Blood - Level 3 Flashcards
Pathology of DIC?
o Widespread activation of coagulation pathways
From release of procoagulants, formation of intravascular thrombi (fibrin)
Depletion of platelets and coagulation factors
• Then increased risk of bleeding
Causes of DIC?
o Malignancy – leukaemia o Sepsis o Trauma o Obstetric events – placental abruption, eclampsia, HELLP o Incompatible blood transfusion o Transplant rejection o Pancreatitis
Signs of DIC?
o Bruising
o Bleeding from at least 3 unrelated sites
o Renal failure – oliguria
o Hypotension
o ARDS
o In chronic/subacute – thrombotic events may dominate - VTE
Bloods in DIC?
o FBC – low platelets
o Clotting – raised PT and APTT, low fibrinogen
o Raised D-dimer
Blood films in DIC?
o Broken RBCs (fragments, paucity of platelets, schistocytes)
What is DIC scoring system?
o Measures platelets, D-dimer, PT, fibrinogen
5 or more – overt DIC – repeat daily
<5 – non-overt DIC – repeat net 1-2 days
Management of DIC - if low risk of bleeding?
o Treat cause
Management of DIC - if high risk of bleeding?
o Treat underlying cause
o Replace platelets
o FFP
2nd line - Cryoprecipitate to replace fibrinogen
o Activated Protein C – severe sepsis and multi-organ failure
Management of DIC - if dominant thrombotic signs?
o Unfractionated Heparin may be used – controversial
Complications of DIC?
o Haemorrhage
o Acute renal failure
o Gangrene and loss of digits
Definition of sickle cell disease?
- Inherited (autosomal recessive) blood disorder in which red blood cells develop abnormally
PAthology of sickle cell disease?
o Mutation in 17th nucleotide of Beta-globin gene changed from thymine to adenine and glutamic acid replaced by valine at position 6 in beta globin chain
o Abnormal beta-globin chain that causes it to polymerize when deoxygenated, which distorts the erythrocyte into a sickle shape
o Deformed erythrocytes form clusters which block blood vessels – damage large and small vessels, sequestered in liver and spleen and cause anaemia, intense pain and infections
What is sickle cell disease and sickle cell trait?
- Sickle cell disease
o Inherit HbS haemoglobin and gene for abnormal haemoglobin variant from other parent (homozygous HbSS, HbSC) - Sickle cell trait
o Inherit HbS haemoglobin and normal HbA haemoglobin (HbAS)
Epidemiology of sickle cell disease?
- Most common haemoglobinopathies
- 1 in every 2000 live births in England, and it is now the most common genetic condition at birth
- Highest prevalence of sickle cell disease is among Black African and Black Caribbean people
- Mortality rate 3% in childhood
Inheritance of sickle cell disease?
- Genetic, autosomal recessive – can be carrier or homogenous
Symptoms of sickle cell disease?
Moderate anaemia, pallor, lethargy, growth restriction with jaundice
Acute crises symptoms of sickle cell disease?
Increased susceptibility to encapsulated organisms (pneumococci, haemophilus influenzae, OSTEOMYELITIS due to Salmonella )
Acute painful Crisis
- Precipitated by cold, dehydration, excessive exercise/stress, hypoxia or infection
- Pain affecting many organs
- Dactylitis with swelling in hands/feet
- Commonest in limbs and spine
Acute chest syndrome
o Severe hypoxia, need ventilation and transfusion
Avascular necrosis
Acute anaemic crises
Priapism
Acute renal impairment
Acute stroke, hemiparesis, speech problems, seizures
Splenomegaly
Investigations in sickle cell disease?
Blood Tests o FBC, reticulocyte count - Blood film o Sickling of red cells
Hb electrophoresis (HPLC)= definitive test
Baseline tests
- U&E, LFT, lung function tests
When to admit acute crisis in sickle cell disease?
- Admission if clinical features of sickle cell crisis and raised temperature
Management of acute crisis in sickle cell disease?
Analgesia within 30 minutes of presentation and monitor
Bolus morphine if severe pain
• Weak opioid if moderate pain
Offer laxative, anti-emetic and antipruritic
Regular paracetamol and NSAIDs in addition
Monitor BP, HR, O2, RR, temperature regularly
Management of acute chest syndrome in sickle cell disease?
o Oxygen
o CPAP
o IV antibiotics
Management of priapism in acute crisis of sickle cell disease?
o Hydration
o Analgesia
o Aspiration and irrigation of corpora cavernosa with adrenaline if prolonged
Management at home if person well with mild pain and no increased temperature - what management measures?
o Avoid other triggers such as cold weather and excessive physical activity.
o Use distraction techniques, such as games, computers, and television
o Increase fluid intake (150% IV or oral)
o Prescribe paracetamol and/or ibuprofen (avoid ibuprofen if the person has renal impairment or significant proteinuria). Add codeine phosphate if these are not effective
o Urgent assessment in hospital if not controlled by these measures
When to screen for sickle cell disease?
- All newborn infant – Guthrie test
- Pregnant women -in high prevalence areas and low prevalence areas if high risk in Family Origins Questionnaire (FOQ)
- High-risk groups undergoing anaesthesia
- Women investigated for infertility
What vaccine to offer children with sickle cell disease?
Up to date with all immunisations
Pneumococcal vaccine at 2 and then every 5 years
Annual influenza vaccine
HepB vaccine at 12, 13 and 18 months
Men ACWY if travelling to high risk area
What vaccine to offer adults with sickle cell disease?
PPV every5 years
HepB on 0, 1 and 6 month schedule
Men ACWY if travelling to high risk area
When to offer antibiotics and folic acid in sickle cell disease?
- Antibiotics
o By 3 months of age:
Phenoxymethylpenicillin (erythromycin) - Oral folic acid to all 400mcg OD (5mg if pregnant/conceiving)
Chronic management of pain in sickle cell disease?
o Determine cause
o Refer to orthopaedic surgeon if persistent for MRI
o Regular medium/long-acting opiates and PRN for breakthrough
o NSAIDs
o CBT
Other chronic management in sickle cell disease?
- Smoking Cessation
- Yearly ophthalmology review and paediatric review
o If pulmonary hypertension – annual Echo - Managing minor priaprism:
o Empty bladder before sleep, jogging, warm baths, analgesia
o If >3 hours – hospital admission - Nocturnal Enuresis
o General advice
Ensure easy access to toilet, empty bladder just before sleep, reward system
o Oral/Nasal desmopressin for short-term
Advice to give people with sickle cell traits?
- Very rarely have symptoms
- Avoid high altitudes, such as travelling in an unpressurized aircraft
- Inform anaesthetist of sickle cell carriers
Secondary care management in sickle cell disease?
- Hydroxycarbamide in patients with severe disease
- Blood transfusion
Follow up in sickle cell disease?
Every 3 months for 1st 2 years then every 6 months til 5 then annually
Complications of sickle cell disease?
- Chronic pain
- Chronic anaemia
- Cognitive impairment
- Epilepsy
- Short stature and delayed puberty
- Adenotonsillar hypertrophy
- Cardiac enlargement and heart failure
- Renal dysfunction
- Pigment Gallstones
- In pregnancy:
o Miscarriage, premature labour, pre-eclampsia, stillbirth, IUGR, death
Prognosis of sickle cell disease?
- Depends on degree of sickle cell disease
o 90% of people survive past 20 - Stem cell transplant only potentially curative treatment
o Given if <17 with sickle brain disease which does nto response to hydroxycarbamide or severe sickle cell disease complications which does not respond to hydroxycarbamide
Description of haemophilia A & B?
- X-linked recessive blood disorder
- Haemophilia A = Factor VIII deficiency (most common)
- Haemophilia B = Factor IX deficiency
- Usually carrier females and affected males
Inheritance of haemophilia A & B?
- Most common inherited coagulation disorder
o Haemophilia A – 1 in 5000 live male births
o Haemophilia B - 1 in 30000 live male births - Males affected more common
Symptoms of haemophilia A & B?
- Most present towards end of first year of life
- Can present in neonatal period with intracranial haemorrhage, bleeding post-circumcision, oozing heel prick
Grading of haemophilia A & B?
o Severe: Spontaneous joint/muscle bleeds, arthropathy/arthritis, haematomas
o Moderate: Bleed after minor trauma
o Mild: Bleed after surgery
Investigations of haemophilia A & B?
- FBC
- Blood film
- Clotting tests
What clotting tests performed in haemophilia A & B?
Prothrombin Time (PT) Tests extrinsic system and expressed as INR, for abnormalities in Factors 1, 2, 5, 7, 10 Prolonged by warfarin, vitK deficiency, liver disease, DIC
Activated Partial Thromboplastin Time (APTT)
Tests intrinsic system, for abnormalities in Factor 1, 2, 5, 8, 9, 10, 11, 12
Prolonged by heparin, haemophilia, DIC and liver disease
Thrombin Time
Prolonged by heparin, DIC, dysfibrinogenaemia
D-Dimers
Fibrin degradation product, released during fibrinolysis
Occurs in DIC, DVT/PE but also malignancy and infection
Other tests to perform in haemophilia A&B?
- Factor 8 & 9 assays
o Diagnose by increased APTT and decreased FVIII/IX assay
Criteria for severity in haemophilia A&B?
o Mild – Factor levels of >0.05 but <0.40 IU/mL
o Moderate – Factor 0.01-0.05 IU/mL
o Severe – Factor <0.01 IU/mL
Management of Haemophilia A&B - prophylaxis, minor bleeds, major bleeds?
- Prophylaxis
o Infusions of Factor VIII/IX to prevent bleeding - Minor bleeds
o Pressure and elevation
o Desmopressin raises Factor VIII - Major bleeds
o Resuscitation
o Discuss need FFP and platelets with haematologist
o Recombinant Factor VIII/IX concentrate IVI
Home treatment can be taught
To 50% of normal (life-threatening bleeds need levels of 100%) - Avoid IM injections, NSAIDs and aspirin
- MDT approach , specialised physio to strengthen muscles and limit damage, psychosocial support and self-help groups
Complications of haemophilia?
- Inhibitors (antibodies to Factor VIII/IX)
o Reduce or inhibit effect of treatment - Transfusion transmitted infections
Physiology of haemoglobin?
- Most haemoglobin have two α chains and two other identical types
- HbA, the most common form of adult haemoglobin, has two α and two β chains
- Fetal haemoglobin (HbF) has two α and two γ components
Description of thalassaemia?
- Autosomal recessive condition characterised by decreased or absence of synthesis of one of the two polypeptide chains (α or β)
Types of thalassaemia?
o α-thalassaemia: reduced rate of α-chain synthesis.
Two alpha-genes on c16
o β-thalassaemia: reduced rate of β-chain synthesis
Due to lack of β-chain synthesis there is ↑ γ-chain synthesis beyond neonatal period ⇒ to more HbF and more HbA2 due to ↑ α-chain synthesis
Disease severity determined by levels of residual HbA and HbF
One B-globin gene on c11
Effects of thalassaemia?
- This precipitates in the RBC membrane bringing cell death within the bone marrow (ineffective erythropoiesis) and premature removal of red cells by spleen
Epidemiology of thalassaemia?
- β-thalassaemia
o Most common in Mediterranean and Middle east - A-thalassaemia
o South-east Asian origin
Types of B-thalassaemia?
o β-thalassaemia major
Most severe, HbA (α2β2) cannot be produced
o β-thalassaemia intermedia
Milder, mutation allows small amount of HbA and large amount of HbF to be produced
o β-thalassaemia trait
Heterozygotes usually asymptomatic, anaemia mild and red cells hypochromic and microcytic
Normal ferritin which distinguishes from iron deficiency anaemia
Types of A-thalassaemia?
o A-thalassaemia major (Barts hydrops fetalis)
Caused by deletion of all 4 A-globin chains so no HbA
Presents in mid-trimester with fetal hydrops (oedema and ascites) which is usually fatal
Need monthly transfusion intrauterine and after birth, usually fatal after birth
o A-thalassaemia HbH disease
Only 3 a-globin chains genes deleted
Mild-moderate anaemia but may need transfusions regularly
o A-thalassaemia trait
Deletion of 1 or 2 a-globin chains
Usually asymptomatic or mild anaemia – red cells microcytic, hypochromic
Symptoms of B-thalassaemia?
o Severe anaemia (hypochromic, microcytic cells) (transfusion dependent from 3-6 months), jaundice
o Failure to thrive
o Hepatosplenomegaly, bone marrow expansion, maxillary overgrowth
o Osteopenia, frontal bossing, skull x-ray shows ‘hair on end’ sign
Symptoms of A-thalassaemia?
o Major needs often transfusions and fatal in utero
o HbH
Moderate anaemia and features of haemolysis
Hepatosplenomegaly, leg ulcers, jaundice
o Alpha-thalassaemia trait
Mild anaemia and low RBC
Investigations in thalassaemia?
o FBC (microcytic, hypochromic anaemia), MCV (reduced) o Blood film o Iron (raised) o Hb electrophoresis - HbA2, HbF o Prenatal diagnosis offered
Imaging in thalassaemia?
o Skull XR – hair on end appearance, maxillary overgrowth, frontal bossing
o MRI used to monitor complications
Screening of thalassaemia?
o Pre-conceptual testing for haemoglobinopathies in at-risk groups
Family origin questionnaire
Management of thalassaemia?
o Promote fitness and healthy diet, folate supplements
o Regular blood transfusions to keep Hb >90
o Iron chelators (SC desferrioxamine/desferasirox)
o Splenectomy if hypersplenism persists and preferably >5 years old
o Bone marrow transplant only cure (reserved for HLA identical siblings)
Management during pregnancy in thalassaemia?
o Discontinue iron chelators 3 months before conception
o Folic Acid 5mg
o Serial biometry scans every 4 weeks from 24w-gestation
Complications of thalassaemia?
- Regular blood transfusions causes iron overload
o Cardiac failure, liver cirrhosis, diabetes, infertility
o Need iron chelators - Hypogonadism
- DM
- Hypothyroidism
- Hypoparathyroidism
Description of thrombophilia?
- Inherited or acquired coagulopathy predisposing to thrombosis, usually venous (DVT/PE)
What is the most common thrombophilia?
- Factor 5 Leiden most common heritable thrombophilia in Caucasians
Inherited causes of thrombophilia?
Activated Protein C(APC) resistance/Factor V Leiden
• Associated with single point mutation in Factor V, so clotting factor not broken down by activated protein C
• Risk of DVT/Pe 5x more in heterozygous &; 50x in homozygous
Prothrombin gene mutation
• Causes high prothrombin levels and increased thrombosis due to down-regulated fibrinolysis by thrombin-activated fibrinolysis inhibitor
Protein C & S deficiency
• These Vitamin-K dependent factors act to cleave and neutralise Factors 5 & 8
Antithrombin Deficiency
• Co-factor of heparin and inhibits thrombin
Acquired causes of thrombophilia?
3rd gen progesterones
Antiphospholipid syndrome
• Serum antiphospholipids found (lupus anticoagulant + anticardiolipin antibody)
Polycythaemia
Risk factors for thrombosis?
o Arterial
Smoking, hypertension, hyperlipidaemia, DM
o Venous
Surgery, trauma, immobility, pregnancy, OCP, age, obesity, varicose veins, HF, malignancy, IBD, nephrotic syndrome, PNH
Symptoms and signs of thrombophilia?
- Strong FHx of VTE
- Spontaneous VTE
- VTE at young age
- Unusual site of VTE
- Recurrent VTE
- Recurrent miscarriage
Indications for thrombophilia screening?
<40 with spontaneous VTE
Patient <60 with Hx of VTE and FHx of VTE/thrombophilia
Patients <60 with unusual site VTE (sagittal sinus, axillary, mesenteric, subclavian)
Hx of recurrent miscarriage
Skin necrosis following warfarin
Arterial thrombosis (TIA, MI, CVA) <40
When to offer thrombophilia testing after VTE?
- For antiphospholipid antibodies if unprovoked DVT/PE planned to stop anticoagulation
- For hereditary thrombophilia if unprovoked DVT/PE and 1st degree relative with DVT/PR if planned to stop anticoagulation
Thrombophilia screening tests include?
FBC, film, clotting screen
Activated protein C resistance
• If APC positive – Factor V leiden mutation and prothrombin
Protein C, S
Antithrombin
Lupus anticoagulant – antocardiolipin antibodies
When to test thrombophilia screening tests?
Well, not pregnant and not anticoagulated for 1 month
Management in thrombophilia? What to give in APS in pregnancy?
- Treat acute VTE as per DVT/PE management
- If recurrent spontaneous VTEs - Lifelong warfarin with target 2-3
- Minimise risk - Stop smoking, low BP, adequate hydration, lower cholesterol
- Avoid oestrogen-containing OCP
- In pregnancy – aspiring 75mg for antiphospholipid syndrome
Definition of thrombocytopenia?
- Decreased numbers of platelets in blood
- Reduces ability to clot and higher bleeding
- Defined = <150x109/L
Causes of thrombocytopenia?
o Decreased platelet production:
Wiskott-Aldrich syndrome, Down’s syndrome, Fanconi’s anaemia
Viral – EBV, HIV, Malaria, TB, CMV, VZV
Aplastic anaemia
Drugs – heparin, digoxin, quinine, anti-epileptics, antipsychotics
Alcohol
Malignancy – metastases, leukaemia, lymphoma, myeloma
B12/Folate deficiency
o Decreased platelet survival:
ITP/TTP/SLE/HUS/DIC
Heparin-induced
o Dilutional thrombocytopenia:
Large volume transfusion
Symptoms and signs of thrombocytopenia?
- Spontaneous cutaneous purpura
- Mucousal bleeding
- Nose bleeds
- Menorrhagia
- Post-partum haemorrhage
Investigations of thrombocytopenia?
- Blood o FBC and blood film, B12 and folate Repeat FBC with blood film if platelet low o Clotting o U&E o LFT o If virus – viral serology
Management of thrombocytopenia in primary care?
o Repeat with blood film
o If <20x109:
Urgent same day assessment
o If <50x109:
Urgent outpatient referral
o If 50-100x109:
Refer if persists >4-6 weeks and unexplained
o If 100-150x109:
Repeat monthly & refer if progressive
When to give platelet transfusion in thrombocytopenia?
o Clinically significant bleeding and platelet count <30x109/L
o Higher platelet threshold if severe bleeding or critical sites (CNS, eyes)
o Prophylactic before surgery if <50x109/L
Causes of thrombocytopenia in pregnancy?
o Causes: gestational, ITP, TTP, pre-eclampsia, HELLP, others in causes
Definition of idiopathic thrombocytopenic purpura?
- Most common acquired childhood bleeding disorder
- Caused by destruction of circulating platelets by anti-platelet IgG autoantibodies
- Reduced platelets associated with compensatory increase in megakaryocytes
Epidemiology of idiopathic thrombocytopenic purpura?
- Incidence 4 per 100,000 children per year
- Often presents between 2-10 years old
Risk factors of idiopathic thrombocytopenic purpura?
- May follow CMV, EBV, parvovirus, VZV or vaccination
Symptoms and signs of idiopathic thrombocytopenic purpura?
- Onset after 1-2 weeks of viral infection
- Develop petechial, purpuric rash and bruising
- Can cause epistaxis or mucosal bleeding but usually not significant in ITP
- Intracranial bleeding occurs in 0.1-0.5%
Investigations of idiopathic thrombocytopenic purpura?
- Blood film o Isolated thrombocytopenia - Blood tests o FBC, U&E, LFTs - Bone marrow examination needed: o Unusual signs (lymphadenopathy, abnormal cells on blood film) o Platelet count not rising - CT if headache or CNS signs
Management of idiopathic thrombocytopenic purpura?
- Gradual resolution over 3 months for 80%
- Chronic form compatible with normal life but avoid contact sports
- Oral prednisolone, IV anti-D or immunoglobulin but only if needed!
- Admit if:
o Unusual features (bleeding excessively)
o Life threatening bleeding requires platelet transfusion
o Romiplostim, Eltrombopag & Rituximab reduces need for splenectomy
o Splenectomy for chronic ITP
Physiology of cell development?
- Bone marrow is responsible for haemopoiesis – usually in central skeleton (vertebrae, sternum, ribs, skull) and proximal long bones
- Pluripotent Stem Cells develop depending on growth factors applied to them:
o 1st differentiate into lymphoid or myeloid stem cells
Lymphoid stem cells – develop into B, T or NK lymphocytes
Myeloid stem cells -develop into erythrocytes, platelets, basophils, monocytes/macrophages, eosinophils and polymorphonuclear leukocytes
Survival times of RBCs, platelets, neutrophils?
o Red cells – 120 days
o Platelets – 8 days
o Neutrophils - 1-2 days
Definition of pancytopenia?
o Reduction in all major cell lines – red cells, white cells and platelets
Inherited causes of pancytopenia?
Fanconi’s anaemia
Diamond-Blackfan anaemia
Acquired causes of pancytopenia - reduced bone marrow production?
- Aplastic anaemia
- Infiltration (acute leukaemia, myelodysplasia, myeloma, lymphoma, solid tumours, TB)
- Chemotherapy
- Ionising radiation
- Megaloblastic anaemia
- Paroxysmal nocturnal haemoglobinuria
- Myelofibrosis
- SLE
- Virus – CMV, EBV, HIV
Acquired causes of pancytopenia - increased peripheral destruction?
- Hypersplenism
- Liver disease
- Drugs - Steroids, NSAIDs, allopurinol, anti-thyroid medications, chloramphenicol, gold
Symptoms and signs of pancytopenia?
- Anaemia
o Tiredness, weakness, pallor, SOB, tachycardia - Neutropenia
o Recurrent or severe infections - Thrombocytopenia
o If <50x109/L – traumatic bleeds, purpura and easy bruising occur
o If <20x109/L – spontaneous bleeding occurs
Initial testing in pancytopenia?
FBC Normocytic, normochromic anaemia Low platelets Neutropenia Blood Film
Further testing in pancytopenia?
o Other bloods: U&Es LFTs CRP B12 and folate Viral Serology Autoimmune profile o Bone Marrow Biopsy Diagnostic information and staging test in lymphoproliferative disorders Take aspirate and trephine from posterior iliac crest • Cytogenics and immunophenotyping
Imaging in pancytopenia?
o Abdominal US
o MRI
o PET scans
Definitive treatment in pancytopenia?
o Bone marrow transplant
Transfusions in pancytopenia - red cell transfusion?
1U raises Hb by 10-15g/L
Transfusion may drop the platelet count so may need to give platelets before/after
Transfusions in pancytopenia - platelets?
Platelets stored at room temperature and must be ABO compatible
If marrow transplant or immunosuppressed then need irradiation to prevent GVHD
Indications for platelets:
• Platelets <10x109/L
• Haemorrhage (DIC)
• Before invasive procedures (biopsy, LP) to increase platelets to >50x109/L
• 4U of platelets raises platelets by 40x109/L
Transfusions in pancytopenia - neutropenia?
Use neutropenic regimen if <0.5x109/L
Definition of neutropenia?
- Definition of <1.5x109/L o Mild 1.5-1 o Moderate 1-0.5 o Severe <0.5 - Neutrophils circulate and defend against bacterial infections
Causes of neutropenia?
o Severe congenital neutropenia and cyclic neutropenia
o Viral infections – HIV, hepatitis, RSV, measles, parvovirus, EBV, CMV
o Bacterial infections – sepsis, typhoid, brucellosis, malaria, leishmania
o Drugs – post-chemo, cytotoxic agents, carbimazole, sulphonamides
o SLE, haemolytic anaemias
o Hypersplenism
o Bone marrow failure
Symptoms of neutropenia?
- Fever, malaise, infection or mouth sores
Bloods done in neutropenia?
o FBC o U&E o LFT o CRP o Blood film
What is MASCC score in neutropenia?
- MASCC score (used to detect risk of septic complications) o 21 and over = low risk o <21 = high risk Solid tumour or lymphoma with no previous fungal infection = 4 Outpatient status at onset of fever = 3 Age <60 = 2 Burden of illness • Mild = 5 • Moderate = 3 • Severe = 0 No hypotension (>90) = 5 No COPD = 4 No dehydration = 3
Neutropenic regimen?
o Full barrier nursing, side room and hand washing
o Avoid IM injections
o Look for infection and take swabs
o Check – FBC, platelets, INR, U&E, LFT, LDH, CRP and cultures, CXR if indicated
o Wash perineum after defaecation, swab moist skin with chlorhexidine
o Oral hygiene and Candida prophylaxis
o TPR 4-hourly, high-calorie diet
MAnagement in severe neutropenia?
- Stop drug immediately (clozapine, antithyroid drugs (thionamides) and sulfasalazine
- Antibiotic prophylaxis
- Recombinant G-CSF (Filgrastim/Lenograstim)
o Promote stem cell proliferation and shorten period of neutropenia
o Only if very severe, not routinely prescribed
Definition of neutropenic sepsis?
- Patients having cancer treatment with neutrophil count <0.5x109/L with either:
o Temperature >38O
o Signs and symptoms of significant sepsis - Typically occurs between 7-14 days post chemotherapy
Epidemiology of neutropenic sepsis?
- Increasing incidence as cancer increases in incidence
- 60-70% fever during neutropenia treated as “fever of unknown origin”
Risk factors of neutropenic sepsis?
o Inpatient chemo regimens
o Prior chemo and immunosuppression
o Abnormal LFTs
o Reduced eGFR
Pathogens in neutropenic sepsis?
o Bacteria Gram positive organisms (70%) • S.Aureus • Coagulase-negative staphylococcus • Alpha and Beta haemolytic streptococcus Gram negative organisms (30%) • E.coli • Klebsiella pneumoniae • Pseudomonas aeruginosa
o Fungi
Candida, Aspergillus, PCP
Signs of neutropenic sepsis?
- Signs of sepsis in neutropenic patients:
o Temperature >38o
o HR > 90
o RR > 20
o New-onset confusion or drowsiness.
o WBC counts greater than 12 x 109/L or less than 4.0 x 109/L
o Blood glucose greater than 7.7 mmol/L (in a non-diabetic person)
o Septic Shock
Hypoperfusion, hypotension
o Bacteremia
History consistent with neutropenic sepsis?
o Chemo drugs & timing, line & access
o Previous episodes
o Localising symptoms – SOURCE?
o Allergies
Investigations of neutropenic sepsis?
o Refer anyone that feels unwell and is neutropenic/anticancer treatment
o BUFALO SEPSIS 6 WITHIN 1 HOUR Bloods • FBC, LFT, U&E, CRP, lactate • Blood culture (x2 (Aerobes, anaerobes), Line & 2 peripheral sets if no line) Urine analysis and culture Fluids Abx Oxygen
o Other Swabs Sputum culture Stool analysis and culture CXR, if respiratory symptoms
Management of neutropenic sepsis?
- Broad spectrum IV antibiotics (as per local guidelines, Tazocin)
o Given within 1 hour of admission to hospital in suspected cases - Assess Risk of Septic Complications
o MASCC index
Low risk (21 and over) – outpatient antibiotics – switch from IV to oral after 48 hours
High risk (<21) – daily review of patient and reassessment of MASCC
o Modified Alexander Rule for children - G-CSF (Filgrastim/Lenograstim)
o Promote stem cell proliferation and shorten period of neutropenia
o Only if very severe, not routinely prescribed
Malignant indications for bone marrow replacement?
o AML o CML o ALL o HL o NHL o Neuroblastoma o Ewing sarcoma o Multiple myeloma o Myelodysplastic syndromes o Gliomas
Non-malignant indications for bone marrow replacement?
o Thalassaemia o Sickle cell anaemia o Aplastic anaemia o Fanconi anaemia o Mucopolysaccharidosis
Types of bone marrow replacement?
o Autologous (patient’s own stem cells) Extraction from patient and storage of harvested cells in freezer o Allogenic (HLA-matched siblings or matched unrelated donor)
Sites of bone marrow replacement?
o Bone Marrow – remove through large bone (pelvis) under GA/LA
o Peripheral blood stem cells – apheresis, SC of G-CSF
o Amniotic fluid
o Umbilical cord blood
Physiology in cancer of bone marrow replacement?
o Destroy cancer cells and immune system by cyclophosphamide + total body irradiation before transplantation
o Repopulation of marrow
Complications of bone marrow replacement?
o Graft-versus-host disease – new marrow attacking patient’s body
Ciclosporin and methotrexate used
o Opportunistic infections
o Relapse
Definition of leukaemia?
- Cancer of the white blood cells
- Arises from malignant proliferation of myeloid, lymphoid, pre-B or T-cell lymphoid precursors
Types of leukaemia?
o Acute lymphoblastic leukaemia (ALL),
o Chronic lymphocytic leukaemia (CLL)
o Acute myeloid leukaemia (AML)
o Chronic myeloid leukaemia (CML)
Acute characterised by rapid increase in number of immature blood cells
Chronic characterised by build-up of relatively mature but still abnormal white blood cells
Lymphoblastic/cytic are of lymphocytes, mainly B-cells
Myeloid are marrow cells that go on to form red blood cells, platelets
Epidemiology of leukaemias?
- 25% of all malignancies
- ALL accounts for 80% of childhood leukaemias
- Incidence highest in white children
- ALL peak – 2-4 years
- AML peak - around 60
- CLL peak – around 50-70
- CML peak - around 50
Aetiology of leukaemia?
o Unknown mostly o Genetic components Down’s syndrome increased risk Philadelphia chromosome occurs in 15-30% - t(9:22) and is associated with poor prognosis (CML) o Environmental Factors Prenatal exposure to x-rays In utero infection
Types of acute lymphoblastic leukaemia?
o B-cell ALL Early pre-B ALL – 10% Common ALL – 50% Pre-B ALL – 10% Mature B-cell ALL (Burkitt’s leukaemia) – 5%
o T-cell ALL
Pre-T ALL – 5-10%
Mature T-cell ALL 15%
Associations of chronic lymphocytic leukaemia?
o Associated with del17p13 mutation
Associations of acute myeloid leukaemia?
MDS – aplastic anaemia, myelofibrosis, PNH, PCV
Down’s syndrome
Chemotherapy
Types of acute myeloid leukaemia?
AML with recurrent genetic abnormalities AML multilineage dysplasia AML therapy related AML other Acute leukaemia of ambiguous lineage
Associations in chronic myeloid leukaemia?
o 90% result from Philadelphia chromosome
Symptoms of leukaemia?
- Duration usually 2-4 weeks
- Symptoms
o Pancytopenia (pallor, infection, bleeding)
o Fatigue
o Anorexia
o Prolonged or recurrent fever
o Bone Pain
o Headaches, nausea & vomiting
o Failure to thrive
Signs of leukaemia?
o Painless lumps in neck, axilla, groin – lymphadenopathy
o Anaemia - pallor
o Neutropenia – severe infection
o Thrombocytopenia – petechiae, purpura, bruising
o Hepatosplenomegaly
o Orchidomegaly
When to refer in primary care for leukaemias?
o Immediate specialist assessment for children with unexplained petechiae or hepatosplenomegaly
o FBC within 48 hours if:
Pallor
Persistent fatigue
Unexplained fever, recurrent infections, bruising, bleeding, petechiae
Generalised lymphadenopathy
Hepatosplenomegaly
Investigations in leukaemias?
- Bloods
o FBC (increased WCC, normochromic normocytic anaemia, low platelets)
o Increased urate and LDH - Blood film
o Blast cells
o Auer rods – AML diagnostic - Bone Marrow biopsy
o Nucleated cells will be blasts - Chest X-ray
- Cytogenic analysis
- Risk Classification
o Low, standard, high risk groups
o Depends on clinical signs, biologic features of lymphoblasts and response to induction chemotherapy
General management of acute lymphoblastic leukaemia?
Blood/Platelet transfusion
IV fluids
Allopurinol (prevent tumour lysis syndrome)
Chemotherapy management of acute lymphoblastic leukaemia?
Induction Phase
• 3-drug induction over 4 weeks
• Intrathecal vincristine + prednisolone + daunorubicin + pegaspargase
• Remission in >95%
Consolidation Phase
• Further chemotherapy over weeks
• Cranial irradiation if CNS signs
Maintenance Phase
• For 2.5 years daily mercaptopurine, weekly methotrexate + vincristine & prednisolone monthly
CNS prophylaxis
• Cranial irradiation + intrathecal methotrexate
Stem cells transplant
Prognosis of acute lymphoblastic leukaemia?
Cure rates 70-90%
Poorer prognosis – Adult, male, Philadelphia chromosome
Definition of remission in ALL?
o Remission = no evidence of leukaemia in blood and normal/recovering blood count and <5% blast cells
Management of chronic lymphocytic leukaemia?
o Fludarabine + cyclophosphamide + rituximab 1st line
o Venetoclax given
o Radiotherapy helps lymphadenopathy and splenomegaly
General management of acute myeloid leukaemia?
Blood/Platelet transfusion
IV fluids
Allopurinol (prevent tumour lysis syndrome)
Definitive management of acute myeloid leukaemia?
o Chemotherapy
Daunorubicin + cytarabine
o Bone Marrow Transplant
PSC extracted from BM or allogenic from HLA-matched siblings or unrelated donors
Indicated during 1st remission in disease with poor prognosis
Ciclosporin + methotrexate
Prognosis of acute myeloid leukaemia?
Lower relapse rates of ~60% but mortality of 10%
Management of chronic myeloid leukaemia?
o Tyrosine Kinase inhibitor
1st line - Imatinib/dasatinib/nilotinib
2nd line – bosutinib, ponatinib and other 1st lines
o Stem cell transplantation
Complications of leukaemias?
- Neutropenic Sepsis
- Hyperuricaemia
- Poor growth
- Cancer elsewhere
- Relapses
Description of thrombotic thrombocytopenic purpura?
Thrombotic microangiopathy presenting with: - Microangiopathic haemolysis - Thrombocytopenia - Neurological abnormalities - Fever - Renal dysfunction MEDICAL EMERGENCY
Causes of thrombotic thrombocytopenic purpura?
Deficiency of vWF cleaving protein, also known as ADAMTS1.
Investigations of thrombotic thrombocytopenic purpura?
Blood film - schistocytes
U&E - raised creatinine
LDH raised
Clotting raised
Management of thrombotic thrombocytopenic purpura?
IV plasma exchange within 4-8 hours
FFP used until exchange possible
Steroids and rituximab used with IV plasma exchange
