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2001 FRACP paper two


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Question 1 top Download PDF

A 60-year-old man is to undergo elective cholecystectomy. He has no significant medical history, and has no symptoms on specific enquiry. Physical examination is normal.
His ECG is shown below.

Which one of the following is most appropriate before proceeding to surgery?
A. Exercise stress test.
B. Dobutamine stress echocardiography.
C. Dipyridamole thallium scan.
D. Coronary angiography.
E. No further cardiac investigation.

Answer: E


RBBB increases with age, and in a large prospective study, there was no association with nor was it a risk factor for, heart disease.  It is likely part of the spectrum of normal ageing.

***Beware Brugada syndrome in the RBBB with incomplete or complete RBBB with ST elevation in leads V1 through V3.

These patients are at risk of VT (fast polymorphic).  Patients who have spontaneous syncope should probably have an ICD inserted


Cardiology: Interpreting ECG


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Question 6 top Download PDF

A 42-year-old woman presents with several weeks of lethargy and is found to be clinically anaemic and mildly icteric. There is no history or clinical evidence of overt blood loss. She has a normal varied diet and is on no medication.
Her full blood count shows:
haemoglobin                                                        67 g/L [120-155]
mean corpuscular volume (MCV)                    129 fL [80-95]
white cell count                                                   3.1 x 109/L [3.5-9.5]
neutrophils                                                           1.4 x 109/L [1.5-6.0]
lymphocytes                                                         0.9 x 109/L [0.7-3.2]
monocytes                                                            0.5 x 109/L [0.2-0.6]
eosinophils                                                           0.2 x 109/L [0-0.4]
basophils                                                              0.1 x 109/L [0.1-0.2]
platelet count                                                       98 x 109/L [130-330]
reticulocyte count                                               4 x 109/L [8-104]
The blood film is shown in the photograph below.


The most likely diagnosis is:
A. pernicious anaemia.
B. Evans’ syndrome (autoimmune haemolytic anaemia and thrombocytopenia).
C. aplastic anaemia.
D. hypothyroidism.
E. alcoholic liver disease.


  • Pancytopenia, with macrocytosis, anisocytosis and hypersegmented neutrophils
  • Classical film and FBC of B12/ Folate deficiency 
  • Pernicious anaemia à B12 deficicency

Evans’ Syndrome

  • Is excluded by normal reticulocyte count

Aplastic anaemia

  • Is characterised by pancytopenia plus absence of reticulocytes indicating bone marrow failure.
  • Red blood cells are usually normocytic but can be macrocytic
  • Cells on blood film are normal but reduced in number


  • Anaemia is usually normochromic, normocytic
  • 10% of those with autoimmune thyroiditis however will have pernicious anaemiaàB12 def
  • They present with macrocytic anaemia with marrow megaloblastosis
  • Otherwise hypothyroidism can cause macrocytosis in absence of anaemia and megaloblastosis
  • Uncommon

Alcoholic liver disease

    • Macrocytosis is usually <110
    • Doesn’t tend to affect other cell lines



    Haematology: Anaemia

    Question 7 top

    Question 8 top Download PDF

    Digoxin is most likely to have an adverse pharmacodynamic (as opposed to pharmacokinetic) interaction with which one of the following drugs?
    A. Gentamicin.
    B. Lithium.
    C. Diltiazem.
    D. Indomethacin.
    E. Amiodarone

    Answer: C
    Pharmacokinetics: “what the body does to the drug”
    • Relationship bw the time course of drug concentrations attained in different regions of the body during and after dosing
    • 4 major processes involved:
      1. Absorption
      2. Drug Distribution
      3. Drug Metabolism
      4. Excretion
    Pharmacodynamics: “what the drug does to the body”
    • Events resulting from the interaction of the drug with its receptor or other primary site of action
    Drug Interactions:
    • Administration of one drug (A) can alter action of another (B) by
      1. modification of the pharmacological effect of B w/o altering its concentration (pharmacodynamic interaction)
      2. alteration of concentration of B that reaches its site of action (pharmacokinetic interaction)
    A. gentamicin
    • increases serum levels of digoxin (pharmacokinetic effect)
    B. lithium
    • depletes potassium and so can ? effect of digoxin recommendation is that K+ is monitored
    C. diltiazem
    • concurrent use of verapamil and diltiazem with digoxin may result in excessive bradycardia due to additive depression of AV nodal conduction (pharmacodynamic)
    D. indomethacin
    • increases serum levels of digoxin (pharmacokinetic effect)
    E. amiodarone
    • increases serum levels of digoxin (pharmacokinetic effect)


    Pharmacology - Systems - Cardiology


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    Question 16
    A 45-year-old woman presents with progressive lethargy over 10 days. There is no history suggestive of infection. There has been no previous medication.
    Initial investigations show:
    haemoglobin                                                        75 g/L [120-155]
    mean corpuscular volume (MCV)                    128 fL [80-95]
    white cell count                                                   10.5 x 109/L [3.5-9.5]
    platelet count                                                       356 x 109/L [130-330]
    bilirubin                                                                 51 μmol/L [<15]
    lactate dehydrogenase (LDH)                          753 U/L [<250]
    direct antiglobulin test C3b                              +++ (strongly positive)

    Which one of the following is most likely to be present on the blood film?
    A. Plasma cells.
    B. Red cell autoagglutination.
    C. Red cell fragmentation.
    D. Hypersegmented neutrophils.
    E. Target cells.

    Answer: B

    Blood Film


    Plasma Cells

    Multiple myeloma (but even then plasmacytosis is rare)

    Red cell autoagglutination

    Occurs during direct antiglobulin test (DAT or direct Coombs test)
    Indicates immune hemolysis
    RBC are mixed with anti-C3 and anti-IgG
    If RBC then become coated w C3 or IgG indicating they clump together (agglutinate)

    Red cell fragmentation

    Indicates fragmentation hemolysis/ microangiopathic haemolytic anaemia
    eg secondary to a mechanical valve, DIC, TITP, HELLP

    Hypersegmented neutrophils

    B12/ Folate deficiency

    Target cells

    have an ↑ surface area-to-volume ratio
    redundant cell membrane causes target  appearance.
    Can be due to:
    1. ↓ cell volume, eg certain hemoglobinopathies, Fe deficiency
    2. Increased cell membrane, as in obstructive liver disease.



    Immune Mediated Haemolytic Anaemia

    • In the adult immune haemolysis is usually due to IgG or IgM antibodies reacting with antigens on the pt’s RBC

    Coombs Test:

    • Major tool for diagnosing immune mediated hemolysis
    • Tests relies on the ability of antibodies specific for IgG or complement (C3) to agglutinate RBCs with these properties
    • With specific anti-IgG and anti-C3 the direct Coombs test detects Ig-G and/or C3 on the RBCs
    • The presence of IgG and/or C3either of these indicates hemolysis and can help define its cause
    • IgG indicates destruction of RBC is most likely due to this antibody
    • If C3 is also deposited on the RBCs, then the IgG ab was able to fix complement and complement may play an additional role in the destruction of the cells.
    • If C3 is not present, complement plays no role in the destruction of the cells


    • C3 can be present w/o IgG because:
    • the antibody is not IgG;
      • eg. in IgM cold agglutinins, IgA antibodies.
    • the antibody is IgG but is poorly fixed to the RBC surface that its removed as the cells are washed in preparation for the test eg if poorly fixed at room temp eg Donald Landsetin ab






    Antibodies to Rh proteins
    Drug induced hemolysis- alpha methyldopa, penicillin



    Antibodies to glycoprotein antigens



    Cold agglutinins
    Donald-Landsteiner antibodies (paroxysmal cold hemoglobinuria)
    Drug related antibodies
    IgG with low affinity
    Activation of complement by immune complexes


    Haematology: Anaemia



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    Question 20 top Download PDF

    A 48-year-old woman presents to the emergency department of a large rural hospital with severe chest pain. An ECG shows 3-4 mm ST elevation in the anteroseptal leads.

    The risk of major haemorrhage complicating thrombolysis therapy is greatest in a patient who:

    A. has polycystic kidneys.
    B. had an open cholecystectomy two weeks ago.
    C. has recurrent heartburn.
    D. is currently menstruating.
    E. had an admission blood pressure of 160/95 mmHg.

    Answer: B
    The greatest consequence of thrombolysis is haemorrhage and of that IC haemorrhage

    Absolute contraindications:

    Previous ICH

    Known intracranial vascular lesion

    Malignant intracranial neoplasm or vascular malformation

    Ischaemic CVA in last three months

    Symptoms or signs suggesting aortic dissection

    Active bleeding or bleeding diathesis (excluding menses)

    Significant closed head  or facial injury with 3/12

    • Pts > 75 yo may get less overall benefit than younger patients
    • BUT advanced age is no longer considered a major contraindication


    Relative contraindications:

    Poorly controlled sBP > 180 and/or dBP >110
         Severe hypertension at presentation can be an absolute  
         contraindication for pts at low risk

    Ischaemic CVA ever

    Recent (with 4/52) internal bleed (GI, retroperitoneal...)

    Dementia (due to ?amyloid angiopathy and higher IC bleed risk)

    Any known intracranial disease that is not absolute contraindication

    Prolonged CPR (<10min)

    Major surgery in last 3/52

    Internal bleeding in last 2-4/52

    Noncompressible vascular punctures

    Prior streptokinase (more than 5/7 ago) – risk of allergy


    Active PUD (not GORD)


    Bleeding as a risk of Thrombolysis:

    GUSTO – 1 largest trial

    • 1.8% incidence in severe bleeding
    • 11.4% moderate bleeding (needs transfusion but no haemodynamic compromise)
    • Bleeding most often procedure related:
      • CABG 3.6%
      • Groin puncture of PCI 2%
    • Most common site of spontaneous bleeding
      • GI tract 1.8%
    • Risk is greater in women than men
    • Risk is greater in combinations of
      • streptokinase + heparin
      • streptokinase + alteplase

    ASSENT-2 trial directly compared tenecteplase to ateplase

    • no difference in
      • overall rate of stroke (1.8 versus 1.7 percent with alteplase) or
      • intracranial hemorrhage (ICH) at 30 days (1 percent in both groups)
    • However, rate of noncerebral bleeding complications (26.4 versus 29 percent) and need for transfusion (4.3 versus 5.5 percent) were significantly lower with tenecteplase

    A. Polycystic Kidneys

    • This is there because of the risk of cerebral aneurysm
    • incidence in ADPKD is approximately 4 percent in young adults
    • ­ with age to as high as 10 percent
    • Those at greatest risk have a family history of intracranial aneurysm or SAH
    • In one study asymptomatic intracranial aneurysms were found in
    • 6 of 27 patients (22 percent) with a positive fam hx
    • 3 of 56 patients (5 percent) without a positive fam hx
    • aneurysm rupture occurs in 65 to 75 percent of affected patients with ADPKD, a value higher than that of non-ADPKD patients with an intracerebral aneurysm
    • most often occurs before the age of 50 and in patients with poorly controlled hypertension
    • pts with one aneurysm clipped following a cerebral bleed may be at increased risk of new aneurysm formation for as long as 15 years after the initial surgery
    • role for radiologic screening of asymptomatic patients with ADPKD is unsettled

    Safety of anticoagulation

    • studies in patients with unruptured intracranial aneurysms (most often not related to ADPKD) have concluded that it is not known if warfarin increases the risk of intracranial bleeding but, if rupture occurs, anticoagulation increases the severity of bleeding.
    • It is reasonable to screen such patients for a cerebral aneurysm.
    • Patients with an aneurysm should be told about the relative risks and benefits of anticoagulation and evaluated for possible nonpharmacologic therapies
    • Those without an aneurysm probably have a risk of cerebral hemorrhage from anticoagulation that is similar to the general population.

    ***I thought this was the answer BUT its not

    B. Open cholecystectomy
    ***this is the answer

    • An open cholecystectomy is MAJOR surgery because its defined as a laparotomy
    • Major surgery in last 3 weeks is a relative contraindication
    • I guess this is the answer because the chance of bleed is potentially higher that in a pt who may or may not have an IC aneurysm

    C. Heart burn

    • Active PUD is a contraindication but GORD has not been shown to increase risk of bleeding

    D. Menstruation

    • 12 menstruating women in GUSTO-I - no significant increase in severe bleeding compared to nonmenstruating women
    • BUT significant increase in moderate bleeding that was offset by the benefits of thrombolytic therapy
    • Their conclusion was menstruating women should not automatically be excluded from thrombolytic therapy.

    E. Hypertension increases the risk of stroke

    • Contraindication at sBP >180mmHg
    • Risk of bleeding/ stroke increases with BPs >140 but below 180 need to look at other risks to stratify

    Predictive model to determine the risk was developed by The Cooperative Cardiovascular Project

      • Independent predictors of ICH included the following:
      • Age greater than or equal to75 years
      • Black race
      • Female sex
      • Prior history of stroke
      • Systolic blood pressure greater than or equal to160 mmHg
      • Weight less than or equal to65 kg for women or less than or equal to80 kg for men
      • International normalized ratio (INR) >4 or prothrombin time (PT) >24
      • Use of alteplase (versus other thrombolytic agent)
      • Get one point for each of the independent predictors.
      • The risk of ICH ranged from 0.69 percent for patients with 0 or 1 points to 4.11 percent for patients with greater than or equal to5 points
      • The 2004 ACC/AHA task force gave a class I recommendation to the use of primary PCI rather than thrombolysis in patients with a risk of ICH greater than or equal to4 percent


      Cardiology: Myocardial infarction

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      Question 35 top Download PDF

      A 65-year-old man with a history of osteoarthritis and mild chronic obstructive pulmonary disease presents with several days of nausea and vomiting and is now confused, febrile and icteric. He has extensive bruising and some oral mucosal bleeding. His medications are intermittent piroxicam and a salbutamol inhaler.
      His full blood count shows:
      haemoglobin                                                        85 g/L [120-155]
      mean corpuscular volume (MCV)                    101 fL [80-95]
      white cell count                                                   10.2 x 109/L [3.5-9.5]
      neutrophils                                                           8.5 x 109/L [1.5-6.0]
      lymphocytes                                                         1.2 x 109/L [0.7-3.2]
      monocytes                                                            0.4 x 109/L [0.2-0.6]
      eosinophils                                                           0.1 x 109/L [0-0.4]
      platelet count                                                       14 x 109/L [130-330]
      reticulocyte count                                               125 x 109/L [8-104]

      Blood film as shown in the photograph below.


      Direct Coombs' test                                            negative
      Coagulation studies:
      prothrombin time-international normalised ratio (PT-INR)                         normal
      activated partial thromboplastin time (APTT)                                               normal
      fibrinogen                                                                                                             normal
      D-dimers                                                                                                               normal


      creatinine                                              0.29 mmol/L [0.07-0.13]
      urea                                                        30.0 mmol/L [2.0-8.5]
      bilirubin                                                 56 μmol/L [<21]
      lactate dehydrogenase (LDH)          950 U/L [<250]
      The most likely diagnosis is:
      A. gram-negative sepsis.
      B. leptospirosis.
      C. disseminated intravascular coagulation.
      D. thrombotic thrombocytopenic purpura.
      E. piroxicam toxicity.

      Answer: D

      Key points from the investigation findings:

          • Anemia with reticulocytosis
      • Hb 85
          • Hemolysis
      • LDH ↑ 950
      • Bili ↑ 56
      • Reticulocytes ↑ 125
          • Unlikely to be autoimmune
      • Direct Coombs negative
          • Likely to be microvascular traumatic hemolysis
      • Blood film shows red cell fragmentation
          • No coagulation abnormalities
      • Can’t be DIC
          • Associated thrombocytopenia


      • Hemolysis due to bacteremia (eg gram neg sepsis) is usually mild and  transient


      • Fulminant often lethal disorder
      • May be initiated by endothelial injury and subsequent release of vWF and other procoagulants from endothelial wall
      • Severe Coombs negative haemolytic anemia with schistocytes, thrombocytopenia and minimal activation of the coagulation system


      1. pregnancy
      2. Metastatic cancer
      3. Mitomycin C
      4. High dose chemo
      5. HIV
      6. Certain drugs eg ticlodipine

      Clinical features:

      • Classic pentad
      1. haemolytic anaemia with schistocytes (fragmentated RBCs) and intravascular hemolysis
      2. Thrombocytopenia
      3. Diffuse and non-focal neurological findings
      4. Impaired renal function
      5. fever
      • minimal activation of coagulation – abnormalities in coags suggests other diagnosis
      • neurological and renal impairment only occur with plt counts <20-30
      • neurological symptoms develop in >90% whose disease ends in death
      • commences with change in mental state can include seizure, hemiparesis, aphasia, coma


      • severity can be estimated by severity of anaemia and thrombocytopenia and LDH


      • due to deficiency in activity of ADAMTS 13 (metalloproteinase)
      • normal plasma constituent
      • cleaves ultra high molecular weight forms of vWF
      • usually get an inhibitory antibody


      • exchange transfusion or plasmapheresis


      • disesase of infancy and early childhood
      • resembles TTP

      Clinical features:

        • Fever
        • thrombocytopenia
        • Microangiopathic haemolytic anaemia
        • Hypertension
        • Acute renal failure
      • Sometimes preceeded by febrile or viral illness
      • As in TTP there is no DIC
      • In contrast to TTP isolated to kidneys – thrombi in afferent arterioles and glomerular capillaries
      • Neuro symptoms are rare



        • No treatment except for dialysis for renal failure
        • Mortality 5%
        • 10-50% have chronic renal impairment


        Haematology: Anaemia

        Question 36 top

        Question 37 top Download PDF

        Digoxin is indicated for use in all of the following except:
        A. prevention of paroxysmal atrial fibrillation.
        B. systolic heart failure unresponsive to angiotensin-converting enzyme (ACE) inhibitors and loop diuretics.
        C. systolic heart failure with co-existing atrial fibrillation.
        D. acute atrial fibrillation with rapid ventricular rate.
        E. diastolic dysfunction with co-existing rapid atrial fibrillation

        Answer: A
        • Digoxin is not indicated in the management of paroxysmal AF (ACC/AHA guidelines Class III B)
        • Digoxin is indicated in:
          • Systolic failure unresponsive to other pharmacotherapy
          • AF with concomitant HF either diastolic or systolic
          • Acute AF in an acute setting

        NB: digoxin is not indicated for diastolic HF in setting of sinus rhythm as there is no issue in that case with contractility and thus digoxin will not provide benefit


        Pharmacology - Systems - Cardiology


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        Question 52 top Download PDF

        A 58-year-old previously well man presents with a two-week history of spontaneous bruising and a large, painful left thigh haematoma following minimal trauma. He is on no medication and his blood count has been documented as normal 18 months earlier prior to elective surgery. There is no previous history of bleeding with trauma or with surgery and no family history of bleeding disorder. Physical examination is normal apart from scattered ecchymoses and the swollen, bruised left thigh. The haematoma is confirmed on ultrasound examination.
        Investigations show:
        Full blood count
        haemoglobin                                                                                        119 g/L [135-170]
        other parameters normal
        prothrombin time-international normalised ratio (PT-INR)         1.1 [1.0-1.3]
        activated partial thromboplastin time (APTT)                               90 seconds [26-38]
        APTT 1:1 mix, normal plasma:patient plasma                             50 seconds [26-38]
        fibrinogen                                                                                             2.7 g/L [2.0-4.0]
        D-dimer                                                                                                 0.2 mg/L [<0.2]
        platelet function tests (aggregometry) normal

        The most likely diagnosis is:
        A. haemophilia A.
        B. haemophilia B.
        C. primary antiphospholipid antibody syndrome.
        D. von Willebrand’s disease.
        E. acquired factor VIIIc inhibitor.

        Key points from the question:

        1. Anaemia – Hb ↓
        2. INR – normal
        3. APTT prolonged
        4. APTT 1:1 mix prolonged
          • As the addition of normal plasma does not correct the prolongation of APTT it suggests a factor inhibitor rather than a deficiency
        1. Platelets normal
        2. D-Dimer/ Fibrinogen normal
        3. New bleeding disorder –unlikely an inherited one given his age


        APTT                – measure of intrinsic and common pathway
        INR                   – measure of extrinsic and common pathway
        1:1 dilution     - assess whether there is factor deficiency or inhibition

        Haemophilia A – Factor VIII deficiency and Haemophilia B – Factor IX deficiency

        • Prolonged APTT and normal INR
        • Should correct with 1:1 dilution with normal factor bc it’s a deficiency
        • Would expect to have had symptoms from birth

        Antiphospholipid antibody syndrome

        • Prolonged APTT and normal INR
        • associated with thrombosis rather than bleeding
        • prolonged APTT is an artifact of antiphospholipid phenomenon
        • presence of antiphospholipid antibody producing lupus anticoagulant is suggested by prolonged APTT that doesn’t correct after 1:1 dilution w normal plasma
        • with addition of phospholipids clotting time corrects 

        von Willebrand’s Disease

        • Can be associated with prolonged APTT and normal INR
        • But in mild disease APTT normal
        • More assoc with mucosal bleeding
        • Would expect to have had symptoms from a younger age
        • Would expect correction with 1:1 dilution

        Acquired factor VIIIc inhibition

        • Normal INR but prolonged APTT
        • Acquired inhibition fits with the failure of the 1:1 dilution to correct
        • Most common autoantibodies affecting coagulation are directed against factor VIII
        • In 50% associated with
        • Pregnancy or post-partum period
        • Rheumatoid arthritis
        • Malignancy (solid tumours)
        • SLE
        • Drug reactions


        • Hallmark is bleeding that is first noted after a surgical procedure
        • Bleeding is often sever
        • Present with
        • Large hematomas
        • Extensive ecchymoses
        • Severe mucosal bleeding inc epistaxis, GI bleeding, hematuria
        • Hemarthrotheses common in hereditary factor VIII deficiency are rare
        • Diagnosis
        1. Prolonged APTT with normal INR
        2. 1:1 dilution with normal plasma – persistence of prolongation of APTT suggesting an inhibitor
        3. Add source of phospholipid to the plasma
        • Correction of the APTT suggests antiphospholipid antibodies
        • If APTT doesn’t correct à Bethesda assay
        1. Bethesda Assay
          • Diagnoses factor VIII inhibitor and quantifies the antibody titre


          Prothrombin Time (INR)

          • Measures the functioning of the extrinsic and common pathways
          • Measures activity of VII, X, V, II (prothrombin), I (fibrinogen)
          • VII, X and II (prothrombin) are vit K dependent and altered by warfarin so is a measure of warf activity


          • Measures the intrinsic and common pathways of coagulation
          • Sensitive for deficiencies of all coag factors except VII, XIII
          • Measure of the activity of heparin
          • Less sensitive than INR to deficiencies of the common pathways (X, V, II-prothrombin, I-fibrinogen)

          PT or APTT on 1:1 mixture

          • After an abnormality in clotting is detected need to differentiate between a factor deficiency or factor inhibition
          • Mix patient’s plasma with normal pooled plasma and repeat abnormal test
          • 3 principles to understand
          • Clotting tests will give normal values when there is 50% activity of involved factor
            • so if clotting test is normal after 1:1 dilution with normal plasma cause of abnormal test was factor deficiency
          • Most agents which inhibit factor activity will not be effectively diluted out by 1: 1 dilution
            • so if test remains abnormal an inhibitor was the cause of the abnormal test
          • Some inhibitors give normal results when tested immediately after 1:1 dilution but then become abnormal again
            • eg factor VIII inhibitors (characteristic)


          • If 1:1 dilution corrects the abnormal test
            • determine deficient factors by individual factor assays
          • If test is not corrected by dilution most common inhibiting factors are:
          • Heparin
          • antiphospholipid antibodies (though most commonly seen in hypercoag state)
          • inhibitors against VIII, IX, X
          • inhibitors of thrombin eg fibrin or fibrinogen degradation products


          Normal INR and APPT


          • thrombocytopenia is the most common acquired bleeding disorder
          • von WILLEBREAD DISEASE
          • Platelet dysfunction
          • Factor XIII deficiency

          Normal INR with Prolonged APTT

          • characteristic of disorder of intrinsic pathway
          • Inherited disorders:
          • Factor VIII (hemophilia A, vW disease)
          • Factor IX (hemophilia B)
          • Factor XI (tend to bleed post-surgical procedures)
          • Acquired disorders/ inhibitors:
          • antiphospholipd antibodies (presents with thrombosis)
          • acquired antibodies to factor VIII (acquired hemophilia), IX, XI

          Prolonged INR and normal APTT

          • indicates an abnormality of the extrinsic pathway and suggests factor VII deficiency
          • Factor VII deficiency can be inherited or acquired
          • Inherited factor VII
            • Phenotypic and molecular heterogeneity
            • Inconsistencies bw clinical picture, underlying clotting and molecular defects and response to prophylaxis with recombinant human factor VIIa
            • Can have no excessive bleeding to severe hemorrhagic tendency
          • Acquired inhibitors are
          • Pattern is more commonly seen due to:
            • Warfarin therapy, Early liver disease
            • Vit K deficiency, Early DIC (rare)

          Prolonged INR and APPT

            • Inherited disorder of common pathway or more complex acquired disorder inv multiple pathways
            • Inherited disorders: deficiency of factor X, V, prothrombin or fibrinogen (rare)
            • Acquired disorders:
            • Supratherapeutic doses of warfarin or heparin can prolong both
            • Vit K deficiency, liver disease, DIC
            • Factor V is vit K independent so can be used as a direct evaluation of hepatic function



            Haematology: Coagulation

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            Question 65 top Download PDF

            A couple comes to see you because they are wanting to start a family. There is a vague history of thalassemia in both families. Which one of the following combinations would cause the least concern to this couple?


            The woman is a carrier for

            The man is a carrier for











            Haemoglobin E





            Answer: E

            β thalassemia carrier = asymptomatic β thalassemia trait  =one abnormal gene
            αo- thalassemia          = asymptomatic carrier = Two gene deletions
            α+ thalassemia              = asymptomatic carrier =One gene deletion

            β thalassemia:

            • Has mendelian inheritance

            When BOTH parents have thalassemia trait, the child may inherit

            • two normal haemoglobin genes
            • or one normal haemoglobin gene and one thalassemia gene
            • or two thalassemia genes

            α thalassemia:

            • is more complex because of the duplicate nature of the genes

            if both parents have αo thalassemia

              • α o = 2 deletions
              • the deletions can be on the same chromosome or different chromosomes
              • this in turn affects inheritance


              • if both parents have a cis deletion (2 deletion on the same gene)








              αα/- -

              αα/ - -




              αα/- -

              - -/ αα

              - -/ - -



              Α trait

              α  trait

              Hydrops fetalis

              • if both parents have the trans deletion (2 deletions but on different genes)








              α-/- α

              α-/ - α








              α trait

              Α trait

              α  trait

              α trait

              • if they have one of each








              αα/- -

              α-/ - α





              - -/α-

              - -/α-


              Asympt carrier (α+)

              Asympt carrier

              Hb F



              If one parent is α+ and the other αo








              αα/α -

              α-/ - α





              - α/α-

              - α/α-


              Asympt carrier (α+)

              Asympt carrier

              α  trait

              α trait









              αα/α -

              - -/ α α



              αα/- -


              - α/- -

              - α/αα


              α trait



              Asympt carrier


              Haemoglobin E

              • Is extremely common in Cambodia, Thailand, Vietnam
              • Is mildly unstable but not enough to affect RBC life span significantly
              • Heterozygotes resemble β thalassemia trait clinically
              • Homozygotes have more marked abnormalities BUT remain asymptomatic (microcytosis, hypochromia)
              • Compound heterozygotes can have β thalassemia intermedia or major depending on severity of co-inherited thalassemia gene
              • Genetic counseling is concerned with interactions bw HbE and β thalassemia rather than HbE homozygosity

              Co-inheritance of alpha and beta thalassemia

              • Co-inheritance of beta thalassemia and α thalassemia can ameliorate the symptoms of β thalassemia by ↓ the amount of free α globin chains and thus ↓ inclusions
              • Assuming the parent with β thalassemia trait has normal α globulin genes the inheritance of α thalassemia will never be more severe than α thalassemia trait









              α-/ - α








              Asympt carrier (α+)

              Asympt carrier

              Asympt carrier

              Asympt carrier










              - -/ αα



              αα/- -


              αα/- -



              α trait


              α trait


              • Assuming the parent with α thalassemia trait has normal β globulin genes the offspring have 50% chance of have β thal trait or normal genes



              Review of normal Haemoglobin

              • Different Hb is produced during embryonic, fetal and adult life
              • Hb is a tetramer of globin polypeptide chains
              • A pair of α chains
              • A pair of β chains

              Major adult Hb



              Minor adult Hb



              Fetal Hb



              • Each globin chain enfolds a single heme moiety
              • Each heme moiety can bind one oxygen molecule
              • So each Hb can bind 4 oxygen molecules


              • Haemoglobin tetramer is highly soluble
              • BUT the individual globin chains are insoluble
              • Unpaired globin precipitates and forms inclusions which damage the cell
              • Normal globin synthesis is balanced

              Development of haemoglobin

              • RBCs appear at 6 weeks gestation
              • Contain embryonic Hb – Hb Portland (ζ2γ2) and Hb Gower I (ζ2ε2) and Gower II
              • At 10 – 11 weeks fetal Hb (α2γ2) predominates
              • Then switches to nearly exclusive synthesis of adult Hb (α2β2) at 38 weeks
              • Small amounts of HbF persist
              • Thus α chains are required for normal embryonic life but not β chains


              Genetics of Hb

              • Hb is encoded on 2 gene clusters
              • α globin coded on 2 genes on Chr 16
              • β globin coded on 1 gene on Chr 11
              • each person has 2 β globin genes and 4 α globin genes
              • production α : β is 1 :1



              • inherited disorders of α or β globin synthesis
              • failure of one or more of the genes to provide enough of one subunit
              • Unbalanced accumulation of α or β subunit occurs bc synthesis of other globin continues at normal rate
              • If β gene fails à β thalassemia
              • If α gene fails à α thalassemia


              There is a spectrum of disease depending on how many genes fail

              • β thalassemia trait – one gene is defective and β globin synthesis is reduced
              • β thalassemia major -  no β globin is synthesised
              • α thalassemia
              1. one deletion – asymptomatic
              2. 2 deletions – α thalassemia trait (microcytic anaemia)
              3. 3 deletions – HbH
              4. 4 deletions – hydrops fetalis which is not compatible with life



              Haematology: Haemoglobinopathies Repeat Question 2002 paper two question 2

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              Question 72 top Download PDF

              A 24-year-old woman who has recently arrived in Australia from Vietnam, presents for evaluation of abnormal menstrual bleeding. There are no abnormalities on examination.
              Investigations show:
              Full blood count
              haemoglobin                                                        113 g/L [120-155]
              red cell count                                                       5.2 x 1012/L [4.1-5.2]
              mean corpuscular volume (MCV)                    71 fL [80-95]
              mean corpuscular haemoglobin (MCH)         22.0 pg [27.0-32.5]
              mean corpuscular haemoglobin
              concentration (MCHC)                                        310 g/L [325-360]
              white cell count                                                   6.6 x 109/L [3.5-9.5]
              differential                                                            normal
              platelet count                                                       212 x 109/L [130-330]

              Blood film shows red cell microcytosis and hypochromasia but is otherwise normal.

              Haemoglobin (Hb) electrophoresis (cellulose acetate, pH 8.6):
              HbA2                                                                      2.7% [1.8-3.5]
              HbF                                                                         0.4% [0-2.0]
              No abnormal bands

              HbH preparation:                                                 HbH inclusions present

              Serum biochemistry:
              iron                                                                         8 μmol/L [7-32]
              transferrin                                                             3.2 g/L [2.1-3.6]
              ferritin                                                                    15 μg/L [7-280]

              The most likely diagnosis is:
              A. homozygous alpha+ thalassemia (−α/−α).
              B. early iron deficiency.
              C. congenital sideroblastic anaemia.
              D. sickle cell anaemia.

              E. heterozygous beta thalassaemia.

              Answer: A


              Key points from question:

              • Microcytic hypochromic anaemia
              • FBC otherwise normal
              • HbA2 and Hb F normal so it can’t be β thalassemia
              • No abnormal bands on Hb electrophoresis makes sickle cell unlikely BUT not impossible bc sickling tests haven’t been done
              • Normal Iron studies excludes sideroblastic anaemia (also wrong sex and age group) and makes iron deficiency unlikely
              • Hb H inclusions is characteristic of α thalassemia Hb H disease but can occur in α thal trait


              • 4 genes on Chr 16 that code for α chain
              • 2 genes on each chromosome and they are inherited in pairs
              • Syndrome is dependent on number of deletions
              • AND whether the deletions are on the same chromosome

              α thalassemia– one deletion

              • asymptomatic silent carrier

              α thalassemia trait – 2 deletions

              • microcytic anaemia mild (asymptomatic)

              Hb H disease – 3 deletion

              • Hb A is only 25-30% normal
              • In adults β chains accumulate and form β4 (HbH)
              • HbH forms few inclusions in erythroblasts but does precipitate in circulating RBCs
              • à moderate to severe hemolytic anaemia with milder ineffective erythropoiesis
              • Survival into mid adulthood w/o transfusion is common; may need transfusion during illness

              Hydrops fetalis – 4 deletions

              • Total absence of α globin synthesis
              • Get no physiologically useful Hb past embryonic stage
              • Excess γ globin forms tetramers γ4 (Hb Barts) has high O2 affinity
              • Delivers almost no oxygen to fetal tissue
              • à tissue asphyxiation and oedema (hydrops fetalis) with intrauterine death

              Diagnosis of Alpha Thalassemia

              • Microcytic, hypochromic anaemia
              • Normal Hb A2 and HbF
              • Hb H inclusions occur in Haemoglobin H disease and occasionally α thal trait
              • DNA diagnosis is available

              SICKLE CELL ANEMIA

              • Sickle cell syndromes are due to a mutation in the β globin gene
              • Changes 6th amino acid from glutamine to valine
              • Resulting molecule is Hb S
              • When Hb S is deoxygenated it reversibly polymerises leading to
              • flexibility of the RBC membrane
              • ↑ viscosity
              • Dehydration due to K+ leakage and calcium influx
              • Also causes the sickle like shape of the cell
              • With repeated sickling the RBC loses the pliability to traverse small capillaries leading to
              • Hemolysis
              • Microvascular occlusion (this predominates the clinical course)


              • Homozygous:               HbSS      Sickle Cell Anaemia
              • Heterozygous               HbS         Sickle Cell Trait (asymptomatic)

              Clinical Manifestations

              • Haemolytic anaemia with reticulocytosis
              • Vasoocclusion
              • Intermittent episodes of painful ischaemia “painful crisis”
              • Most common manifestation
              • Can develop anywhere; duration of hours to weeks
              • Provoked by fever, infection, ↑ exercise, change in temp, hypoxia
              • Repeated microinfarction leads to end organ damage
              • Splenic, retinal, renal, pulmonary, bone and joint infarcts
              • Renal failure common late cause of death in adults
              • Stroke is  common in children but rare in adults
              • Chronic leg ulcers


              • Heterogenous syndrome
              • Symptoms ameliorated by co-inheritance of HbE, thalassemia, HbC


              • Hb electrophoresis
              • Important to distinguish bw sickle thalassemia, Hb SC as have better prognosis
              • Need to genotype family

              Factors associated with ↑ morbidity and ↓ survival

              • > 3 painful crises/ year requiring hospitalisation
              • chronic neutrophilia
              • history of splenic sequestration or hand foot crisis
              • 2nd episode of acute chest syndrome


              • Of acute painful crisis: hydration, analgesia and evaluate for underlying cause
              • Hydroxyurea used in those with severe symptoms
              • BM transplant only safe and effective in children


                • X linked
                • Due to deficient activity of erythroid form of ALA synthetase à ineffective erythropoiesis
                • Typically male
                • Develop refractory haemolytic anaemia, pallor and weakness in infancy
                • Secondary hypersplenism
                • Become iron overloaded and can develop hemosiderosis
                • Severity depends on residual ALA synthetase activity
                • Hypochromic, microcytic anaemia with anisocytosis, poikilocytosis and polychromasia
                • Pyroxidine supplementation is treatment


                Haematology: Anaemia Repeat Question 2003 paper two question 93


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                Question 78
                A 64-year-old man presents to hospital seven hours after onset of severe chest pain. His ECG shows 4-5 mm ST elevation in leads II, III and aVF, and complete heart block with a ventricular rate of 50/minute. His blood pressure is 115/60 mmHg which falls transiently to 90/50 mmHg with the administration of streptokinase, before returning to 120/55 mmHg.
                Four hours later, he is reviewed in the coronary care unit. His heart rate is 50/minute and his blood pressure is 85/60 mmHg. His jugular venous pressure is 4 cm with cannon waves. A third sound is audible but there are no murmurs. Breath sounds are normal. The patient complains of mild chest pain which is relieved by sitting up. The ECG remains unchanged. Urine output has declined to 5 mL/h for the last two hours.

                What is the most appropriate next step in management?

                A. Insert a temporary pacing wire to increase the heart rate to about 80/minute.
                B. Increase intravenous fluid administration.
                C. Organise immediate rescue percutaneous transluminal coronary angioplasty
                D. Commence an intravenous dobutamine infusion.
                E. Insert a Swan-Ganz catheter for haemodynamic monitoring.

                Answer: B

                • The pattern of ECG changes indicate an inferior MI
                • Inferior AMIs required fluid resuscitation to increase preload
                • He is now hypotensive, has poor UO (reflecting poor CO), and his JVP is elevated (with cannon waves) but heart sounds are dual.
                • The only thing the myocardium will respond to is increasing the IV fluid to stretch the myocardium and drive CO.
                • There are two settings in which more volume support is required:  RV infarct (need high filling Pa to maximize filling of LV) and the venodilatation and hypotension with inferior MI.


                Cardiology: Myocardial infarction


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