Haematology

Cheat sheet

24 December 2020

21:00

24 December 2020

14:03

Myeloma: features

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

Clinical features

· bone disease: bone pain, osteoporosis + pathological fractures (typically vertebral), osteolytic lesions

· lethargy

· infection

· hypercalcaemia (see below)

· renal failure

· other features: amyloidosis e.g. Macroglossia, carpal tunnel syndrome; neuropathy; hyperviscosity

Investigations

· monoclonal proteins (usually IgG or IgA) in the serum and urine (Bence Jones proteins)

· increased plasma cells in the bone marrow

· historically a skeletal survey has been done to look for bone lesions. However, whole-body MRI is increasingly used and is now recommended in the 2016 NICE guidelines

· 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). Note that a very similar, but subtly different finding is found in primary hyperparathyroidism - 'pepperpot skull'

The diagnostic criteria for multiple myeloma requires one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of multiple myeloma.

Major criteria

· Plasmacytoma (as demonstrated on evaluation of biopsy specimen)

· 30% plasma cells in a bone marrow sample

· Elevated levels of M protein in the blood or urine

Minor criteria

· 10% to 30% plasma cells in a bone marrow sample.

· Minor elevations in the level of M protein in the blood or urine.

· Osteolytic lesions (as demonstrated on imaging studies).

· Low levels of antibodies (not produced by the cancer cells) in the blood.

Hypercalcaemia in myeloma

· primary factor: due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells

· much less common contributing factors: impaired renal function, increased renal tubular calcium reabsorption and elevated PTH-rP levels

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24 December 2020

14:03

Direct oral anticoagulants

The table below summaries the three direct oral anticoagulants (DOACs): dabigatran, rivaroxaban and apixaban.

	Dabigatran	Rivaroxaban	Apixaban
UK brand name	Pradaxa	Xarelto	Eliquis
Mechanism of action	Direct thrombin inhibitor	Direct factor Xa inhibitor	Direct factor Xa inhibitor
Route	Oral	Oral	Oral
Excretion	Majority renal	Majority liver	Majority faecal
NICE indications	Prevention of VTE following hip/knee surgery Treatment of DVT and PE Prevention of stroke in non-valvular AF*	Prevention of VTE following hip/knee surgery Treatment of DVT and PE Prevention of stroke in non-valvular AF*	Prevention of VTE following hip/knee surgery Treatment of DVT and PE Prevention of stroke in non-valvular AF*
Reversal	Idarucizumab	Andexanet alfa**	Andexanet alfa**

*NICE stipulate that certain other risk factors should be present. These are complicated and differ between the DOACs but generally require one of the following to be present:

· prior stroke or transient ischaemic attack

· age 75 years or older

· hypertension

· diabetes mellitus

· heart failure

**Andexanet alfa is a recombinant form of human factor Xa protein

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24 December 2020

14:03

G6PD deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red blood cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in an X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad (fava) beans

Pathophysiology

· G6PD is the first step in the pentose phosphate pathway, which converts glucose-6-phosphate→ 6-phosphogluconolactone

o this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH

o i.e. glucose-6-phosphate + NADP → 6-phosphogluconolactone + NADPH

· NADPH is important for converting oxidizied glutathine back to it's reduced form

· reduced glutathine protects red blood cells from oxidative damage by oxidants such as superoxide anion (O2-) and hydrogen peroxide

· ↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress

Features

· neonatal jaundice is often seen

· intravascular haemolysis

· gallstones are common

· splenomegaly may be present

· Heinz bodies on blood films. Bite and blister cells may also be seen

Diagnosis is made by using a G6PD enzyme assay

· levels should be checked around 3 months after an acute episode of hemolysis, RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false negative results

Some drugs causing haemolysis

· anti-malarials: primaquine

· ciprofloxacin

· sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas

Some drugs thought to be safe

· penicillins

· cephalosporins

· macrolides

· tetracyclines

· trimethoprim

Comparing G6PD deficiency to hereditary spherocytosis:

Comparison of G6PD deficiency to hereditary spherocytosis

	G6PD deficiency	Hereditary spherocytosis
Gender	Male (X-linked recessive)	Male + female (autosomal dominant)
Ethnicity	African + Mediterranean descent	Northern European descent
Typical history	• Neonatal jaundice • Infection/drugs precipitate haemolysis • Gallstones	• Neonatal jaundice • Chronic symptoms although haemolytic crises may be precipitated by infection • Gallstones • Splenomegaly is common
Blood film	Heinz bodies	Spherocytes (round, lack of central pallor)
Diagnostic test	Measure enzyme activity of G6PD	Osmotic fragility test

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24 December 2020

14:03

Iron deficiency anaemia

Iron deficiency anaemia is the most common anaemia worldwide. Iron is needed to make the haemoglobin in red blood cells, therefore a deficiency of iron leads to a reduction in red blood cells/haemoglobin i.e. anaemia. Iron deficiency anaemia has the highest incidence amongst preschool-age children. The main causes are excessive blood loss, inadequate dietary intake, poor intestinal absorption and increased iron requirements.

Epidemiology

· Globally, iron deficiency is the most common cause of anaemia

· Preschool-age children have the highest prevalence of iron deficiency anaemia

Causes

· Excessive blood loss: blood loss due to menorrhagia is the most common cause in pre-menopausal women, whereas gastrointestinal bleeding is the most common cause in men (always suspect colon cancer) and post-menopausal women.

· Inadequate dietary intake: as meat is a good source of iron, vegans and vegetarians are more likely to develop iron deficiency anaemia due to a lack of meat in their diet. However dark green leafy vegetables are another good source of iron, therefore people who don’t eat meat can still receive enough iron through purely dietary sources.

· Poor intestinal absorption: conditions which affect the small intestine, such as coeliac disease, can prevent sufficient iron being absorbed.

· Increased iron requirements: children have increased iron demands during periods of rapid growth. Women also have increased demands during pregnancy as the baby will receive their iron supply from the mother. In addition, an increase in plasma volume during pregnancy causes iron deficiency anaemia through dilution i.e. the proportion of fluid in comparison to red blood cells increases.

Features

· Fatigue

· Shortness of breath on exertion

· Palpitations

· Pallor

· Nail changes: this includes koilonychia (spoon-shaped nails)

· Hair loss

· Atrophic glossitis

· Post-cricoid webs

· Angular stomatitis

Investigations

· Taking a history is the most important step in looking for potential causes of iron deficiency. It is useful to inquire about: changes in diet, medication history, menstrual history, weight loss, change in bowel habit

· Full blood count (FBC) demonstrates hypochromic microcytic anaemia

· Serum ferritin this will likely be low, as serum ferritin correlates with iron stores. However, it is important to recognise that ferritin can be raised during states of inflammation; so a raised ferritin does not necessarily rule out iron deficiency anaemia if the is co-occurring inflammation. For patients with co-occurring inflammatory disease, other iron studies can be performed.

· Total iron-binding capacity (TIBC)/transferrin this will be high. A high TIBC reflects low iron stores. . Note that the transferrin saturation will however be low

· Blood film anisopoikilocytosis (red blood cells of different sizes and shapes) , target cells, 'pencil' poikilocytes

· Endoscopy to rule out malignancy, males and post-menopausal females who present with unexplained iron-deficiency anaemia should be considered for further gastrointestinal investigations. Post-menopausal women with a haemoglobin level ≤10 and men with a haemoglobin level ≤11 should be referred to a gastroenterologist within 2 weeks.

Management

· The underlying cause of the iron-deficiency anaemia must be identified and managed. It is particularly important that malignancy has been excluded by taking an adequate history and appropriate investigations if warranted

· Oral ferrous sulfate: patients should continue taking iron for 3 months after the iron deficiency has been corrected in order to replenish iron stores. Common side effects of iron supplementation include nausea, abdominal pain, constipation, diarrhoea

· Iron-rich diet: this includes dark-green leafy vegetables, meat, iron-fortified bread

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24 December 2020

14:03

Sickle-cell crises

Sickle cell anaemia is characterised by periods of good health with intervening crises

A number of types of crises are recognised:

· thrombotic, 'painful crises'

· sequestration

· acute chest syndrome

· aplastic

· haemolytic

Thrombotic crises

· also known as painful crises or vaso-occlusive crises

· precipitated by infection, dehydration, deoxygenation

· painful vaso-occlusive crises should be diagnosed clinically - there isn't one test that can confirm them although tests may be done to exclude other complications

· infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain

Sequestration crises

· sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia

Acute chest syndrome

· dyspnoea, chest pain, pulmonary infiltrates, low pO2

· the most common cause of death after childhood

Aplastic crises

· caused by infection with parvovirus

· sudden fall in haemoglobin

Haemolytic crises

· rare

· fall in haemoglobin due an increased rate of haemolysis

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Acute chest crisis management:

· Hydration

· O2 therapy

· Broad spectrum IV Abx

· Pain relief

· Incentive spirometry (if able)

· Bronchodilators is element of bronchospasm

· Transfusion

either top-up or exchange

Need to be aware of patients’ baseline

· Early involvement of haematology and critical care

24 December 2020

14:03

Von Willebrand's disease

Von Willebrand's disease is the most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst 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: partial reduction in vWF (80% of patients)

· type 2*: abnormal form of vWF

· type 3**: total lack of vWF (autosomal recessive)

Investigation

· prolonged bleeding time

· APTT may be prolonged

· factor VIII levels may be moderately reduced

· defective platelet aggregation with ristocetin

Management

· tranexamic acid for mild bleeding

· desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells

· factor VIII concentrate

*type 2A VWD is caused by defective platelet adhesion due to decreased high molecular weight VWF multimers (i.e. the VWF protein is too small). Type 2B is characterised by a pathological increase of VWF-platelet interaction. Type 2M is caused by a decrease in VWF-platelet interaction (not related to loss of high molecular weight multimers). Type 2N is caused by abnormal binding of the VWF to Factor VIII. There is no clear correlation between symptomatic presentation and type of VWD however common themes amongst patients include excessive mucocutaneous bleeding, bruising in the absence of trauma and menorrhagia in females.

**type 3 von Willebrand's disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients have type 1 disease

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24 December 2020

14:03

Blood products: CMV negative and irradiated blood

Cytomegalovirus (CMV) is transmitted in leucocytes. As most blood products (except granulocyte transfusions) are now leucocyte depleted CMV negative products are rarely required.

Irradiated blood products are depleted of T-lymphocytes and used to avoid transfusion-associated graft versus host disease (TA-GVHD) caused by engraftment of viable donor T lymphocytes.

The table below shows the indications for CMV and irradiated blood:

Situation	CMV negative	Irradiated
Granulocyte transfusions	✓	✓
Intra-uterine transfusions	✓	✓
Neonates up to 28 days post expected date of delivery	✓	✓
Pregnancy: Elective transfusions during pregnancy (not during labour or delivery)	✓
Bone marrow / stem cell transplants		✓
Immunocompromised (e.g. chemotherapy or congenital)		✓
Patients with/previous Hodgkins Disease		✓
HIV

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24 December 2020

14:04

Chronic myeloid leukaemia

The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML). It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal

Presentation (60-70 years)

· anaemia: lethargy

· weight loss and sweating are common

· splenomegaly may be marked → abdo discomfort

· an increase in granulocytes at different stages of maturation +/- thrombocytosis

· decreased leukocyte alkaline phosphatase

· may undergo blast transformation (AML in 80%, ALL in 20%)

Management

· imatinib is now considered first-line treatment

· hydroxyurea

· interferon-alpha

· allogenic bone marrow transplant

Imatinib

· inhibitor of the tyrosine kinase associated with the BCR-ABL defect

· very high response rate in chronic phase CML

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24 December 2020

14:04

Hereditary spherocytosis

Basics

· most common hereditary haemolytic anaemia in people of northern European descent

· autosomal dominant defect of red blood cell cytoskeleton

· the normal biconcave disc shape is replaced by a sphere-shaped red blood cell

· red blood cell survival reduced as destroyed by the spleen

Presentation

· failure to thrive

· jaundice, gallstones

· splenomegaly

· aplastic crisis precipitated by parvovirus infection

· degree of haemolysis variable

· MCHC elevated

Diagnosis

· the osmotic fragility test was previously the recommend investigation of choice. However, it is now deemed unreliable and is no longer recommended

· the British Journal of Haematology (BJH) guidelines state that 'patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration[MCHC], increase in reticulocytes) do not require any additional tests

· if the diagnosis is equivocal the BJH recommend the cryohaemolysis test and EMA binding

· for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice

Management

· acute haemolytic crisis:

o treatment is generally supportive

o transfusion if necessary

· longer term treatment:

o folate replacement

o splenectomy

Comparing G6PD deficiency to hereditary spherocytosis:

Comparison of G6PD deficiency to hereditary spherocytosis

	G6PD deficiency	Hereditary spherocytosis
Gender	Male (X-linked recessive)	Male + female (autosomal dominant)
Ethnicity	African + Mediterranean descent	Northern European descent
Typical history	• Neonatal jaundice • Infection/drugs precipitate haemolysis • Gallstones	• Neonatal jaundice • Chronic symptoms although haemolytic crises may be precipitated by infection • Gallstones • Splenomegaly is common
Blood film	Heinz bodies	Spherocytes (round, lack of central pallor)
Diagnostic test	Measure enzyme activity of G6PD	EMA binding test

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24 December 2020

14:04

Platelet transfusion: active bleeding

Active bleeding

Offer platelet transfusions to patients with a platelet count of <30 x 10 9 with clinically significant bleeding (World Health organisation bleeding grade 2- e.g. haematemesis, melaena, prolonged epistaxis)

Platelet thresholds for transfusion are higher (maximum < 100 x 10 9) for patients with severe bleeding (World Health organisation bleeding grades 3&4), or bleeding at critical sites, such as the CNS.

It should be noted that platelet transfusions have the highest risk of bacterial contamination compared to other types of blood product.

Pre-invasive procedure (prophylactic)

Platelet transfusion for thrombocytopenia before surgery/ an invasive procedure. Aim for plt levels of:

· > 50×109/L for most patients

· 50-75×109/L if high risk of bleeding

· >100×109/L if surgery at critical site

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

For example, do not perform platelet transfusion for any of the following conditions:

· Chronic bone marrow failure

· Autoimmune thrombocytopenia

· Heparin-induced thrombocytopenia, or

· Thrombotic thrombocytopenic purpura.

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24 December 2020

14:04

Sickle-cell anaemia

Sickle-cell anaemia is an autosomal recessive condition that results for synthesis of an abnormal haemoglobin chain termed HbS. It is more common in people of African descent as the heterozygous condition offers some protection against malaria. Around 10% of UK Afro-Caribbean's are carriers of HbS (i.e. heterozygous). Such people are only symptomatic if severely hypoxic.

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

Pathophysiology

· polar amino acid glutamate is substituted by non-polar valine in each of the two beta chains (codon 6). This decreases the water solubility of deoxy-Hb

· in the deoxygenated state the HbS molecules polymerise and cause RBCs to sickle

· HbAS patients sickle at p02 2.5 - 4 kPa, HbSS patients at p02 5 - 6 kPa

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

Investigations

· definitive diagnosis of sickle cell disease is by haemoglobin electrophoresis

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24 December 2020

14:04

Venous thromboembolism: risk factors

Common predisposing factors include malignancy, pregnancy and the period following an operation. The comprehensive list below is partly based on the 2010 SIGN venous thromboembolism (VTE) guidelines:

General

· increased risk with advancing age

· obesity

· family history of VTE

· pregnancy (especially puerperium)

· immobility

· hospitalisation

· anaesthesia

· central venous catheter: femoral >> subclavian

Underlying conditions

· malignancy

· thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency

· heart failure

· antiphospholipid syndrome

· Behcet's

· polycythaemia

· nephrotic syndrome

· sickle cell disease

· paroxysmal nocturnal haemoglobinuria

· hyperviscosity syndrome

· homocystinuria

Medication

· combined oral contraceptive pill: 3rd generation more than 2nd generation

· hormone replacement therapy: the risk of VTE is higher in women taking oestrogen + progestogen preparations compared to those taking oestrogen-only preparations

· raloxifene and tamoxifen

· 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.

From <https://www.passmedicine.com/review/textbook.php?s=#>

· Congenital thrombophilias (i.e antithrombin deficiency, protein Cor S deficiency, prothrombin gene mutaions)

· Acquired: Antiphospholipid syndrome, Myeloproliferative conditions

· Inflammatory states: malignancy, surgery

· Poor mobility

· Compression

24 December 2020

14:04

Vitamin B12 deficiency

Vitamin B12 is mainly used in the body for red 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 deficiency

· pernicious anaemia: most common cause

· post gastrectomy

· vegan diet or a poor diet

· disorders/surgery of terminal ileum (site of absorption)

o Crohn's: either diease activity or following ileocaecal resection

· metformin (rare)

Features of vitamin B12 deficiency

· macrocytic anaemia

· sore tongue and mouth

· neurological symptoms

o the dorsal column is usually affected first (joint position, vibration) prior to distal paraesthesia

· neuropsychiatric symptoms: e.g. mood disturbances

Management

· if no neurological involvement 1 mg of IM hydroxocobalamin 3 times each week for 2 weeks, then once every 3 months

· if a patient is also deficient in folic acid then it is important to treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord

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24 December 2020

14:04

Blood products: red bloods cells

NICE published guidelines on the use of blood products in 2015.

They recommended the following thresholds for transfusion:

	Patients without ACS	Patients with ACS
Transfusion threshold	70 g/L	80 g/L
Target after transfusion	70-90 g/L	80-100 g/L

(ACS = acute coronary syndrome)

Please note that these thresholds should not be used in patients with ongoing major haemorrhage or patients who require regular blood transfusions for chronic anaemia.

Practical points

· red blood cells should be stored at 4°C prior to infusion

· in a non-urgent scenario, a unit of RBC is usually transfused over 90-120 minutes

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24 December 2020

14:04

Chronic lymphocytic leukaemia: features and investigation

Chronic lymphocytic leukaemia (CLL) 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.

Features

· often none: may be picked up by an incidental finding of lymphocytosis

· constitutional: anorexia, weight loss

· bleeding, infections

· lymphadenopathy more marked than chronic myeloid leukaemia

Investigations

· full blood count:

o lymphocytosis

o anaemia

· blood film: smudge cells (also known as smear cells)

· immunophenotyping is the key investigation

Image sourced from Wikipedia

Peripheral blood film showing smudge B cells

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24 December 2020

14:04

Hodgkin's lymphoma

Hodgkin's lymphoma is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades

Features

· lymphadenopathy (75%) - painless, non-tender, asymmetrical

· systemic (25%): weight loss, pruritus, night sweats, fever (Pel-Ebstein)

· alcohol pain in HL

· normocytic anaemia, eosinophilia

· LDH raised

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24 December 2020

14:04

Polycythaemia vera: features

Polycythaemia vera (previously called polycythaemia rubra vera) is a myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has recently been established that a mutation in JAK2 is present in approximately 95% of patients with polycythaemia vera and this has resulted in significant changes to the diagnostic criteria. The incidence of polycythaemia vera peaks in the sixth decade.

Features

· hyperviscosity

· pruritus, typically after a hot bath

· splenomegaly

· haemorrhage (secondary to abnormal platelet function)

· plethoric appearance

· hypertension in a third of patients

· low ESR

Following history and examination, the British Committee for Standards in Haematology (BCSH) recommend the following tests are performed

· full blood count/film (raised haematocrit; neutrophils, basophils, platelets raised in half of patients)

· JAK2 mutation

· serum ferritin

· renal and liver function tests

If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests:

· red cell mass

· arterial oxygen saturation

· abdominal ultrasound

· serum erythropoietin level

· bone marrow aspirate and trephine

· cytogenetic analysis

· erythroid burst-forming unit (BFU-E) culture

Other features that may be seen in PRV include a low ESR and a raised leukocyte alkaline phosphatase

The diagnostic criteria for polycythaemia vera have recently been updated by the BCSH. This replaces the previous polycythaemia vera Study Group criteria.

JAK2-positive polycythaemia vera - diagnosis requires both criteria to be present

Criteria	Notes
A1	High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
A2	Mutation in JAK2

JAK2-negative PRV - diagnosis requires A1 + A2 + A3 + either another A or two B criteria

Criteria	Notes
A1	Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women
A2	Absence of mutation in JAK2
A3	No cause of secondary erythrocytosis
A4	Palpable splenomegaly
A5	Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells
B1	Thrombocytosis (platelet count >450 * 109/l)
B2	Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers)
B3	Radiological evidence of splenomegaly
B4	Endogenous erythroid colonies or low serum erythropoietin

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24 December 2020

14:04

Post-thrombotic syndrome

It is increasingly recognised that patients may develop complications following a DVT. Venous outflow obstruction and venous insufficiency result in chronic venous hypertension. The resulting clinical syndrome is known as post-thrombotic syndrome. The following features maybe seen:

· painful, heavy calves

· pruritus

· swelling

· varicose veins

· venous ulceration

Compression stockings have in the past been offered to patients with deep vein thrombosis to help reduce the risk of post-thrombotic syndrome.

However, Clinical Knowledge Summaries now state the following:

Do not offer elastic graduated compression stockings to prevent post-thrombotic syndrome or VTE recurrence after a proximal DVT. This recommendation does not cover the use of elastic stockings for the management of leg symptoms after DVT.

However, once post-thrombotic syndrome has developed compression stockings are a recommended treatment. Other recommendations including keeping the leg elevated.

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24 December 2020

14:04

Thrombophilia: causes

Inherited

Gain of function polymorphisms

· factor V Leiden (activated protein C resistance): most common cause of thrombophilia

· prothrombin gene mutation: second most common cause

Deficiencies of naturally occurring anticoagulants

· antithrombin III deficiency

· protein C deficiency

· protein S deficiency

The table below shows the prevalence and relative risk of venous thromboembolism (VTE) of the different inherited thrombophilias:

Condition	Prevalence	Relative risk of VTE
Factor V Leiden (heterozygous)	5%	4
Factor V Leiden (homozygous)	0.05%	10
Prothrombin gene mutation (heterozygous)	1.5%	3
Protein C deficiency	0.3%	10
Protein S deficiency	0.1%	5-10
Antithrombin III deficiency	0.02%	10-20

Acquired

Antiphospholipid syndrome

Drugs

· the combined oral contraceptive pill

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24 December 2020

14:04

Tumour lysis syndrome

Tumour lysis syndrome (TLS) is a potentially deadly condition related to the treatment of high-grade lymphomas and leukaemias. It can occur in the absence of chemotherapy but is usually triggered by the introduction of combination chemotherapy. On occasion, it can occur with steroid treatment alone. Awareness of the condition is critical as prophylactic medication can be given to prevent the potentially deadly effects of tumour cell lysis.

Patients at high risk of TLS should be given IV allopurinol or IV rasburicase immediately prior to and during the first days of chemotherapy. Rasburicase is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Allantoin is much more water-soluble than uric acid and is, therefore, more easily excreted by the kidneys. Patients in lower-risk groups should be given oral allopurinol during chemotherapy cycles in an attempt to avoid the condition. Rasburicase and allopurinol should not be given together in the management of tumour lysis syndrome as this reduces the effect of rasburicase.

TLS occurs from the breakdown of the tumour cells and the subsequent release of chemicals from the cell. It leads to a high potassium and high phosphate level in the presence of a low calcium. It should be suspected in any patient presenting with an acute kidney injury in the presence of a high phosphate and high uric acid level.

From 2004 TLS has been graded using the Cairo-Bishop scoring system -

Laboratory tumor lysis syndrome: abnormality in two or more of the following, occurring within three days before or seven days after chemotherapy.

· uric acid > 475umol/l or 25% increase

· potassium > 6 mmol/l or 25% increase

· phosphate > 1.125mmol/l or 25% increase

· calcium < 1.75mmol/l or 25% decrease

Clinical tumor lysis syndrome: laboratory tumour lysis syndrome plus one or more of the following:

· increased serum creatinine (1.5 times upper limit of normal)

· cardiac arrhythmia or sudden death

· seizure

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24 December 2020

14:05

Abnormal coagulation

Cause	Factors affected
Heparin	Prevents activation factors 2,9,10,11
Warfarin	Affects synthesis of factors 2,7,9,10
DIC	Factors 1,2,5,8,11
Liver disease	Factors 1,2,5,7,9,10,11

Interpretation blood clotting test results

Disorder	APTT	PT	Bleeding time
Haemophilia	Increased	Normal	Normal
von Willebrand's disease	Increased	Normal	Increased
Vitamin K deficiency	Increased	Increased	Normal

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Antiphospholipid syndrome: pregnancy

Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)

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 seven-fold

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Beta-thalassaemia trait

The 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 asymptomatic

Features

· mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia

· HbA2 raised (> 3.5%)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Blood products

Whole blood fractions

Fraction	Key points
Packed red cells	Used for transfusion in chronic anaemia and cases where infusion of large volumes of fluid may result in cardiovascular compromise. Product obtained by centrifugation of whole blood.
Platelet rich plasma	Usually administered to patients who are thrombocytopaenic and are bleeding or require surgery. It is obtained by low speed centrifugation.
Platelet concentrate	Prepared by high speed centrifugation and administered to patients with thrombocytopaenia.
Fresh frozen plasma	· Prepared from single units of blood. · Contains clotting factors, albumin and immunoglobulin. · Unit is usually 200 to 250ml. · Usually used in correcting clotting deficiencies in patients with hepatic synthetic failure who are due to undergo surgery. · Usual dose is 12-15ml/Kg-1. · It should not be used as first line therapy for hypovolaemia.
Cryoprecipitate	· Formed from supernatant of FFP. · Rich source of Factor VIII and fibrinogen. · Allows large concentration of factor VIII to be administered in small volume.
SAG-Mannitol Blood	Removal of all plasma from a blood unit and substitution with: · Sodium chloride · Adenine · Anhydrous glucose · Mannitol Up to 4 units of SAG M Blood may be administered. Thereafter whole blood is preferred. After 8 units, clotting factors and platelets should be considered.

Cell saver devices

These collect patients own blood lost during surgery and then re-infuse it. There are two main types:

· Those which wash the blood cells prior to re-infusion. These are more expensive to purchase and more complicated to operate. However, they reduce the risk of re-infusing contaminated blood back into the patient.

· Those which do not wash the blood prior to re-infusion.

Their main advantage is that they avoid the use of infusion of blood from donors into patients and this may reduce risk of blood borne infection. It may be acceptable to Jehovah's witnesses. It is contraindicated in malignant disease for risk of facilitating disease dissemination.

Blood products used in warfarin reversal

In some surgical patients the use of warfarin can pose specific problems and may require the use of specialised blood products

Immediate or urgent surgery in patients taking warfarin(1) (2):

1. Stop warfarin

2. Vitamin K (reversal within 4-24 hours)

-IV takes 4-6h to work (at least 5mg)

-Oral can take 24 hours to be clinically effective

3. Fresh frozen plasma

Used less commonly now as 1st line warfarin reversal

-30ml/kg-1

-Need to give at least 1L fluid in 70kg person (therefore not appropriate in fluid overload)

-Need blood group

-Only use if human prothrombin complex is not available

4. Human Prothrombin Complex (reversal within 1 hour)

-Bereplex 50 u/kg

-Rapid action but factor 6 short half life, therefore give with vitamin K

References

1. Dentali, F., C. Marchesi, et al. (2011). 'Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis.' Thromb Haemost 106(3): 429-438.

2. http://www.transfusionguidelines.org/docs/pdfs/bbt-03warfarin-reversal-flowchart-2006.pdf

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Burkitt's lymphoma

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

· endemic (African) form: typically involves maxilla or mandible

· sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV

Burkitt's lymphoma is associated with the c-myc gene translocation, usually t(8:14). The Epstein-Barr virus (EBV) 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

Management is with chemotherapy. This tends to produce a rapid response which may cause 'tumour lysis syndrome'. Rasburicase (a recombinant version of urate oxidase, an enzyme which 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

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Cryoprecipitate

· Blood product made from plasma

· Usually transfused as 6 unit pool

· Indications include massive haemorrhage and uncontrolled bleeding due to haemophilia

Composition

Agent	Quantity
Factor VIII	100IU
Fibrinogen	250mg
von Willebrand factor	Variable
Factor XIII	Variable

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Disseminated intravascular coagulation - diagnosis

Under homeostatic conditions, coagulation and fibrinolysis are coupled. The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin; the stable fibrin clot being the final product of hemostasis. The fibrinolytic system breaks down fibrinogen and fibrin. Activation of the fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides (fibrin degradation products). In a state of homeostasis, the presence of plasmin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for fibrinolysis.

In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein (tissue factor =TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumour necrosis factor, and 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 DIC

· sepsis

· trauma

· obstetric complications e.g. aminiotic fluid embolism or hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)

· malignancy

Diagnosis

A typical blood picture includes:

· low platelets

· prolonged APTT, prothrombin and bleeding time

· fibrin degradation products are often raised

· schistocytes due to microangiopathic haemolytic anaemia

Disorder	Prothrombin time	APTT	Bleeding time	Platelet count
Warfarin administration	Prolonged	Normal	Normal	Normal
Aspirin administration	Normal	Normal	Prolonged	Normal
Heparin	Often normal (may be prolonged)	Prolonged	Normal	Normal
DIC	Prolonged	Prolonged	Prolonged	Low

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Factor V Leiden

Factor V Leiden (activated protein C resistance) is the most common inherited thrombophilia, being present in around 5% of the UK population.

It is due to a gain of function mutation in the Factor V Leiden protein. The result of the mis-sense mutation is that activated factor V (a clotting factor) is inactivated 10 times more slowly by activated protein C than normal. This explains the alternative name for factor V Leiden of activated protein C resistance,

Heterozygotes have a 4-5 fold risk of venous thrombosis. Homozygotes have a 10 fold risk of venous thrombosis but the prevalence is much lower at 0.05%.

Screening for factor V Leiden is not recommended, even after a venous thromboembolism. The logic behind this is that a previous thromboembolism itself is a risk factor for further events and this should dictate specific management in the future, rather than the particular thrombophilia identified.

The table below shows the prevalence and relative risk of venous thromboembolism (VTE) of the different inherited thrombophilias:

Condition	Prevalence	Relative risk of VTE
Factor V Leiden (heterozygous)	5%	4
Factor V Leiden (homozygous)	0.05%	10
Prothrombin gene mutation (heterozygous)	1.5%	3
Protein C deficiency	0.3%	10
Protein S deficiency	0.1%	5-10
Antithrombin III deficiency	0.02	10-20

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Haemophilia

Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition. Haemophilia A is due to a deficiency of factor VIII whilst in haemophilia B (Christmas disease) there is a lack of factor IX

Features

· haemoarthroses, haematomas

· prolonged bleeding after surgery or trauma

Blood tests

· prolonged APTT

· bleeding time, thrombin time, prothrombin time normal

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

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Immune thrombocytopenia (ITP) in adults

Immune (or idiopathic) thrombocytopenic purpura (ITP) is an immune-mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex.

Children with ITP usually have an acute thrombocytopenia that may follow infection or vaccination. In contract, adults tend to have a more chronic condition.

ITP in adults

Epidemiology

· more common in older females

Presentation

· may be detected incidentally following routine bloods

· symptomatic patients may present with

o petichae, purpura

o bleeding (e.g. epistaxis)

o catastrophic bleeding (e.g. intracranial) is not a common presentation

Management

· first-line treatment for ITP is oral prednisolone

· pooled normal human immunoglobulin (IVIG) may also be used

· splenectomy is now less commonly used

Evan's syndrome

· ITP in association with autoimmune haemolytic anaemia (AIHA)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Macrocytic anaemia

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

Megaloblastic causes	Normoblastic causes
· vitamin B12 deficiency · folate deficiency	· alcohol · liver disease · hypothyroidism · pregnancy · reticulocytosis · myelodysplasia · drugs: cytotoxics

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:05

Management of suspected haematological malignancy in young people

Any of the following features in a person aged 0-24 years should prompt a very urgent full blood count (within 48 hours) to investigate for leukaemia:

· Pallor

· Persistent fatigue

· Unexplained fever

· Unexplained persistent infections

· Generalised lymphadenopathy

· Persistent or unexplained bone pain

· Unexplained bruising

· Unexplained bleeding

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Myelofibrosis

Overview

· a myeloproliferative disorder

· thought to be caused by hyperplasia of abnormal megakaryocytes

· the resultant release of platelet derived growth factor is thought to stimulate fibroblasts

· haematopoiesis develops in the liver and spleen

Features

· e.g. elderly person with symptoms of anaemia e.g. fatigue (the most common presenting symptom)

· massive splenomegaly

· hypermetabolic symptoms: weight loss, night sweats etc

Laboratory findings

· anaemia

· high WBC and platelet count early in the disease

· 'tear-drop' poikilocytes on blood film

· unobtainable bone marrow biopsy - 'dry tap' therefore trephine biopsy needed

· high urate and LDH (reflect increased cell turnover)

Blood film showing the typical 'tear-drop' poikilocytes of myelofibrosis

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Neutropenic sepsis

Neutropenic sepsis is a relatively common complication of cancer therapy, usually as a 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:

· a temperature higher than 38ºC or

· other signs or symptoms consistent with clinically significant sepsis

Prophylaxis

· if it is anticipated that patients are likely to have a neutrophil count of < 0.5 * 109 as a consequence of their treatment they should be offered a fluoroquinolone

Management

· antibiotics must be started immediately, do not wait for the WBC

· NICE recommends starting empirical antibiotic therapy with piperacillin with tazobactam (Tazocin) immediately

· many units add vancomycin if the patient has central venous access but NICE do not support this approach

· following this initial treatment patients are usually assessed by a specialist and risk-stratified to see if they may be able to have outpatient treatment

· if patients are still febrile and unwell after 48 hours an alternative antibiotic such as meropenem is often prescribed +/- vancomycin

· if patients are not responding after 4-6 days the Christie guidelines suggest ordering investigations for fungal infections (e.g. HRCT), rather than just starting therapy antifungal therapy blindly

· there may be a role for G-CSF in selected patients

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Polycythaemia

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

Relative causes

· dehydration

· stress: Gaisbock syndrome

Primary

· polycythaemia rubra vera

Secondary causes

· COPD

· altitude

· obstructive sleep apnoea

· excessive erythropoietin: cerebellar haemangioma, hypernephroma, hepatoma, uterine fibroids*

To differentiate between true (primary or secondary) polycythaemia and relative polycythaemia red cell mass studies are sometimes used. In true polycythaemia the total red cell mass in males > 35 ml/kg and in women > 32 ml/kg

*uterine fibroids may cause menorrhagia which in turn leads to blood loss - polycythaemia is rarely a clinical problem

From <https://www.passmedicine.com/review/textbook.php?s=#>

Whole blood viscosity is dependent upon Hct, red cell deformability and plasma viscosity.

pt should be venesected on a weekly basis initially to a Hct of around 0.45.

An elevated Hct is associated particularly with an increased risk of cerebro vascular accident and myocardial infarction.

The degree of elevation of his platelet count and his history of TIA’s make anti-platelet therapy with Aspirin and treatment to reduce his platelet count (cyto-reductive therapy e.g. interferon or hydroxycarbamide) into the normal range appropriate.

Anti-coagulant therapy is not indicated as he doesn’t have atrial fibrillation to suggest this as a cause of his transient ischaemic attacks.

Anti-coagulation therapy has no role in the routine management of primary polycythaemia

The risk/benefit balance of Aspirin in this situation outweighs that of Warfarin because of the risks of bleeding associated with anti-coagulant therapy.

From <https://mle.ncl.ac.uk/cases/page/15729/>

24 December 2020

14:06

Thrombocytosis

Thrombocytosis is an abnormally high platelet count, usually > 400 * 109/l.

Causes of thrombocytosis

· reactive: platelets are an acute phase reactant - platelet count can increase in response to stress such as a severe infection, surgery. Iron deficiency anaemia can also cause a reactive thrombocytosis

· malignancy

· essential thrombocytosis (see below), or as part of another myeloproliferative disorder such as chronic myeloid leukaemia or polycythaemia rubra vera

· hyposplenism

Essential thrombocytosis

Essential thrombocytosis is one of the myeloproliferative disorders which overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis. Megakaryocyte proliferation results in an overproduction of platelets.

Features

· platelet count > 600 * 109/l

· both thrombosis (venous or arterial) and haemorrhage can be seen

· a characteristic symptom is a burning sensation in the hands

· a JAK2 mutation is found in around 50% of patients

Management

· hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count

· interferon-α is also used in younger patients

· low-dose aspirin may be used to reduce the thrombotic risk

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Aplastic anaemia

Characterised by pancytopenia and a hypoplastic bone marrow

Peak incidence of acquired = 30 years old

Features

· normochromic, normocytic anaemia

· leukopenia, with lymphocytes relatively spared

· thrombocytopenia

· may be the presenting feature acute lymphoblastic or myeloid leukaemia

· a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia

Causes

· idiopathic

· congenital: Fanconi anaemia, dyskeratosis congenita

· drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold

· toxins: benzene

· infections: parvovirus, hepatitis

· radiation

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) may be divided in to 'warm' and 'cold' types, according to at what temperature the antibodies best cause haemolysis. It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, infection or drugs. AIHA is characterised by a positive direct antiglobulin test (Coombs' test)

Warm AIHA

In warm AIHA the antibody (usually IgG) causes haemolysis best at body temperature and haemolysis tends to occur in extravascular sites, for example the spleen. Management options include steroids, immunosuppression and splenectomy

Causes of warm AIHA

· autoimmune disease: e.g. systemic lupus erythematosus*

· neoplasia: e.g. lymphoma, CLL

· drugs: e.g. methyldopa

Cold AIHA

The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C. Haemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Raynaud's and acrocynaosis. Patients respond less well to steroids

Causes of cold AIHA

· neoplasia: e.g. lymphoma

· infections: e.g. mycoplasma, EBV

*systemic lupus erythematosus can rarely be associated with a mixed-type autoimmune haemolytic anaemia

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Beta-thalassaemia major

Overview

· absence of beta chains

· chromosome 11

Features

· presents in first year of life with failure to thrive and hepatosplenomegaly

· microcytic anaemia

· HbA2 & HbF raised

· HbA absent

Management

· repeated transfusion → iron overload

· s/c infusion of desferrioxamine

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Blood films: pathological cell forms

Pathological red cell forms

Abnormality	Associated condition(s)	Appearance
Target cells	Sickle-cell/thalassaemia Iron-deficiency anaemia Hyposplenism Liver disease
'Tear-drop' poikilocytes	Myelofibrosis
Spherocytes	Hereditary spherocytosis Autoimmune hemolytic anaemia
Basophilic stippling	Lead poisoning Thalassaemia Sideroblastic anaemia Myelodysplasia
Howell-Jolly bodies	Hyposplenism
Heinz bodies	G6PD deficiency Alpha-thalassaemia
Schistocytes ('helmet cells')	Intravascular haemolysis Mechanical heart valve Disseminated intravascular coagulation
'Pencil' poikilocytes	Iron deficency anaemia
Burr cells (echinocytes)	Uraemia Pyruvate kinase deficiency
Acanthocytes	Abetalipoproteinemia

Other blood film abnormalities:

· hypersegmented neutrophils: megaloblastic anaemia

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Graft versus host disease

Graft versus host disease (GVHD) is a multi-system complication of allogeneic bone marrow transplantation. Less frequently, it may also occur following solid organ transplantation or transfusion in immunocompromised patients. The disease occurs when T cells in the donor tissue (the graft) mount an immune response toward recipient (host) cells. It is not to be confused with transplant rejection (in which recipient immune cells activate an immune response toward the donor tissue). Prognosis is generally poor.

Three conditions required for diagnosis of GVHD, known as the Billingham criteria 1:

· The transplanted tissue contains immunologically functioning cells

· The recipient and donor are immunologically different

· The recipient is immunocompromised

Estimates of incidence vary from 9-50% post allogeneic bone marrow transplant despite prophylaxis with calcineurin inhibitors. The following principal risk factors have been identified 2:

· Poorly matched donor and recipient (particularly HLA)

· Type of conditioning used prior to transplantation

· Gender disparity between donor and recipient

· Graft source (bone marrow or peripheral blood source associated with higher risk than umbilical cord blood)

Acute and chronic GVHD are considered separate syndromes:

Acute GVHD

· Is classically defined as onset is classically within 100 days of transplantation*

· Usually affects the skin (>80%), liver (50%), and gastrointestinal tract (50%)

· Multi-organ involvement carries a worse prognosis**

Chronic GVHD

· May occur following acute disease, or can arise de novo

· Classically occurs after 100 days following transplantation

· Has a more varied clinical picture: often lung and eye involvement in addition to skin and GI, although any organ system may be involved

Signs and symptoms - note that diagnosis is largely clinical and based on the exclusion of other pathology:

Acute GVHD

· Painful maculopapular rash (often neck, palms and soles), which may progress to erythroderma or a toxic epidermal necrolysis-like syndrome

· Jaundice

· Watery or bloody diarrhoea

· Persistent nausea and vomiting

· Can also present as a culture-negative fever

Chronic GVHD

· Skin: Many manifestations including poikiloderma, scleroderma, vitiligo, lichen planus

· Eye: Often keratoconjunctivitis sicca, also corneal ulcers, scleritis

· GI: Dysphagia, odynophagia, oral ulceration, ileus. Oral lichenous changes are a characteristic early sign (2)

· Lung: my present as obstructive or restrictive pattern lung disease

Investigations (largely dependent on which organs are involved):

· LFTs may demonstrate cholestatic jaundice. Hepatitis screen/ultrasound may be useful to exclude other causes

· Abdominal imaging may reveal air-fluid levels and small bowel thickening ('ribbon sign')

· Lung function testing

· Biopsy of affected tissue may aid in diagnosis if there is uncertainty

Management consists of immunosuppression and supportive measures. Intravenous steroids are the mainstay of immunosuppressive treatment in severe cases of acute GVHD. Extended courses of steroid therapy are often needed in chronic GVHD and dose tapering is vital. Second-line therapies include anti-TNF, mTOR inhibitors and extracorporeal photopheresis. Excessive immunosuppression may predispose patients to infection, and also limit the beneficial graft-versus-tumour effect of the transplant.

Topical steroid therapy may be sufficient in mild disease with limited cutaneous involvement.

*Please note that there is some contention as to whether timeframe or clinical features should be used to define acute vs chronic GVHD. Persistent, recurrent or late-onset acute GVHD may occur, while chronic GVHD may manifest before the 100 day cutoff. As such, diagnosis is often based on clinical manifestation as well as timeframe.

**A prognostic staging system for acute GVHD exists based on serum bilirubin, abdominal imaging findings and level of cutaneous involvement, but is beyond the scope of these notes.

References

1. Ferrara, J., Levine, J., Reddy, P. & Holler, E. Graft-versus-host disease. The Lancet 373, 1550-1561 (2009).

2. Lazaryan, A. et al. Risk Factors for Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation with Umbilical Cord Blood and Matched Sibling Donors. Biology of Blood and Marrow Transplantation 22, 134-140 (2016).

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Granulocyte-colony stimulating factors

Recombinant human granulocyte-colony stimulating factors are used to increase neutrophil counts in patients who are neutropenic secondary to chemotherapy or other factors.

Examples include:

· filgrastim

· perfilgrastim

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Haematological malignancies: genetics

Below is a brief summary of the common translocations associated with haematological malignancies

t(9;22) - Philadelphia chromosome

· present in > 95% of patients with CML

· 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 in excess of normal

· poor prognostic indicator in ALL

t(15;17)

· seen in acute promyelocytic leukaemia (M3)

· fusion of PML and RAR-alpha genes

t(8;14)

· seen in Burkitt's lymphoma

· MYC oncogene is translocated to an immunoglobulin gene

t(11;14)

· Mantle cell lymphoma

· deregulation of the cyclin D1 (BCL-1) gene

t(14;18)

· follicular lymphoma

· increased BCL-2 transcription

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Haematological malignancies: infections

Viruses

· EBV: Hodgkin's and Burkitt's lymphoma, nasopharyngeal carcinoma

· HTLV-1: Adult T-cell leukaemia/lymphoma

· HIV-1: High-grade B-cell lymphoma

Bacteria

· Helicobacter pylori: gastric lymphoma (MALT)

Protozoa

· malaria: Burkitt's lymphoma

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Haemolytic anaemias: by cause

Hereditary haemolytic anaemias can be subdivided into membrane, metabolism or haemoglobin defects

Hereditary causes

· membrane: hereditary spherocytosis/elliptocytosis

· metabolism: G6PD deficiency

· haemoglobinopathies: sickle cell, thalassaemia

Acquired haemolytic anaemias can be subdivided into immune and non-immune causes

Acquired: immune causes

· autoimmune: warm/cold antibody type

· alloimmune: transfusion reaction, haemolytic disease newborn

· drug: methyldopa, penicillin

Acquired: non-immune causes

· microangiopathic haemolytic anaemia (MAHA): TTP/HUS, DIC, malignancy, pre-eclampsia

· prosthetic cardiac valves

· paroxysmal nocturnal haemoglobinuria

· infections: malaria

· drug: dapsone

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Hyposplenism

Causes

· splenectomy

· sickle-cell

· coeliac disease, dermatitis herpetiformis

· Graves' disease

· systemic lupus erythematosus

· amyloid

Features

· Howell-Jolly bodies

· siderocytes

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Iron deficiency anaemia vs. AOCD

	Iron deficiency anaemia	Anaemia of chronic disease
Serum iron	Low < 8	Low < 15
TIBC	High	Low
Transferrin saturation	Low	Low
Ferritin	Low	High

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Laboratory findings in haematological disease

The table below shows some very selective laboratory findings that are commonly tested in the exam:

Test	Interpretation
Haptoglobin (Remember haptoglobin binds to free haemoglobin)	Decrease · intravascular haemolysis
MCHC	Increased · hereditary spherocytosis · autoimmune haemolytic anemia* Decreased · microcytic anaemia (e.g. iron deficiency)

*associated with spherocytosis

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Lead poisoning

Along with acute intermittent porphyria, lead poisoning should be considered in questions giving a combination of abdominal pain and neurological signs. Lead poisoning results in defective ferrochelatase and ALA dehydratase function.

Features

· abdominal pain

· peripheral neuropathy (mainly motor)

· fatigue

· constipation

· blue lines on gum margin (only 20% of adult patients, very rare in children)

Investigations

· the blood lead level is usually used for diagnosis. Levels greater than 10 mcg/dl are considered significant

· full blood count: microcytic anaemia. Blood film shows red cell abnormalities including basophilic stippling and clover-leaf morphology

· raised serum and urine levels of delta aminolaevulinic acid may be seen making it sometimes difficult to differentiate from acute intermittent porphyria

· urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased)

· in children, lead can accumulate in the metaphysis of the bones although x-rays are not part of the standard work-up

Management - various chelating agents are currently used:

· dimercaptosuccinic acid (DMSA)

· D-penicillamine

· EDTA

· dimercaprol

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Lymphadenopathy

There are many causes of generalised lymphadenopathy

Infective

· 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

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Microcytic anaemia

Causes

· iron-deficiency anaemia

· thalassaemia*

· congenital sideroblastic anaemia

· anaemia of chronic disease (more commonly a normocytic, normochromic picture)

· lead poisoning

A question sometimes seen in exams gives a history of a normal haemoglobin level associated with a microcytosis. In patients not at risk of thalassaemia, this should raise the possibility of polycythaemia rubra vera which may cause an iron-deficiency secondary to bleeding.

New onset microcytic anaemia in elderly patients should be urgently investigated to exclude underlying malignancy.

*in beta-thalassaemia minor the microcytosis is often disproportionate to the anaemia

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Myelodysplastic syndrome

Overview

· also known as myelodysplasia

· acquired neoplastic disorder of hematopoietic stem cells

· pre-leukaemia, may progress to AML

Features

· more common with age

· presents with bone marrow failure (anaemia, neutropaenia, thrombocytopenia)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Myeloma

Myeloma classically causes hypercalcaemia, pancytopenia and an AKI.

Multiple myeloma (MM) is a haematological malignancy characterised by plasma cell proliferation. It arises due to genetic mutations which occur as B-lymphocytes differentiate into mature plasma cells. MM is the second most common haematological malignancy.

Presentation:

The median age at presentation is 70-years-old.

Use the mnemonicCRABBI:

· Calcium

o Hypercalcaemia occurs as a result of increased osteoclast activity within the bones

o This leads to constipation, nausea, anorexia and confusion

· Renal

o Monoclonal production of immunoglobulins results in light chain deposition within the renal tubules

o This causes renal damage which presents as dehydration and increasing thirst

o Other causes of renal impairment in myeloma include amyloidosis, nephrocalcinosis, nephrolithiasis

· Anaemia

o Bone marrow crowding suppresses erythropoiesis leading to anaemia

o This causes fatigue and pallor

· Bleeding

o bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising

· Bones

o Bone marrow infiltration by plasma cells and cytokine-mediated osteoclast overactivity creates lytic bone lesions

o This may present as pain (especially in the back) and increases the risk of fragility fractures

· Infection

o a reduction in the production of normal immunoglobulins results in increased susceptibility to infection

Investigations

· Bloods will show anaemia (FBC) and thrombocytopenia (FBC); raised urea and creatinine (U&E) and raised calcium

· Peripheral blood film: rouleaux formation

· Serum or urine protein electrophoresis: raised concentrations of monoclonal IgA/IgG proteins will be present in the serum. In the urine, they are known as Bence Jones proteins

· Bone marrow aspiration and trephine biopsy: confirms the diagnosis if the number of plasma cells is significantly raised

· Whole-body MRI (or CT if MRI is not suitable) is used to survey the skeleton for bone lesions

A common X-ray finding is a 'rain-drop' skull. This is numerous randomly placed dark spots seen on X-ray which occur due to bone lysis.

Diagnosis

It is important to accurately diagnose multiple myeloma, as unlike its pre-malignant counterparts (Monoclonal gammopathy of undetermined significance and Smoldering myeloma), treatment must begin immediately due to the risk of complications occurring as a result on end-organ damage.

Symptomatic multiple myeloma is defined at diagnosis by the presence of the following three factors:

· Monoclonal plasma cells in the bone marrow >10%

· Monoclonal protein within the serum or the urine (as determined by electrophoresis)

· Evidence of end-organ damage e.g. hypercalcaemia, elevated creatinine, anaemia or lytic bone lesions/fractures

Management

Myeloma is a chronic relapsing and remitting malignancy which is currently deemed incurable. Management aims to control symptoms, reduce complications and prolong survival.

For those who have just been diagnosed with symptomatic multiple myeloma, treatment begins with induction therapy:

· For patients who are suitable for autologous stem cell transplantation* induction therapy consists of Bortezomib + Dexamethasone

· For patients who are unsuitable for autologous stem cell transplantation*, induction therapy consists of Thalidomide + an Alkylating agent + Dexamethasone

Typically it is younger, healthier patients who are suitable for stem cell transplantation and rigorous chemotherapy regimes.

After completion of treatment, patients are monitored every 3 months with blood tests and electrophoresis. Many will achieve remission and will not need further therapy for some time.

Many patients do relapse after initial therapy. If this occurs the 1st line recommended treatment is Bortezomib monotherapy. Some patients may also be suitable for a repeat autologous stem cell transplant*, but this is decided on a case-by-case basis.

Complications

A large part of multiple myeloma treatment involves managing complications:

· Pain: treat with analgesia (using the WHO analgesic ladder)

· Pathological fracture: Zoledronic acid is given to prevent and manage osteoporosis and fragility fractures as these are a large cause of morbidity and mortality, particularly in the elderly.

· Infection: patients receive annual influenza vaccinations. They may also receive Immunoglobulin replacement therapy.

· VTE prophylaxis

· Fatigue: treat all possible underlying causes. If symptoms persist consider an erythropoietin analogue.

*An autologous stem cell transplant is used after high dose chemotherapy administration which targets stem cells. It involves the removal of a patient's own stem cells prior to chemotherapy, which are then replaced after chemotherapy. This is different from Allogenic stem cell transplantation where stem cells are sourced from HLA matching donors. Allogenic stem cell transplantation is currently only used as part of clinical trials when treating multiple myeloma.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:06

Neutropaenia

Neutropaenia refers to a low neutrophil counts, < 1.5 * 109. A normal neutophil count is 2.0 - 7.5 * 109.

It is important to recognise as it predisposes to severe infection.

Neutropaenia may be further subdivided as follows:

Severity	Neutrophil count
Mild	1.0 - 1.5 * 109
Moderate	0.5 - 1.0 * 109
Severe	< 0.5 * 109

Causes

· viral

o HIV

o Epstein-Barr virus

o hepatitis

· drugs

o cytotoxics

o carbimazole

o clozapine

· benign ethnic neutropaenia

o common in people of black African and Afro-Caribbean ethnicity

o requires no treatment

· haematological malignancy

o myelodysplastic malignancies

o aplastic anemia

· rheumatological conditions

· systemic lupus erythematosus: mechanisms include circulating antineutrophil antibodies

· rheumatoid arthritis: e.g. hypersplenism as in Felty's syndrome

· severe sepsis

· haemodialysis

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Non-Hodgkin's lymphoma

Lymphoma is the malignant proliferation of lymphocytes which accumulate in lymph nodes or other organs. Lymphoma may be classified as either Hodgkin's lymphoma (a specific type of lymphoma characterized by the presence of Reed-Sternberg cells) or non-Hodgkin's lymphoma (every other type of lymphoma that is not Hodgkin's lymphoma). Non-Hodgkin's lymphoma is the 6th most common cause of cancer in the UK. Non-Hodgkin's lymphoma may affect either B or T-cells and can be further classified as high grade or low grade.

Epidemiology

· Non-Hodgkin's lymphoma is much more common than Hodgkin's lymphoma

· While different subtypes can affect different ages, it typically affects the elderly with one-third of cases occurring in those over 75 years of age

· The incidence rate is 28 for men and 20 for females per 100,000 of the population

Risk factors

· Elderly

· Caucasians

· History of viral infection (specifically Epstein-Barr virus)

· Family history

· Certain chemical agents (pesticides, solvents)

· History of chemotherapy or radiotherapy

· Immunodeficiency (transplant, HIV, diabetes mellitus)

· Autoimmune disease (SLE, Sjogren's, coeliac disease)

Symptoms

· Painless lymphadenopathy (non-tender, rubbery, asymmetrical)

· Constitutional/B symptoms (fever, weight loss, night sweats, lethargy)

· Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)

While differentiating Hodgkin's lymphoma from non-Hodgkin's lymphoma is done by biopsy certain elements of the clinical presentation can help point towards one rather than the other.

· Lymphadenopathy in Hodgkin's lymphoma can experience alcohol-induced pain in the node

· 'B' symptoms typically occur earlier in Hodgkin's lymphoma and later in non-Hodgkin's lymphoma

· Extra-nodal disease is much more common in non-Hodgkin's lymphoma than in Hodgkin's lymphoma

Signs

· Signs of weight loss

· Lymphadenopathy (typically in the cervical, axillary or inguinal region)

· Palpable abdominal mass - hepatomegaly, splenomegaly, lymph nodes

· Testicular mass

· Fever

Investigations

· Excisional node biopsy is the diagnostic investigation of choice (certain subtypes will have a classical appearance on biopsy such as Burkitt's lymphoma having a 'starry sky' appearance)

· CT chest, abdomen and pelvis (to assess staging)

· HIV test (often performed as this is a risk factor for non-Hodgkin's lymphoma)

· FBC and blood film (patient may have a normocytic anaemia and can help rule out other haematological malignancy such as leukaemia)

· ESR (useful as a prognostic indicator)

· LDH (a marker of cell turnover, useful as a prognostic indicator)

· Other investigations can be ordered as the clinical picture indicates (LFT's if liver metastasis suspected, PET CT or bone marrow biopsy to look for bone involvement, LP if neurological symptoms)

Staging

- The most common staging system used for non-Hodgkin's lymphoma is the Ann Arbor system.

· → Stage 1 - One node affected

· → Stage 2 - More than 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 e.g. Spleen, bone marrow or CNS

· The stage is combined with the letter A or B to indicate the presence of 'B' symptoms. With the letter A indicating no B symptoms present and B indicating any of the beta symptoms present. For example, a patient with a single node affected and no 'B' symptoms would be stage 1A.

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.

· All patients will receive flu/pneumococcal vaccines

· 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 e.g. 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

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Normocytic anaemia

Causes of normocytic anaemia include

· anaemia of chronic disease

· chronic kidney disease

· aplastic anaemia

· haemolytic anaemia

· acute blood loss

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Pregnancy: DVT/PE

Overview

· pregnancy is a hypercoagulable state

· majority occur in last trimester

Pathophysiology

· increase in factors VII, VIII, X and fibrinogen

· decrease in protein S

· uterus presses on IVC causing venous stasis in legs

Management

· warfarin contraindicated

· S/C low-molecular weight heparin preferred to IV heparin (less bleeding and thrombocytopenia)

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Primary immunodeficiency

Primary immunodeficiency disorders may be classified according to which component of the immune system they affect.

Neutrophil disorders

Disorder	Underlying defect	Notes
Chronic granulomatous disease	Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species	Causes recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus) Negative nitroblue-tetrazolium test Abnormal dihydrorhodamine flow cytometry test
Chediak-Higashi syndrome	Microtubule polymerization defect which leads to a decrease in 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

B-cell disorders

Disorder	Underlying defect	Notes
Common variable immunodeficiency	Many varying causes	Hypogammaglobulinemia is seen. May predispose to autoimmune disorders and lymphona
Bruton's (x-linked) congenital agammaglobulinaemia	Defect in Bruton's tyrosine kinase (BTK) gene that leads to a severe block in B cell development	X-linked recessive. Recurrent bacterial infections are seen Absence of B-cells with reduced immunoglogulins of all classes
Selective immunoglobulin A deficiency	Maturation defect in B cells	Most common primary antibody deficiency. Recurrent sinus and respiratory infections Associated with coeliac disease and may cause false negative coeliac antibody screen Severe reactions to blood transfusions may occur (anti-IgA antibodies → analphylaxis)

T-cell disorders

Disorder	Underlying defect	Notes
DiGeorge syndrome	22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches	Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate

Combined B- and T-cell disorders

Disorder	Underlying defect	Notes
Severe combined immunodeficiency	Many varying causes. Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency	Recurrent infections due to viruses, bacteria and fungi. Reduced T-cell receptor excision circles Stem cell transplantation may be successful
Ataxic telangiectasia	Defect in DNA repair enzymes	Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
Wiskott-Aldrich syndrome	Defect in WASP gene	X-linked recessive. Features include recurrent bacterial infections, eczema, thrombocytopaenia. Low IgM levels Increased risk of autoimmune disorders and malignancy
Hyper IgM Syndromes	Mutations in the CD40 gene	Infection/Pneumocystis pneumonia, hepatitis, diarrhoea

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Sickle-cell anaemia: management

Crisis management

· analgesia e.g. opiates

· rehydrate

· oxygen

· consider antibiotics if evidence of infection

· blood transfusion

· exchange transfusion: e.g. if neurological complications

Longer-term management

· Hydroxyurea (Hydroxycarbamide)

o increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes

· NICE CKS suggest that sickle cell patients should receive the pneumococcal polysaccharide vaccine every 5 years

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Sickle-cell crises: management

General management

· analgesia e.g. opiates

· rehydrate

· oxygen

· consider antibiotics if evidence of infection

· blood transfusion

· exchange transfusion: e.g. if neurological complications

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Thrombocytopenia

Causes of severe thrombocytopenia

· ITP

· DIC

· TTP

· haematological malignancy

Causes of moderate thrombocytopenia

· heparin induced thrombocytopenia (HIT)

· drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)

· alcohol

· liver disease

· hypersplenism

· viral infection (EBV, HIV, hepatitis)

· pregnancy

· SLE/antiphospholipid syndrome

· vitamin B12 deficiency

Pseudothrombocytopenia has been reported in association with the use of EDTA as an anticoagulant

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Thrombotic thrombocytopenic purpura

Pathogenesis of thrombotic thrombocytopenic purpura (TTP)

· abnormally large and sticky multimers of von Willebrand's factor cause platelets to clump within vessels

· in TTP there is a deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns ('cleaves') large multimers of von Willebrand's factor

· overlaps with haemolytic uraemic syndrome (HUS)

Features

· rare, typically adult females

· fever

· fluctuating neuro signs (microemboli)

· microangiopathic haemolytic anaemia

· thrombocytopenia

· renal failure

Causes

· post-infection e.g. urinary, gastrointestinal

· pregnancy

· drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir

· tumours

· SLE

· HIV

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Thymoma

Thymomas are the most common tumour of the anterior mediastinum and is usually detected between the sixth and seventh decades of life.

Associated with

· myasthenia gravis (30-40% of patients with thymoma)

· red cell aplasia

· dermatomyositis

· also : SLE, SIADH

Causes of death

· compression of airway

· cardiac tamponade

© Image used on license from Radiopaedia

Chest x-ray and accompanying CT scan of a patient with a thymoma. In the chest x-ray there is a partially delineated mediastinal mass (anterior mediastinum) with regular borders, bulging the left upper mediastinal contour.

© Image used on license from Radiopaedia

CT slice at the bifurcation of the main bronchus showing an invasive thymoma presenting as an anterior mediastinal mass

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:07

Tranexamic acid

Tranexamic acid is a synthetic derivative of lysine. Its primary mode of action is as an antifibrinolytic that reversibly binds to lysine receptor sites on plasminogen or plasmin. This prevents plasmin from binding to and degrading fibrin.

Tranexamic acid is most commonly prescribed to help treat menorrhagia.

The role of tranexamic acid in trauma was investigated in the CRASH 2 trial and has been shown to be of benefit in bleeding trauma when administered in the first 3 hours. Tranexamic acid is given as an IV bolus followed by an infusion in cases of major haemorrhage.

There is also ongoing research looking at the role of tranexamic acid in traumatic brain injury.

From <https://www.passmedicine.com/review/textbook.php?s=#>

24 December 2020

14:08

Waldenstrom's macroglobulinaemia

Waldenstrom's macroglobulinaemia is an uncommon condition seen in older men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein

Features

· monoclonal IgM paraproteinaemia

· systemic upset: weight loss, lethargy

· hyperviscosity syndrome e.g. visual disturbance

o the pentameric configuration of IgM increases serum viscosity

· hepatosplenomegaly

· lymphadenopathy

· cryoglobulinaemia e.g. Raynaud's

From <https://www.passmedicine.com/review/textbook.php?s=#>

21 December 2020

21:49

Blood product transfusion complications

Blood product transfusion complications may be broadly classified into the following:

· immunological: acute haemolytic, non-haemolytic febrile, allergic/anaphylaxis

· infective

· transfusion-related acute lung injury (TRALI)

· transfusion-associated circulatory overload (TACO)

· other: hyperkalaemia, iron overload, clotting

The table below summaries some of the key features:

Reaction	Features	Management
Non-haemolytic febrile reaction Thought to be caused by antibodies reacting with white cell fragments in the blood product and cytokines that have leaked from the blood cell during storage	Fever, chills Red cell transfusion (1-2%) Platelet transfusion (10-30%)	Slow or stop the transfusion Paracetamol Monitor
Minor allergic reaction Thought to be caused by foreign plasma proteins	Pruritus, urticaria	Temporarily stop the transfusion Antihistamine Monitor
Anaphylaxis Can be caused by patients with IgA deficiency who have anti-IgA antibodies	Hypotension, dyspnoea, wheezing, angioedema.	Stop the transfusion IM adrenaline ABC support · oxygen · fluids
Acute haemolytic reaction ABO-incompatible blood e.g. secondary to human error	Fever, abdominal pain, hypotension	Stop transfusion Confirm diagnosis · check the identity of patient/name on blood product · send blood for direct Coombs test, repeat typing and cross-matching Supportive care · fluid resuscitation
Transfusion-associated circulatory overload (TACO) Excessive rate of transfusion, pre-existing heart failure	Pulmonary oedema, hypertension	Slow or stop transfusion Consider intravenous loop diuretic (e.g. furosemide) and oxygen
Transfusion-related acute lung injury (TRALI) Non-cardiogenic pulmonary oedema thought to be secondary to increased vascular permeability caused by host neutrophils that become activated by substances in donated blood	Hypoxia, pulmonary infiltrates on chest x-ray, fever, hypotension	Stop the transfusion Oxygen and supportive care

Further information is provided below:

Acute haemolytic transfusion reaction

Acute haemolytic transfusion reaction results from a mismatch of blood group (ABO) which causes massive intravascular haemolysis. This is usually the result of red blood cell destruction by IgM-type antibodies.

Symptoms begin minutes after the transfusion is started and include a fever, abdominal and chest pain, agitation and hypotension.

Treatment should include immediate transfusion termination, generous fluid resuscitation with saline solution and informing the lab

Complications include disseminated intravascular coagulation, and renal failure

Non-haemolytic febrile reaction

Febrile reactions

· due to white blood cell HLA antibodies

· often the result of sensitization by previous pregnancies or transfusions

· paracetamol may be given

Allergic/anaphylaxis reaction

Allergic reactions to blood transfusions are caused by hypersensitivity reactions to components within the transfusion. Symptoms typically arise within minutes of starting the transfusion and severity can range from urticaria to anaphylaxis with hypotension, dyspnoea, wheezing, and stridor, or angioedema.

Simple urticaria should be treated by discontinuing the transfusion and with an antihistamine. Once the symptoms resolve, the transfusion may be continued with no need for further workup.

More severe allergic reaction or anaphylaxis should be treated urgently. The transfusion should be permanently discontinued, intramuscular adrenaline should be administered and supportive care. Antihistamine, corticosteroids and bronchodilators should also be considered for these patients.

Transfusion-related acute lung injury (TRALI)

A rare but potentially fatal complication of blood transfusion. Characterised by the development of hypoxaemia / acute respiratory distress syndrome 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 resulting in pulmonary oedema. As well as features of pulmonary oedema the patient may also by hypertensive, a key difference from patients with TRALI.

Infective

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:

o from late 1999 onward, all donations have undergone removal of white cells (leucodepletion) in order to reduce any vCJD infectivity present

o 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

o from 2004 onward, recipients of blood components have been excluded from donating blood

From <https://www.passmedicine.com/review/textbook.php?s=#>

Mnemonic for transfusion reactions:

Got a bad unit

G raft vs. Host disease

O verload

T hrombocytopaenia

A lloimmunization

B lood pressure unstable

A cute haemolytic reaction

D elayed haemolytic reaction

U rticaria

N eutrophilia

I nfection

T ransfusion associated lung injury

From <https://www.passmedicine.com/question/questions.php?q=0#>

21 December 2020

21:50

Deep vein thrombosis: diagnosis and management

NICE updated their guidelines on the investigation and management of venous thromboembolism (VTE) in 2020. Some of the key changes include recommending the following:

· the use of direct oral anticoagulants (DOACs) as first-line treatment for most people with VTE, including as interim anticoagulants before a definite diagnosis is made

· the use of DOACs in patients 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:

Two-level DVT Wells score

Clinical feature	Points
Active cancer (treatment ongoing, within 6 months, or palliative)	1
Paralysis, paresis or recent plaster immobilisation of the lower extremities	1
Recently bedridden for 3 days or more or major surgery within 12 weeks requiring general or regional anaesthesia	1
Localised tenderness along the distribution of the deep venous system	1
Entire leg swollen	1
Calf swelling at least 3 cm larger than asymptomatic side	1
Pitting oedema confined to the symptomatic leg	1
Collateral superficial veins (non-varicose)	1
Previously documented DVT	1
An alternative diagnosis is at least as likely as DVT	-2

Clinical probability simplified score

· DVT likely: 2 points or more

· DVT unlikely: 1 point or less

If a DVT is 'likely' (2 points or more)

· a proximal leg vein ultrasound scan should be carried out within 4 hours

o if the result is positive then a diagnosis of DVT is made and anticoagulant treatment should start

o if the result is negative a D-dimer test should be arranged. A negative scan and negative D-dimer makes the diagnosis unlikely and alternative diagnoses should be considered

· if a proximal leg vein ultrasound scan cannot be carried out within 4 hours a D-dimer test should be performed and interim therapeutic anticoagulation administered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours)

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

o NICE updated their guidance in 2020. They now recommend using an anticoagulant that can be continued if the result is positive.

o this means normally a direct oral anticoagulant (DOAC) such as apixaban or rivaroxaban

· if the scan is negative but the D-dimer is positive:

o stop interim therapeutic anticoagulation

o offer a 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

o this should be done within 4 hours. If not, interim therapeutic anticoagulation should be given until the result is available

o if the result is negative then DVT is unlikely and alternative diagnoses should be considered

o if the result is positive then a proximal leg vein ultrasound scan should be carried out within 4 hours

o if a proximal leg vein ultrasound scan cannot be carried out within 4 hours interim therapeutic anticoagulation should be administered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours)

D-dimer tests

· NICE recommend either a point-of-care (finger prick) or laboratory-based test

· age-adjusted cut-offs should be used for patients > 50 years old

Management

The 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 anticoagulant

· the big change in the 2020 guidelines was the increased use of DOACs

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

o instead of using low-molecular weight heparin (LMWH) until the diagnosis is confirmed, NICE now advocate using a DOAC once a diagnosis is suspected, with this continued if the diagnosis is confirmed

o if neither apixaban or rivaroxaban are suitable then either LMWH followed by dabigatran or edoxaban OR LMWH followed by a vitamin K antagonist (VKA, i.e. warfarin)

· if the patient has active cancer

o previously LMWH was recommended

o the new guidelines now recommend using a DOAC, unless this is contraindicated

· if renal impairment is severe (e.g. < 15/min) then LMWH, unfractionated heparin or LMWH followed by a VKA

· 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

o a provoked VTE is due to an obvious precipitating event e.g. immobilisation following major surgery. The implication is that this event was transient and the patient is no longer at increased risk

o 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 provoked the treatment is typically stopped after the initial 3 months (3 to 6 months for people with active cancer)

· if the VTE was unprovoked then treatment is typically continued for up to 3 further months (i.e. 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 bleeding

o the HAS-BLED score can be used to help assess the risk of bleeding

o 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

From <https://www.passmedicine.com/review/textbook.php?s=#>

21 December 2020

21:40

Chronic lymphocytic leukaemia: complications

Complications

· anaemia

· hypogammaglobulinaemia leading to recurrent infections

· warm autoimmune haemolytic anaemia in 10-15% of patients

· transformation to high-grade lymphoma (Richter's transformation)

Richter's transformation

Ritcher's transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin's lymphoma. Patients often become unwell very suddenly.

Ritcher's transformation is indicated by one of the following symptoms:

· lymph node swelling

· fever without infection

· weight loss

· night sweats

· nausea

· abdominal pain

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Score: 30%

From <https://www.passmedicine.com/question/questions.php?q=0>

22 December 2020

20:42

Hodgkin's lymphoma: histological classification and prognosis

Hodgkin's lymphoma is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades

Histological classification

Type	Frequency	Prognosis	Notes
Nodular sclerosing	Most common (around 70%)	Good prognosis	More common in women. Associated with lacunar cells
Mixed cellularity	Around 20%	Good prognosis	Associated with a large number of Reed-Sternberg cells
Lymphocyte predominant	A*round 5%	Best prognosis
Lymphocyte depleted	Rare	Worst prognosis

'B' symptoms also imply a poor prognosis

· weight loss > 10% in last 6 months

· fever > 38ºC

· night sweats

Other factors associated with a poor prognosis identified in a 1998 NEJM paper included:

· age > 45 years

· stage IV disease

· haemoglobin < 10.5 g/dl

· lymphocyte count < 600/µl or < 8%

· male

· albumin < 40 g/l

· white blood count > 15,000/µl

*Reed-Sternberg cells with nuclei surrounded by a clear space

From <https://www.passmedicine.com/question/questions.php?q=0#>

21 December 2020

21:49

Blood films: typical pictures

Hyposplenism e.g. post-splenectomy, coeliac disease (occurs in around 30% of coeliac patients)

· target cells

· Howell-Jolly bodies

· Pappenheimer bodies

· siderotic granules

· acanthocytes

Iron-deficiency anaemia

· target cells

· 'pencil' poikilocytes

· if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed microcytic and macrocytic cells

Myelofibrosis

· 'tear-drop' poikilocytes

Intravascular haemolysis

· schistocytes

Megaloblastic anaemia

· hypersegmented neutrophils

From <https://www.passmedicine.com/review/textbook.php?s=#>

21 December 2020

21:49

Blood products: FFP, cryoprecipitate and prothrombin complex

NICE published guidelines on the use of blood products in 2015.

Fresh frozen plasma (FFP)

· most suited for 'clinically significant' but without 'major haemorrhage' in patients with a prothrombin time (PT) ratio or activated partial thromboplastin time (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

· example use cases include disseminated intravascular coagulation, liver failure and hypofibrinogenaemia secondary to massive transfusion. It may also be used in an 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 with either severe bleeding or a head injury with suspected intracerebral haemorrhage

· can be used prophylactically in patients undergoing emergency surgery depending on the particular circumstance

From <https://www.passmedicine.com/review/textbook.php?s=#>

22 December 2020

20:14

Hodgkin's lymphoma: staging

Hodgkin's lymphoma is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades

Ann-Arbor staging of Hodgkin's lymphoma

· I: single lymph node

· II: 2 or more lymph nodes/regions on same side of diaphragm

· III: nodes on both sides of diaphragm

· IV: spread beyond lymph nodes

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)

From <https://www.passmedicine.com/question/questions.php?q=0#>

Lymphocyte-depleted Hodgkin lymphoma is the rarest form of Hodgkin's lymphoma as well as the most aggressive . It is typically seen in young adults aged 30-37 years of age. Risk factors include a family history and being immunocompromised. Treatment of Lymphocyte-depleted Hodgkin lymphoma is typically adjusted for prognostic factors and the cancer stage (Stage IV being associated with the worst prognosis).

Negative prognostic factors include:

· The presence of B symptoms (night sweats, weight loss and fever)

· Male gender

· Being aged >45 years old at diagnosis

· High WCC, low Hb, high ESR or low blood albumin

From <https://www.passmedicine.com/question/questions.php?q=0#>

Acute promyelocytic leukemia

29 December 2020

15:14

The most common symptoms and their causes are:

· Anaemia – breathlessness, fatigue

· Low white cells – frequent, persistent infections

· Low platelets – bruising and/or bleeding

· DIC – bruising/bleeding which may be very severe

From <https://www.leukaemiacare.org.uk/support-and-information/information-about-blood-cancer/blood-cancer-information/leukaemia/acute-promyelocytic-leukaemia/>

t(15;17)

· seen in acute promyelocytic leukaemia (M3)

· fusion of PML and RAR-alpha genes

From <https://www.passmedicine.com/question/questions.php?q=0>

APL is diagnosed by tests which may include:

· Blood tests

· Bone marrow samples

Other tests may be done

Occasionally, it is not clear from the blood film whether the abnormal cells are promyelocytes. By examining the proteins found on the outside of the cell, called cell markers, it is possible to identify the cells with certainty.

Another test looks for an abnormality called PML-RARA. This is an abnormal “fusion gene” – PML and RARA are two genes which are normally found on different chromosomes. In APL the two chromosomes swap over part of their DNA, which joins the PML and RARA genes together. This test is important because the main drugs used to treat APL work directly on the PML-RARA gene; in the very rare cases of APL without PML-RARA, other treatments can be used.

These tests may be repeated from time to time during your treatment. This is to find out how the APL is responding to treatm

From <https://www.leukaemiacare.org.uk/support-and-information/information-about-blood-cancer/blood-cancer-information/leukaemia/acute-promyelocytic-leukaemia/>

Treatment of patients who are suspected of having APL should be treated immediately, even before the diagnosis is made, because they can quickly develop potentially life-threatening bleeding or blood clotting symptoms. A firm diagnosis of APL using genetic testing can be performed later, and treatment can be discontinued if APL is not confirmed.

Patients with APL are generally subdivided into the following two groups according to their white blood count as treatment recommendations can differ for each group:

· Low- to intermediate-risk: patients with a white blood cell count of 10,000 cells per microlitre of blood or less.

· High-risk: patients with a white blood cell count of more than 10,000 cells per microlitre of blood.

From <https://www.leukaemiacare.org.uk/support-and-information/information-about-blood-cancer/blood-cancer-information/leukaemia/acute-promyelocytic-leukaemia/>

Treatment of patients who are suspected of having APL should be treated immediately, even before the diagnosis is made, because they can quickly develop potentially life-threatening bleeding or blood clotting symptoms. A firm diagnosis of APL using genetic testing can be performed later, and treatment can be discontinued if APL is not confirmed.

Patients with APL are generally subdivided into the following two groups according to their white blood count as treatment recommendations can differ for each group:

· Low- to intermediate-risk: patients with a white blood cell count of 10,000 cells per microlitre of blood or less.

· High-risk: patients with a white blood cell count of more than 10,000 cells per microlitre of blood.

From <https://www.leukaemiacare.org.uk/support-and-information/information-about-blood-cancer/blood-cancer-information/leukaemia/acute-promyelocytic-leukaemia/>

First-line treatment

First-line treatment for APL includes all-trans retinoic acid (ATRA), which is an active by- product of vitamin A. ATRA blocks the effect of the PML-RARA gene that prevents the promyelocyte cells maturing into normal white blood cells (differentiation).

ATRA is not a chemotherapeutic drug and is called a differentiating agent. It is given in combination with another drug in patients with APL to prevent any drug resistance.

ATRA can sometimes be given with chemotherapy drugs called anthracyclines. Anthracyclines, such as daunorubicin and idarubicin, interfere with the DNA and reproduction of white blood cells, including the leukaemia cells. ATRA is given as a capsule, while anthracyclines are given intravenously.

In 2018, NICE approved a drug called arsenic trioxide (ATO) for the first-line treatment of APL in previously untreated patients, with low- to intermediate-risk disease and patients whose APL has returned (relapsed) or did not respond to chemotherapy (refractory). ATO is also a differentiating agent and acts in a similar way to ATRA.

Because differentiating agents have less side effects to chemotherapy drugs, especially anthracyclines, the combination of ATRA and ATO alone is a preferred first-line therapy, particularly as studies found it to be at least as effective as the combination of ATRA and anthracyclines, if not more so, with a reduced risk of disease relapse.

Induction treatment

To achieve remission (induction therapy), the 2019 guidelines from the European Leukaemia Network (European LeukemiaNet) recommend the following regimens:

· Low-to-intermediate risk patients: ATRA and ATO

· High-risk patients: Both of the following regimens achieve similar results; however, ATO is not approved for high-risk patients by NICE as yet.

o ATRA and ATO plus a cytoreductive chemotherapy such as cytarabine. Cytoreductive means that the chemotherapy reduces the number of cells.

o ATRA plus anthracyclines. The most frequently used regimen being called AIDA.

The treatment for APL that has developed as a consequence of prior chemotherapy is normally similar to APL associated with the PML-RARA gene, although your doctor may choose to use a different drug in this situation.

In addition to induction treatment, patients with APL require supportive care in the form of blood product transfusions to maintain the platelet count and the blood clotting indicators as normal as possible and to prevent the risk of bleeding. Blood chemical levels (particularly potassium and magnesium which are important for electrical conduction in the heart) will be monitored closely. Sometimes it is necessary to also give potassium and/or magnesium supplements.

Consolidation treatment

To consolidate remission in patients who have not received chemotherapy-based treatment, four courses of ATO and seven courses of ATRA are recommended. This can usually be given as an outpatient.

For patients who received ATRA and chemotherapy regimens, two to three courses of anthracycline- based chemotherapy should be given for consolidation therapy. This is usually given as an inpatient.

Maintenance treatment

For low- to intermediate-risk patients, maintenance treatment after consolidation with ATO and ATRA is not recommended, but for high-risk patients on ATRA and chemotherapy who are showing clinical benefit, maintenance may be initiated with tablets for two years.

Second-line treatment

First-line treatment is generally successful in most patients with APL. However, for patients who haven’t gone into first remission or who have relapsed, second-line treatment options are available.

Relapse or being refractory to first-line treatment can occur in any patient with APL, regardless of whether they have been treated with ATRA with ATO or ATRA with chemotherapy. However, these events are uncommon in low- to intermediate-risk patients.

The second-line treatment you have for relapsed or refractory APL will depend mainly on which first- line treatment you were given. If you have had ATRA with ATO as first-line treatment, then you will receive ATRA with chemotherapy, and vice-versa (you will be given ATRA with ATO if you had ATRA with chemotherapy as first-line treatment).

In young, fit patients, an autologous stem cell transplant can be performed. With an autologous stem cell transplant, you are given intensive chemotherapy to destroy all the leukaemia cells. However, as the chemotherapy will also kill your own bone marrow cells, you are given a transplant of your own healthy stem cells which were collected before the intensive chemotherapy. However, in patients who were responding well to ATO and then relapsed, a transplant is not always necessary.

From <https://www.leukaemiacare.org.uk/support-and-information/information-about-blood-cancer/blood-cancer-information/leukaemia/acute-promyelocytic-leukaemia/>