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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_958_Библиотеки_им_академика_М_И_Перельмана
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Autosomal recessive disorders of alpha- or beta-globin production causing HbA
https://t.me/med1917
Chapter 5: Haematology 65
Prognosis (major):
Beta-thalassaemia
→ β-thalassaemia major: both genes abnormal = no HbA = very severe
anaemia
→ β-thalassaemia minor: 1 gene abnormal = almost normal Hb with marked
low MCV (60s)
• Severe anaemia from 3 to 6m old (when HbF runs out) → transfusion
• Jaundice & pallor
• Hepatosplenomegaly if untreated
• Characteristic facies (frontal bossing) if untreated
• Lifelong monthly blood transfusions
• Iron chelation (prevent Fe overload of heart & liver from transfusions)
• BM transplant = only cure
Alpha-thalassaemia
→ Deletion of all 4 α-globin genes: α-thalassaemia major/ Hb Barts hydrops
fetalis = death in utero
→ Deletion of 3 α-globin genes: HbH disease = mild/moderate anaemia
(some HbA) → may need transfusions
→ Deletion of 1–2 α-globin genes: α-thalassaemia trait = asymptomatic
(some HbA) → marked low MCV
90% live >40y if Tx-compliant
Risk factors for beta-thalassaemia:
Indian, Mediterranean, Middle-Eastern ethnicity
Complications of long-term transfusion:
1. Fe deposition
• Heart = cardiomyopathy
• Liver = cirrhosis
• Pancreas = diabetes
• Skin = hyperpigmentation
2. Antibody formation (in 10%)
3. Venous access problems – may need CVL
Risk factors for alpha-thalassaemia:
South-East Asian ethnicity
1. FBC & iron studies – microcytic, hypochromic anaemia
2. Blood film: ‘target cells’ or nucleated RBCs
3. Hb HPLC – proportions of HbA, HbF, HbA
Fig. 5.3 Blood film features of thalassaemia:
• target cells
• pale hypochromic cells
2
Diagnosis is confirmed with genetic testing
HbA HbA
β-thalassaemia major X
β-thalassaemia minor
2
HbF HbS
α-thalassaemia Normal
Sickle cell disease X
Sickle cell trait
HbA2 = normal variant of Hb with levels higher than normal in thalassaemias
Prenatal diagnosis (CVS):
• offered if one/both parents affected
• 2 affected parents = 1 in 4 chance of each
X
child being affected
X
Medicine
66 Chapter 5: Haematology
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Risk factors for SCD:
Black, Afro-Caribbean ethnicity
= common genetic disorder in children → 1 in 2000 → autosomal recessive
Cause
Mutation in β-globin gene which produces an abnormal HbS chain
rather than HbA.
If low O2, infection or acidosis, it polymerises and bends RBC into a sickle shape.
PROGNOSIS: most severe form = 50% die by
40y from complications
Long-term problems:
• Shor t stature / delayed puberty
• Stroke & neuro damage
• Heart failure & renal dysfunction
• Pigment gallstones
Fig. 5.4 Sickle cells & target cells.
Pathogenesis
Sickle-shaped RBCs have lifespan → get stuck & occlude vessels, causing
infarction
Type Hb Symptomatic?
Sickle cell anaemia (HbSS) Homozygous for abnormal HbS Yes (no HbA)
HbSC disease (HbSC) 1 HbS gene + 1 abnormal HbC Yes (less severe than SCA)
Sickle β-thalassaemia (HbSA) 1 HbS + β-thalassaemia trait Yes
Sickle cell trait (HbSA) 1 HbS gene + 1 normal HbA
No (some HbA → carrier)
Clinical presentation
• Moderate anaemia: (60–100g/L)
• Jaundice (clinically detectable)
• Infection ( susceptibility especially pneumococcus & H. influenzae)
• Splenomegaly – due to acute sequestration (children only)
• Painful vaso-occlusive crises:
▶ hands & feet – dactylitis &
swelling
▶ bones of limbs – avascular
necrosis of femoral head
• Acute anaemia (aplastic crisis):
▶ sudden Hb ± abdo pain ± hepatosplenomegaly
→ Triggers: infection, accumulation of sickle cells in spleen, parvovirus
due to hyposplenism from
chronic infarction
▶ lungs – acute chest syndrome
= EMERGENCY (Tx: CPAP +
exchange transfusion)
▶ penis – priapism
Diagnosis
asymptomatic for 6–8w after birth
due to persistent HbF
Triggers of vaso-occlusive crises: cold,
infection, dehydration, hypoxia/altitude, drugs
Management of vaso-occlusive crises7:
1. ABCDE – IV fluids, O2 only if sats <93%
2. Analgesia*: IV/SC morphine and
paracetamol/ibuprofen (co-prescribe
laxatives & anti-emetics)
3. FBC, reticulocytes, infection screen
4. Cross-match & transfusion
5. Enoxaparin
*Most patients have a “pain plan”
Medicine
1. Screening: pregnant women &
neonates (Guthrie heel-prick test)
2. FBC & iron studies = Hb, low MCV,
3. Blood film = sickle cells & target cells
4. LFTs & bilirubin = raised
5. Hb HPLC = HbS ± HbA
normal Fe
Management
1. Infection prophylaxis: vaccines
+ daily PO penicillin lifelong (for
hyposplenism)
2. Daily folate supplementation
(lifelong)
3. risk vaso-occlusive crises:
dress warmly, stay hydrated, avoid
excessive exercise/stress
4. Treat vaso-occlusive crises:
PO/IV analgesia (morphine +
5,6
5. Hydroxycarbamide to HbF:
if recurrent VO crises / acute chest
6. Blood transfusion: if acute
complication (stroke, sepsis, aplastic
crisis) & pre-operatively
7. BM transplant: only cure (for very
severe cases)
8. New treatments: crizanlizumab →
antibody binds P-selectin and stops
RBCs sticking to endothelium
ABX/O2 if needed)
5
British Society of Haematology (2018) Guidelines for the use of hydroxycarbamide in children and
adults with sickle cell disease
6
British Society of Haematology (2016) Guidelines for transfusion in sickle cell disease part I & II
7
NICE (2012) Sickle cell disease: managing acute painful episodes in hospital [CG143]
Combination of anaemia, leukopenia & thrombocytopenia
https://t.me/med1917
Aetiology
1. Reduced blood cell production (bone marrow failure)
2. Increased blood cell destruction (immune-mediated)
3. Increased blood cell sequestration (in big spleen/liver)
Dierentials
More common Less common
• Acute leukaemia
• Multiple myeloma
• Hypersplenism – cirrhosis, PVT,
Felty’s syndrome
• Chemotherapy/radiotherapy
• B12/folate deficiency
• Some non-Hodgkin lymphoma
• Myelodysplasia
• Myelofibrosis
• Aplastic anaemia
• Haemophagocytic lymphohistiocytosis (HLH)
• Drug-induced
• Autoimmune (SLE, RA)
• Paroxysmal nocturnal haemoglobinuria
• Parvovirus in haemolytic anaemias
• Transfusion-related GVHD
• Hairy cell leukaemia
• Non-haematological malignancy (infiltrating
bone marrow)
• Infection: HIV, hepatitis, CMV
Chapter 5: Haematology 67
Investigations
1. Thorough history – PMHx, FHx, symptoms (bleeding, fatigue, recurrent
infections, weight loss)
2. Physical examination – petechiae/purpura, lymphadenopathy,
abdominal mass
3. Blood tests – FBC, retics, haemolysis screen, LFTs, clotting screen, B12, folate,
HIV antibodies, serum electrophoresis
4. Bone marrow aspirate & biopsy
5. Imaging – CT or PET if lymphoma
Management
Immediate: RBC + platelet transfusion ± antibiotics
Further management: determine and treat underlying cause
requires urgent haematology referral
Medicine
68 Chapter 5: Haematology
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Complications:
• Thrombosis
• Bleeding
• Evolution (to AML or 2° myelofibrosis)
Bone marrow disorders with differentiated myeloid cell subtype expansion
in blood (e.g. Hb, platelets or white cells). Known as myeloproliferative
NEOPLASMS (MPNs)
Investigations
• Blood tests (FBC, LFTs)
• Bone marrow biopsy for CML and primary myelofibrosis (PMF)
• Genetic tests
→ must rule out BCR–ABL fusion gene (suggesting CML), before diagnosing
any other MPN
Types
Disorder Cell type affected /
increased
Polycythaemia
rubra vera
Essential
thrombocythaemia
Chronic myeloid
leukaemia
Primary
myelofibrosis
• RBCs high
• Plts normal or
• Platelets high
• Rest normal
• WBCs very high
(basophilia)
• Plts usually high
• Anaemia
• Scar tissue
(prevents cell production)
Symptoms Treatment Prognosis
• Headaches
• Fatigue
• Blurred vision
• Pruritus
• HTN
• Sx due to blood clots
• Abdominal pain
• Mottled skin
• Stroke
• Burning hands/feet
(erythromelalgia)
• Infection
• Fatigue
• Bruises/bleeds
• Bone pain
• Abdominal pain (splenomegaly)
• Night sweats
• Weight loss
• Fatigue
• Shortness of breath
• Bruises/bleeds
• Abdominal pain (splenomegaly)
• Bone pain
• Night sweats
• Weight loss
• Gout
Reduce clot risk:
Venesection + low dose aspirin (tablet
chemotherapy if platelets also high)
Reduce stroke risk:
Low dose aspirin (tablet chemotherapy
if >60y & platelets high)
Targeted therapy:
Tablets which target the BCR–ABL gene
→ effectively ‘cures’ most patients
Bone marrow transplant if targeted
Tx unsuccessful
1. Blood transfusions / EPO
2. Low dose aspirin if plts
3. Allopurinol for gout
4. JAK2 inhibitors if JAK2 mutation
5. Chemotherapy + stem cell
transplant if young
Normal life expectancy
Normal life expectancy
Mostly normal life
expectancy with
targeted therapy
Depends on degree of
low blood counts
Some may only live
months
Medicine
Malignant clonal proliferation of plasma cells (due to B cell mutations)
https://t.me/med1917
→excess secretion on one type of paraprotein / light chain (e.g. IgG, IgA).
Median age = 70y
Clinical presentation
Chapter 5: Haematology 69
C HyperCalcaemia
R Renal dysfunction
A Anaemia BM crowding suppresses erythropoiesis
B Bleeding BM crowding suppresses platelets
B Bone pain/lesions
I Infection
osteoclast activity → fluids + bisphosphonates
Deposition of light chain Ig → fluids + dexamethasone
osteoclast activity → bisphosphonates + surgery
Reduction in normal Igs → vaccinations, CSGF
Investigations
• FBC ( Hb, WCC, plts)
• ESR (raised)
• U&Es (deranged in 20%)
• Ca (raised)
• ALP (normal)
• Serum free light chains / paraprotein (IgG/IgA)
• Lytic lesions (‘pepper-pot’)
Green text denotes treatment options
Emergency presentations:
• Pathological vertebral fracture
• Bone pain
• Acute renal failure
• Spinal cord compression
• Hyperviscosity
• Hypercalcaemia
= lethargy, constipation, thirst, nausea, polyuria
• Lytic lesions
• >10% plasma cells = myeloma
• <10% plasma cells = MGUS
Management
Several lines of chemo + immuno-modulatory agents
+ bone protection with bisphosphonates
+ infection prophylaxis (vaccinations, antiviral)
+ radiotherapy for pain in isolated sites
→ Bone marrow transplant if fit (to prolong remission)
Medicine
70 Chapter 5: Haematology
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Age <1 or >10y
WBC >50 × 109/L
CNS involvement
Cytogenic abnormalities in tumour cells
Persisting blast cells after initial chemo
Acute lymphoblastic (ALL) Acute myeloid (AML)
Cancer of the white blood cells
Acute leukaemias
Pathogenesis Rapidly proliferating lymphocyte stem cells = accumulation of
immature lymphoblast cells (can be B-cell or T-cell)
Peak age 2–5y
(80% of childhood leukaemias)
Symptoms Rapid onset (1–2w)
May see mediastinal mass in T-cell ALL
• Anaemia: lethargy, pallor, SOB
• Neutropenia: sore throat, recurrent fevers, infections
• Thrombocytopenia: bruising, petechiae, nose bleeds
• End organ infiltration: lymphadenopathy, splenomegaly
• General: fatigue, malaise, anorexia, bone pain
WCC May be high (immature blast cells) or may have pancytopenia
Investigations
1. FBC: Hb, plts, neutrophils, or WCC
2. Peripheral blood film: blast cells (± Auer rods in AML)
3. Clotting screen: may have DIC
4. Bone marrow biopsy → diagnostic & prognostic (gene mutations)
5. CXR: mediastinal mass (characteristic of T-cell ALL)
Malignancy of myeloid stem cells = accumulation
of immature myeloblasts
>60y
Fig. 5.5 Blast cells.
Management
1. Pre-chemo: dexamethasone ( lymphoblasts)
2. Chemotherapy: induce* → intensify → maintain (2–3y
maintenance)
3. Concurrent treatment: intrathecal chemo (MTX)
Prognosis Children: 90% cure rate
Adults: 35–40% 5y survival
Medicine
1. Pre-chemo: hydroxyurea (lower WCC)
2. Intensive chemotherapy: 3–4 cycles
3. Risk stratification for further Tx
→ Further chemotherapy
→ Stem cell transplant
Depends on age, genetics and response
*Risk stratification:
• after induction to decide next step
• adults often need BM transplant
• children almost never need BM transplant
Chapter 5: Haematology 71
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Chronic leukaemias
Chronic lymphocytic (CLL) Chronic myeloid (CML)
Pathogenesis Accumulation of apoptosis-resistant B cells Increased production of myeloid progenitors
→ 95% have Philadelphia chromosome (9:22)
Peak age 70y M>F = 2:1
(most common adult leukaemia)
40–60y
Symptoms Often asymptomatic (usually incidental finding)
• Anaemia: lethargy, pallor, SOB
• Neutropenia: recurrent infections
• Thrombocytopenia: bruising, petechiae
→ no bone marrow failure
• General: tiredness/lethargy
• Massive splenomegaly (abdominal discomfort)
• B symptoms: malaise, night sweats, weight loss
WCC WCC normal to very high (mature lymphocytes) Very high WCC (neutrophils, eosinophils & basophils*)
*the only cause of significant basophilia
Investigations
1. FBC: Hb, plts, WCC, lymphocytes (if advanced
disease)
2. Peripheral blood film: smudge cells
3. Flow cytometry on blood to identify CLL cells
4. Bone marrow biopsy
1. FBC: plts, WCC, neutrophils, basophils
2. Peripheral blood film: mature myeloid cells
3. BM biopsy → diagnostic & prognostic
4. Cytogenetics: blood/BM (Philadelphia Chr)
5. Molecular assessment: mutation t(9,22) (BCR–ABL
→ to look for prognostic genetic markers
Management If no symptoms: watch & wait
1. Tyrosine kinase inhibitors (TKI): imatinib
→ Monitor response
1. Chemotherapy: more intensive if younger
→ Some develop resistance to TKIs & need BMT
2. Targeted therapy: BTK inhibitors, BCL2 inhibitors,
monoclonal antibodies
Prognosis 85% 5y survival
A few transform into aggressive lymphoma = very bad
prognosis
70% 5y survival
Without treatment transform into AML = very bad
prognosis
Medicine
72 Chapter 5: Haematology
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→ solid malignancies of immune system
→ due to lymphocyte proliferation in LNs, spleen, thymus, BM
→ about 70 different types
Hodgkin lymphoma (10%)
Reed–Sternberg cells
Aetiology Reed–Sternberg cells (mutated B cell)
→ More common in patients on immunosuppression or
Non-Hodgkin lymphoma (90%)
no Reed–Sternberg cells
with autoimmune disease
High grade: rapid & aggressive
→ curable but if relapse then poor prognosis
Low grade: slow growing
→ not generally curable but very good long-term
prognosis as many effective treatments
Peak age Bimodal: 15–35y and 60y 70y
Symptoms • Painless lymphadenopathy (usually cervical)
▶ may be mass effects (SVC/bronchi obstruction)
• Painless lymphadenopathy (cervical or abdo)
▶ often cause mass effects
• Abdo symptoms (mass/pain)
• B symptoms (in 40%)
• B symptoms (in 20%)
Investigations • FBC & blood film
• Lymph node biopsy/excision = diagnostic (Reed–Sternberg cells in HL)
• Bone marrow biopsy
Fig. 5.6
Reed–Sternberg cells.
• CT or FDG-PET – stage & grade
Management B-cell: immunochemotherapy ± radiotherapy
T-cell: depends on type → poorer prognosis
Immunochemotherapy (chemo + MAB) or just chemotherapy
• Low grade: follicular, marginal, mantle zone
▶ Watch & wait if asymptomatic
▶ OR multi-agent chemo + monoclonal Abs
▶ Radiotherapy if stage 1 disease
• High grade: Burkitt / diffuse large B-cell
▶ Multi-agent chemo + monoclonal Abs
▶ ± radiotherapy
New treatments: bispecific antibodies and CAR-T (GM modified T cells which target cancer)
Medicine
Primary haemostasis
https://t.me/med1917
Chapter 5: Haematology 73
1. Vasoconstriction – slows blood for plt adhesion
2. Platelet Adhesion then Activation then Aggregation
3. Haemostatic plug – platelets + fibrinogen = soft 1° plug
• Mucocutaneous bleeds: bruising, petechiae, epistaxis, menorrhagia,
gumbleeds
• Intra-op / immediate post- op bleeding
1. / impaired vWF (vWF disease) = platelets can’t bind endothelium
2. Impaired platelet function
• Congenital – Bernard–Soulier, Glanzmann’s
• Medications – antiplatelet drugs
• Other – uraemia, myeloproliferative disorders
3. Reduced platelet number: thrombocytopenia
(<150, but problems unlikely if >30, unless trauma or surgery)
Causes of thrombocytopenia
Increased destruction Non-immune:
• Sepsis, DIC, TTP
Immune:
• ITP
• Post-transfusion
• Drugs (NSAIDs, heparin, vancomycin, quinine)
Decreased production • Alcohol
• Cytotoxic drugs
• Leukaemia / aplastic anaemia / myelodysplasia
• BM malignancy
• Infections
Other • Congenital
• Hypersplenism
• Haemodilution
(3 As)
Mechanism of plug formation:
→ Vessel wall damage exposes vWF &
collagen
→ Platelet glycoproteins bind vWF &
collagen which activates platelets and allows
binding to fibrinogen
→ Soft haemostatic plug forms
Antiplatelet drugs:
1. Aspirin & NSAIDs:
= PGs & TXA = plt aggregation
2. Clopidogrel & ticagrelor:
= no platelet activation or binding
3. ABCIXIMAB/eptifibatide:
= inhibits plt binding & activation
1° or 2° prevention of atherothrombotic events
(e.g. MI in angina, stroke in AF)
2° prevention of cardiovascular event post
MI/stroke
bleeds)
= autoantibodies against platelets
Secondary haemostasis
→ After initial platelet aggregation, the platelet membrane ‘flips’ & provides
asurface for binding of coagulation factors
→ This stabilises the fibrinogen plug
→ Activation of clotting cascade: chain reaction resulting in cleaving
offibrinogen → fibrin
• Muscular/soft tissue bleeds: extensive bruising
• Haemarthrosis
• Delayed post-op bleeding & poor wound healing
Reduced coagulation factors:
• Congenital: haemophilia
• Acquired: anticoagulant drugs, dilution post-transfusion, liver dysfunction, DIC
Result: isolated thrombocytopenia with no
other clear cause
Presentation: acute, persistent (>3m) or
chronic (>12m) features of 1° dysfunction →
Treatment: steroids ± IVIg
(2nd line = rituximab, splenectomy,
immunosuppressants)
Vit K dependent clotting factors:
2, 7, 9, 10
Medicine
74 Chapter 5: Haematology
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Disseminated intravascular coagulation
Consumption of CFs & plts → if severe can cause organ dysfunction, infarction,
and bleeding
Infection, trauma/burns, malignancy, severe liver failure, obstetric complications,
ABO mismatch transfusion
Bruising, excessive bleeding, renal failure (AKI due to hypoperfusion)
• FBC = low plts
• Coag screen = PT & APTT
• d-dimers & fibrinogen
Haemophilia A: factor VIII deficiency
(1 in 5000)
Haemophilia B: factor IX deficiency
(1 in 30,000)
Severity based on amount of clotting factor:
Mild: >5%
Mod: 1–5%
Severe: <1%
• Aggressive resuscitation
• Treat cause
• Support with FFP/cryoprecipitate only if active bleeding
Haemophilia
Nearly always males
Mild: bleed after surgery
Moderate: bleed after minor trauma
Severe: spontaneous joint/muscle
bleeds (haemarthrosis)
• FBC, blood film, LFTs
• Coag screen: APTT & normal bleed time
• CF assays: low factor VIII or IX
• For any acute bleeds:
▶ Elevation, compression & tranexamic acid
▶ IV recombinant factor VIII/IX → given ASAP (parents taught how to
administer at home)
• For mild disease: desmopressin (DDAVP) = antidiuretic that causes secretion
of factor VIII & vWF into plasma
• For severe disease or before major surgery: regular prophylactic IV factor
(with intracranial haemorrhage / post
circumcision bleed)
Risk of hyponatraemia
Medicine
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