoma & Hodgkin's lymphoma (Biopsy) and also Clinically : Non-Hodgkin's lymphoma

Later 'B' Symptoms in non-Hodgkin's lymphoma ↑↑↑↑ common Extra-nodal disease

Hodgkin's lymphoma alcohol-induced pain in the node Lymphadenopathy Earlier 'B' symptoms

Signs1.Signs of weight loss2.Lymphadenopathy (typically cervical, axillary or inguinal region)3.Palpable abdominal mass - hepatomegaly, splenomegaly, lymph nodes4.Testicular mass5.Fever

Investigations

1.Excisional node biopsy investigation of choice . Certain subtypes "classical appearance on biopsy" Burkitt's lymphoma having a 'starry sky' appearance)

2.CT chest, abdomen and pelvis (to assess staging)3.HIV test (often performed as this is a risk factor for non-Hodgkin's lymphoma)4.FBC and blood film (may normocytic anaemia rule out other haematological malignancy such as leukaemia)5.ESR (useful as a prognostic indicator)6.LDH (a marker of cell turnover, useful as a prognostic indicator)7.Other (LFT's if liver metastasis suspected, PET CT or bone marrow biopsy to look for bone involvement, LP if neurological

symptoms)

Staging "Ann Arbor system" Stage 1 - One node affected Stage 2 - > one node affected on the same side of the diaphragm Stage 3 - One node affected on either side of the diaphragm Stage 4 - Extra-nodal involvement Spleen, bone marrow or CNS Subtypes

A No B symptomsB 'B' symptoms.

Management Management is dependent on the specific sub-type of non-Hodgkin's lymphoma and will typically take the form of watchful

waiting, chemotherapy or radiotherapy.1.All patients will receive flu/pneumococcal vaccines2.Patients with neutropenia may require antibiotic prophylaxis

Complications Bone marrow infiltration causing anaemia, neutropenia or thrombocytopenia Superior vena cava obstruction Metastasis Spinal cord compression Complications related to treatment Side effects of chemotherapy

Prognosis Low-grade non-Hodgkin's lymphoma has a better prognosis High-grade non-Hodgkin's lymphoma has a worse prognosis but a higher cure rate

Hodgkin's lymphoma

malignant proliferation of lymphocytes + presence of the Reed-Sternberg cell. bimodal age (3rd & 7 th ) decades Histological classification

Type Frequency Prognosis NotesNodular sclerosing Most common (70%)Good prognosis ↑↑in women. ↑↑lacunar cellsMixed cellularity Around 20% Good prognosis ↑↑ Reed-Sternberg cells "nuclei surrounded by a clear

space"Lymphocyte predominantA*round 5% Best prognosisLymphocyte depleted Rare Worst prognosis

'B' symptoms also imply a poor prognosis1. weight loss > 10% in last 6 months2. fever > 38ºC3. night sweats

Other factors associated with a poor prognosis:1. age > 45 years2. stage IV disease3. haemoglobin < 10.5 g/dl4. lymphocyte count < 600/µl or < 8%5. male6. albumin < 40 g/l7. white blood count > 15,000/µl

Ann-Arbor staging of Hodgkin's lymphoma I: single lymph nodeII: 2 or more lymph nodes/regions on same side of diaphragmIII: nodes on both sides of diaphragmIV: spread beyond lymph nodes

Each stage may be subdivided into A or B A = no systemic symptoms other than pruritus B = weight loss > 10% in last 6 months, fever > 38c, night sweats (poor prognosis)

Burkitt's lymphoma High-grade B-cell neoplasm. There are two major forms:

1. Endemic (African) form:

Epstein-Barr virus (EBV Typically involves maxilla or mandible large jaw tumour.CNS involvement and bone marrow infiltration

2. Sporadic form: abdominal (ileo-caecal) tumours are the most common form. More common in patients with HIV

t(8:14) c-myc gene translocation ,is strongly implicated in the development of the African form of Burkitt's lymphoma and to a lesser extent the sporadic form.

Microscopy findings 'starry sky' appearance lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells

Management1. chemotherapy. This tends to produce a rapid response which may cause 'tumour lysis syndrome' Rasburicase (a

recombinant version of urate oxidase, an enzyme catalyses the conversion of uric acid to allantoin*) is often given before the chemotherapy to reduce the risk of this occurring.

Complications of tumour lysis syndrome include: hyperkalaemia hyperphosphataemia hypocalcaemia hyperuricaemia acute renal failure

*allantoin is 5-10 times more soluble than uric acid, so renal excretion is more effective

Superior vena cava obstructionOncological emergency caused by compression of the SVC OR thrombus OR direct tumour invasion causing obstruction of the SVC. It occurs in 5–10% of patients with a Rt-sided thoracic malignancy It is most commonly lung cancer . 70% of all casesFeatures

dyspnoea is the most common symptom

swelling of the face, neck and arms conjunctival and periorbital oedema may be seen headache often worse in the mornings visual disturbance pulseless jugular venous distension

Causes1.Common 1ry malignancies (60-85% )of cases: small cell lung cancer, lymphoma

2.other malignancies: metastatic seminoma, Kaposi's sarcoma, breast cancer3.Syphilitic thoracic   aortic aneurysm 4.mediastinal fibrosis5.goitre6.SVC thrombosis

Investigation urgent CT chest 

Management1.General

Dexamethason e ↓↓ inflammatory response to a tumour and swelling balloon venoplasty, stenting

2.small cell chemotherapy + radiotherapy3.non-small cell radiotherapy

Spinal metastasesSpinal cord compression is an oncological emergency and affects up to 5% of cancer patients. Extradural compression majority of cases due to vertebral body metastases. (ung, breast and prostate cancer) Features

1. back pain the earliest and most common symptom may be worse on lying down and coughing

2. lower limb weakness3. sensory changes: sensory loss and numbness4. Lesions above L1 UMN signs in the legs and a sensory level. ↑↑ Tendon reflexes 5. Lesions below L1 LMN legs and perianal numbness. absent Tendon reflexes

Investigation If any neurological features are present Urgent whole MRI spine   within 24 hours of presentation

Without neurological features whole spine MRI within one week. The whole spine should be imaged as patients commonly present with multi-level disease

Management high-dose oral dexamethasone urgent oncological assessment for consideration of radiotherapy or surgery

Patients may present with spinal metastases before developing metastatic spinal cord compression. It is, therefore, important to detect these patients early before any neurological compromise develops. Symptoms and findings 

1. Unrelenting lumbar back pain2. Any thoracic or cervical back pain3. Worse with sneezing, coughing or straining4. Nocturnal5. Associated with tenderness

then spinal cord compression must be suspected and acted on promptly within 24 hour.. Bone metastases

Most common tumour (descending order)

Most common site (in descending order)

features

1. prostate2. breast3. lung

1.spine2.pelvis3.ribs4.skull5. long bones

1.bone pain2.pathological

fractures3.hypercalcaemia4.raised ALP

Isosotope bone scan (using technetium-99m labelled diphosphonates which accumulate in the bones) multiple, irregular, randomly distributed foci of high grade activity 

cytotoxic agents . Alkylating agents

CytotoxicMechanism of action Adverse effects

Cyclophosphamide Causes cross-linking in DNA 1. Haemorrhagic cystitis Prevention by Hydration + Mesna

(2-mercaptoethane sulfonate Na) a metabolite of cyclophosphamide called Acrolein is toxic to

urothelium

mesna binds to and inactivates acrolein helping to prevent

CytotoxicMechanism of action Adverse effects

haemorrhagic cystitis2. Myelosuppression, 3. Transitional cell carcinoma4. Hyponitremia

Cytotoxic antibioticsBleomycin Degrades preformed DNA Lung fibrosisDoxorubicin Stabilizes DNA-topoisomerase II complex inhibits DNA &

RNA synthesisCardiomyopathy

Ant metabolitesMethotrexate (- -) dihydrofolate reductase and thymidylate

synthesis1. Myelosuppression, 2. Mucositis3. liver fibrosis,   lung

fibrosisFluorouracil (5-FU) Capecitabine prefared to 5-FU as it is

orally administered prodrug (enzymatically converted to 5-fluorouracil in the tumour

Pyrimidine analogue inducing cell cycle arrest and apoptosis by blocking thymidylate synthase (works during S phase)

1. Myelosuppression,2. mucositis, 3. dermatitis

6-mercaptopurine Purine analogue that is activated by HGPRTase ↓↓ purine synthesis

Myelosuppression

Cytarabine Pyrimidine antagonist Interferes with DNA synthesis (S-phase of the cell cycle & inhibits DNA polymerase

Myelosuppression, ataxia

Acts on microtubules1.Vincristine,2.vinblastine

Inhibits formation of microtubules Vincristine  1. Peripheral neuropathy (reversible) Urinary

hesitancy may develop secondary to bladder atony 2. paralytic ileus3. Hyponitremia, Alopecia & Constipation.

Vinblastine: myelosuppression(Taxanes) Docetaxel"Non metastatic breast

Prevents microtubule depolymerisation & disassembly in

Neutropaenia

cancer" metaphase stage, decreasing free tubulin

Topoisomerase InhibitorsCytotoxic Mechanism of action Adverse effectsIrinotecan Inhibits topoisomerase I which prevents relaxation of

supercoiled DNAMyelosuppression

Other cytotoxic drugsCisplatin Causes cross-linking in DNA 1. Ototoxicity, 

2. peripheral neuropathy3. hypomagnesaemia

(Seizures) Hydroxyurea (hydroxycarbamide)

Inhibits ribonucleotide reductase, decreasing DNA synthesis

Myelosuppression

Anti-oestrogen drugs1.Selective oEstrogen Receptor Modulators (SERM)

Tamoxifen oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor-positive breast cancer.Adverse effects

A. menstrual disturbance : vaginal bleeding, amenorrhoeaB. hot flushes - 3% of patients stop taking tamoxifen due to climacteric side-effectsC. venous thromboembolism D. endometrial cancer (Esrogen agonist effect) E. osteoporosis

2.Aromatase inhibitors Anastrozole and letrozole ↓↓ peripheral oestrogen synthesis. (aromatisation accounts for the majority of oestrogen production in   postmenopausal women and therefore anastrozole is used for ER +ve breast cancer in this group.

Adverse effectsA.Osteoporosis (most potential)

↑↑ bone loss rate by 1-2% DEXA scan when initiating a patient on aromatase inhibitors for breast cancer

B.hot flushes

C.arthralgia, myalgia D. insomnia

Chemotherapy side-effects: nausea and vomitingNausea and vomiting are common side-effects of chemotherapy. Risk factors:

anxiety age < 50 years old concurrent use of opioids the type of chemotherapy used

Treatment1. For patients at low-risk of symptoms → metoclopramide may be used first-line. 2. For high-risk →5HT3 receptor antagonists such as ondansetron effective if + dexamethasone3. Dexamethasone preventing the delayed emesis phase of CINV. 4. Aprepitant blocks the neurokinin 1 (NK1) receptor. It is a substance P antagonists (SPA).

Chemotherapy-induced nausea and vomiting (CINV) and prevention of postoperative nausea and vomiting. It is also been shown to be effective in treating clinical depression. 

Tumour lyses' syndrome Deadly condition Treatment of high-grade lymphomas and leukaemias breakdown of the tumour cells ( ↑ K + , ↑ P + , ↓↓ Ca ++ ) It can occur in the absence of chemotherapy but triggered by the introduction of combination chemotherapy. steroid treatment

alone. Prophylactic medication can be given to prevent the potentially deadly effects of tumour cell lysis. 

IV allopurinol or IV rasburicase  immediately prior to and during the first days of chemotherapy. Rasburicase  recombinant version of urate oxidase (Enz metabolizes uric acid to allantoin " much more water-soluble"

easily excreted by the kidneys) Oral allopurinol lower-risk groups during chemotherapy cycles. Rasburicase and allopurinol should not be given together in the management of tumour lysis syndrome ↓↓ the effect of

rasburicase.

Features suspected in any patient presenting (AKI + ↑↑ P + ↑↑ uric acid ).  Cairo-Bishop scoring system – 

1. Laboratory tumor lysis syndrome ≥ 2 within 3 days before OR 7 days after chemotherapy . uric acid > 475umol/l or 25% increase K+ > 6 mmol/l or 25% increase

P+ > 1.125mmol/l or 25% increase Ca++ < 1.75mmol/l or 25% decrease

2. Clinical tumor lysis syndrome laboratory   tumour lysis syndrome + ≥ 2 of the following: i↑↑ serum creatinine (1.5 times upper limit of normal) cardiac arrhythmia or sudden death seizure

NeutropaeniaNeutropaenia low neutrophil counts < 1.5 * 109 (N = 2.0 - 7.5 * 109)predisposes to severe infection.

1. Mild 1.0 - 1.5 * 1092. Moderate 0.5 - 1.0 * 1093. Severe < 0.5 * 109

Causes1.viral

Epstein-Barr virus HIV Hepatitis

2.Drugs Cytotoxics Carbimazole Clozapine

3.benign ethnic neutropaenia common in people of black African and Afro-Caribbean ethnicity requires no treatment

4.haematological malignancy myelodysplastic m alignancies Aplastic anemia

5.rheumatological conditions6.systemic lupus erythematosus: mechanisms include circulating antineutrophil antibodies7. rheumatoid arthritis . hypersplenism as in Felty's syndrome8.severe sepsis9.haemodialysiS

Neutropenic sepsis common complication of cancer therapy, consequence of chemotherapy. It most commonly occurs 7-14 days after chemotherapy. It may be defined as a neutrophil count of < 0.5 * 109 in a patient who is having anticancer treatment and has one of the following:

1. a temperature > 38ºC or2. other signs or symptoms Significant sepsis

Most common pathogen & most commonly endogenous organisms  gram + Ve Organism . Gram-negative bacilli (Previously) Staphylococcus Epidermidis , then staphylococci and streptococci species

Prophylaxis likely to have a Neutrophil count of < 0.5 * 109 following treatment offered a Fluoroquinolone

Adult patients (>18 years old) with acute leukaemias stem cell transplants solid tumours W excepecting neutrophils drop.

Management1.Antibiotics must be started immediately, do not wait for the WBC2.Empirical antibiotic therapy Piperacillin + Tazobactam (Tazocin) immediately3.many units add Vancomycin if the patient has central venous access but NICE do not support this approach4.Patients are assessed by a specialist and risk-stratified if could outpatient treatment5.Febrile and unwell after 48 hours alternative antibiotic Meropenem +/- vancomycin6.Not responding after 4-6 days investigations for fungal infections (HRCT), rather starting antifungal blindly(Amphotercin B)7.There may be a role for Granulocyte colony-stimulating factor " G-CSF" in selected patients

Granulocyte-colony stimulating factorsRecombinant human granulocyte-colony stimulating factors used to ↑↑ neutrophil counts in patients who are neutropenic 2ry to chemotherapy or other factors.Examples include:

1.filgrastim2.Perfilgrastim

Not needed in all types of chemotherapy and is not routinely used unless high risk of neutropenia (>20% risk of developing febrile neutropenia). 

1. The elderly2. Specific malignancies (non-Hodgkin's lymphoma, acute lymphoblastic leukaemia)3. Previous neutropenic episodes4. Those receiving combination chemotherapy and radiation therapy

Neutrophils count is checked before each cycle If Neutropnea G-CSF It helps the neutrophil count recover quicker ↓↓ risk of neutropenic sepsis/ prevent delays or dose reductions in the chemotherapy regime. The largest benefit chemotherapy with intent to cure or prolong remission, or when there is a risk of febrile neutropenia

>40%. Non-Hodgkin's lymphoma , relapsed Hodgkin's lymphoma, germ cell tumours and acute lymphoblastic

leukaemia (ALL) Myeloablative therapy followed by bone marrow transplantation , or in patients with a severe congenital, cyclic, or

idiopathic neutropenia Not recommended Myeloid malignancies (may in fact   +++   some of these cancers).  well tolerated by most patients S/E is bone pain 15-20% of patients.

Eastern Cooperative Oncology Group ECOG score

is a 'performance status' scale measures the functional status a patient. It is used to decide if a patient is a good or poor candidate for future oncological therapies.Those with a poor functional status is a poor candidate for further chemotherapy. 0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (light house work, office work

2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and > 50% of waking hours

3 Capable of only limited selfcare confined to bed or chair > 50% of waking hours4 Completely disabled cannot carry on any selfcare; totally confined to bed or chair5 Dead

Venous thromboembolism: risk factorsThrombophilia screening

not offered if patients will be on lifelong warfarin (i.e. won't alter management)

consider testing for antiphospholipid antibodies if unprovoked DVT or PE consider testing for hereditary thrombophilia unprovoked DVT or PE and who have a first-degree relative who has had

DVT or PE Common predisposing factors

General1. increased risk with advancing age2. obesity3. family history of VTE4. Pregnancy (especially puerperium)5. Immobility6. Hospitalisation7. Anaesthesia8. Central venous catheter: femoral >> subclavian

Underlying conditions1. Malignancy2. Thrombophilia: ( Activated protein C resistance, protein C and S deficiency3. Heart failure4. Antiphospholipid syndrome5. Behcet's

6. polycythaemia7. Nephrotic syndrome8. Sickle cell disease9. paroxysmal nocturnal haemoglobinuria

10. Hyperviscosity syndrome11. Homocystinuria

Medication1. combined oral contraceptive pill: 3rd generation > 2nd generation2. hormone replacement therapy: the risk of VTE is higher in women taking oestrogen + progestogen than taking oestrogen only

preparations3. Raloxifene and Tamoxifen4. antipsychotics (especially Olanzapine) have recently been shown to be a risk factor

It should be remembered however that around 40% of patients diagnosed with a PE have no major risk factors.

Management the use of direct oral anticoagulants (DOACs) as first-line treatment for most people with VTE with active cancer, as opposed to low-molecular weight heparin as was the previous recommendation routine cancer screening is no longer recommended following a VTE diagnosis If a patient is suspected of having a DVT a two-level DVT Wells score should be performed:

Clinical feature PointsActive cancer (treatment ongoing, within 6 months, or palliative) 1Paralysis, paresis or recent plaster immobilisation of the lower extremities 1Recently bedridden ≥ 3 days or major surgery within 12 weeks requiring general or regional anaesthesia

1

Localised tenderness along the distribution of the deep venous system 1Entire leg swollen 1Calf swelling ≥ 3 cm larger than asymptomatic side 1Pitting oedema confined to the symptomatic leg 1Collateral superficial veins (non-varicose) 1Previously documented DVT 1An alternative diagnosis is at least as likely as DVT -2

Clinical probability simplified score1. DVT likely: ≥ 2 points or more2. DVT unlikely ≤1 point or less

If a DVT is 'likely' ( ≥ 2 points)1. a proximal leg vein ultrasound scan should be carried out within 4 hours

if positive then a diagnosis of DVT is made and anticoagulant treatment should start if negative a D-dimer test should be arranged negative scan and negative D-dimer makes the diagnosis unlikely and

alternative diagnoses.2. if a proximal leg vein ultrasound scan cannot be carried out within   4 hours D-dimer test should be performed and interim

therapeutic anticoagulationadministered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours)

3. interim therapeutic anticoagulation used to mean giving low-molecular weight heparin

NOW normally a direct oral anticoagulant (DOAC) such as apixaban or rivaroxaban unless CI

4. if the scan is negative but the D-dimer is positive: stop interim therapeutic anticoagulation repeat proximal leg vein ultrasound scan 6 to 8 days later

If a DVT is 'unlikely' (1 point or less) perform a D-dimer test

within 4 hours. If not, interim therapeutic anticoagulation should be given until the result is available if –Ve DVT is unlikely and alternative diagnoses should be considered if +Ve proximal leg vein ultrasound scan should be carried out within 4 hours D-dimer tests either a point-of-care (finger prick) or laboratory-based test Age-adjusted cut-offs should be used for patients > 50 years old

ManagementThe cornerstone of VTE management is anticoagulant therapy. This was historically done with warfarin, often preceded by heparin until the INR was stable. However, the development of DOACs, and an evidence base supporting their efficacy, has changed modern management.

Choice of anticoagulant1. apixaban or rivaroxaban (both DOACs) should be offered first-line following the diagnosis of a DVT

using a DOAC once a diagnosis is suspected, with this continued if the diagnosis is confirmed if neither apixaban or rivaroxaban are suitable either LMWH followed by dabigatran or edoxaban OR LMWH followed

by a vitamin K antagonist

2. if the patient has active cancer previously LMWH was recommended the new guidelines now recommend using a DOAC, unless this is contraindicated

3. if renal impairment is severe (< 15/min) then LMWH, unfractionated heparin or LMWH followed by a VKA4. if the patient has antiphospholipid syndrome (specifically 'triple positive' in the guidance) then LMWH followed by a VKA

should be used

Length of anticoagulation all patients should have anticoagulation for at least 3 months continuing anticoagulation after this period is partly determined by whether the VTE was provoked or unprovoked

a provoked VTE e.g. immobilisation following major surgery stopped after the initial 3 months(3 to 6 months for people with active cancer)

an unprovoked VTE occurs in the absence of an obvious precipitating event, i.e. there is a possibility that there are unknown factors (e.g. mild thrombophilia) making the patient more at risk from further clots

if the VTE was unprovoked then treatment is typically continued for up to 3 further months (6 months in total)o NICE recommend that whether a patient has a total of 3-6 months anticoagulant is based upon balancing a person's risk of VTE

recurrence and their risk of bleedingo the HAS-BLED score can be used to help assess the risk of bleedingo NICE state: 'Explain to people with unprovoked DVT or PE and a low bleeding risk that the benefits of continuing anticoagulation

treatment are likely to outweigh the risks. '. The implication of this is that in the absence of a bleeding risk factors, patients are generally better off continuing anticoagulation for a total of 6 months

Pregnancy: DVT/PEpregnancy is a hypercoagulable state, majority occur in last trimester due to

1. ↑↑ factors VII, VIII, X and fibrinogen2. ↓↓ in protein S3. uterus presses on IVC causing venous stasis in legs

Management1.warfarin contraindicated2.S/C low-molecular weight heparin preferred to IV heparin (less bleeding and thrombocytopenia)

Disseminated intravascular coagulation - diagnosis Coagulation and fibrinolysis are coupled. The activation of the coagulation ++ Thrombin that converts ( fibrinogen fibrin ) the stable fibrin clot being the final product of

hemostasis. The fibrinolytic system breaks down fibrinogen and fibrin generates plasmin (in the presence of thrombin), which is

responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin polypeptides (fibrin degradation products). Presence of plasmin is critical it is the central proteolytic enzyme of coagulation and is also necessary for fibrinolysis. In DIC, the processes of coagulation and fibrinolysis are deregulated widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. Tissue Factor

Transmembrane glycoprotein One critical mediator released in DIC present on the surface of many cell types (Endothelial cells, Macrophages, and Monocytes) Normally not in contact with the general circulation but is exposed to the circulation after vascular damage. TF is released in response to exposure to cytokines (particularly IL 1), TNF& Endotoxin. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon activation, TF binds with coagulation factors

that then triggers the extrinsic pathway (via Factor VII) which subsequently triggers the intrinsic pathway (XII to XI to IX) of coagulation.

Causes of DIC1. sepsis2. trauma3. obstetric complications e.g. aminiotic fluid embolism or hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)4. malignancy

Diagnosis A typical blood picture includes:1. ↓↓ Platelets2. ↑↑ (APTT, prothrombin and bleeding time)3. fibrin degradation products are often ↑↑4. Schistocyte s due to microangiopathic hemolytic anaemia

Disorder Prothrombin time APTT Bleeding time Platelet countWarfarin Prolonged Normal Normal Normal

Disorder Prothrombin time APTT Bleeding time Platelet countAspirin Normal Normal Prolonged NormalHeparin Often normal (may ↑↑) Prolonged Normal NormalDIC Prolonged Prolonged Prolonged Low

Sideroblastic Anaemia A condition where RBCs fail to completely form haem, 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

1.Congenital cause delta-aminolevulinate synthase-2 deficiency2.Acquired causes

myelodysplasia alcohol lead anti-TB medications

Investigations hypochromic microcytic anaemia (more so in congenital) bone marrow: sideroblasts and increased iron stores

Management supportive treat any underlying cause pyridoxine may help

Thrombophilia: 1. Inherite d

A.Gain of function polymorphisms factor V Leiden (activated protein C resistance)

Most common cause of thrombophilia It is due to mis-sense mutation gain of function mutation in the Factor V (a clotting factor) Leiden protein. Leads to ↓↓↓ Inactivation of "Activated factor V" to 10 times more slowly by activated protein C than normal "Activated

protein C resistance" Homogeneous mutation 10 times risk of VSE Heterogenous mutation 4-5 folds

Prothrombin Gene mutation : 2nd most common cause

B.Deficiencies of naturally occurring anticoagulants Antithrombin III deficiency protein C deficiency protein S deficiency

Ant thrombin III deficiency AD fashion cause of thrombophilia 1:3,000. Also acquired Anti- Trombin III might be lost in CKD (Nephrotic S) Normally Antithrombin III inhibits:

clotting factors , primarily thrombin, factor X and IX, mediates the effects of heparin heterogeneous group of disorders a deficiency of normal antithrombin III OR produce abnormal antithrombin III

Features recurrent venous thromboses arterial thromboses do occur but are uncommon

Management1. Thromboembolic events are treated with lifelong Warfarinisation2. heparinisation during pregnancy anti-Xa levels should be monitored carefully to ensure adequate anticoagulation)3. Antithrombin III concentrates (often using during surgery or childbirth).

Protein C deficiency AD causes an increased risk of thrombosis Features

1. Venous thromboembolism2. skin necrosis following the commencement of warfarin

When warfarin is first started ↓↓ biosynthesis of protein C temporary procoagulant state, normally avoided by concurrent heparin administration.

Thrombosis may occur in venules leading to skin necrosis.

Prevalence and relative risk of venous thromboembolism (VTE) of the Different inherited thrombophilias:Condition Prevalence Relative risk of VTEFactor V Leiden (heterozygous) 5% 4Factor V Leiden (homozygous) 0.05% 10Prothrombin gene mutation (heterozygous) 1.5% 3Protein C deficiency 0.3% 10

Condition Prevalence Relative risk of VTEProtein S deficiency 0.1% 5-10Antithrombin III deficiency 0.02% 10-20

2. Acquired A. Antiphospholipid syndrome

primary disorder or secondary to other conditions, most commonly (SLE)acquired disorder The most common cause of 1st trimester spontaneous recurrent fetal loss 15% of women with recurrent miscarriage, prevalence of aPL in women with a low risk obstetric history is < 2%and thrombocytopenia In pregnancy the following complications may occur: recurrent miscarriage IUGR pre-eclampsia placental abruption pre-term delivery venous thromboembolism

Management low-dose aspirin should be commenced once the pregnancy is confirmed on urine testing

low molecular weight heparin once a fetal heart is seen on ultrasound . This is usually discontinued at 34 weeks gestation these interventions increase the live birth rate 7 Folds

B. Drugs the combined oral contraceptive pill

Thrombocytosisan abnormally high platelet count, usually > 400 * 109/l. Causes

1.Reactive : platelets are an acute phase reactant ↑↑response (Severe infection, surgery, Iron deficiency anaemia can also cause a reactive Thrombocytosis)

2.Malignancy

3.Hyposplenism 4.Essential thrombocytosis as part of another myeloproliferative( CML or PCRV)

Essential thrombocytosisMyeloproliferative disorders chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis (Megakaryocyte proliferation results in ↑↑↑platelets).Features

1.platelet count > 600 * 109/l2.Both thrombosis (venous or arterial) and haemorrhage can be seen3.Characteristic symptom is a burning sensation in the hands4.Genetic Mutation

JAK2 mutation 50% of patient JAK-2 negative CALR (calreticulin) is a more commonly found gene mutation in ET in around 20% MPL (myeloproliferative leukaemia protein) is less common < 10%.

Management1.Hydroxyurea (hydroxycarbamide) is widely used to ↓↓platelet count

2.Interferon- α used in younger patients

3.low-dose aspirin used to ↓↓thrombotic risk

Polycythaemia Polycythaemia may be relative, primary (polycythaemia rubra vera) or secondary

Relative causes1.dehydration2.Stress Gaisbock syndrome

Primarypolycythaemia rubra vera

Secondary causes1.COPD

2.altitude3.obstructive sleep apnoea4.↑↑↑ Erythropoietin Cerebellar haemangioma, Hypernephroma, Hepatoma, Uterine fibroids (menorrhagia

blood loss - polycythaemia is rarely a clinical problem)

DD. True (1ry or 2ry) polycythaemia and relative polycythaemia red cell mass studies In true polycythaemia the total red cell mass in males > 35 ml/kg and in women > 32 ml/kg

Polycythaemia vera: features is a myeloproliferative disorder proliferation of a marrow stem cell ↑↑ RBCs volume, + ↑↑ neutrophils and platelets .Peak 6th

decade Mutation in JAK2 95% of patients with polycythaemia vera .

Features1.hyperviscosity2.pruritus, typically after a hot bath3.splenomegaly4.haemorrhage (secondary to abnormal platelet function)5.plethoric appearance6.hypertension 1/3 patients7.↓↓ ESR ↑↑Leucocytic ALP

Investigation 1.full blood count/film (↑↑↑ haematocrit; neutrophils, basophils, platelets raised 50% patients)2.JAK2 mutation3.serum ferritin4.renal and liver function tests

If the JAK2 mutation is -Ve and there is no obvious secondary causes:1.red cell mass2.arterial oxygen saturation3.abdominal U/S4.serum erythropoietin level5.bone marrow aspirate and trephine6.Cytogenetic analysis7.erythroid burst-forming unit (BFU-E) culture

DiagnosisJAK2 (+Ve) diagnosis requires both criteria to be present

Criteria NotesA1 ↑↑ red cell mass (>25% above predicted) OR ↑↑ haematocrit (>0.52 in men,

>0.48 in women)A2 Mutation in JAK2

JAK2 (-Ve) - diagnosis requires (A1 + A2 + A3) + either another A OR 2 B criteria Criteria NotesA1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in

men, >0.56 in womenA2 Absence of mutation in JAK2A3 No secondary cause erythrocytosisA4 Palpable splenomegalyA5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the

haematopoietic cellsB1 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 splenomegalyB4 Endogenous erythroid colonies or ↓↓ serum erythropoietin

Management1.aspirin2.Venesection - first line treatment3.hydroxyurea slight ↑ risk of 2ry leukaemia4.phosphorus-32 therapy

Prognosis Thrombotic events are a significant cause of morbidity and mortality 5-15% of patients Myelofibrosis 5-15% of patients acute leukaemia (risk ↑↑ with chemotherapy treatment)

Myeloma

Multiple myeloma is a neoplasm of the bone marrow plasma cells. The peak 60-70 years .

Clinical features (CRAB) Hypercalcaemia, Renal failure, Anemia, high total Protein, Bone Pain = myeloma

1. bone disease: bone pain, osteoporosis + pathological fractures (typically vertebral), osteolytic lesions2. Lethargy3. Infection4. Hypercalcaemia (see below)5. Renal Failure6. Other features Amyloidosis (Macroglossia, Carpal tunnel syndrome, Neuropathy, Hyperviscosity

Investigations1. Electrophoresis Monoclonal proteins (IgG or IgA) in the serum and urine (Bence Jones proteins ) 2. ↑↑ plasma cells in the bone marrow3. Reently, whole-body MRI is increasingly used and is now recommended.4. Historically, skeletal survey has been done to look for bone lesions. 5. X-rays: 'Rain-drop Skull' (likened to the pattern rain forms after hitting a surface and splashing, where it leaves a random

pattern of dark spots). 6. Note that a very similar, but subtly different finding is found in primary hyperparathyroidism - 'pepperpot skull'

The diagnostic criteria 1 major + 1 minor criteria OR 3 minor + signs or symptoms of multiple myeloma.

Major criteria1. Plasmacytoma (as demonstrated on evaluation of biopsy specimen)2. 30% plasma cells in a bone marrow sample3. ↑↑↑ levels of M protein in the blood or urine

Minor criteria1. 10% to 30% plasma cells in a bone marrow sample.2. Minor elevations in the level of M protein in the blood or urine.3. Osteolytic lesions (as demonstrated on imaging studies).4. ↓↓ levels of antibodies (not produced by the cancer cells) in the blood.

Hypercalcaemia in myeloma1. 1ry factor  ↑↑ osteoclastic bone resorption caused by local cytokines (IL-1, TNF) released by the myeloma cells2. ↓↓↓↓common contributing factors ↓↓ renal function, ↑↑renal tubular calcium reabsorption and ↑↑ PTH-rP levels

Management1.If not complete Criteria of diagnosis called ( smoldering multiple myeloma) is typically to watch and wait 2.Early treatment

Delay progression of the disease but did not have significant effects on mortality or response rate. Early treatment may have ↑↑ risk of acute leukaemia

PrognosisB2-microglobulin is a marker of prognosis ↑↑ levels imply poor prognosis . ↓↓ Albumin are also associated with a poor prognosis

Stage Criteria Median survival (months)I B2 microglobulin < 3.5 mg/l 

Albumin > 35 g/l62 (60)

II Not I or III 45 (50)III B2 microglobulin > 5.5 mg/l 29 (30)

Monoclonal gammopathy of undetermined significance (MGUS) Also known as "benign paraproteinaemia and monoclonal gammopathy" is a common condition that causes a paraproteinaemia and is often mistaken for myeloma. Risk to develop myeloma 10% at 10 years/ 50% at 15 years

Features1. usually asymptomatic2. NO ( bone pain or increased risk of infections)3. 10-30% demyelinating neuropathy

Differentiating features from myeloma1. Normal immune function2. Normal beta-2 microglobulin levels3. Lower level of paraproteinaemia than myeloma (< 30g/l IgG, or < 20g/l IgA)4. Stable level of paraproteinaemia5. No clinical features of myeloma (Lytic lesions on X-rays or Renal disease

Myelofibrosis Myeloproliferative disorder hyperplasia of abnormal megakaryocytes The resultant release of platelet derived growth factor is thought to stimulate fibroblasts Haematopoiesis develops in the liver and spleen

Features1. Elderly Person W symptoms of anaemia Fatigue (The most common presenting symptom)2. Massive Splenomegaly 3. Hypermetabolic symptoms weight loss, night sweats.

Laboratory findings Anaemia ↑↑↑ ( WBC & Platelet) early in the disease ↓↓↓ in late Disease. Blood Film 'Tear-Drop' poikilocytes. Unobtainable bone marrow biopsy 'dry tap' Trephine biopsy needed high urate and LDH (reflect increased cell turnover)

10.

Eosinophilia Pulmonary causes

1. asthma2. allergic bronchopulmonary aspergillosis3. Churg-Strauss syndrome4. Loffler's syndrome5. tropical pulmonary eosinophilia6. eosinophilic pneumonia7. hypereosinophilic syndrome

Infective causes1. Schistosomiasis2. Nematodes: Toxocara, Ascaris, Strongyloides3. Cestodes: Echinococcus

Other causes1. Drugs sulfasalazine, nitrofurantoin2. psoriasis/eczema3. eosinophilic leukaemia (very rare)

Blood films: pathological cell forms

Hyposplenism e.g. post-splenectomy1. target cells2. Howell-Jolly bodies3. Pappenheimer bodies 4. siderotic granules5. acanthocytes

Iron-deficiency anaemia1. target cells2. 'pencil' poikilocytes3. if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed microcytic and macrocytic cell

Myelofibrosis 'tear-drop' poikilocytes

Intravascular haemolysis schistocytes

Abnormality Associated condition(s) AppearanceTarget cells 1. Sickle-cell/

thalassaemia2. Iron-deficiency

anaemia3. Hyposplenism4. Liver diseas

'Tear-drop' poikilocytes

Myelofibrosis

Spherocytes 1. Hereditary spherocytosis

2. Autoimmune hemolytic anaemia

Abnormality Associated condition(s) AppearanceBasophilic stippling

1. Lead poisoning2. Thalassaemia3. Sideroblastic anaemia4. Myelodysplasia

Howell-Jolly bodies

Hyposplenism

Heinz bodies 1. G6PD deficiency2. Alpha-thalassaemia

Schistocytes ('helmet cells')

1. Intravascular haemolysis

2. Mechanical heart valve

3. DIC

Abnormality Associated condition(s) Appearance'Pencil' poikilocytes

Iron deficency anaemia(Pencil Poikilocytes + Howelljolly Celiac D

Burr cells (Echinocytes)

UraemiaPyruvate kinase deficiency

Acanthocytes A betalipoproteinemia

Other blood film abnormalities: hypersegmented neutrophils  megaloblastic anaemia

Drug-induced pancytopaeniaDrug causes of Pancytopaenia

1. Cytotoxics2. Antibiotics Trimethoprim, Chloramphenicol3. Anti-rheumatoid Gold, penicillamine4. Carbimazole Causes both Agranulocytosis and Pancytopaenia

5. Anti-epileptics Carbamazepine6. Sulphonylureas Tolbutamide

MethaemoglobinaemiaHb oxidised from Fe2+ to Fe3+ Fe3+ cannot bind oxygen→ hypoxia →oxidation dissociation curve is moved to the left This is normally regulated by NADH metHb reductase, → transfers electrons from NADH to methaemoglobin →reduction of metHb Hb.

Congenital causes haemoglobin chain variants HbM, HbH NADH methaemoglobin reductase deficiency

Acquired causes ↓↓ NADH Drugs: sulphonamides, nitrates (including recreational nitrates amyl nitrite 'poppers'), dapsone, Na nitroprusside, primaquine Chemicals: aniline dyes

Features1. 'chocolate' cyanosis2. dyspnoea, anxiety, headache3. severe: acidosis, arrhythmias, seizures, coma4. normal pO2 but decreased oxygen saturation

Management NADH Methaemoglobinaemia Reductase deficiency  ascorbic acid IV Methylthioninium Chloride (Methylene blue) if acquired

Paroxysmal nocturnal haemoglobinuria (PNH)haemolysis (mainly intravascular) of haematological cells ↑↑ sensitivity of RBCs membranes to complement due to a ↓↓ (GPI) Glycoprotein Glycosyl-Phosphatidylinositol which is anchor attaches surface proteins to the cell membrane Patients are more prone to venous thrombosisPathophysiology

1.GPI can be an anchor which attaches surface proteins to the cell membrane2.complement-regulating surface proteins (Ex: Decay-Accelerating Factor (DAF), are not properly bound to the cell membrane

due a lack of GPI3.Thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation

Features

Hemolytic anemia+ pancytopenia + venous thrombosis1.haemolytic anaemia2.red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present3.Haemoglobinuria classically dark-coloured urine in the morning (although has been shown to occur throughout the day)4.Thrombosis Budd-Chiari syndrome5.Aplastic anaemia may develop in some patients

Diagnosis Flow cytometry of blood ↓↓ levels of CD59 and CD55 has now replaced Ham's test as the gold standard investigation in PNH Ham's test acid-induced haemolysis (normal red cells would not)

Management blood product replacement Anticoagulation Eculizumab a monoclonal Abs directed against terminal protein C5, is currently being trialled and is showing promise ↓↓ intravascular

haemolysis stem cell transplantation

Idiopathic thrombocytopenic purpura (ITP) Immune mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib complex ITP can be divided into acute and chronic forms (Menorrhagia, Rash, Bleeding)

1.Acute ITP more commonly seen in children equal sex incidence may follow an infection or vaccination usually runs a self-limiting course over 1-2 weeks

2.Chronic ITP more common in young/middle-aged women tends to run a relapsing-remitting course

3. Evan's syndrome ITP in association with autoimmune haemolytic anaemia (AIHA)

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 leukaemia

Management Oral prednisolone (80% of patients respond) Splenectomy if platelets < 30 after 3 months of steroid therapy IV immunoglobulins immunosuppressive drugs cyclophosphamide

Thrombotic thrombocytopenic purpura (TTP) abnormally large and sticky von Willebrand's factor platelets adhesion

Acquired (Autoimmune) ↓↓ ADAMTS13  (a metalloprotease enzyme) which breakdowns ('cleaves') large von Willebrand's factor A congenital deficiency in this protein is a rare cause (Upshaw-Schulman Syndrome).  overlaps with haemolytic uraemic syndrome (HUS) DD The combination of (Neurological features + renal failure + pyrexia +

thrombocytopaenia) thrombotic thrombocytopenic purpura

Features1.rare, typically adult females2.fever3.fluctuating neuro signs (microemboli)4.microangiopathic haemolytic anaemia5.thrombocytopenia6.renal failure

Causes1.Post-infection . urinary, gastrointestinal2.Pregnancy3.Drugs ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir4.Tumours5.SLE6.HIV

Investigation 1. CBC ↓↓ ( Hb , Platle t , Reticulocytosis)2. KFT ↑↑3. Blood film showed schistocytosis .

Management1. No antibiotics may worsen outcome2. plasma exchange is the treatment of choice as untreated mortality of up to 90% 3. Steroids IV methylprednisolone after completed plasma exchange 4. Immunosuppressants5. Vincristine

Schistocytosis on the blood film erythrocyte fragment shearing and is 2ry to TTP/DIC/HUS.

Haemophilia X-linked recessive disorder of coagulation 30% of patients have no family history of the condition. Haemophilia A deficiency of factor VIII (90% of Hemophalia) Haemophilia B (Christmas disease) ↓↓ lack of factor IX Features

1.haemoarthroses, haematomas2.prolonged bleeding after surgery or trauma3.↑↑ APTT 4.Other bleeding test are normal bleeding time, thrombin time, prothrombin time normal

Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment.

Von Willebrand's disease AD the commonest inherited bleeding disorder. Epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas 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

Types Type 1

The Commenest Type (80% of patients) Partial reduction in vWF

Type 2 Abnorma l form of Vwf too small VWF protein defective platelet adhesion Type 2B pathological ↑↑ VWF-platelet interaction Type 2M ↓↓ VWF-platelet interaction (not related to loss of high molecular weight multimers). Type 2N Abnormal binding of the VWF to Factor VIII.

Type 3 AR Moat severe form Total lack of vWF

FeaturesThere is no clear correlation between symptomatic presentation and type of VWD common excessive mucocutaneous bleeding, bruising in the absence of trauma and menorrhagia in females

Investigation ↑↑↑ Bleeding time (Abnormal platlet adhesion) ↑↑↑ APTT factor VIII levels may be moderately↓↓

defective platelet aggregation with ristocetin

Management1. Tranexamic acid for mild bleeding

2. Desmopressin (DDAVP) ++ release of vWF from Weibel-Palade bodies in endothelial cells Can ↓↓ risk of bleeding due to tooth extraction (Type1 )

3. factor VIII concentrate Should be avoided when possible to ↓↓ risk of transfusion acquired viral illnesses

Autoimmune haemolytic anaemia (AIHA ) may be divided in to 'warm' and 'cold' types temperature the antibodies best cause haemolysisCauses idiopathic OR 2ry lymphoproliferative disorder \ infection \ Drugs. Ch.Ch +Ve direct antiglobulin test (Coombs' test)

A. Classification by Ab type

1. Warm AIHA Usually IgG haemolysis best at body temperature Extravascular sites (Ex: Spleen). Management steroids, immunosuppression and splenectomy Causes

Autoimmune disease  systemic lupus erythematosus (can rarely with a mixed-type AIHA) Neoplasia lymphoma, CLL Drugs methyldopa

2. Cold AIHA Usually IgM  haemolysis best at 4 deg C mediated by complement and commonly intravascular. Features Raynaud's and acrocynaosis. Patients respond less well to steroids Causes

Neoplasia lymphoma Infections mycoplasma, EBV

B. Classification by site 1. Intravascular haemolysis

Free Hb is released which binds to haptoglobin when haptoglobin saturated Hb binds to albumin forming Methaemalbumin (detected by Schumm's test).

Free haemoglobin is excreted in the urine as haemoglobinuria, haemosiderinuria ↓↓↓ Haptoglobin (consumed) if the rate of haemolysis is greater than the rate of haptoglobin production. 

1. Mismatched blood transfusion

2. G6PD deficiency* (might be extra vascular also)3. Red cell fragmentation heart valves, TTP, DIC, HUS4. Paroxysmal nocturnal haemoglobinuria5. cold autoimmune haemolytic anaemia

2. Extravascular haemolysis: causes 1.Haemoglobinopathies Sickle cell, Thalassaemia2.Hereditary spherocytosis3.Haemolytic disease of newborn4.Warm autoimmune haemolytic anaemia

G6PD deficiency the commonest RBCs enzyme defect .↑↑ the Mediterranean and Africa X-linked recessive fashion . Many drugs can precipitate a crisis as well as infections and broad (fava) beans Pathophysiology ↓ G6PD → ↓ glutathione → ↑↑ RBCs susceptibility to oxidative stress Features

1. Neonatal jaundice is often seen2. intravascular haemolysis3. gallstones are common4. splenomegaly may be present5. Heinz bodies on blood films. Bite and blister cells may also be seen

Diagnosis using a G6PD enzyme assay

Drugs causing haemolysis1. anti-malarials: primaquine2. ciprofloxacin3. sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas

Drugs thought to be safe1. penicillins2. cephalosporins3. macrolides4. tetracyclines5. Trimethoprim

G6PD deficiency Hereditary spherocytosisGender Male (X-linked recessive) Male + female (AD)Ethnicity African + Mediterranean descent Northern European descentTypical history• Neonatal jaundice

• Infection/drugs precipitate haemolysis• Gallstones

• Neonatal jaundice• Chronic symptoms haemolytic crises may be precipitated by infection• Gallstones• Splenomegaly is common

Blood film Heinz bodies Spherocytes (round, lack of central pallor)Diagnostic testMeasure enzyme activity of G6PDOsmotic fragility test

Hereditary spherocytosis most common hereditary haemolytic anaemia in people of northern European descent AD defect of RBCs cytoskeleton the normal biconcave disc shape is replaced by a sphere-shaped red blood cell ↓↓ RBCs survival as destroyed by the spleen Presentation

1.Failure to thrive2.jaundice, gallstones (Biliary Colic & Abd pain due to chronic hemolysis)3.splenomegaly4.Aplastic crisis precipitated by parvovirus infection (↓↓Hb, ↓↓Reticulocyte count)5.degree of haemolysis variable6.MCHC elevated

Diagnosis1.the osmotic fragility test was is no longer recommended2.family history of HS + Typical features + Labs (Spherocytes, ↑↑ [MCHC], Reticulocytosis) do not require any additional

tests3.If the diagnosis is equivocal Cryohaemolysis test & EMA "Eosin-5′-maleimide" binding Attach to PBCs membrane and

traced. 4.Atypical presentations Electrophoresis analysis of erythrocyte membranes is the method of choice

Management acute haemolytic crisis: generally supportive (Fluids & ↑↑ Dose of folic Acid ) transfusion if necessary longer term treatment:

1.folate replacement2.splenectomy

CryoglobulinaemiaImmunoglobulins which undergo reversible precipitation at 4 deg C, dissolve when warmed to 37 deg C. 1/3 cases are idiopathic

Type I Type II Type III 25% Monoclonal - IgG or IgM Associations

1. multiple myeloma, 2. Waldenstrom macroglobulinaemia

Raynaud's only seen in type I

(25%) Mixed monoclonal and polyclonal usually

W RF Associations

1. Hepatitis C2. RA,

50% Polyclonal usually with RF Associations

1. RA 2. Sjogren's

3. Sjogren's, lymphoma

Symptoms (if present in high concentrations)Meltzer's triad (Arthralgia + weakness + palpable purpura) are common to all types of cryoglobulinaemia

cutaneous: vascular purpura, distal ulceration, ulceration arthralgia renal involvement (diffuse glomerulonephritis)

Tests ↓↓complement (esp. C4) ↑↑ESR

Treatment1. immunosuppression2. plasmapheresis

DD. Henoch-Schönlein purpura /vasculitis affecting small-sized vessels / children / ↑↑ IgA .

Sickle-cell anaemiaAR synthesis of an abnormal haemoglobin chain (HbS)Heterozygous condition

African descentoffers some protection against malaria.10% of UK Afro-Caribbean's are carriers of HbS (heterozygous). only symptomatic W severe hypoxia.

Homozygotes Symptoms in don't tend to develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.

Genotype Disease severity

HbAA NormalHbAS sickle cell trait, usually asymptomaticHb SC/ Sβ+

moderate sickle cell disease (sickle cell beta + thalassemia indicates the blood has some normal Hb)

Hb SS/ Sβ0

severe sickle cell disease/ Sickle cell beta 0 thalassemia (the zero indicates the blood has no normal Hb)

Pathophysiology Polar amino acid glutamate is substituted by non-polar valine in the 2 beta chains (codon 6). ↓↓water solubility of deoxy-Hb

Hypoxia The HbS molecules polymerise cause RBCs to sickle HbAS patients sickle at P02 (2.5 – 4) kPa HbSS patients P02 (5 – 6) kPa

sickle cells are fragile and haemolyse; they block small blood vessels and cause infarction

Investigations definitive diagnosis by haemoglobin electrophoresis

Types of crises 1.Thrombotic crises

also known as painful crises or vaso-occlusive crises precipitated by infection, dehydration, deoxygenation infarcts occur in various organs including the bones (avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and

brain

2.Sequestration crises Sickling within organs ( spleen or lungs causes pooling of blood with worsening of the anaemia Abdominal Pain & Enlaged

Spleen. Early childhood repeated sequestration and infarction of the spleen gradually results in an auto-splenectomy. A sequestration crisis may result in severe anaemia, marked pallor and cardiovascular collapse due to loss of effective circulating

volume.

3.Acute chest syndrome   fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on chest X-ray dyspnoea, chest pain, pulmonary infiltrates, low pO2 the most common cause of death after childhood  Initial management

1. Oxygen therapy to maintain saturations > 95%2. IV fluids to ensure euvolaemia3. Adequate pain relief4. Incentive spirometry all patients presenting with rib or chest pain 5. Antibiotics with cover for atypical organisms

6. Blood transfusion7. Exchange transfusion: if neurological complication8. Early consultation with the critical care team and haematology

Either for simple or exchange transfusion W Hb target of 100-110g/L4.Aplastic crises

caused by infection with parvovirus sudden fall in haemoglobin No jaundice & ↓↓ Reticulocytes DD. It from Hemolytic crisis

5.Haemolytic crises rare fall in haemoglobin due an increased rate of haemolysis

Chronic management Attempts to prevent acute episodes and prevent or treat the complications 1.Hydroxycarbamide (Hydroxyurea) is first line

prevention of acute crises in sickle cell ↑↑foetal haemoglobin (HbF) production ↑↑ affinity for oxygen left shift of the oxygen-haemoglobin dissociation prevents desaturation of RBCs ↓↓ intravascular pathological HbS ( polymerisation and precipitation). 

3 or more vaso-occlusive painful crises per year, or any history of severe/recurrent acute chest syndrome. ↓↓ mortality, hospitalisation and vaso-occlusive crises.

2.Acetaminophen analgesic ( inhibit cyclooxygenase enzyme) mild pain Not useful in preventing attacks and unlikely very helpful alone for management of acute episodes (severe pain)

3.regular incentive spirometry and chronic blood transfusions reduce incidence of acute chest crises indicated after failing hydroxycarbamide therapy.

4. pneumococcal polysaccharide vaccine every 5 years

Beta-thalassaemia major absence of beta chains  variant of Hb A with 2 delta chains replacing the normal 2 beta chain s small amounts (1.5 – 3%) in healthy adults of

total haemoglobin chromosome 11 presents in first year of life with failure to thrive and hepatosplenomegaly low level of hemolysis microcytic anaemia (MCV is slightly low but might be significant Hb decrease ) Disproportionate

microcytosis

Haptoglobin would be normal or mildly reduced, as it binds to free haemoglobin released from erythrocytes after haemolysis. ↑↑↑ HbA2 & HbF HbA absent Management

1. repeated transfusion → iron overload2. s/c infusion of desferrioxamine

Haemoglobin H is found in severe alpha thalassaemia and consists of 4 beta chains

Beta-thalassaemia traitThe thalassaemias are a group of genetic disorders characterised by a reduced production rate of either alpha or beta chains. Beta-thalassaemia trait is an autosomal recessive condition characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomaticFeaturesmild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia

HbA2 raised (> 3.5%)

Macrocytic anaemiaMacrocytic anaemia can be divided into causes associated with a megaloblastic bone marrow and those with a normoblastic bone marrow

Megaloblastic causes Normoblastic causesvitamin B12 deficiencyfolate deficiency

1. alcohol2. liver disease3. hypothyroidism4. pregnancy5. reticulocytosis6. myelodysplasia7. drugs: cytotoxics

Vitamin B12 deficiencyred blood cell development and also maintenance of the nervous system. It is absorbed after binding to intrinsic factor (secreted from parietal cells in the stomach) and is actively absorbed in the terminal ileum. A small amount of vitamin B12 is passively absorbed without being bound to intrinsic factor.

Causes of vitamin B12 deficiency1. pernicious anaemia: most common cause2. post gastrectomy

3. vegan diet or a poor diet4. disorders of terminal ileum (site of absorption): Crohn's, blind-loop etc5. Metformin (rare)

Features of vitamin B12 deficiency1. macrocytic anaemia2. sore tongue and mouth3. Neurological symptoms

the dorsal column is usually affected first (joint position, vibration) prior to distal paraesthesia4. neuropsychiatric symptoms: e.g. mood disturbances

 InvestigatingInvestigation for pernicious anaemia and checking Folate levels (combined B12 and folate deficiency are common).

1. Anti-gastric parietal cell antibodies 90% patients with PA (but also 5-10% patients without PA). 2. Anti-intrinsic factor antibodies (↑↑ specific but less sensitive) (present in 50%). 3. In the past, Schilling tests using radioisotope labelled B12 were used. 

Management No neurological involvement 1 mg of IM hydroxocobalamin/ 3 times/ week (2 weeks) Once/ 3 months Deficient in folic acid Oral Folic Acid it is important to treat the B12 deficiency first to avoid precipitating subacute combined

degeneration of the cord

Aplastic anaemia: management 1. Supportive

blood products prevention and treatment of infection

2. Anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) prepared in animals (rabbits or horses) by injecting human lymphocytes ↑↑↑ allergenic and may cause serum sickness (fever, rash, arthralgia), Steroid cover usually given Immunosuppression using agents (ciclosporin) may also be given

3. Stem cell transplantation allogeneic transplants have a success rate of up to 80%

Porphyrias abnormality in enzymes responsible for the biosynthesis of haem overproduction of intermediate compounds (porphyrins)

may be acute or non-acuteAcute intermittent porphyria (AIP) Porphyria cutanea tarda (PCT) Variegate porphyria1. AD defect in porphobilinogen

de a minase 2. female and 20-40 year 3. Abdominal symptoms,

neuropsychiatric symptoms4. HTN and tachycardia common5. urine turns deep red on standing

1. defect in uroporphyrinogen de ca rboxylase 2. most common hepatic porphyria may be

caused by hepatocyte damage (alcohol, oestrogens

3. Photosensitive rash with bullae, skin fragility on face and dorsal aspect of hands

4. Urine ↑↑ uroporphyrinogen and pink fluorescence of urine under Wood's lamp

5. TTT chloroquine

1. AD defect in protoporphyrinogen oxidase

2. photosensitive blistering rash3. abdominal and neurological

symptoms4. ↑↑South Africans

Acute intermittent porphyriaAcute intermittent porphyria (AIP) is a rare   autosomal dominant  condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem. The results in the toxic accumulation of (delta aminolaevulinic acid and porphobilinogen). It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40 year olds. AIP is more common in females (5:1)

The classical presentation is a combination of abdominal+ neurological + psychiatric symptoms: abdominal: abdominal pain, vomiting neurological: motor neuropathy (Limbs pain and weakness) psychiatric: depression, low mood hypertension and tachycardia common

Diagnosis  classically urine turns deep red on standing ↑↑urinary porphobilinogen (elevated between attacks "most characteristic" and to a greater extent during acute

attacks) assay of red cells for porphobilinogen deaminase raised serum levels of delta aminolaevulinic acid and porphobilinogen

DD. Lead poisoning similar presentation but the darkening of urine on sun exposure is only found in AIP. Porphyria cutanea tarda presents with photosensitive skin bullae.

Lead poisoningAlong with acute intermittent porphyria, lead poisoning should be considered giving a combination of Abdominal pain + Neurological signs.

Lead poisoning results in defective ferrochelatase and ALA dehydratase function.

Features1.abdominal pain2.peripheral neuropathy (mainly motor)3.fatigue4.constipation5.blue lines on gum margin (only 20% of adult patients, very rare in children)

Investigations1.blood lead level is usually used for diagnosis. > 10 mcg/dl are considered significant2.Microcytic anaemia.3. Blood film RBCs abnormalities (Basophilic stippling & Clover-leaf morphology)4.↑↑ serum and urine delta aminolaevulinic acid may be seen making it sometimes difficult to differentiate from acute intermittent

porphyria5.↑↑ Urinary Co-proporphyrin +/- urinary porphobilinogen and uroporphyrin 6.Children  lead can accumulate in the metaphysis of the bones, but x-rays are not part of the standard work-up

Management - Various chelating agents are currently used:1.dimercaptosuccinic acid (DMSA)2.D-penicillamine3.EDTA4.Dimercaprol

Sideroblastic anaemiaA condition of   ineffective erythropoiesis leading to poor incorporation of iron into the nucleus of erythroblasts RBCs fail to completely form haem ( biosynthesis takes place partly in the mitochondrion) This leads to deposits of iron in the mitochondria form a ring around the nucleus called a ring sideroblast. It may be congenital or acquiredCongenital cause Delta-aminolevulinate synthase-2 deficiency

Acquired causes1. Myelodysplasia2. Alcohol3. lead4. anti-TB medications

Investigations Hypochromic microcytic anaemia (more so in congenital) bone marrow Sideroblasts stained with Perl's stain shows ring sideroblasts : and ↑↑ iron stores

Management supportive treat any underlying cause pyridoxine may help

LymphadenopathyInfective

infectious mononucleosis HIV, including seroconversion illness eczema with secondary infection rubella toxoplasmosis CMV tuberculosis roseola infantum

Neoplastic leukaemia lymphoma

Others autoimmune conditions: SLE, rheumatoid arthritis graft versus host disease sarcoidosis drugs: phenytoin and to a lesser extent allopurinol, isoniazid

Kawasaki disease causes only cervical lymphadenopathyWiskott-Aldrich syndrome

Leucocyte alkaline phosphatase

Raised in ↑↑ Mture WBCs1.myelofibrosis2.leukaemoid reactions (Left Shift of Neutrophils)3.polycythaemia rubra vera4.infections5.steroids, Cushing's syndrome6.pregnancy, oral contraceptive pill

Low in indicates undeveloped leukocytes1.chronic myeloid leukaemia, Acute Myeloid Leukemia.2.pernicious anaemia3.paroxysmal nocturnal haemoglobinuria4.infectious mononucleosis

HyposplenismCauses

1. splenectomy2. sickle-cell

3. coeliac disease, dermatitis herpetiformis

4. Graves' disease

5. systemic lupus erythematosus

6. amyloid

Features1. Howell-Jolly bodies2. Siderocytes

LymphadenopathyInfective

1. infectious mononucleosis2. HIV, including seroconversion illness3. Eczema with secondary infection4. rubella

5. Toxoplasmosis6. CMV7. Tuberculosis8. roseola infantum

Neoplastic1. leukaemia2. lymphoma

Others1. Autoimmune conditions: SLE, rheumatoid arthritis2. graft versus host disease3. sarcoidosis4. drugs: phenytoin and to a lesser extent allopurinol, isoniazid

Kawasaki disease causes only cervical Lymphadenopathy

IgG4-related disease IgG4-related disease virtually every organ system (analogous to sarcoidosis)

1. the biliary tree Possibly sjogren's and primary biliary cirrhosis2. Autoimmune pancreatitis3. Periaortitis/periarteritis/Inflammatory aortic aneurysm4. salivary glands Kuttner's Tumour (submandibular glands) & Mikulicz Syndrome (salivary and lacrimal glands)5. periorbital tissues Mediastinal and Retroperitoneal Fibrosis6. thyroid Riedel's Thyroiditis

The histopathological features are similar across organs, regardless of the site. ↑↑↑IgG4 in tissue and serum can be helpful in diagnosing IgG4 disease, but neither is a specific diagnostic marker.

T9:22 - Chronic myeloid leukaemia - 9 ABL (oncogene - an aberrant tyrosine kinase) + 22 B cell receptor

T15:17 - Acute pro-myelocytic leukaemia - 15 Promyelocytic gene + 17 Retinoid acid receptor alpha (Fusion protein binds retinoid acid receptor and promotes transcription).

T8:14 - Burkitt's Lymphoma - 8 c-myc (oncogene) + 14 Ig heavy constant region

T14:18 - Follicular Lymphoma - 14 Ig heavy constant region + 18 Bcl2 (anti-apoptotic gene)

T11:14 - Mantle Cell Lymphoma - 11 - Cyclin D (oncogene) + 14 Ig heavy constant region