Haematology Flashcards
What is ALL?
Uncontrolled proliferation of immature lymphoid precursor cells within bone marrow leading to bone marrow failure and presence of increased lymphoblasts in peripheral blood
Epidemiology of ALL?
Most common leukaemia in children
Peak incidence between 2 and 5 years
Second peak in older adults
Aetiology of ALL?
Genetic syndromes; Downs syndrome, klinefelter’s syndrome, fanconi anaemia
Exposure to ionising radiation
Classification of ALL?
B cell lineage
T cell lineage
Signs and symptoms of ALL?
Fatigue
Bleeding/ bruising
Infection
Painless lymphadenopathy
Hepatosplenomegaly
CNS involvement
Testicular infiltration
Differentials for ALL?
Aplastic anaemia
CLL
Non hodgkin lymphoma
Investigations to diagnose ALL?
FBC; leukocytosis
Blood film/ bone marrow; lymphoblast
Immunophenotyping; differentiate immunological subtype
Periodic acid- Schiff stains for carbohydrate in ALL
NICE guidance for urgent FBC?
Pallor
Persistent fatigue
Unexplained fever
Unexplained persistent or recurrent infection
Generalized lymphadenopathy
Unexplained bruising
Unexplained bleeding
Unexplained petechiae
Hepatosplenomegaly
Management of ALL?
Combination chemotherapy
CNS prophylactic agents
Maintenance therapy
Which sites are considered sanctuary sites in ALL?
Testes
Blood brain barrier
How is response to ALL treatment monitored?
Blast count should be below <5%
PCR
Immunoglobulin genes in B-cell ALL
T-cell receptor genes in T-cell ALL
Complications of ALL?
Infections
Bleeding
CNS
Chemotherapy related toxicities
Poor prognostic factors for ALL?
Age <1 year and >10 years
Male sex
WCC >50 × 109/l (higher pretreatment WCC predicts poor prognosis)
CNS disease
poor cytogenetic features, such as t(9;22)
T-ALL – prognosis is worse than for B-ALL
Incomplete response to therapy
What is AML?
Uncontrolled proliferation of myeloid precursors in the bone marrow leading to bone marrow failure and accumulation of immature blast cells in peripheral blood
Epidemiology of AML?
Higher incidence in older adults
Exposure to ionising radiation, nuclear disaster increase risk
Signs and symptoms of AML?
Bone marrow failure – anaemia, bleeding, infections
Signs of tissue infiltration, including hepatomegaly, splenomegaly and gum hypertrophy
Central nervous system involvement is rare
Constitutional symptoms such as fever and unintentional weight loss
Differentials for AML?
Myelodysplastic syndrome
ALL
Aplastic anaemia
Investigations to diagnose AML?
Bloods; leucocytosis
Blood film; blast cells
Bone marrow biopsy; hypercellular marrow, presence of blast cells, auer rods
Cytochemistry
Cytogenetics
Immunophenotyping
Management of AML?
Chemotherapy
Bone marrow transplant
Prophylactic antibiotics
Blood products
Treatment related toxicities for leukaemia?
Myelosuppression
Mucositis
Increased risk of secondary malignancies.
Cardiorespiratory complications
Endocrine dysfunction
Infertility
Avascular necrosis of the hip – due to prolonged steroid exposure
Neuropsychological effects
Complications of AML?
Infections
Bleeding
Organ infiltration; hepatomegaly, splenomegaly
Treatment related toxicities
Prognosis of AML?
Without treatment death in 2 months
3 year survival is 20%
What is amyloidosis?
Deposition of extracellular insoluble fibrils composed of misfolded proteins in organs and blood vessels leading to organ dysfunction
Epidemiology of amyloidosis?
8-12 cases per million
More common in men
Presents in 5th to 7th decade of life
Pathophysiology of amyloidosis?
Systemic dissemination of protein deposits
Focal deposition such as cerebral deposition in alzheimers disease
Classification of amyloidosis?
Primary; AL amyloidosis due to deposition of monoclonal light chains in tissues
Secondary; AA amyloidosis due to underlying chronic inflammatory conditions such as malignancy, chronic microbial infection affecting any organ not the brain related to high density lipoprotein
Clinical features of amyloidosis?
Kidneys – nephrotic syndrome/renal failure
Gastrointestinal system – macroglossia, malabsorption or hepatosplenomegaly
Neurological system – neuropathies
Vasculature – periorbital purpura (“racoon eyes”)
Joints – painful asymmetrical large joint inflammation
Features of AA amyloidosis;
Nephrotic syndrome (one-third of patients)
Neuropathy (usually sensory and symmetrical)
Cardiomyopathy (usually restrictive in nature)
Hepatomegaly
Autonomic neuropathy
Features of AL amyloidosis;
Proteinuria with and without nephrotic syndrome, plus uraemia – 50% of patients die of renal failure if not treated with dialysis
Visceromegaly (spleen, liver and kidneys) is common
Investigations to diagnose amyloidosis?
Tissue biopsy; apple green bifringence when stained with congo red and viewed under polarised light
Radio labelled serum amyloid P scan
Echo, ECG, BNP, proteinuria, serum free light chains, monocloncal immunoglobulins, prothrombin time, APTT
Management of amyloidosis?
Guidance from national amyloid centre in London
Manage cardiac, gastrointestinal and renal complications
In AA amyloid; manage chronic infection and inflammation
In AL amyloid; dexamethasone and bortezomib
In hereditary amyloid consider hepatic transplantation
What is anaemia of chronic disease?
Low haemoglobin levels, decreased erythrocyte production and altered iron metabolism in response to chronic inflammatory/ infectious/ autoimmune or malignancy
Aetiology of anaemia of chronic disease?
Inflammatory Conditions: Rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
Chronic Infections: Tuberculosis, HIV, and osteomyelitis.
Malignancies: Leukaemia, lymphoma, and solid tumours.
Chronic Kidney Disease: Impaired erythropoietin production and iron metabolism.
Autoimmune Disorders: Systemic inflammation can lead to ACD.
Chronic Liver Disease: Hepcidin release is altered, impacting iron regulation.
Pathophysiology of anaemia of chronic disease?
Chronic inflammation increases IL-1, IL-6.
IL-6 stimulates release of hepcidin from liver which inhibits iron absorption by reducing activity of ferroportin leading to decreased haemoglobin production
Where is ferroportin found?
Basolateral surface of gut enterocytes and plasma membrane of reticuloendothelial cells
Signs and symptoms of anaemia?
Fatigue
Weakness
Pallor
Shortness of breath
Rapid heartbeat
Anorexia and weight loss
Frequent infections due to increased susceptibility
Mild splenomegaly (rare)
Differentials for anaemia of chronic disease?
Iron deficiency anaemia
Haemolytic anaemia
Vitamin B12 and folate deficiency
Chronic kidney disease
Bone marrow disorders
Investigations to diagnose anaemia of chronic disease?
FBC; low Hb, low MCV
Blood film; normocytic normochromic
Iron studies
CRP
Bone marrow aspiration and biopsy
Management of anaemia of chronic disease?
Treat underlying medical condition
Consider EPO agents
What is aplastic anaemia?
Bone marrow failure leading to a significant reduction in the production of all types of blood cells causing pancytopenia
Criteria to diagnose aplastic anaemia?
Atleast 2 of the following;
Anaemia: haemoglobin <10 g/dL
Thrombocytopenia: platelets <50 x 10^9/L
Neutropenia: absolute neutrophil count <1.5 x 10^8/L
Epidemiology of aplastic anaemia?
2-6 cases per million
More common in younger people
Acquired causes are toxins/ drugs/ virus induced
Aetiology of aplastic anaemia?
Acquired;
Immune mediated
Environmental; toxins, benzene, chloramphenicol, phenytoin, NSAIDs
Viral; EBV, hepatitis, parvovirus b19
Pregnancy
Inherited;
Fanconi anaemia
Dyskeratosis congenita
Shwachman diamond syndrome
Signs and symptoms of aplastic anaemia?
Fatigue
Pallor
Infection
Bleeding/ bruising
Assess history;
Drug exposure in the last 6 months
Occupational exposure to chemicals
Recent infections
Co-morbidities
Genetic testing
Differentials for aplastic anaemia?
Myelodysplastic syndrome
Leukaemia
Hypersplenism
Infection
Investigations to diagnose aplastic anaemia?
FBC
Bone marrow aspiration and biopsy
Cytogenetic testing
Haematopoetic stem cell studies
Immunological assays
Management of aplastic anaemia?
Supportive care
Haematopoetic stem cell transplant
Immunosuppressive therapy; antithymocyte therapy, cyclosporine, chemotherapy
Blood transfusion
Prognosis of aplastic anaemia?
Haematopoetic stem cell transplant offers best chance of cure
Lifespan of blood components?
RBCs, 90–120 days
platelets, 10 days
neutrophils, 4 days
Features of red blood cells for transfusion?
Generally stored at 4 °C for up to 35 days
In vivo, RBCs typically have a lifespan of about 120 days; however, it is important to note that transfused red cells last around 50–60 days
Features of FFP for transfusion?
Stored at –30 °C, with a shelf life of a year
Used in patients with coagulopathy (impaired blood coagulation) to replace clotting factors
The type of FFP used depends on the patient’s blood group
Features of cryoprecipitate?
Cryoprecipitate is made by thawing FFP overnight at 4–8 °C
It has a shelf life of 1 year stored at –30 °C
It contains fibrinogen, factor VIII and von Willebrand factor
It is generally used in patients with massive bleeding and low fibrinogen
Acute transfusion reactions?
Allergy
Acute haemolytic transfusion reaction
Febrile non haemolytic transfusion reaction
Transfusion related acute lung injury
Transfusion associated circulatory overload
Late transfusion reactions?
Delayed haemolytic transfusion reaction
Transfusion associated graft vs host disease
Iron overload
What is acute haemolytic transfusion reaction?
Caused by giving an incompatible blood bag to a patient
Early signs include fever, abdominal pain, hypotension and anxiety
Late complications include generalised bleeding secondary to DIC
Management of acute haemolytic transfusion reaction?
Stop transfusion
Give saline
Treat DIC
Features of febrile non haemolytic transfusion reaction?
Mild;
A temperature rise of 1 - 2°C leading to pyrexia ≥38°C, but <39°C
And/or pruritus or a rash
WITHOUT other features
Moderate;
Temperature ≥39°C OR a rise of ≥2°C from baseline
AND/OR systemic symptoms such as chills, rigors, myalgia, nausea or vomiting)
What is TRALI?
Pulmonary oedema resulting in acute respiratory distress syndrome
Management of TRALI?
Stop transfusion
Give saline
Supplemental oxygen
Management of transfusion associated circulatory overload?
Stop transfusion
Furosemide
Supplemntal oxygen
What is basophilic stippling?
Blue staining of ribosomal precipitates within cytoplasm of red blood cells
In which conditions is basophilic stippling seen?
Megaloblastic anaemia
Thalassemia, in particular alpha
Sideroblastic anaemia
Lead poisoning
Alcohol abuse
Pyrimidine 5@- nucleotidase deficiency
What are Howell Jolly bodies?
Single peripheral bodies within red cells representing DNA material typically removed by spleen
Presence of these bodies can represent hyposplenism
What is schistocytes?
Fragments of red cells seen in microangiopathic haemolytic anaemia
Irregularly shaped, jagged and have 2 end points
Causes of macroangiopathic haemolytic anaemia?
Isolated syndrome
Haemolytic uraemic syndrome
Thrombotic thrombocytopenia purpura
Disseminated intravascular coagulation
What is left shift?
Presence of immature cells including presence of band cells due to unlobed neutrophil nucleus present as a band
Causes of left shift?
Acute infection
Myeloproliferative disorder
Chronic myeloid leukaemia
Myelofibrosis
Acute leukaemia
What is right shift?
Signifies neutrophil maturation and presence of hypermature neutrophils with more than 5 lobes
When is right shift seen?
Chronic infections
Use of granulocyte- colony stimulating factor therapy
Megaloblastic anaemia
What is reticulocytosis?
Presence of immature red blood cells indicating high red cell turnover and increased bone marrow production and released
Causes of reticulocytosis?
Haemolysis
Acute bleeding
What are target cells?
Non specific blood film finding
When are target cells seen?
Obstructive liver disease
Haemoglobinopathies; thalassaemia, sickle cell
Post splenectomy
What is rouleaux formation?
Stacks of aggregated red blood cells when plasma protein concentration is high
Causes of rouleaux formation?
Multiple myeloma
Waldenstorm’s macroglobulinaemia
Inflammatory disorders
Malignancies
What is leukoerythroblastosis?
Presence of immature red blood cells and left shift
Causes of leukoerythroblastosis?
Marrow fibrosis
Invasion
Primary myelofibrosis
Metastatic cancer
TB
Gaucher’s disease
What is anisocytosis?
Variation in red blood cell size (MCV)
Causes of anisocytosis?
Iron deficiency anaemia; most common
Sickle cell anaemia
Anaemia of chronic disease
Thalassaemia
What are acanthocytes?
Red blood cells that appear irregularly spiked on a blood film due to altered lipid/ protein composition of the red blood cells plasma membrane
Causes of acanthocytes?
Liver disease
Neuroacanthocytosis, anorexia nervosa, hypothyridism, myelodysplasia
What is a cabot ring?
Round red blood cell inclusions, slender loops seen in cytoplasm of
Causes of cabot rings?
Megaloblastic anaemia
Lead poisoning
Leukaemia
What are burr cells?
Red cells with small irregularly distributed projections across cell surface
Causes of burr cells?
Liver disease
Vitamin E deficiency
End stage renal disease
Haemolytic enzyme disorder
What is CLL?
Accumulation of mature monoclonal B lymphocytes in blood, bone marrow and lymphoid tissue
Epidemiology of CLL?
Most common in men over age of 60 years
Most common leukaemia in western countries
Aetiology of CLL?
Genetic and environmental factors
Family history
Presentation of CLL?
Non-tender symmetrical lymphadenopathy
Hepatosplenomegaly
B symptoms – weight loss, night sweats and fever
Bone marrow failure; infection, anaemia, bleeding
Differentials for CLL?
Hairy cell leukemia
Small lymphocytic lymphoma
Infection
Investigations to diagnose CLL?
FBC
Blood film
Immunophenotyping; CD5/ CD23 positive, FMC negative
Direct antiglobulin test positive
System used to stage CLL?
Binet’s system
Based on lymphoid tissue enlargement, haemoglobin and platelets
Management of CLL?
Chemotherapy, rituximab
Allogenic stem cell transplant
Steroids
Antibiotics
Complications of CLL?
Infections
Transformation to diffuse large B-cell lymphoma
Autoimmune haemolytic anaemia
Factors that affect prognosis of CLL?
Disease stage
Atypical lymphocyte morphology
Lymphocyte doubling time <12 months
Bone marrow trephine showing diffuse involvement
Chromosomal/genetic abnormalities, in particular TP53
Unmutated immunoglobulin VH (IGVH) gene status
Male sex
High expression CD38
Prognosis of CLL?
CLL is a very variable disease: 1/3 of cases don’t progress, 1/3 of cases progress slowly, and 1/3 of cases progress actively.
What is CML?
Myeloproliferative neoplasm characterised by presence of Philadelphia chromosome resulting in uncontrolled proliferation of myeloid cells in bone marrow
What is the philadelphia chromosome?
Reciprocal translocation of genetic material between chromosomes 9 and 22, leading to the formation of the BCR-ABL1 fusion gene
Epidemiology of CML?
Middle aged patients 40-50 years
More common in men than women
Aetiology of CML?
BCR-ABL1 fusion gene
Previous high dose ionising radiation
Presentation of CML?
Weight loss
Tiredness
Fever
Sweating
Massive splenomegaly
Bleeding
Gout
Hyperleukocytosis;
Visual disturbance
Confusion
Priapism
Deafness
Differentials for CML?
Reactive leukocytosis
Polycytaemia vera
Essential thrombocythemia
Investigations for CML?
FBC; raised myeloid cells, anaemia
Blood film; blast cells, leucocytosis
Bone marrow analysis; hyperplasia, fibrosis, granulocyte predominance
High vitamin B12
Philadelphia chromosome
Management of CML?
Tyrosine kinase inhibitor- imatinib
Hydroxycarbamide
Stem cell transplantation
Side effects of TKI?
Nausea
Thrombocytopenia
Neutropenia
Fluid retention
Complications of CML?
Blast crisis
Resistance to TKI
Secondary malignancies
Prognosis of CML?
Chronic phase lasts 2-5 years
Median survival of 5-6 years
What is a DVT?
A deep vein thrombosis (DVT) is a blood clot or thrombus that blocks a deep vein, commonly in the legs or pelvis.
Risk factors for DVT?
Thrombophilia
Hormonal (COCP, pregnancy and the postpartum period, HRT)
Relatives (family history of VTE)
Older age (>60)
Malignancy
Bone fractures
Obesity
Smoking
Immobilisation (long-distance travel, recent surgery or trauma)
Sickness (e.g. acute infection, dehydration)
Epidemiology of DVT?
Affects 1-2 per 1000
Common in unwell patients in hospital and affects upto 37% of critically ill patients
Signs and symptoms of DVT?
Unilateral erythema, warmth, swelling and pain in the affected area
Pain on palpation of deep veins
Distention of superficial veins
Difference in calf circumference if the leg is affected
This should be measured 10cm below the tibial tuberosity
3cm difference between the legs is significant
Differentials for DVT?
Cellulitis
Calf muscle tear
Superficial thrombophlebitis
Compartment syndrome
Investigations to diagnose DVT?
If wells score under 1;
Order D-dimer and if positive order leg vein ultrasound
If wells score over 2; perform leg vein ultrasound scan
Baseline bloods; FBC, U+E, LFT, CRP, TFT, coagulation
Management of DVT?
DOAC; apixaban, rivaroxaban is first line, LMWH is second line
Anticoagulation for 3 months, 3-6 months in cancer patients
In provoked DVTs with risk factor identifiable treatment can be stopped in 3 months and reviewed with baseline bloods
If provoked consider testing for thrombophilia with antiphospholipid antibodies
Complications of DVT?
Pulmonary embolism
Post thrombotic syndrome
Anticoagulation complications
What is DIC?
Inappropriate activation of clotting cascade resulting in thrombus formation leading to depletion of clotting factors and platelets
Aetiology of DIC?
Major trauma or burns
Multi-organ failure
Severe sepsis or infection
Severe obstetric complications
Solid tumours or haematological malignancies
Acute promyelocytic leukaemia (APL) is an uncommon subtype of AML that is associated with DIC
Signs and symptoms of DIC?
Excessive bleeding e.g. epistaxis, gingival bleeding, haematuria, bleeding/oozing from cannula sites
Fever
Confusion
Potential coma
Petechiae
Bruising
Confusion
Hypotension
Differentials for DIC?
Coagulopathies
Sepsis
Multiorgan failure
Investigations to diagnose DIC?
Blood tests, including:
FBC (thrombocytopenia)
Blood film may show schistocytes due to microangiopathic haemolytic anaemia (MAHA)
Raised d-dimer (a fibrin degradation product)
Clotting profile - increased prothrombin time (due to consumption of clotting factors), increased APTT, decreased fibrinogen (consumed due to microvascular thrombi)
Management of DIC?
Treat cause
Transfusion of platelets, clotting factors
Anticoagulation
Mode of inheritance of G6PD deficiency?
X- linked recessive
Pathophysiology of G6PD deficiency?
G6PD enzyme generates NADP, NADPH and glutathione – important for maintaining the integrity of the RBC membrane
It also helps to protect the red cells against oxidative damage
Epidemiology of G6PD deficiency?
Males are affected and females tend to be carriers
More common in west african, southern europe, middle east and south east asia
Usually asymptomatic until significant intravascular haemolysis is triggered by oxidative stress
Triggers of G6PD deficiency?
Intercurrent illness or infection (often forgotten)
Fava beans – the disease was historically known as ‘favism’
Henna
Medications (eg. primaquine, sulpha-drugs, nitrofurantoin, dapsone, and nonsteroidal anti-inflammatory drugs/aspirin)
Investigations to diagnose G6PD deficiency?
Blood film; Heinz bodies, red cell fragmentation, bite cells, spherocytosis, reticulocytosis
G6PD enzyme assay
Direct antiglobulin test is negative
Management of G6PD deficiency?
Avoidance of precipitants
Maintaining good hydration
Rarely blood transfusions may be required by some patients
Inheritance of hereditary spherocytosis?
Autosomal dominant
Pathophysiology of hereditary spherocytosis?
Mutation in red cell membrane protein resulting in abnormal red cell cytoskeleton due to deficiency in spectrin, ankyrin and band 3
This makes red cells more fragile and prone to osmotic fragility
Clinical presentation of hereditary spherocytosis?
Jaundice
Gallstones
Anaemia
Splenomegaly
Investigations to diagnose hereditary spherocytosis?
FBC
Blood film; spherocytes
Direct antiglobulin test
Management of hereditary spherocytosis?
Folic acid supplementation
Splenectomy before age of 5 can be curative
Inheritance of pyruvate kinase deficiency?
Autosomal recessive
Pathophysiology of pyruvate kinase deficiency?
Deficiency of pyruvate kinase (involved in the glycolytic pathway) leads to unstable RBC enzymes, with reduced ATP production
Investigations to diagnose pyruvate kinase deficiency?
Blood film; echinocytes/ burr cells, reticulocytosis
LDH and haptoglobin elevated
Pyruvate kinase levels assay
Clinical features of pyruvate kinase deficiency?
Jaundice
Gallstone
Bone marrow expansion
Management of pyruvate kinase deficiency?
Supportive
Splenectomy
What is essential thrombocytosis?
Myeloproliferative disorder caused by dysregulated megakaryocyte proliferation
Often due to JAK2 or V617F mutation
Epidemiology of essential thrombocytosis?
The disease is most common in women aged 50–70 years.
Median survival is 10–15 years.
Signs and symptoms of essential thrombocytosis?
50% of patients are asymptomatic, with only an incidental FBC finding
Thrombosis (arterial or venous)
Bleeding (gastrointestinal or intracranial)
Hyperviscosity-related - dizziness/syncope, headache
Splenomegaly
Hyposplenism (caused by multiple splenic infarcts)
Erythromelalgia (a red/blue discolouration of the extremities, often accompanied by a burning pain)
Livedo reticularis (a net-like purple rash)
Differentials for essential thrombocytosis?
Transient thrombocytosis can be triggered by infection, bleeding, thrombosis, iron deficiency, hyposplenism or trauma
Investigations to diagnose essential thrombocytosis?
FBC; platelets over 450x10*9
JAK2 or V617F mutation
Trephine biopsy- hypercellular bone marrow and pathological megakaryocytic clumping
How are patients with essential thrombocytosis classified?
Low risk;
Age under 40 years AND
Platelet count <1500 × 109/l
No history of thrombosis or haemorrhage
No cardiovascular risk factors (diabetes, hypertension, obesity and smoking)
Intermediate risk;
In between high and low risk
High risk;
Age over 60
Platelet count >1500 × 109/l
Previous history of thrombosis or haemorrhage
Diabetes or hypertension
Management of essential thrombocytosis?
Low risk; aspirin alone
Intermediate risk; hydroxycarbamide and aspirin OR aspirin alone
High risk; hydroxycarbamide and aspirin
What is pancytopenia?
Anaemia, thrombocytopenia, leukopenia
Causes of pancytopenia?
Chemotherapy, radiotherapy
Vitamin B12, folate deficiency
Marrow infiltration
Myelofibrosis
Multiple myeloma
Inherited causes; fanconi’s anaemia
Liver conditions; autoimmune hepatitis
Drug induced
What is neutrophilia?
High neutrophil count
Causes of neutrophilia?
Severe stress;
Trauma
Surgery
Necrosis
Burns
Haemorrhage
Seizures
Active inflammation;
Polyarteritis nodosa
Myocardial infarction
Disseminated malignancy
What is neutropenia?
Neutrophil count below 0.5 x10*9
Causes of neutropenia?
Severe sepsis
Viral infection
Drugs - such as chemotherapy
Marrow failure (due to malignancy or infiltration
Hypersplenism (less common)
Felty’s syndrome (less common)
SLE (less common)
What is agranulocytosis?
Associated with depleted levels of basophils and eosinophils
Drugs that cause agranulocytosis?
Carbamazepine
Carbimazole
Clozapine
What is lymphocytosis?
Raised lymphocytes
Causes of lymphocytosis?
Acute viral infection (especially EBV and CMV)
Chronic atypical infection (tuberculosis, brucella, toxoplasmosis)
Lymphoproliferative disorders (chronic lymphocytic leukaemia and lymphoma)
Causes of eosinophilia?
Infections e.g. parasitic worms
Allergy including drug reactions
Inflammatory diseases e.g. eosinophilic granulomatosis and polyangiitis
What is thrombocytopenia?
Low platelet count caused by decreased production or increased consumption?
What is thrombocytosis?
Elevated platelet count over 450 x 10*9
Causes of thrombocytosis?
Primary (essential) thrombocytosis is caused by dysregulated megakaryocyte (platelet precursor) proliferation. This is often due to a JAK2 V617F mutation, present in over half of patients with the condition.
Secondary thrombocytosis is triggered by a precipitant (eg. infection, bleeding, thrombosis, iron deficiency, hyposplenism or trauma)
Triggers for G6PD deficiency?
Medications; antibiotics (trimethoprim and quinolones such as ciprofloxacin), antimalarials (primaquine, quinidine, chloroquine), aspirin, NSAIDs, dapsone
Infection
Fava beans
Chemical exposure
Mental/ physical stress
Tonic water, soy products
Signs and symptoms of G6PD deficiency?
Most individuals with G6PD deficiency remain asymptomatic until exposed to triggers
Jaundice: Caused by increased bilirubin levels due to haemolysis. Babies may present with neonatal jaundice.
Pallor: Resulting from anaemia.
Dark Urine: Due to haemoglobinuria, a consequence of haemolysis.
Fatigue and weakness: May result from chronic, low-level haemolysis.
Gallstones (pigmented)
Differentials for G6PD deficiency?
Autoimmune haemolytic anaemia
Hereditary spherocytosis
Thalassemia
Complications of G6PD deficiency?
Acute haemolysis
Chronic anaemia
Infection susceptibility
What is haemolytic anaemia?
Premature destruction of red blood cells leading to a decreased lifespan
Classification of haemolytic anaemia?
Hereditary haemolytic anaemia; sickle cell, thalassemia, hereditary spherocytosis
Acquired haemolytic anaemia; malaria, medication, mechanical trauma
Intravascular haemolysis;
Intrinsic cellular injury (eg. G6PD deficiency)
Intravascular complement-mediated lysis (some autoimmune haemolytic anaemias)
Paroxysmal nocturnal haemoglobinuria and acute transfusion reactions
Mechanical injury – microangiopathic haemolytic anaemia and cardiac valves
Autoimmune haemolytic anaemia (AIHA)
Extravascular haemolysis;
Abnormal red cells (e.g. sickle cell anaemia and hereditary spherocytosis)
Normal cells having been marked by antibodies for splenic phagocytosis
Warm autoimmune haemolytic anaemia; SLE, lymphoproliferative neoplasm (CLL, lymphoma), methyldopa
Cold autoimmune haemolytic anaemia; post infection, lymphoproliferative disorders
Non autoimmune haemolytic anaemia;
Microangiopathic haemolytic anaemia
Paroxysmal nocturnal haemoglobinuria (PNH)
Physical lysis of red cells (e.g. malaria, patients with mechanical heart valves)
Haemolytic uraemic syndrome (HUS) – often caused by E. coli 0157:H7
Infectious causes of disseminated intravascular coagulation (DIC) such as fulminant meningococcaemia
Signs and symptoms of Haemolytic anaemia?
Fatigue
Pallor
Jaundice - Haemolysis releases bilirubin into the bloodstream, causing yellowing of the skin and sclera
Splenomegaly - The spleen becomes enlarged as it works to remove and destroy the damaged red blood cells.
Dark Urine
Gallstones - Excess bilirubin can accumulate in the gallbladder, increasing the risk of gallstone formation.
Leg Ulcers - In severe cases, reduced blood flow and oxygen supply can lead to painful leg ulcers.
Shortness of Breath
Heart Palpitations
Sickle Cell Disease: Vaso-occlusive pain, acute chest syndrome, and strokes.
Thalassemias: Profound anaemia, skeletal deformities, and organ enlargement.
Hereditary Spherocytosis: Splenomegaly and fatigue due to haemolysis.
Autoimmune Haemolytic Anaemia: Variable symptoms linked to haemolysis extent and underlying autoimmune conditions.
Infections (e.g., Malaria): Fever, fatigue, and organ dysfunction.
Medication-Induced: Variable symptoms, jaundice, and specific drug-related effects.
Investigations to diagnose autoimmune haemolytic anaemia?
FBC
Blood film; reticulocytosis
LFT
Raised LDH
Raised urinary urobilinogen
Management of autoimmune haemolytic anaemia?
Supportive care
Immunosuppression; corticosteroids
Splenectomy
Inheritance pattern of haemophilia?
X linked recessive
What factor is deficient in haemophilia A?
Factor VIII
What factor is deficient in haemophilia B?
Factor IX
Epidemiology of haemophilia?
1 in 5000 men in Haemophilia A
1 in 25000 men in haemophilia B
Signs and symptoms of haemophilia?
Spontaneous deep and severe bleeding into soft tissue, joint and muscles
Excessive bleeding from trauma or surgical intervention
Cerebral haemorrhage can cause mortality
Differentials for haemophilia?
Von willebrand disease
Factor V, VII, X, XI, XIII deficiency
Platelet disorder
Liver disease
Haematological malignancy
Trauma
Infectious disease
Vasculitis
Drug induced thrombocytopenia
Investigations to diagnose haemophilia?
Factor VIII/ IX assay
Clotting profile - APTT is elevated
vWF antigen is normal in haemophilia A
Defective platelet function
Management of haemophilia?
Recombinant factor VIII/ IX
Desmopressin in minor bleeds
Tranexamic acid
Causes of high INR?
Overdose of anticoagulant medication
Drug interaction (e.g. antibiotics, antifungals, Aspirin, Amiodarone)
Herbal products
Increase in alcohol consumption
Decrease in consumption of foods containing vitamin K
Liver failure
Infection
Assessment of high INR?
History;
Dosing history of anticoagulant
Concurrent illness
Change in medications
Change in diet/lifestyle (including alcohol and tobacco use)
History of any falls/injuries
History of blood loss;
Haemoptysis
Haematemesis
Melaena
Bleeding from the gums
Examination;
Evidence of bleeding
Overt blood loss
Bruising
Bloods;
Full blood count to check for concurrent anaemia, signs of infection
Clotting screen to check for other clotting abnormalities
Management of high INR?
Consider CT head
Major bleeding;
Stop anticoagulants
Administer IV vitamin K
Administer prothrombin complex (preferred to FFP)
Minor bleeding;
Stop anticoagulants
Administer IV vitamin K
Repeat INR after 24 hours, may need further vitamin K
No bleeding with INR > 8;
Stop anticoagulants
Administer IV or oral vitamin K
Repeat INR after 24 hours
No bleeding with INR > 5;
Withhold 1-2 doses of anticoagulant
Review maintenance dose of anticoagulant
What is Hodgkin lymphoma?
Hodgkin lymphoma is malignant lymphoma characterised by the presence of Reed–Sternberg cells.
Risk factors for hodgkin lymphoma?
Epstein–Barr virus
HIV
Immunosuppression
Cigarette smoking
Clinical presentation of hodgkins lymphoma?
Cervical/ supraclavicular lymphadenopathy
B symptoms
Hepatomegaly
Splenomegaly
Histological subtypes of hodgkins lymphoma?
Lymphocyte predominant (infiltration of T cells)
Nodular sclerosing (bands of fibrous tissue separate nodules of Hodgkin’s disease)
Mixed picture
Lymphocyte depleted (no infiltrating lymphocytes
Ann arbor staging of hodgkins lymphoma?
Stage I – involvement of a single nodal group
Stage II – involvement of two or more nodal groups on the same side of the diaphragm
Stage III – involvement of nodal groups on both sides of the diaphragm
Stage IV – disseminated disease with involvement of extralymphatic organs (eg. the bones or lung)
Additional staging variables include:
(A) if the patient is asymptomatic or (B) if the patient presents with B symptoms (fever, night sweats or weight loss; often confers poorer prognosis)
X if there is bulky nodal disease (>10 cm or >1/3 of the intrathoracic diameter)
(S) if there is splenic involvement
(E) if there is extranodal disease
Investigations to diagnose hodgkins lymphoma?
FBC, CRP, ESR
Lymph node biopsy
LDH
CT/ PET scan
Management of hodgkin lymphoma?
Chemotherapy; ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine and dacarbazine)
Second line therapy; ESHAP (etoposide, cytosine arabinoside, methylprednisolone (high dose steroids) and cisplatin)
Autologous transplant
Prognosis of hodgkins lymphoma?
Variable
Depends on
Histopathological disease type – lymphocyte-predominant has the best prognosis; lymphocyte-depleted has the worst prognosis
Disease bulk
Clinical stage
What is ITP?
Autoimmune condition characterised by reduction in number of circulating platelets
Type II hypersensitivity reaction where spleen produces antibodies to GP IIb/ IIIa
Epidemiology of ITP?
More common in children following viral infection
More common in firls
Aetiology of ITP?
Viral infection
Autoimmune conditions (i.e. systemic lupus erythematosus)
Infections (i.e. H pylori and CMV)
Medications
Lymphoproliferative disorders
Signs and symptoms of ITP?
Easy/ excessive bleeding
Superficial bleeding petechiae
Prolonged bleeding from cuts
Spontaneous bleeding from gums/ nose
Blood in urine/ stools
Heavy menstrual flow
Differentials for ITP?
Aplastic anaemia
Leukaemia
Thrombotic thrombocytopenic purpura
Investigations to diagnose ITP?
FBC
Blood film
Inflammatory markers
Bone marrow biopsy
Management of ITP?
Tranexamic acid
IVIG
Steroids
Splenectomy
Complications of ITP?
Significant bleeds
Intracranial haemorrhage
Prognosis of ITP?
Self limiting
1 in 5 children have chronic course
What is Iron deficiency anaemia?
Haematological disorder as a result of insufficient iron resulting in low haemoglobin and low oxygen carrying capacity
Epidemiology of IDA?
More common in young children and women of child bearing age
More common in elderly
Aetiology of IDA?
Dietary Insufficiency: Inadequate iron intake, especially in individuals with restrictive diets or limited access to iron-rich foods.
Chronic Blood Loss: Gastrointestinal bleeding, heavy menstrual periods, and other sources of chronic blood loss (e.g. angiodysplasia) can deplete iron stores.
Malabsorption Disorders: Conditions like coeliac disease, inflammatory bowel disease and atrophic gastritis can hinder iron absorption in the gut. Hookworms are a more prominent cause in tropical setting.
Increased Demand: During pregnancy and rapid growth phases, the body’s iron requirements can surpass the available supply. This can also occur if there is chronic haemolysis
Signs and symptoms of iron deficiency anaemia?
Tiredness
Lethargy
Weakness
Palpitations: An increased heart rate may be noticeable, especially when at rest.
Cognitive Impairment: Some patients may exhibit difficulty concentrating or memory issues
Cold Intolerance
Headaches and dizziness
Brittle Nails: Changes in the nails, such as brittleness and spoon-shaped deformities (koilonychia), can be observed.
Angular stomatitis
Atrophic glossitis
Pica
Differentials for IDA?
Colorectal malignancy
Tha;assaemias
Chronic inflammatory conditions; rheumatoid arthritis, IBD, anaemia of chronic disease
Investigations to diagnose IDA?
FBC; low Hb, low MCV, hypochromic, microcytic red cells, on blood film pencil cells/ target cells
Reticulocyte count
TIBC; high
Ferritin; low, if low is diagnostic for IDA
FIT test
Management of IDA?
Oral ferrous sulphate
Increase dietary intake
Address cause and treat it
Complications of leukaemia treatment?
Secondary malignancy
Cardiorespiratory complications
Endocrine dysfunction
Infertility
Avascular necrosis of the hip – due to prolonged steroid exposure
Neuropsychological effects
What is macrocytic anaemia?
Red cells are larger than normal, it can be wither megaloblastic or non-megaloblastic with presence of hyper segmented neutrophils
Epidemiology of macrocytic anaemia?
Megaloblastic anaemia is more common in older people with folate or B12 deficiency being most common
Non-megaloblastic is more common in younger people and alcohol/ pregnancy is more common
Causes of megaloblastic anaemia?
B12 deficiency; dietary, malabsorption
Folate deficiency
Drugs; hydroxycarbmide, azathioprine, cystosine arabinoside, azidothymidine
Causes of non-megaloblastic anaemia?
Liver disease
Alcohol
Hypothyroidism
Myelodysplastic syndrome
Hypothyroidism
Pregnancy (usually a mild macrocytosis)
Signs and symptoms of macrocytic anaemia?
Fatigue and Weakness
Pallor
Shortness of Breath
Glossitis
Neurological symptoms; paraesthesia, ataxia, cognitive impairment
Differentials for macrocytic anaemia?
Haemolysis
Liver disease
Medications; chemotherapy, methotrexate, antiretroviral drugs
Myelodysplastic syndromes
Investigations to diagnose macrocytic anaemia?
FBC
Haematinics
Blood film; macrocytosis, presence of hypersegmented neutrophils
TFT, LFT, antibodies for intrinsic factor
Markers for haemolysis; bilirubin, LDH
Management of macrocytic anaemia?
Hydroxocobalamin and folate supplementation
Non megaloblastic anaemia; treat underlying cause, such as addressing alcohol consumption or providing support during pregnancy
What is methaemoglobinaemia?
haematological disorder marked by the abnormal accumulation of methaemoglobin, a form of haemoglobin unable to bind oxygen efficiently
Epidemiology of methaemoglobinaemia?
Can affect all ages
More common in infants due to immature enzymes or those exposed to specific chemicals or medications
Aetiology of methaemoglobinaemia?
Congenital causes, enzyme deficiencies
Exposure to nitrates, local anaesthetics, benzene derivatives
Signs and symptoms of methaemoglobinaemia?
Cyanosis
Dyspnoea
Headache
Dizziness
Fatigue
Altered mental status
Seizures, coma or cardiac arrhythmia
Differentials for methaemoglobinaemia?
Congenital heart disease
Respiratory disorders
Carbon monoxide poisoning
Investigations to diagnose methaemoglobinaemia?
Measure methaemoglobin in blood using co-oximetry/ spectrophotometry
Management of methaemoglobinaemia?
Oxygen therapy
Methylene blue, ascorbic acid supplementation
Supportive care
Complications of methaemoglobinaemia?
Hypoxic tissue injury
Metabolic acidosis
Seizures
Coma
Cardiovascular collapse
Prognosis of methaemoglobinaemia?
Depends on cause and severity
What is methotrexate?
DMARD that inhibits DNA synthesis by inhibiting enzyme dihydrofolate reductase resulting in immunosuppressive and cytotoxic effects
Side effects of methotrexate?
Gastrointestinal upset (e.g. nausea, diarrhoea, abdominal pain)
Stomatitis and mucosal ulcers
Anorexia
Headache
Hair loss
Fatigue
Increased risk of infection; may reactivate latent infections
Teratogenicity
Myelosuppression with subsequent anaemia, leukopenia and thrombocytopenia
Hepatotoxicity including liver cirrhosis
Renal toxicity
Pulmonary toxicity especially pneumonitis; increased risk in rheumatoid arthritis
Photosensitivity reactions - may present with blistering or papular rashes and swelling of affected skin
Investigations to perform prior to starting methotrexate treatment?
Blood pressure
Weight and height
Pregnancy testing if appropriate
Full blood count (FBC)
U&Es for renal function (dose reduction may be needed; avoid methotrexate in severe impairment)
Liver function tests (avoid if baseline hepatic impairment)
Hepatitis B and C and HIV serology
Consider screening for tuberculosis and other lung disease e.g. with a chest X-ray
Monitoring whilst on methotrexate treatment?
FBC, U&Es and LFTs should be checked every 2 weeks until the dose of methotrexate is stable
They should then be checked monthly for 3 months, then at least every 3 months thereafter
More frequent monitoring may be required in patients at increased risk of toxicity
Contraindications to methotrexate?
Active infection - methotrexate should be paused during acute infections
Immunodeficiency syndromes
Ascites or significant pleural effusion (increases the risk of methotrexate accumulation unless drained)
Significant hepatic or renal impairment
Current peptic ulceration
Pregnancy or breast-feeding
Co-administration of another anti-folate medication e.g. co-trimoxazole
Cautions for methotrexate use?
Excess alcohol intake (increases hepatotoxicity risk)
Renal impairment (may need to reduce dose)
Pre-existing haematological abnormalities e.g. anaemia, thrombocytopenia
Chronic respiratory disease
History of recurrent infections (e.g. urinary tract infections, chronic obstructive pulmonary disease exacerbations)
Frail or elderly patients (may require dose reduction)
Dehydration - may need to pause treatment e.g. if the patient develops diarrhoea or vomiting
Interactions with mehtotrexate?
NSAIDs
Trimethoprim/ co-trimoxazole
Anti-epileptic medications
Theophylline
Advice to women when taking methotrexate?
Contraception is recommended
Methotrexate should be stopped 6 months prior to conception
Breast feeding is contraindicated
What agent is used in methotrexate toxicity?
Folinic acid- e.g calcium folinate
Guidance surrounding vaccination while taking methotrexate?
Annual influenza
One off pneumpococcal vaccine prior to starting treatment
Covid vaccination
If over 50 years, shingles vaccine
Avoid live vaccines
What is microcytic anaemia?
Microcytic anaemia is defined by the presence of RBCs that are smaller than normal, with a mean corpuscular volume (MCV) typically below the reference range (around <76 fl).
Signs specific for Iron deficiency anaemia?
Nail changes such as koilonychia (spoon-shaped nails)
Atrophic glossitis
Angular stomatitis
Pica: Iron-deficiency anaemia may manifest as pica, with cravings for non-food substances like ice (pagophagia) or clay (geophagia).
Signs and symptoms of microcytic anaemia?
Fatigue and Weakness
Pallor
Shortness of Breath
Palpitations
Cold intolerance
Causes of microcytic anaemia?
Iron deficiency of anaemia
Thalassaemias
Lead poisoning
Anaemia of chronic disease
Sideroblastic anaemia
Investigations to diagnose Microcytic anaemia?
FBC, MCV
Blood film; microcytic, hypochromic red cells
Iron studies; low serum iron, low ferritin
low transferrin saturation
Hb electrophoresis
Lead levels
Bone marrow biopsy
Management of microcytic anaemia?
Iron supplementation
Blood transfusion
Treat cause; Thalassaemia, lead poisoning
Advice to patients taking levothyroxine and iron supplementation?
Take both medications 4 hours apart and iron reduces levothyroxine absorption
What is myelodysplasia?
Spectrum of disorders where the bone marrow fails to produce normal and functional blood cells. It is often a precursor to acute myeloid leukemia (AML) and is characterized by dysplastic changes in blood cell precursors.
Epidemiology of myelodysplasia?
Disease of elderly, median age at diagnosis 75 years
2-5 cases per 100,000
Pathophysiology of myelodysplasia?
Combination of genetic mutations, microenvironment and exposure to environmental toxins contributes to clonal proliferation of aberrant haematopoetic stem cells resulting in impaired differentiation, maturation and increased apoptosis leading to cytopenia and anaemia
Risk factors for myelodysplastic syndrome?
Age: Advanced age is the most significant risk factor for MDS.
Genetic Predisposition: Specific genetic mutations increase the risk.
Chemotherapy and Radiation Therapy: Previous cancer treatments can lead to secondary MDS.
Environmental Exposures: Prolonged exposure to toxins, such as benzene, may contribute.
Aetiology of myelodysplastic syndrome?
Idiopathic
Genetic mutations; TP53, SF3B1
Radiotherapy
Signs and symptoms of myelodysplastic syndrome?
Fatigue
Anaemia
Easy bruising
Recurrent infections
Bleeding tendencies
Petechiae
Paleness
Enlarged spleen (splenomegaly)
Differentials for myelodysplastic syndrome?
Aplastic anaemia
Leukaemia
Nutritional deficiency
Autoimmune disease
Investigations to diagnose myelodysplastic syndrome?
FBC
Blood smear; nucleated RBC, howell- jolly bodies, large agranular platelets, basophilic stippling
Bone marrow biopsy
Cytogenetic studies
MRI/ CT scan
Management of myelodyspalstic syndrome?
Supportive care
Haematopoetic stem cell transplant
Azacitidine and decitabine can help slow progression to AML
Lenalidomide can also be used depending on mutation
What condition is myelodysplasia a pre-cursor to?
AML
Complications of myelodysplasia?
Transformation to acute leukaemia (AML)
Severe infections due to neutropaenia
Progression to more advanced MDS subtypes
Reduced quality of life due to anaemia and transfusion dependency.
What is myelofibrosis?
Chronic myeloproliferative neoplasm characterised by gradual replacement of normal bone marrow tissue with fibrous tissue resulting in bone marrow scarring, peripheral blood abnormalities and splenomegaly
Epidemiology of myelofibrosis?
Rare with incidence of 2 per 100,000
Affects older adults over the age of 65
No significant geographical variation
Aetiology of myelofibrosis?
Genetic mutations; JAK2, CALR, myeloproliferative leukaemia virus oncogene (MPL)
Signs and symptoms of myelofibrosis?
Constitutional symptoms – weight loss, fever, night sweats
Marrow failure – anaemia, recurrent infection, and abnormal bleeding/bruising
Bone pain
Haemorrhage and thrombosis (less common in myelofibrosis than in other myeloproliferative disorders)
Hepatomegaly
Splenomegaly
Differentials for myelofibrosis?
Primary vs secondary myelofibrosis
Myelodysplastic syndrome
Leukaemia
Investigations to diagnose myelofibrosis?
FBC
Blood film; tear shaped poikilocytes
Trephine biopsy; hypercellular tissue, reduced fat space, increased reticulin staining
Urate and LDH is high
JK2 V517F positive in 50% of cases
Management of myelofibrosis?
Allogenic stem cell transplant; in under 70 years with good performance status and high risk disease
JAK-2 inhibitors; ruxolitinib
Cytotoxic agents; thalidomide, splenic irradiation
Complications of myelofibrosis?
Transformation to acute leukaemia
Splenomegaly related complication; abdominal discomfort, early satiety, infection
CVD and thrombotic events; MI, DVT, PE
What is multiple myeloma?
Plasma cell dyscrasia characterised by abnormal clonal proliferation of post germinal B cells
Epidemiology of multiple myeloma?
Second most common haematological malignancy accounting for 1% of malignancies
More common in older people
More common in men
Afro- caribbean twice as affected as caucasian
Aetiology of multiple myeloma?
Genetic
Exposure to radiation
Immunosuppressive conditions
Exposure to chemicals
Features of multiple myeloma?
Hypercalcaemia; renal stones, GI symptoms, fatigue, memory loss, psychosis
Renal impairment due o light chain deposition in kidney
Anaemia
Osteolytic lesions
Hyperviscosity; VTE
Amyloidosis
Infections
Differentials for myeloma?
Monoclonal gammopathy of undetermined insignificance
Waldenstrom macroglobulinaemia
Amyloidosis
Investigations to diagnose myeloma?
FBC; anaemia
U+E; renal impairment
ESR
Skeletal survey; X-ray, CT, MRI
Serum/ urine electrophoresis
Serum free light chain assay (bence jones proteins); kappa/ lambda proteins
Bone marrow aspiration and biopsy; >10% plasma cells in bone marrow
What is diagnostic for multiple myeloma?
> 10% plasma cells in bone marrow
Management of multiple myeloma?
Acute presentations;
Acute renal failure – swift treatment of volume depletion is critical, as well as early involvement of renal physicians
Hypercalcaemia – fluid and bisphosphonates needed
Hyperviscosity – requires plasmapheresis
Spinal cord compression – should be treated as a radiotherapy emergency
Induction therapy; bortezomib, thalidomide, dexamethasone
Daratumumab- monoclonal antibody binding to CD38
Autologous stem cell transplant
Complication of multiple myeloma?
Bone disease; bone distuction, pathological fractures
Renal dysfunction
Infections
Anaemia
Markers which can be used to inform prognosis of multiple myeloma?
B2 microglobulin
LDH
CRP
FISH
Cytogenetics
What is agranulocytosis?
Depleted levels of basophils and eosinophils
What is neutropenic sepsis?
Reduced absolute neutrophil count below 0.5x10^9 and a temperature over 38 degrees
Aetiology of neutropenia?
Chemotherapy; most common cause
Gram positive bacteria; staph aureus, strep pneumoniae, strep epidermididis
Gram negative bacteria; E.coli, pseudomonas
Fungal pathogens
Signs and symptoms of neutropenia?
Fever
Rigors
Hypotension
Tachycardia
Respiratory distress
Altered mental status
Differentials for neutropenia?
Benign ethnic neutrpenia; african and middle eastern
Aplastic anaemia
Viral infections
Drug induced neutropenia
Autoimmune neutropenia
Inflammatory disorders
Malignancy
B12 and folate deficiency
Congenital; schwachman- Diamond syndrome
Investigations to diagnose neutropenia?
Bedside observations
FBC, CRP
CXR, CT
LP
Bronchoscopy
Management of neutropenia?
Empirical antibiotics; piperacillin- tazobactam
Fluid resuscitation
Supportive care
Haematopoetic growth factors
Fungal prophylaxis
What is non hodgkins lymphoma?
Malignancy affecting lymphoid system with the absence of reed sternberg cells
Epidemiology of non hodgkins lymphoma?
Most common haematological malignancy
More common in males
Aetiology of non hodgkins lymphoma?
Helicobacter pylori – gastric MALT (mucosa-associated lymphoma tissue) lymphoma
Epstein–Barr virus/HIV – Burkitt lymphoma (high-grade NHL) and AIDS-related CNS lymphoma
hepatitis C virus – diffuse large B-cell lymphoma and splenic marginal zone lymphoma
human T-cell lymphotropic virus type 1 (HTLV1) – T-cell lymphoma
immunodeficiency states (eg. HIV/AIDS and post-organ transplant)
autoimmune disorders (eg. Sjögren’s disease and coeliac disease)
inherited disorders affecting DNA repair (eg. ataxia telangiectasia and Fanconi anaemia)
Classification of non hodgkins lymphoma?
Over 30 types
Classified as B or T cell origin
High grade is aggressive, low grade is indolent
Diffuse large B cell lymphoma and follicular lymphoma are most common
What is DLBCL?
High grade lymphoma with 60-70% cure rate
What is follicular lymphoma?
Low grade lymphoma of B cell germinal centre
Signs and symptoms of non hodgkins lymphoma?
Painless lymphadenopathy
B symptoms
Splenomegaly
Hepatomegaly
Common sites of extra nodal disease in Non hodgkins lymphoma?
Gut
Skin
Investigations to diagnose non hodgkins lymphoma?
LDH
FBC- normocytic anaemia
Blood film; nucleated red blood cells, left shift
Biopsy
CT/ PET scan for staging
Cytogenetics
Cytogenetic results for mantle cell lymphoma?
t (11;14)
Management of non hodgkins lymphoma?
Low grade indolent non hodgkins lymphoma;
Stage 1; local radiotherapy
Advanced systemic disease consider rituximab
High grade;
Gold standard; R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone + rituximab)
Burton tyrosine kinase inhibitors; ibrutinib
Autologous and allogenic transplant
Complications of non hodgkin lymphoma?
Infection
Neurological complications; peripheral neuropathy
Paraneoplastic syndrome
Bleeding and coagulopathy
Secondary malignancy
Causes of normocytic anaemia?
Recent bleeding
Anaemia of chronic disease
Combined iron & B12/folate deficiency
Most non-haematinic-deficiency causes
Causes of microcytic anaemia?
Iron deficiency
α-thalassaemia, β-thalassaemia, HbE, HbC
Anaemia of chronic disease (this more often causes normochromic normocytic anaemia)
Lead poisoning
Sideroblastic anaemias (rare)
Causes of macrocytic anaemia?
Normoblastic;
Liver disease
Alcohol
Hypothyroidism
Myelodysplastic syndrome
Hypothyroidism
Pregnancy (usually a mild macrocytosis)
Megaloblastic;
B12 deficiency; reduced intake, pernicious anaemia, IBD, gastrectomy
Folate deficiency
Drugs; hydroxycarbamide, azathioprine, cytosine arabinoside, azidothymidine
Management principles of anaemia?
Nutritional deficiency coorrection
Erythropoiesis stimulating agents
Treat underlying condition
Blood transfusions
Bone marrow stimulants; G-CSF
Supportive care
Regular monitoring
What is primary paraproteinaemia?
Build up of monoclonal protein in the serum or urine
Monoclonal plasma cells may be present in marrow, soft tissue and circulation
Classification of primary paraproteinaemia?
Premalignant; MGUS
Malignant; multiple myeloma, waldenstorm macroglobulinaemia, solitary plasmacytoma
What is MGUS?
Presence of monoclonal proteins on electrophoresis, 1% undergo malignant transformation to multiple myeloma
Monoclonal protein levels under 30 g/l and marrow biopsy is <10% monoclonal plasma proteins
What is waldenstorms macroglobulinaemia?
Low grade lymphoma with monoclonal plasmacytoid lymphocytes that secrete monoclonal IgM
Clinical features of waldenstorms macroglobulinaemia?
IgM deposition – hyperviscosity, polyneuropathy
organ infiltration – hepatosplenomegaly, lymphadenopathy
bone marrow infiltration – pancytopenia
What is solitary plasmacytoma?
Tender swelling affecting bone or soft tissue (Extramedullary; most commonly occuring in head/ neck)
What is secondary paraproteinaemia?
Paraproteinaemia in association with lymphoma (particularly NHL) or leukaemia (particularly CLL)
What is cryoglobulinaemia?
Col sensitive paraproteinaemia that precipitates in reduced temperatures
Type of cryoglobulinaemia?
Type 1 – monoclonal IgM cryoglobulin
seen in Waldenström macroglobulinaemia
clinical features are primarily hyperviscosity
Type 2 – mixed monoclonal/polyclonal cryoglobulin
seen in chronic infections (eg. hepatitis)
Type 3 – polyclonal cryoglobulin
seen in connective tissue disease (e.g. Sjögren’s disease or SLE).
What is paroxysmal nocturnal haemoglobinuria (PNH)?
Defective red cells membranes makes RBC more suscpetible to haemolysis
Pathophysiology of PNH?
Somatic mutation in PIGA gene in haematopoetic stem cells leading to absence in GPI anchored proteins on the cell surface making RBC, WBC and platelets more susceptible to complement mediated haemolysis
What is responsible for PNH?
Deficiency in GPI anchored proteins
Signs and symptoms of PNH?
Nocturnal episodes of intravascular haemolysis – it is not known why this occurs at night
Dark/coca-cola-coloured urine (haemoglobinuria) in the morning due to nocturnal haemolysis
Repeated urinary infections (leukopenia)
Mucocutaneous bleeding (thrombocytopenia)
Fatigue (occasionally can have a pancytopaenic picture)
Symptoms of thrombosis depending on site - headache and visual disturbances (cerebral vessels), abdominal pain (abdominal vessels), chest pain (PE), leg/calf pain (DVT)
Investigations to diagnose PNH?
FBC; haemolysis, pancytopenia, thrombocytopenia
USS/ CT/ MRI to look for thrombosis
Bone marrow aspiration and biopsy
Ham’s test; diagnostic test for PNH
Flow cytometry
Management of PNH?
Red cell transfusion
Anticoagulation; warfarin is given is platelet count is below 50x10*9
Eculizumab; monoclonal antibody directed against complement C5
Folic acid and iron supplementation
Bone marrow supplementation if progression to AML
Complications of PNH?
Thrombosis
Bone marrow failure
Anaemia
Infections
Progression to AML
What is pernicious anaemia?
Autoimmune destruction of gastric parietal cells resulting in reduced intrinsic factor and hence B12 resulting in macrocytic anaemia
Pathophysiological changes in pernicious anaemia?
Autoimmune attack
Intrinsic factor deficiency
B12 deficiency
Megaloblastic changes
Haemolysis
Epidemiology of pernicious anaemia?
More common in northern european, scandivianian and african descent
More common in adults over the age of 60
More common if history of other autoimmune disease
Signs and symptoms of pernicious anaemia
Fatigue
Pallor
Glossitis - inflammation of the tongue, leading to a smooth, beefy-red appearance.
Neurological Symptoms and subacute combined degeneration of the cord: Pernicious anaemia may cause neuropathy, affecting balance, sensation, and coordination.
Jaundice - due to haemolysis
Cognitive Impairment - memory problems, confusion, and mood changes may occur
Differentials for pernicious anaemia?
Iron deficiency anaemia
Folate deficiency
Myelodysplastic syndrome
Investigations to diagnose pernicious anaemia?
FBC; low Hb, high MCV, High MCH, normal MCHC, low reticulocyte count
Blood film; oval shaped RBC
Haematinics
Parietal cell antibodies
Bone marrow aspiration and biopsy
Management of pernicious anaemia?
Lifelong hydroxycobalamin replacement
Concurrent folate replacement
Complications of pernicious anaemia?
Gastric cancer
Peripheral neuropathy
Subacute combined degeneration of the cord
Optic atrophy
Dementia
Other autoimmune disorder
What is polycythaemia?
Increase in haematocrit, red cell count and haemoglobin concentration
Classification of polycythaemia?
Relative is due o low plasma volume and can be caused by;
Dehydration
Chronic alcohol intake
Excess diuretic use
Pyrexia
Diarrhoea and vomiting
Gaisbock syndrome
Absolute polycythaemia is when plasma volume is normal and red cell mass if higher
Primary causes; polychythaemia ruby vera is due to JAK2 gene mutations leading to uncontrolled red blood cell production
Secondary is due to excess EPO secretion casued by chronic hypoxia, anabolic steroid use, renal neoplasms, CKD, cyanotic heart disease
Signs and symptoms of polycythaemia?
Fatigue
Headache
Visual disturbances (secondary to hyperviscosity)
Pruritus (typically after a hot bath)
Erythromelalgia (a painful burning sensation in the fingers and toes)
Arterial thrombosis (eg. myocardial infarction or stroke)
Venous thrombosis (eg. pulmonary embolus or deep vein thrombosis)
Haemorrhage (intracranial or gastrointestinal)- paradoxical increased bleeding risk (due to impaired platelet function)
Increased risk of gout (caused by hyperuricaemia secondary to increased cell turnover).
Facial redness on examination (plethora)
Splenomegaly
Hypertension
Peptic ulceration
Hyperviscosity symptoms; chest pain, myalgia, weakness, headache, blurred vision
Ruddy complexion
Splenomegaly
Investigations to diagnose polycythaemia?
Pulse oximetry
FBC; raised Hb, raised haematocrit, raised red cell mass
U+E
Vitamin B12
JAK2 V617F mutation
Bone marroe biopsy
USS
Management of polycythaemia?
Venesection
Aspirin 75mg daily
Cryoreductive hterapy; hydroxycarbamide, interferon (JAK-2 inhibitors such as ruxolitinib) and busulfan
Allopurinol
Antihistamines
Aims for haematocrit in polycythaemia treatment?
Haematocrit <45% in primary polycythaemia
Haematocrit <55% in secondary polycythaemia
What is sickle cell anaemia?
Inherited genetic condition where HbS is present resulting in deoxygenation and distortion of RBC
Epidemiology of sickle cell anaemia?
More common in central and western african descent
Pathophysiology of sickle cell disease?
The 6th amino acid glutamic acid (GAA) is replaced by valine (GTA) on the beta globin chain
In its deoxygenated state HbS undergoes polymerisation forming crystals that cause polymers to form leading to sickling of RBC
Abnormal shape RBC thrombose in microvasculture
Inheritance of sickle cell anaemia?
Autosomal recessive
Pathophysiology of hyposplenism in sickle cell disease?
Sequestration of red blood cells in spleen leads to extravascular haemolysis leading to splenic congestion and splenomegaly
Followed by splenic infarction leading to hyposplenism
This leads to reduced immune function
Complications of sickle cell disease?
Vaso-occlusive crises; microvascular obstruction due to RBC sickling
Acute chest crisis
Splenic infarction and subsequent immunocompromise
Sequestration crisis
Osteomyelitis
Stroke
Dactylitis
Poor growth
Chronic renal disease
Gallstones
Retinal disorders
Priapism
Pulmonary fibrosis and pulmonary hypertension
Iron overload from repeated blood transfusions
Red cell aplasia (due to parvovirus B19 infection in the presence of chronic haemolytic anaemia)
Investigations to diagnose sickle cell anaemia?
FBC; microcytic anaemia, reticulocytosis
Blood film; target cells, polychromasia, howell- jolly bodies, nucleated red cells, reticulocytosis
Hb electrophoresis
Management of sickle cell disease?
Acute cell crises;
High-flow oxygen
IV fluids and analgesia
Top-up transfusions – required in some severe cases
Chronic disease;
Hydroxycarbamide
Exchange transfusion
Vaccination and antibiotic prophylaxis
Crizaniluzumab (p-selectin inhibitor) for treatment of pain crises
Bone marrow transplantation
What is sideroblastic anaemia?
Group of blood disorders characterised by impaired ability of bone marrow to produce normal red blood cells
Defective sideroblast cells have ringed pattern with iron loaded mitochondria
Epidemiology of sideroblastic anaemia?
More common in elderly
Pathophysiology of sideroblastic anaemia?
Ineffective erythropoiesis leading to increased iron absorption and deposition within bone marrow and other organs
Aetiology of sideroblastic anaemia?
Congenital; X linked recessive or dominant
Acquired; drug toxicity, myelodysplastic syndrome, alcohol abuse, lead poisoning, isoniazid use
Sigs and symptoms of sideroblastic anaemia?
Fatigue
Weakness
Pallor
Tachycardia
Differentials for sideroblastic anaemia?
Iron deficiency anaemia
Thalassaemia
Anaemia of chronic disease
Investigations to diagnose sideroblastic anaemia?
FBC
Ferritin and iron levels; elevated
Blood film; red cell cytoplasm inclusions (target cells)
Bone marrow biopsy; iron deposition and ringed sideroblasts
Management of sideroblastic anaemia?
Chelation therapy
B6 supplementation
Blood transfusion
Stem cell transplant
Indications for splenectomy?
Indications for emergency splenectomy include trauma and rupture (e.g. in EBV infection).
An elective splenectomy may need to be done in cases of hypersplenism, where the spleen has a preference for platelets resulting in increased uptake, which leads to sequestration of cells in the spleen
Indications for elective splenectomy include haemolytic anaemia (hereditary or immune) and idiopathic thrombocytopenic purpura.
What is seen on blood film post splenectomy?
Howell- Jolly bodies
Pappenheimer bodies
Vaccination in patients post splenectomy?
Pneumococcal vaccination (with regular boosters every 5 years).
Seasonal influenza vaccination (yearly, typically every autumn).
Haemophilus influenza type B vaccination (one-off).
Meningitis C vaccination (one-off).
Antibiotic of choice post splenectomy?
Low dose prophylaxis typically for life of phenoxymethylpenicillin V
If allergic then clarithromycin/ erythromycin
Target INRs
For patients with atrial fibrillation: 2-3
For patients with metallic valve replacements: 2-3 (aortic valve); 2.5-3.5 (mitral valve)
Following venous thromboembolism (VTE): 2-3 (if recurrent then 3-4)
What is thalassaemia?
Inherited disorders characterised by abnormal haemoglobin production as a result in a defect in either the alpha or beta globin chain leading to a reduction in haemoglobin quantity
Epidemiology of thalassemia?
More prevalent in mediterranean european, central africa, middle east and indian subcontinent
Inheritance of alpha thalassaemia?
Autosomal recessive
Pathophysiology of alpha thalassaemia?
Spectrum of disease caused by non functioning copies of the 4 alpha globin genes on chromosome 16
Symptomatic disease occurs when 2 or more copies of the gene are lost
Presentation of alpha thalassaemia?
Patients with two defective copies have a mild asymptomatic anaemia – so-called α-thalassaemia trait
Those with three defective copies have symptomatic haemoglobin H disease
Microcytic anaemia (Hb approximately 70 g/l)
Haemolysis
Splenomegaly
Normal survival is to be expected
Inheritance of four defective copies (hydrops fetalis) is incompatible with life
The lack of α-globin chains results in excess γ-chains (creating Hb Barts), which are poor carriers of oxygen owing to their high affinity for oxygen
It may affect the fetus in utero
Signs and Symptoms;
Jaundice
Fatigue
Facial bone deformities
Investigations to diagnose alpha thalassaemia?
FBC will reveal a microcytic anaemia.
Hb electrophoresis – can be normal, so DNA analysis is required to make the diagnosis
Management of alpha thalassaemia?
Blood transfusion
Stem cell transplantation
Splenectomy
Folic acid supplementation
Pathophysiology of beta thalassaemia?
Spectrum of disease caused by non functioning copies of the two beta globin genes
Variants of beta thalassaemia?
The mildest variant of β-thalassaemia is β-thalassaemia minor (also known as thalassaemia trait)
Patients typically have one functioning and one dysfunctional copy of the β-globin gene
The most severe form of β-thalassaemia (known as β-thalassaemia major) is caused by a complete absence of β-globin synthesis (null mutations in both copies of the β-globin gene)
Signs and symptoms of beta thalassaemia?
β-thalassaemia minor - patients are typically asymptomatic
β-thalassaemia major:
Severe symptomatic anaemia at 3–9 months of age
Becomes evident when levels of HbF, which does not contain β-globin, fall and should be replaced by HbA (made up of two α- and two β-globin chains), which is lacking in β-thalassaemia major
Ineffective haematopoiesis results in extramedullary haematopoesis, which results in
Frontal bossing (hair-on-end appearance on Skull XR)
Maxillary overgrowth and prominent frontal/parietal bones (hypertrophy of ineffective marrow) - “Chipmunk facies”
Hepatosplenomegaly
Failure to thrive in infancy
Investigations to diagnose beta thalassaemia?
β-thalassaemia minor
Isolated microcytosis (MCV approximately 63–77 fl) and mild anaemia (Hb typically not <100 g/l)
The degree of anaemia is often less severe than would be expected for the degree of microcytosis
Blood film - target cells and basophilic stippling
Increased red cell count
Hb electrophoresis (diagnostic) shows raised HbA2 (>3.5%) – can be lowered by the presence of iron deficiency
Can be confused with iron deficiency – ferritin in β-thalassaemia minor is usually normal or high
β-thalassaemia major
Profound microcytic anaemia; reduced MCV and reduced MCHC
Increased reticulocytes
Blood film – marked anisopoikilocytosis, target cells and nucleated RBCs. Teardrop cells from extramedullary haematopoeisis may also be present
Methyl blue stains – RBC inclusions with precipitated α-globin
High-performance liquid chromatography (HPLC) or electrophoresis (diagnostic) – mainly shows HbF
HbA2 may be normal or mildly elevated
Haemolysis
Management of beta thalassaemia?
Regular blood transfusions
Hydroxycarbamide
Allogenic bone marrow transplant
Iron chelation
Iron chelating agents?
Desferrioxamine;
Used for decompensated organ dysfunction
Given via subcutaneous pump over 2–5 days each week
Compliance may be an issue
Deferiprone’
Oral, given in three divided doses
Particularly good for cardiac iron overload
Side effects include: Nausea, Arthralgia, Agranulocytosis – weekly FBC needed, LFT disturbance, Zinc deficiency
Deferasirox;
A newer oral iron chelator
Removes iron in the bile and faeces
Once daily suspension with similar efficacy to desferrioxamine
Side effects include: Gastrointestinal upset. Cytopenias, Increased creatinine
Monitoring requirements for patients on iron chelation?
Cardiac/liver T2* MRI
Endocrine tests
Audiology and ophthalmology
Complications of beta thalassaemia?
Cardiomyopathy/ cardiac arrhythmia/ cardiac failure
Acute sepsis
Liver failure/ cirrhosis
Hypocalcaemia Hypoparathyroidism
Iron overload
What is thrombophilia?
Increased risk of VTE and can be due to genetic mutations such as factor V Leiden, prothrombin gene mutation, antiphospholipid syndrome
Epidemiology of thrombophilia?
Varies based on specific condition
Factor V leiden and prothrombin gene mutation have prevalence of 5-7%
Antiphospholipid syndrome is more common in those with autoimmune conditions
Acquired thrombophilias are associated with cancer/ hormones
Aetiology of thrombophilia?
Deficiency in protein C, protein S, antithrombin III
Genetic mutation in Factor V Leiden or prothrombin gene
Acquired;
Lupus anticoagulant/antiphospholipid antibodies
Polycythaemia
Essential thrombocythaemia
Signs and symptoms of thrombophilia?
DVT
PE
Cerebral venous sinus thrombosis
Pregnancy related complications; recurrent miscarriage
Investigations to diagnose thrombophilia?
Coagulation studies; aPTT, PT
Genetic testing; Factor V Leiden mutation, prothrombin gene mutation
Antithrombin, protein C and protein S deficiency
Methylenetetrahydrofolate reductase; elevated homocysteine levels
Antiphospholipid antibody testing; lupus anticoagulant , anticardiolipin, Anti- beta-2 glycoprotein I antibodies
Imaging; doppler USS, CTPA, MRI
Homocysteine levels; hyperhomocysteinaemia
Cancer testing/ hormonal assessments
What is the most common inherited thrombophilia?
Factor V Leiden
Pathophysiology of protein C and S deficiency?
Protein C, together with its cofactor protein S, inactivates clotting factors V and VIII
Inactivating mutations in protein C or S increase the risk of thrombosis
Epidemiology of Protein C and Protein S deficiency?
The prevalence is higher in Southeast Asian patients
Homozygosity for protein C deficiency is fatal in neonates unless it is rapidly treated
What is thrombotic thrombocytopenic purpura?
Abnormally cleaved vWF due to abnormal ADAMST13 activity leading to platelet aggregation, thrombus formation and systemic microangiopathy
Causes of TTP?
Hereditary: Congenital mutation of ADAMST13
Auto-immune: AI inhibition of ADAMST13
Features of TTP?
Fever
Microangiopathic haemolytic anaemia (MAHA)
Thrombocytopaenic purpura
CNS involvement: headache, confusion, seizures
AKI
Investigations to diagnose TTP?
Urine dipstick; haematuria, non nephrotic range proteinuria
FBC; normocytic anaemia, thrombocytopenia
U&E shows a raised urea and creatinine
Clotting is typically normal
The blood film will reveal reticulocytes (secondary to haemolysis) and schistocytes (fragmented red cells)
LFT, LDH, D-dimer will be raised and haptopglobins will be low consistent with haemolysis
Low ADAMST13 activity is diagnostic
Management of TTP?
Fresh frozen plasma (FFP) – contains vWF-cleaving protease and complement components
Plasma exchange – removes antibodies and toxins associated with the pathogenesis of the disease
High-dose steroids, low-dose aspirin and rituximab can also be given
What is tumour lysis syndrome?
Metabolic disorder caused by rapid death of tumour cells in response to chemotherapy resulting in massive release of intracellular contents into blood stream leading to significant electrolyte imbalances
Electrolyte disturbance in TLS?
Hyperuricaemia
Hyperphosphataemia
Hyperkalaemia
Hypocalcaemia
Aetiology of TLS?
Aggressive rapidly proliferating tumours such as leukaemia, high grade lymphoma
More likely following initiation of cytotoxic therapy
Signs and symptoms of TLS?
Dysuria or oliguria
Abdominal pain
Weakness
Nausea or vomiting
Muscle cramps
Seizures
Cardiac arrhythmias
Gout/joint swelling
Differentials for TLS?
AKI
Isolated hyperkalaemia
Isolated hyperphosphataemia
Isolated hypocalcaemia
Investigations to diagnose TLS?
Basic observations
U&E: Potassium and phosphate are usually raised, raised Cr suggestive of AKI/renal failure.
Calcium: Typically low in tumour lysis syndrome.
Uric acid: Usually elevated.
ECG: To assess risk of arrhythmias caused by electrolyte abnormalities.
Hyperkalaemia may cause tented T waves, broad QRS, flattened P-wave and a prolonged PR interval.
Hypocalcaemia may cause a prolonged QT interval
Management of TLS?
Correct electrolyte abnormality
Sever hyperkalaemia; calcium gluconate followed by insulin- dextrose infusion
Parenteral replacement of hypocalcaemia
IV fluids
Dialysis
Rasburicase; urate oxidase enzyme
Prevention;
Low/intermediate risk patients can be managed with a combination of adequate hydration and allopurinol.
Rasburicase (a recombinant form of the urate oxidase enzyme) can be used as a prophylactic agent in adults with hyperuricaemia that is inadequately managed by allopurinol or febuxostat.
What is von willebrand disease?
Inherited bleeding disorder characterised by reduced quantity or function of vWF
Epidemiology of VWD?
Most common inherited bleeding disorder
Affects 1% of population
Equally common in men and women but women are more likely to experience symptoms
Aetiology of VWD?
Genetic mutation resulting in deficiency or dysfunction of VWF
Classification of VWD?
Type 1 VWD: Partial quantitative deficiency in VWF
Type 2 VWD: Qualitative defects in VWF (e.g. decreased adhesion to platelets or factor VIII)
Type 3 VWD: Almost complete deficiency of VWF
Signs and symptoms of VWD?
Excess or prolonged bleeding from minor wounds
Excess or prolonged bleeding post-operatively
Easy bruising
Menorrhagia
Epistaxis
GI bleeding
Differentials for VWD?
Haemophilia
Inherited bleeding disorders
Investigations for VWD?
Clotting tests reveal normal PT, TT and prolonged APTT
Normal platelet count
vWF level and activity assay
Management of VWD?
Medication/ blood transfusion to replace VWF; desmopressin
