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Blood - Level 3 Flashcards

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1
Q

Pathology of DIC?

A

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

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2
Q

Causes of DIC?

A 
o	Malignancy – leukaemia
o	Sepsis
o	Trauma
o	Obstetric events – placental abruption, eclampsia, HELLP
o	Incompatible blood transfusion
o	Transplant rejection
o	Pancreatitis
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3
Q

Signs of DIC?

A

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

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4
Q

Bloods in DIC?

A

o FBC – low platelets
o Clotting – raised PT and APTT, low fibrinogen
o Raised D-dimer

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5
Q

Blood films in DIC?

A

o Broken RBCs (fragments, paucity of platelets, schistocytes)

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6
Q

What is DIC scoring system?

A

o Measures platelets, D-dimer, PT, fibrinogen
 5 or more – overt DIC – repeat daily
 <5 – non-overt DIC – repeat net 1-2 days

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7
Q

Management of DIC - if low risk of bleeding?

A

o Treat cause

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8
Q

Management of DIC - if high risk of bleeding?

A

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

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9
Q

Management of DIC - if dominant thrombotic signs?

A

o Unfractionated Heparin may be used – controversial

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10
Q

Complications of DIC?

A

o Haemorrhage
o Acute renal failure
o Gangrene and loss of digits

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11
Q

Definition of sickle cell disease?

A
  • Inherited (autosomal recessive) blood disorder in which red blood cells develop abnormally
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12
Q

PAthology of sickle cell disease?

A

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

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13
Q

What is sickle cell disease and sickle cell trait?

A
  • 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)
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14
Q

Epidemiology of sickle cell disease?

A
  • 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
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15
Q

Inheritance of sickle cell disease?

A
  • Genetic, autosomal recessive – can be carrier or homogenous
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16
Q

Symptoms of sickle cell disease?

A

Moderate anaemia, pallor, lethargy, growth restriction with jaundice

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17
Q

Acute crises symptoms of sickle cell disease?

A

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

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18
Q

Investigations in sickle cell disease?

A 
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

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19
Q

When to admit acute crisis in sickle cell disease?

A
  • Admission if clinical features of sickle cell crisis and raised temperature
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20
Q

Management of acute crisis in sickle cell disease?

A

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

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21
Q

Management of acute chest syndrome in sickle cell disease?

A

o Oxygen
o CPAP
o IV antibiotics

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22
Q

Management of priapism in acute crisis of sickle cell disease?

A

o Hydration
o Analgesia
o Aspiration and irrigation of corpora cavernosa with adrenaline if prolonged

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23
Q

Management at home if person well with mild pain and no increased temperature - what management measures?

A

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

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24
Q

When to screen for sickle cell disease?

A
  • 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
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25
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
26
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
27
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)
28
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
29
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
30
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
31
Secondary care management in sickle cell disease?
- Hydroxycarbamide in patients with severe disease | - Blood transfusion
32
Follow up in sickle cell disease?
Every 3 months for 1st 2 years then every 6 months til 5 then annually
33
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
34
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
35
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
36
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
37
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
38
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
39
Investigations of haemophilia A & B?
- FBC - Blood film - Clotting tests
40
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
41
Other tests to perform in haemophilia A&B?
- Factor 8 & 9 assays | o Diagnose by increased APTT and decreased FVIII/IX assay
42
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
43
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
44
Complications of haemophilia?
- Inhibitors (antibodies to Factor VIII/IX) o Reduce or inhibit effect of treatment - Transfusion transmitted infections
45
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
46
Description of thalassaemia?
- Autosomal recessive condition characterised by decreased or absence of synthesis of one of the two polypeptide chains (α or β)
47
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
48
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
49
Epidemiology of thalassaemia?
- β-thalassaemia o Most common in Mediterranean and Middle east - A-thalassaemia o South-east Asian origin
50
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
51
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
52
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
53
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
54
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 ```
55
Imaging in thalassaemia?
o Skull XR – hair on end appearance, maxillary overgrowth, frontal bossing o MRI used to monitor complications
56
Screening of thalassaemia?
o Pre-conceptual testing for haemoglobinopathies in at-risk groups  Family origin questionnaire
57
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)
58
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
59
Complications of thalassaemia?
- Regular blood transfusions causes iron overload o Cardiac failure, liver cirrhosis, diabetes, infertility o Need iron chelators - Hypogonadism - DM - Hypothyroidism - Hypoparathyroidism
60
Description of thrombophilia?
- Inherited or acquired coagulopathy predisposing to thrombosis, usually venous (DVT/PE)
61
What is the most common thrombophilia?
- Factor 5 Leiden most common heritable thrombophilia in Caucasians
62
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
63
Acquired causes of thrombophilia?
3rd gen progesterones Antiphospholipid syndrome • Serum antiphospholipids found (lupus anticoagulant + anticardiolipin antibody) Polycythaemia
64
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
65
Symptoms and signs of thrombophilia?
- Strong FHx of VTE - Spontaneous VTE - VTE at young age - Unusual site of VTE - Recurrent VTE - Recurrent miscarriage
66
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
67
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
68
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
69
When to test thrombophilia screening tests?
 Well, not pregnant and not anticoagulated for 1 month
70
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
71
Definition of thrombocytopenia?
- Decreased numbers of platelets in blood - Reduces ability to clot and higher bleeding - Defined = <150x109/L
72
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
73
Symptoms and signs of thrombocytopenia?
- Spontaneous cutaneous purpura - Mucousal bleeding - Nose bleeds - Menorrhagia - Post-partum haemorrhage
74
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 ```
75
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
76
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
77
Causes of thrombocytopenia in pregnancy?
o Causes: gestational, ITP, TTP, pre-eclampsia, HELLP, others in causes
78
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
79
Epidemiology of idiopathic thrombocytopenic purpura?
- Incidence 4 per 100,000 children per year | - Often presents between 2-10 years old
80
Risk factors of idiopathic thrombocytopenic purpura?
- May follow CMV, EBV, parvovirus, VZV or vaccination
81
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%
82
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 ```
83
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
84
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
85
Survival times of RBCs, platelets, neutrophils?
o Red cells – 120 days o Platelets – 8 days o Neutrophils - 1-2 days
86
Definition of pancytopenia?
o Reduction in all major cell lines – red cells, white cells and platelets
87
Inherited causes of pancytopenia?
 Fanconi’s anaemia |  Diamond-Blackfan anaemia
88
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
89
Acquired causes of pancytopenia - increased peripheral destruction?
* Hypersplenism * Liver disease * Drugs - Steroids, NSAIDs, allopurinol, anti-thyroid medications, chloramphenicol, gold
90
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
91
Initial testing in pancytopenia?
``` FBC  Normocytic, normochromic anaemia  Low platelets  Neutropenia Blood Film ```
92
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 ```
93
Imaging in pancytopenia?
o Abdominal US o MRI o PET scans
94
Definitive treatment in pancytopenia?
o Bone marrow transplant
95
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
96
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
97
Transfusions in pancytopenia - neutropenia?
 Use neutropenic regimen if <0.5x109/L
98
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 ```
99
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
100
Symptoms of neutropenia?
- Fever, malaise, infection or mouth sores
101
Bloods done in neutropenia?
``` o FBC o U&E o LFT o CRP o Blood film ```
102
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 ```
103
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
104
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
105
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
106
Epidemiology of neutropenic sepsis?
- Increasing incidence as cancer increases in incidence | - 60-70% fever during neutropenia treated as “fever of unknown origin”
107
Risk factors of neutropenic sepsis?
o Inpatient chemo regimens o Prior chemo and immunosuppression o Abnormal LFTs o Reduced eGFR
108
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
109
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
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History consistent with neutropenic sepsis?
o Chemo drugs & timing, line & access o Previous episodes o Localising symptoms – SOURCE? o Allergies
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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 ```
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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
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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 ```
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Non-malignant indications for bone marrow replacement?
``` o Thalassaemia o Sickle cell anaemia o Aplastic anaemia o Fanconi anaemia o Mucopolysaccharidosis ```
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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) ```
116
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
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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
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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
119
Definition of leukaemia?
- Cancer of the white blood cells | - Arises from malignant proliferation of myeloid, lymphoid, pre-B or T-cell lymphoid precursors
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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
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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
122
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 ```
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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%
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Associations of chronic lymphocytic leukaemia?
o Associated with del17p13 mutation
125
Associations of acute myeloid leukaemia?
 MDS – aplastic anaemia, myelofibrosis, PNH, PCV  Down’s syndrome  Chemotherapy
126
Types of acute myeloid leukaemia?
```  AML with recurrent genetic abnormalities  AML multilineage dysplasia  AML therapy related  AML other  Acute leukaemia of ambiguous lineage ```
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Associations in chronic myeloid leukaemia?
o 90% result from Philadelphia chromosome
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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
129
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
130
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
131
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
132
General management of acute lymphoblastic leukaemia?
 Blood/Platelet transfusion  IV fluids  Allopurinol (prevent tumour lysis syndrome)
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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
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Prognosis of acute lymphoblastic leukaemia?
 Cure rates 70-90% |  Poorer prognosis – Adult, male, Philadelphia chromosome
135
Definition of remission in ALL?
o Remission = no evidence of leukaemia in blood and normal/recovering blood count and <5% blast cells
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Management of chronic lymphocytic leukaemia?
o Fludarabine + cyclophosphamide + rituximab 1st line o Venetoclax given o Radiotherapy helps lymphadenopathy and splenomegaly
137
General management of acute myeloid leukaemia?
 Blood/Platelet transfusion  IV fluids  Allopurinol (prevent tumour lysis syndrome)
138
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
139
Prognosis of acute myeloid leukaemia?
 Lower relapse rates of ~60% but mortality of 10%
140
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
141
Complications of leukaemias?
- Neutropenic Sepsis - Hyperuricaemia - Poor growth - Cancer elsewhere - Relapses
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Description of thrombotic thrombocytopenic purpura?
``` Thrombotic microangiopathy presenting with: - Microangiopathic haemolysis - Thrombocytopenia - Neurological abnormalities - Fever - Renal dysfunction MEDICAL EMERGENCY ```
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Causes of thrombotic thrombocytopenic purpura?
Deficiency of vWF cleaving protein, also known as ADAMTS1.
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Investigations of thrombotic thrombocytopenic purpura?
Blood film - schistocytes U&E - raised creatinine LDH raised Clotting raised
145
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
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