Miscellaneous Flashcards
What is polycythaemia vera?
Myeloproliferative disorder
Caused by clonal proliferation of haematopoietic progenitor cells
What is primary polycythaemia?
Due to mutation - inherited or acquired
Main cause is polycythaemia vera
What is secondary polycythaemia?
Due to increased EPO production
Hypoxia induced rise:
smoking, CLD, COPD, obesity, OSA
Inappropriate EPO rise
Renal cell cancer, Wilm’s
Adrenal tumours
Illicit EPO use
Androgen use, testosterone replacement
What is relative polycythaemia?
Increase in haematocrit or Hb count in presence of normal red cell mass
Decrease in plasma volume
Dehydration e.g. diarrhoea, vomiting, diuretics use
What is the pathogenesis of polycythaemia vera?
98% patients have JAK2 mutation - tyrosine kinase
V617F mutation, mutations in exon 12
Mutations result in proliferation of haematopoeitic precursors
What are the clinical features of polycythaemia vera?
Some asymptomatic with raised Hb/haematocrit incidentally on blood tests
If presenting symptomatic - may have gradual creeping onset, non-specific due to increased blood viscosity
Headache, visual disturbance
Tinnitus, itching, fatigue
Vertigo, paraesthesia
Bruising, excoriation, conjunctival infection, splenomegaly, erythromelalgia
What are the investigations for polycythaemia vera?
FBC raised Hb or haematocrit
Raised serum EPO suggestive of secondary polycythaemia
Raised WCC and platelet count suggestive of PV
Serum ferritin, serum uric acid
Genetic testing for JAK2 V617F in exon 14 or mutations in exon 12
Bone marrow biopsy to distinguish PV from secondary polycythaemia
USS to identify splenomegaly, identify renal or hepatic tumours;
CT, MRI, PET-CT
When can a diagnosis of polycythaemia vera be made following investigations?
- High haematocrit (> 0.52 in men, > 0.48 in women) OR raised red cell mass (>25% above predicted)
- Mutation in JAK2
What is masked polycythaemia vera?
Haemoglobin and haemtocrit count normal despite presence of disease
Typically occurs in setting of iron deficiency where effect of JAK2 mutation blunted
What is the management of polycythaemia vera?
Reduce complications, symptoms and reduce risk of transformation to myelofibrosis or acute leukaemia
Maintain haematocrit at <0.45
Venesection - 200-500mls at a time
Low dose aspirin, 75mg once daily to reduce thrombotic events
Cytoreduction therapy in high risk patients -
hydroxycarbamide (antimetabolite)
or interferon-alpha, ruxolitinib and busulfan
Who can be considered for cytoreductive therapy?
Age >65 years and/pr
Prior PV associated arterial or venous thrombosis
Also considered in low risk with Thrombocytosis Progressive splenomegaly Progressive leucocytosis Poor tolerance of venesection
What is Budd Chiari syndrome?
Hepatic vein thrombosis
Lead to tender hepatomegaly, ascites, and sudden severe abdominal pain
What complication can arise from Polycythaemia Vera?
AML transformation
What is primary myelofibrosis?
Proliferation of haematopoietic stem cells in the marrow and at other sites leading to fibrosis
Marrow is replaced with scar tissue
At what age is primary myelofibrosis most prevalent?
60yo
What signs and symptoms are commonly seen in primary myelofibrosis?
Typically elderly present with anaemia
B Symptoms
Massive splenomegaly
\+/- Spontaneous bleeding DCIS Oesophageal varices Petechiae
What investigation findings would you expect with myelofibrosis?
Anaemia
WCC and platelets high in early disease then low
Bone marrow aspiration = dry tap
So need to do trephine biopsy
“Tear drop” poikilocytes (RBC’s) on blood film
Poikilocytosis - varying sizes of red blood cells
and immature red and white cell blasts
High urate and LDH
Homozygous JAK2 or MPL mutation
How is primary myelofibrosis managed?
Allogenic stem cell transplant is the only cure
What is the palliative/symptomatic management for primary myelofibrosis?
Red cell transfusion/EPO for anaemia
hydroxyurea or splenectomy - splenomegaly
prednisolone - cytopenic
What are the complications of primary myelofibrosis?
progress to blast phase - like AML
portal hypertension
splenic infarct
immune deficiency
What is essential thrombocythaemia?
Failure in platelet production regulation
Malignant megakaryocyte proliferation
At what age do people get essential thrombocythaemia?
60yo
What are the common signs and symptoms of essential thrombocythaemia?
Burning sensation in hands
Mixed thrombosis and bleeding in any system:
Dusky extremities
TIA and amaurosis fugax
Arterial and Venous thrombosis (leg, MI, hepatic, renal)
Bleeding - GI, gums, eyes, urinary
Sweating/Fever
Hepato/splenomegaly
Why can you see bleeding in essential thrombocythaemia?
clotting factors run out
How do you diagnose essential thrombocythaemia?
Diagnosis of exclusion
What is found in investigations of essential thrombocythaemia?
Platelet count >600
High WCC, RBC but low Hb
thrombocytes on blood spear
hypercellular bone marrow with giant megakaryocytes and increased reticulin
Impaired platelet aggregation
Philadelphia chromosome absent
Heterozygous JAK2 or MPL mutation
What factors puts a patient with essential thrombocythaemia at high risk?
> 60yo
History of thrombosis
Very high platelet count
How do you manage Essential Thrombocythaemia patients?
Aspirin
Hydroxyurea
Interferon-alpha
Why is hydroxyurea used in essential thrombocythaemia?
anti-metabolite –> reduce platelets
What are the main complications of essential thrombocythaemia?
Thrombosis
Haemorrhage
AML transformation
What is encompassed in a VTE?
Pulmonary embolism (PE): acute/chronic occlusion of pulmonary arteries. Clot breaks off and travels to the lungs (emboli).
Deep vein thrombosis (DVT): acute/chronic occlusion of deep vein(s). Commonly affects the lower limbs through the formation of a clot forms (thrombus).
Where can a DVT be located?
Distal - below popliteal trifurcation, can resolve spontaneously without symptoms
Proximal - above popliteal, may affect popliteal, femoral or iliac veins
50% develop PE within 3 months
Other - name according to vessel or location of thrombus
What can cause a DVT?
Provoked - transient or persistent risk factors, typically within three months of event
Unprovoked - no identifiable risk factor, not easily correctable
What are some of the risk factors for VTE?
Intrinsic factors Hx of DVT Cancer Obesity Acquired or inherited thrombophilia Inflammatory disorders Varicose veins Smoking Male sex Older age >60 years
Transient factors Hospitalisation Recent major surgery Recent major trauma Significant immobility Hormone therapy e.g. COCP or HRT Long distance flights Dehydration Acute infection Pregnancy + 6 weeks PP
What is Virchow’s triad?
Pathophysiology of DVT based on this
Venous stasis
Hypercoaguable state
Endothelial injury
What are the clinical features of DVT?
Classically with painful, unilateral leg swelling
Warm to touch, surrounding erythema
Calf asymmetry - diameter >3cm increases likelihood
Venous distention
Oedema
Tenderness along deep veins
What are some examples of thrombophilias?
Antiphospholipid syndrome (this is the one to remember for your exams) Antithrombin deficiency Protein C or S deficiency Factor V Leiden Hyperhomocysteinaemia Prothombin gene variant Activated protein C resistance
What VTE prophylaxis is given when admitted to hospital?
If at increased risk
LMWH e.g. enoxaparin unless contraindicated (active bleeding or existing anticoagulation with warfarin or NOAC)
Antiembolic stockings (unless significant peripheral arterial disease)
What is the Well’s score and its meaning?
10 criteria, score 0-9
Score >2 - DVT likely, proximal leg vein US within 4 hours or d-dimer, interim anticoagulant, US in 24 hrs
Score <1 - DVT 5%
D-dimer
If positive, proceed to leg vein US testing
What is the d-dimer test?
D-dimer is fibrin degradation product
Created when blood clots broken down by fibrinolytic system
What should be done if d-dimer positive but scan negative?
Interim anticoagulation should be stopped
Patient offered repeat proximal leg vein ultrasound in 6-8 days
Looks for possible extension of a distal DVT into the proximal veins that require treatment
What anticoagulation is given in DVT?
LMWH
DOACs
Vit K antagonists e.g. warfarin
If stable, no renal impairment or co-morbidities - apixiban, rivaroxaban
Active cancer DOAC e.g. edoxaban
Renal impairment LMWH
If starting warfarin, must have two consecutive INR readings >2 before stopping LMWH (bridging therapy)
What long term management is required for DVT?
Minimum of 3 months
3-6 months for active cancer
Exploration of cause if unprovoked DVT
Thrombophilia testing
Cancer
What is a classical complication of DVT?
Most concerning is PE
Post thrombotic syndrome - chronic swelling, pain, skin changes from venous stasis
What cell lineages are affected in myeloproliferative diseases?
Myelofibrosis - haematopoietic stem cell
Polycythaemia vera - erythroid cells
Megakaryocyte - essential thrombocytopenia
What is myelofibrosis and its pathophysiology?
Can be result of primary myelofibrosis, PV or ET.
Proliferation of cell line causes fibrosis of bone marrow, replaced by scar tissue - because cytokines released from proliferating cells e.g. fibroblast growth factor.
Means haematopoiesis starts to occur elsewhere - liver and spleen
Hepatomegaly, splenomegaly, portal hypertension
If occurs round the spine can cause spinal cord compression
What is the presentation of myeloproliferative disorders?
Can be asymptomatic
Fatigue, weight loss, night sweats, fever
Anaemia, splenomegaly, abdo pain, portal hypertension - ascites, varices, abdo pain
Low platelets
Thrombosis
What are three key signs on examination in polycythaemia vera?
Conjunctival plethora - excessive redness to the conjunctiva in the eyes
A ‘ruddy’ complexion
Splenomegaly
What is myelodysplastic syndrome?
Caused by myeloid bone marrow cells not maturing properly
Not producing healthy blood cells
Causes anaemia, neutropenia, thrombocytopenia
Who is myelodysplastic syndrome more common in?
Those over 60
Patients who have previously had treatment with chemo or radiotherapy
What is the management of myelodysplastic syndrome?
Watchful waiting
Supportive treatment e.g. blood transfusions if severely anaemia
Chemotherapy
Stem cell transplant
Risk of transforming into acute myeloid leukaemia
What are differentials of abnormal or prolonged bleeding?
Thrombocytopenia (low platelets)
Haemophilia A and haemophilia B
Von Willebrand Disease
Disseminated intravascular coagulation (usually secondary to sepsis)
What is the management for ITP?
Prednisolone (steroids)
IV immunoglobulins
Rituximab (a monoclonal antibody against B cells)
Splenectomy
What is HIT?
Heparin induced thrombocytopenia
Development of antibodies against platelets in response to exposure to heparin
Target protein on the platelets called platelet factor 4
Binds to platelets, activates clotting mechanisms
Causes hypercoaguable state
Leads to thrombosis
Breaks down platelets, causes thrombocytopenia
What are the functions of the spleen?
Production and maturation of T, B and Plasma cells
Removal of unwanted bacteria - encapsulated
Reservoir for blood cells
How does splenomegaly present?
LUQ mass
Early satiety
Abdominal discomfort
Pancytopaenia
What is noted on examination of a splenic mass?
Heads towards RLQ
Moves on respitation
Dull to percuss
Can’t palpate above
What causes MASSIVE splenomegaly?
CML Myelofibrosis Malaria Gaucher's syndrome (hereditory) Visceral Leischmaniasis (parasite)
What FBC results would you see with hyperspenism and why?
Pancytopaenia due to pooling and destruction of cells
Where are blood cells destroyed in the spleen?
Reticulo-endothelial system
How does hypersplenism present?
Anaemia
Infection
Bleeding
What are the causes of splenomegaly?
Haematological: malignancies, haemolytic anaemia, sickle cell sequestration crisis
Infectious: Hep, TB, malaria, EBV
Congestive: HF, splenic vein obstruction, liver cirrhosis, Budd-Chiari
Abscess or cyst
Autoimmune/inflammatory: SLE, RA, sarcoid
What are the indications for splenectomy?
Spontaneous rupture
Hypersplenism
Malignant Infiltration
Idiopathic thrombocytopaenic purpura
What are the complications of splenectomy?
How could you prevent the consequences of one of these complications?
thrombocytosis –> peak within 7-10 days. Give prophylactic aspirin
infection with encapsulated bacteria
Give examples of encapsulated bacteria
Haemophilus Influenzae
Neisseria Meningitidis
Streptococcus Pneumoniae
Salmonella Typhi
If a patient has raised Hb but low circulating volume, what is this indicative of?
Relative polycythaemia i.e. concentrated
lower plasma volume caused by burns, dehydration, fluid loss –> apparent Hb rise
You find a raised Hb and then note that circulating volume, WCC and platelets are all high, what does this indicate?
primary polycythaemia - usually polycythaemia vera
Hb and circulating volume high
WCC and platelets low
What does this indicate?
secondary polycythaemia
Hypoxia = EPO release (COPD, local renal hypoxia, sleep apnoea, altitude)
EPO production increased (Cushings, cerebellar haemangioma)
Exogenous intake (often athletes)
What diseases can cause increased EPO production?
hydronephrosis Polycystic kidneys/liver Renal/Hepatic carcinoma Cushings Cerebella haemangioma
What are signs of primary causes of raised platelets?
symptoms
+
hepatosplenomegaly
What can cause a raised platelet count?
Reactive: infection, surgery Iron deficiency anaemia Myeloproliferative disorder Other malignancy Hyposplenism
What can cause a low platelet count (thrombocytopenia)?
Marrow damage: malignancy, virus, alcohol
Increased clearance: DIC, TTP, ITP, HELLP
Splenomegaly eg malaria, liver cirrhosis
Dilutional following red cell transfusion
What can cause neutropenia?
Drugs: clozapine, carbimazole Virus: HIV, EBV Marrow failure: malignancy Reduced B12 or folate Immune diseases: RA, SLE Benign ethnic neutropenia
What can cause neutrophilia?
reactive: infection, inflammation (IBD, RA)
malignancy: myeloproliferative, CML
Hypo/asplenism
Hypoxia
Drugs: lithium, steroids
What can cause lymphadenopathy
Malignancy
Infection
Granulomatous diseases: TB, sarcoid
Collagen vascular diseases: SLE, RA, sjogrens
where is a bone marrow sample often taken from?
Posterior superior iliac crest
What is the difference between a bone marrow aspiration and a trephine?
aspiration is liquid portion of the marrow
trephine take a solid piece
What is advanced care planning and what is an advanced decision to refuse treatment?
Care planning: not legally binding but sets out the persons wishes on any aspect of future care
ADRT: legally binding if valid and applicable. It states which treatments under which circumstances a person does not wish to have
What is lead time bias?
Cancer picked up early so although screening appears to prolong life, life is not prolonged just time with cancer is longer
What is length time bias?
Screening picks up slow growing cancers that the person may never have noticed or been harmed by. Screening appears to prolong life of those found +ve whereas actually it may never have harmed them
In what cancers can Cushing’s syndrome be seen
SCLC
NSCLC
Pancreatic cancer
What causes Cushing’s syndrome?
Excess production of ACTH precursors
How does Cushing’s syndrome present?
Rapid onset weakness
Hyperpigmentation
Metabolic disturbance
How is Cushing’s syndrome treated?
Depend on cancer
Bilateral adrenalectomy OR
Metyrapone
What cancers can cause hypercalcaemia?
NSCLC
Head and neck cancers
Renal tumours
What cancers cause peripheral neuropathy?
SCLC Myeloma Hodgkins Breast GI
How do cancers cause peripheral neuropathy?
Autoimmune axonal degeneration/demyelination
What are key investigations for investigating metastatic disease of unknown primary?
FBC, U&Es, LFT, calcium, urinalysis, LDH
Chest-xray
CT chest abdomen pelvis
AFP and hCG
Myeloma screen if lytic bone lesions Endoscopy directed towards symptoms PSA in men CA 125 in women with peritoneal malignancy or ascites Testicular US in germ cell tumours Mammography
What cancers if AFP associated with?
Liver cancer, germ cell tumours e.g. testicular cancer
What is B2M associated with?
Myeloma
CLL
Lymphoma
What is bHCG associated with?
Choriocarcinoma
Germ cell tumours
What is CA15-3 and CA27.29 associated with?
Breast cancer
What is CA19-9 associated with?
Pancreas, gallbladder, bile duct, gastric cancers
What is CA125 associated with?
Ovarian cancer
What cancer is calcitonin associated with?
Medullary thyroid cancer
What is CEA associated with?
Carcinoembryonic antigen
Associated with colorectal cancer
What is CgA associated with?
Neuroendocrine tumours
Chromogranin A
What is fibrin/fibrinogen in the urine associated with?
Bladder cancer
What is LDH associated with?
Melanoma, leukaemia, lymphoma
What is PSA associated with?
Prostate cancer
