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Phase 2A > Haematology 2 > Flashcards

Haematology 2 Flashcards

1
Q

what causes acquired haemolytic anaemia?

A

due to immunological destruction of red blood cells mediated by autoantibodies directed against antigens on the patient’s red blood cells

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2
Q

how is autoimmune haemolytic anaemia classified?

A

classified according to whether the antibody reacts best at body temperature (warm antibodies) or at lower temperatures (cold antibodies)

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3
Q

what is the pathophysiology of autoimmune haemolytic anaemia?

A

Immunoglobulin (Ig) G or IgM antibodies attach to the red cell, resulting in extravascular haemolysis through sequestration in the spleen, or in intravascular haemolysis through activation of complement

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4
Q

what is the Coombs’ test? what can it help diagnose?

A
  • this is a test for antibodies or complement attached to the surface of red blood cells
  • the red blood cells of the patient are reacted with antiserum or monoclonal antibodies prepared against the various immunoglobulins and the third component of complement (C3d)
  • if either or both of these are present on the red cell surface, agglutination of red cells will be detected
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5
Q

what is the temperature at which antibody attaches best to red cells in warm vs cold autoimmune haemolytic anaemia?

A

warm: 37C
cold: lower than 37C

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6
Q

what is the type of antibody in warm vs cold autoimmune haemolytic anaemia?

A

warm: IgG
cold: IgM

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7
Q

what is the direct Coombs’ test result in warm vs cold autoimmune haemolytic anaemia?

A

warm: strongly positive
cold: positive

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8
Q

what are secondary causes of warm autoimmune haemolytic anaemia?

A
  • autoimmune disorders, e.g. SLE
  • lymphomas
  • CLL
  • carcinomas
  • many drugs, e.g. methyldopa
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9
Q

what are secondary causes of cold autoimmune haemolytic anaemia?

A
  • infections e.g. Mycoplasma spp., infectious mononucleosis
  • lymphomas
  • paroxysmal cold
  • haemoglobinuria
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10
Q

what are clinical features of warm autoimmune haemolytic anaemia?

A
  • occurs at all ages in both sexes
  • variable clinical picture, ranging from mild haemolysis to life-threatening anaemia
  • may be primary or secondary
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11
Q

what is the investigation of warm autoimmune haemolytic anaemia?

A
  • evidence of haemolysis

- direct Coombs’ test is positive

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12
Q

what is the management of warm autoimmune haemolytic anaemia?

A
  • high-dose steroids (e.g. prednisolone 1 mg/kg daily) induce remission in 80% of cases.
  • splenectomy is useful in those failing to respond to steroids.
  • occasionally, immunosuppressive drugs such as azathioprine and rituximab are beneficial.
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13
Q

what are clinical features of cold autoimmune haemolytic anaemia?

A
  • IgM antibodies (cold agglutinins) attach to red cells in the cold peripheral parts of the body and cause agglutination and complement-mediated intravascular haemolysis.
  • after certain infections (e.g. Mycoplasma, Epstein–Barr virus), there is increased synthesis of cold agglutinins (normally produced in insignificant amounts) and transient haemolysis.
  • a chronic idiopathic form occurs in elderly people, with recurrent haemolysis and peripheral cyanosis.
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14
Q

what is the investigation of cold autoimmune haemolytic anaemia?

A
  • there is evidence of haemolysis and direct Coombs’ test is positive.
  • examination of a peripheral blood film at room temperature shows red cell agglutination.
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15
Q

what is the management of cold autoimmune haemolytic anaemia?

A

treat underlying condition and avoid exposure to cold

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16
Q

what are the two mechanisms for drug-induced haemolysis?

A
  • in the most common form, the drug may associate with structures on the red cell membrane and thus be part of the antigen in a haptenic reaction. there is severe complement-mediated intravascular haemolysis which resolves quickly after drug withdrawal.
  • the drug may induce a subtle alteration of one component of the red cell membrane, rendering it antigenic. there is extravascular haemolysis and a protracted clinical course.
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17
Q

what is the pathophysiology of paroxysmal nocturnal haemoglobulinuria?

A
  • there is an inability to produce the glycosylphosphatidylinositol (GPI) anchor, which tethers several proteins to the cell membrane.
  • deficiency of two of these proteins, CD59 (membrane inhibitor of reactive lysis) and CD55 (decay-accelerating factor), renders the red cell exquisitely sensitive to the haemolytic action of complement
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18
Q

what is the clinical presentation of paroxysmal nocturnal haemoglobulinuria?

A
  • the clinical manifestations of this rare disease are related to abnormalities in haemopoietic function, including intravascular haemolysis, venous thrombosis and bone marrow aplasia.
  • haemoglobinuria typically manifests as dark urine at night and in the morning on waking.
  • progression to myelodysplasia and acute leukaemia can also occur.
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19
Q

what is the diagnosis of paroxysmal nocturnal haemoglobulinuria?

A
  • paroxysmal nocturnal haemoglobinuria should be considered in any patient with chronic or episodic haemolysis.
  • diagnosis is made by demonstrating deficiency of the GPI-anchored proteins on haematopoietic cells by flow cytometry
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20
Q

what is treatment of paroxysmal nocturnal haemoglobulinuria?

A
  • treatment is supportive (e.g. with blood transfusions) and with eculizumab, a monoclonal antibody that binds to the C5 component of complement, prevents its activation and reduces haemolysis.
  • BMT has been successful in selected patients.
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21
Q

what are examples of mechanical haemolytic anaemia?

A
  • leaking prosthetic heart valves: damage to red cells in their passage through the heart
  • march haemoglobinuria: damage to red cells in the feet from prolonged marching
  • microangiopathic haemolysis: fragmentation of red cells in abnormal microcirculation caused by malignant hypertension, haemolytic-uraemic syndrome or disseminated intravascular coagulation (DIC).
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22
Q

what is secondary polycythemia? what are presentations and treatments of it?

A
  • secondary polycythaemia presents with similar clinical features to primary polycythaemia, although the white cell and platelet counts are usually normal and the spleen is not enlarged.
  • in patients with tumours the primary disease must be treated to lower the level of erythropoietin.
  • in hypoxic patients, oxygen therapy may reduce the Hb, and a small-volume phlebotomy (400 mL) may help those with severe symptoms.
  • smokers should be advised to stop smoking.
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23
Q

what is essential thrombocythaemia?

A
  • patients have normal Hb levels and white cell count but elevated platelet count.
  • platelet size and function are abnormal, and presentation may be with bleeding or thrombosis.
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24
Q

what are differential diagnoses of a raised platelet count?

A
  • reactive thrombocytosis
  • autoimmune rheumatic disorders
  • chronic infections
  • inflammatory bowel disease
  • malignancy
  • haemorrhage
  • surgery
  • splenectomy and functional hyposplenism
  • primary thrombocythaemia
  • polycythaemia vera
  • myelofibrosis
  • myelodysplasia
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25
Q

what is myelofibrosis?

A

myelofibrosis is characterized by haemopoietic stem cell proliferation associated with marrow fibrosis (abnormal megakaryocyte precursors release fibroblast-stimulating factors, such as platelet-derived growth factor).

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26
Q

what are clinical features of myelofibrosis?

A
  • there is an insidious onset of weakness, weight loss and lethargy.
  • bleeding occurs in the thrombocytopenic patient.
  • there is hepatomegaly and massive splenomegaly caused by extramedullary haemopoiesis.
  • the most common causes of death are transformation to acute myeloid leukaemia, progression of myelofibrosis, cardiovascular disease and infection.
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27
Q

what is seen on a blood count of myelofibrosis?

A
  • anaemia

- white cell and platelet counts are high initially, but fall with disease progression due to marrow fibrosis

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28
Q

what is seen on a blood film in myelofibrosis?

A
  • leucoerythroblastic picture (immature red cells caused by marrow infiltration)
  • teardrop shaped red cells
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29
Q

what are genetic components of myelofibrosis?

A
  • bone marrow is usually unobtainable by aspiration (‘dry tap’); trephine biopsy shows increased fibrosis.
  • the Philadelphia chromosome is absent; this and the bone marrow appearance helps to distinguish myelofibrosis from chronic myeloid leukaemia, which may present similarly.
  • JAK2 mutation is present in approximately half of the cases.
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30
Q

what is the management of myelofibrosis?

A
  • transfusions are given for anaemia and allopurinol to decrease serum uric acid levels.
  • historically, symptomatic splenomegaly was managed using hydroxycarbamide, busulfan, radiotherapy or splenectomy. splenectomy is associated with significant morbidity and mortality in myelofibrosis and the other treatments are largely ineffective.
  • ruxolitinib results in substantial spleen reduction, improved life expectancy and reduction in symptoms.
  • allogeneic stem cell transplantation
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31
Q

what is myelodysplasia? what are clinical presentations of it?

A
  • myelodysplasia is a group of acquired bone marrow disorders caused by a defect in stem cells.
  • there is progressive bone marrow failure, which may evolve into acute myeloid leukaemia.
  • the myelodysplastic syndromes are predominantly diseases of the elderly
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32
Q

how is myelodysplasia diagnosed?

A
  • may be diagnosed on a routine FBC or when patients present with anaemia, infection or bleeding due to pancytopenia
  • made on the basis of characteristic blood film and marrow appearances
  • the paradox of peripheral pancytopenia and a hypercellular bone marrow reflects premature cell loss by apoptosis.
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33
Q

what is the treatment of myelodysplasia?

A
  • supportive treatment (red cell and platelet transfusions) is given to elderly patients with symptomatic disease.
  • for younger patients, intensive chemotherapy (as used for acute myeloblastic leukaemia) or allogeneic BMT are used.
  • lenalidomide (a thalidomide analogue) is used in the treatment of early-stage disease.
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34
Q

what are features and functions of the spleen?

A
  • the spleen, situated in the left hypochondrium, is the largest lymphoid organ in the body.
  • its main functions are phagocytosis of old red blood cells, immunological defence and to act as a ‘pool’ of blood from which cells may be rapidly mobilized.
  • pluripotent stem cells are present in the spleen and proliferate in severe haematological stress (extramedullary haemopoiesis), e.g. haemolytic anaemia.
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35
Q

what is splenomegaly? what can it cause?

A
  • enlargement of the spleen
  • the spleen is only palpable once it has almost doubled in size.
  • splenomegaly may cause hypersplenism, which results in pancytopenia, increased plasma volume and haemolysis.
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36
Q

what is splenectomy mainly performed for?

A
  • trauma
  • idiopathic thrombocytopenic purpura
  • haemolytic anaemias
  • hypersplenism
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37
Q

what are causes of massive (extending into right iliac fossa) splenomegaly?

A
  • CML
  • myelofibrosis
  • chronic malaria
  • Kala-azar
  • Gaucher’s disease (rarely)
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38
Q

what are causes of moderate splenomegaly?

A
  • lymphoma
  • leukaemia
  • myeloproliferative disorders
  • haemolytic anaemia
  • acute infection, e.g. endocarditis, typhoid
  • chronic infection, e.g. TB, brucellosis
  • parasitic, e.g. malaria
  • RA
  • sarcoidosis
  • SLE
  • storage diseases e.g. Gaucher’s
  • tropical splenomegaly
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39
Q

what are complications after splenectomy?

A

complications after splenectomy are an increased platelet count (thrombophilia) in the short term and overwhelming infection in the long term, particularly with Streptococcus pneumoniae, H. influenzae and the meningococci

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40
Q

what vaccinations are given for splenectomy?

A
  • pneumoccocal, Haemophilus, meningococcal group C and influenza vaccination is given before elective splenectomy.
  • meningococcal polysaccharide vaccine is given for travellers to Africa and Saudi Arabia.
  • in addition, the patient is given lifelong penicillin V 500 mg twice daily or erythromycin if they are allergic to penicillin.
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41
Q

what are the features of the rhesus (Rh) system of blood groups?

A
  • most of the population carry RhD antigens (Rh +ve) on red cells and can receive any RhD type blood
  • RhD negative patients should receive RhD negative blood
  • exposure to RhD positive blood through transfusion or pregnancy will lead to development of anti-D
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42
Q

what is the antigen and antibody in blood group A?

A

red cell antigen: A

antibody in patient’s plasma: anti-B

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43
Q

what is the antigen and antibody in blood group B?

A

red cell antigen: B

antibody in patient’s plasma: anti-A

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44
Q

what is the antigen and antibody in blood group AB?

A

red cell antigen: AB
antibody in patient’s plasma: no antibodies to A or B
universal acceptors

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45
Q

what is the antigen and antibody in blood group O?

A

red cell antigen: no A or B
antibody in patient’s plasma: anti-A and anti-B
universal donor

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46
Q

what blood can be given without any transfusion investigations?

A
  • O RhD negative blood
  • after massive bleed when immediate transfusion is necessary
  • should only be used on rare occasions
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47
Q

how should patients receiving a blood transfusion be monitored?

A
  • temperature, pulse rate and BP should be recorded before start of each unit, 15 mins after the start and then at hourly intervals during the transfusion
  • temperature rise of 1C or greater above baseline may indicate an acute haemolytic transfusion reaction due to incompatibility and is an indication to stop
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48
Q

what are features of ABO incompatibility in a blood transfusion?

A
  • ABO incompatibility is the most serious complication.
  • within minutes of starting the transfusion there is pyrexia, rigors, dyspnoea, hypotension, loin and back pain.
  • intravascular haemolysis leads to dark urine.
  • emergency treatment may be needed to maintain the blood pressure
  • autoimmune haemolysis may develop about a week after transfusion in patients alloimmunized by previous transfusions in whom the antibody level is too low to be detected during compatibility testing.
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49
Q

what are complications of blood transfusion?

A
  • ABO compatibility
  • febrile reactions are usually the result of anti-leucocyte antibodies in the recipient acting against transfused leucocytes, leading to the release of pyrogens. these reactions are less common since the introduction of leucocyte-depleted blood.
  • anaphylactic reactions are seen in patients lacking IgA but who produce anti-IgA that reacts with IgA in the transfused blood. this is a medical emergency
  • urticarial reactions are treated by slowing of the infusion and giving intravenous antihistamines, e.g. chlorphenamine (chlorpheniramine) 10 mg intravenously (i.v.).
  • transmission of infection
  • heart failure
  • hypocalcaemia, hyperkalaemia and hypothermia due to massive transfusion (>10 units within 24 hours)
  • post-transfusion purpura
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50
Q

what is leucocytosis?

A

increase (>11 x 10^9/L) in total circulating white cells

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51
Q

what is leucopenia?

A

decrease (<4 x 10^9/L) in total circulating white cells

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52
Q

what is the function of neutrophils?

A

to ingest and kill bacteria, fungi and damaged cells

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53
Q

what is neutrophil leucocytosis?

A

increase (>10 x 10^9/L) in total circulating neutrophils

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54
Q

when does neutrophil leucocytosis occur?

A
  • bacterial infection
  • tissue necrosis
  • inflammation
  • corticosteroid therapy
  • myeloproliferative disease
  • acute haemorrhage, haemolysis
  • leukaemoid reaction (excessive leucocytosis characterized by the presence of immature cells in the peripheral blood)
  • leucoerythroblastic anaemia (immature red and white cells appear in the peripheral blood in marrow infiltration, e.g. malignancy, myeloid leukaemia, severe anaemia)
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55
Q

what is a left shift in leucocytosis? when does it occur?

A

a ‘left shift’ describes the presence of immature white cells (promyelocytes, myelocytes and metamyelocytes) in the peripheral blood and occurs with infection and in leukoerythroblastic anaemia.

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56
Q

what is neutropenia?

A

decrease in circulating neutrophils in the peripheral blood (<1.5 x 10^9/L)

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57
Q

what are causes of neutropenia?

A
  • race (black Africans)
  • viral infection
  • severe bacterial infection
  • megaloblastic anaemia
  • pancytopenia
  • drugs (marrow aplasia or immune destruction)
  • inherited abnormalities
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58
Q

what is severe neutropenia?

A
  • absolute neutrophil count of <0.5 x 10^9/L

- may be associated with life-threatening infections

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59
Q

what is monocytosis? when does it occur?

A
  • monocytes are precursors of tissue macrophages.
  • normal range 0.04–0.44 × 109/L, 1–6% of total white cells
  • occurs in chronic bacterial infections (e.g. tuberculosis), myelodysplasia and malignancy, particularly chronic myelomonocytic leukaemia.
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60
Q

what is the function of eosinophils?

A

play a part in allergic responses and in the defence against infections with helmonths and protozoa

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61
Q

what is eosinophilia? when does it occur?

A
  • normal range 0.04-0.44 x 10^9/L, 1-6% of total white cells
  • occurs in asthma and allergic disorders, parasitic infections (e.g. Ascaris), skin disorders (urticaria, pemphigus and eczema), malignancy and the hyper-eosinophilic syndrome (restrictive cardiomyopathy hepatosplenomegaly and very high eosinophil count).
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62
Q

when does lymphocytosis occur?

A

in response to viral infection, chronic infections (e.g. tuberculosis and toxoplasmosis), chronic lymphocytic leukaemia and some lymphomas.

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63
Q

what is eosinopenia?

A

form of agranulocytosis where the number of eosiophil granulocytes is lower than expected

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64
Q

what can induce eosinopenia?

A
  • stress reactions
  • Cushing’s syndrome
  • steroids
  • burns and acute infections
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65
Q

what is monocytopenia?

A

deficiency of monocytes

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66
Q

what are causes of monocytopenia?

A
  • acute infections
  • stress
  • treatment with glucocorticoids
  • aplastic anaemia
  • hairy cell leukaemia
  • AML
  • treatment with myelotoxic drugs
  • genetic syndromes
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67
Q

what is lymphocytosis?

A

increase in number or proportion of lymphocytes in the blood

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68
Q

what is lymphocytopenia?

A

abnormally low level of lymphocytes in the blood

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69
Q

what is haemostasis?

A
  • haemostasis is the process of blood clot formation at the site of vessel injury.
  • when a blood vessel wall breaks, the haemostatic response must be quick, localized to the site of injury, and carefully regulated.
  • abnormal bleeding or a propensity to non-physiological thrombosis (i.e. thrombosis not required for haemostatic regulation) may occur when specific elements of these processes are missing or dysfunctional.
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70
Q

what is the role of the vessel wall in haemostasis?

A
  • platelet adhesion and thrombus formation is inhibited on the intact endothelium by its negative charge and also by antithrombotic factors (thrombomodulin, heparin sulphate, prostacyclin, nitric oxide, plasminogen activator).
  • injury to vessels leads to immediate vasoconstriction, thus reducing blood flow to the injured area, and endothelial damage results in loss of antithrombotic properties.
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71
Q

what leads to and mediates platelet adherence?

A

intimal injury and exposure of subendothelial elements lead to platelet adherence, via the platelet membrane receptor glycoprotein Ib, to collagen and vWF in the subendothelial matrix

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72
Q

what follows platelet adherence?

A
  • GpIIb/IIIa receptor on platelet surface is exposed, forming a second binding site for vWF
  • deficiency of GPIb or vWF leads to congenital bleeding disorders
73
Q

what causes Bernard-Soulier disease?

A

deficiency of GPIb receptor on platelets - bleeding disorder

74
Q

what causes von Willebrand’s disease?

A

deficiency of vWF - bleeding disorder

75
Q

what happens in platelet aggregation? what leads to it?

A
  • following adhesion, platelets spread along the subendothelium and release the contents of their cytoplasmic granules containing adenosine diphosphate (ADP), serotonin, thromboxane A2, fibrinogen and other factors.
  • ADP leads to a conformational change in the GpIIb/IIIa receptor allowing it to bind to fibrinogen, a dimer that acts as a bridge between platelets and so binds them into aggregates (platelet aggregation).
  • during aggregation, platelet membrane receptors are exposed, providing a surface for the interaction of coagulation factors and ultimately the formation of a stable haemostatic plug.
76
Q

what is the role of ADP in haemostasis?

A

ADP leads to a conformational change in the GpIIb/IIIa receptor allowing it to bind to fibrinogen, a dimer that acts as a bridge between platelets and so binds them into aggregates (platelet aggregation).

77
Q

how does tissue damage cause coagulation?

A

exposes tissue factor which binds to factor VII and this complex has a dual effect of converting factor X to factor Xa and Factor IX to factor IXa

78
Q

what is the role of the tissue factor-factor VII complex in coagulation?

A

this complex has a dual effect of converting factor X to factor Xa and Factor IX to factor IXa

79
Q

what is the effect of factor VIII in coagulation?

A

increases the activity of factor IXa by about 200000 fold

80
Q

what is vWF synthesised by?

A

endothelial cells and megakaryocytes

81
Q

what are the vitamin K dependent enzymes?

A

prothrombin (II), VII, IX and X

82
Q

what catalyses the conversion of factor X to Xa?

A
  • complex VIIa-TF
  • complex IXa-VIIIa
  • TFPI inhibits it
83
Q

what is prothrombin converted into? what catalyses this?

A
  • prothrombin -> thrombin

- Xa and Va catalyse

84
Q

what is the action of thrombin in coagulation?

A
  • thrombotic activation of Va, IXa-VIIIa complex and XI

- converts fibrinogen to fibrin

85
Q

what is the action of factor XI?

A

converted into factor IX

86
Q

what converts fibrinogen into fibrin?

A

thrombin

87
Q

what are physiological limitations of coagulation?

A
  • coagulation would lead to dangerous occlusion of blood vessels if it was not limited to the site of injury by protective mechanisms.
  • antithrombin binds to and forms complexes with coagulation factors, thereby inactivating them. its activity is increased by heparin.
  • activated protein C inactivates factors V and VIII and this is enhanced by the cofactor, protein S.
  • inherited deficiency or abnormality of these natural anticoagulant proteins is termed thrombophilia and places the patient at increased risk of venous thromboembolism
88
Q

what are some anticoagulant proteins?

A
  • antithrombin
  • protein C
  • protein S
89
Q

what is thrombophilia?

A

inherited deficiency or abnormality of natural anticoagulant proteins (antithrombin, protein C and S)

90
Q

what is the action of antithrombin?

A
  • bind to and forms complexes with coagulation factors, thereby inactivating them
  • its activity is increased by heparin
91
Q

what is the action of activated protein C?

A
  • inactivates factors V and VIII

- activity is enhanced by its cofactor protein S

92
Q

what is fibrinolysis?

A
  • fibrinolysis is a normal haemostatic response that helps to restore vessel patency after vascular damage.
  • the plasma protein plasminogen is converted to plasmin by activators (principally tissue plasminogen activator, tPA) released from endothelial cells.
  • plasmin breaks down fibrin and fibrinogen into fragments collectively known as fibrin degradation products (FDPs), which include D-dimers.
93
Q

what is the action of plasmin?

A

breaks down fibrin and fibrinogen into fragments called fibrin degradation products, which include D-dimers

94
Q

what converts plasminogen into plasmin?

A

activators (principally tissue plasminogen activator, tPA) released from endothelial cells

95
Q

what are hereditary blood vessel defects leading to bleeding disorders?

A
  • hereditary haemorrhagic telangiectasia

- connective tissue disorders, e.g. Marfan’s, Ehlers–Danlos syndromes

96
Q

what are acquired blood vessel defects leading to bleeding disorders?

A
  • severe infections, e.g. meningococcal, typhoid
  • drugs: steroids, sulphonamides
  • allergic: Henoch–Schönlein purpura, autoimmune rheumatic disorders
  • others: scurvy, senile purpura, easy bruising syndrome
97
Q

what are platelet defects which lead to bleeding disorders?

A
  • thrombocytopenia
  • platelet dysfunction:
    inherited, e.g. Bernard–Soulier syndrome
    acquired: renal and liver disease, paraproteinaemias, platelet inhibitory drugs, e.g. aspirin
98
Q

what are hereditary coagulation defects which lead to bleeding disorders?

A

haemophilia A or B, von Willebrand’s disease

99
Q

what are acquired coagulation defects which lead to bleeding disorders?

A

anticoagulant treatment, liver disease, disseminated intravascular coagulation

100
Q

what is vascular/platelet bleeding characterised by?

A
  • characterized by bruising of the skin and bleeding from mucosal membranes.
  • bleeding into the skin is manifest as petechiae (small capillary haemorrhages, a few millimetres in diameter) and superficial ecchymoses (larger areas of bleeding).
101
Q

what does the prothrombin time show?

A
  • evaluates extrinsic pathway and common pathway of coagulation
  • prolonged with abnormalities of factors VII, X, V, II or I, liver disease or if the patient is on warfarin
102
Q

what is INR?

A
  • international normalised ratio

- ratio of the patient’s prothrombin to a normal control when using the international reference preparation

103
Q

what causes a prolonged PT?

A

prolonged with abnormalities of factors VII, X, V, II or I, liver disease or if the patient is on warfarin

104
Q

what is the APTT? which factors does it measure?

A
  • activated partial thromboplastin time
  • characterises coagulation of the blood
  • monitors treatment effect of heparin
  • measures intrinsic and common pathways of coagulation; I, II, V, VIII, X, XI and XII
105
Q

which factors does the PT measure?

A

I, II, V, VII, X

106
Q

when is APTT prolonged?

A
  • prolonged with deficiencies or inhibitors of one or more of the following factors: XII, XI, IX, VIII, X, V or I (but not factor VII).
  • heparin prolongs the APTT.
107
Q

what is TT?

A
  • thrombin time
  • blood tests that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added
  • used to diagnose coagulation disorders and to assess the effectiveness of fibrinolytic therapy
  • compares rate of clot formation to that of a sample of normal pooled plasma
108
Q

when is TT prolonged?

A

prolonged with fibrinogen deficiency, dysfibrinogenaemia (normal levels but abnormal function), heparin treatment or DIC.

109
Q

what is the bleeding time? when is it abnormal?

A

The bleeding time is a measure of the interaction of platelets with the blood vessel wall and is abnormal in von Willebrand’s disease, in blood vessel defects, and when there is a decrease in the number or function of platelets.

110
Q

what is the definition of thrombocytopenia?

A

platelet count <150 x 10^9/L

111
Q

what are causes of platelet disorders?

A
  • thrombocytopenia
  • disorders of platelet function e.g. those with aspirin treatment and uraemia
  • congenital abnormalities of platelet number (e.g. Fanconi’s anaemia, Wiskott-Aldrich syndrome) or function (e.g. Bernard-Soulier syndrome) are all rare
112
Q

what are causes of impaired production of platelets which leads to thrombocytopenia?

A
  • bone marrow failure
  • megaloblastic anaemia
  • leukaemia
  • myeloma
  • myelofibrosis
  • myelodysplasia
  • solid tumour infiltration
  • aplastic anaemia
  • HIV infection
113
Q

what are causes of excessive destruction of platelets which leads to thrombocytopenia?

A
  • immune
  • autoimmune; ITP
  • secondary immune (SLE, CLL, viruses, drugs)
  • post-transfusion purpura
  • DIC
  • TTP
  • haemolytic uraemic syndrome
  • sequestration
  • hypersplenism
  • dilutional
  • massive transfusion
114
Q

what is Haemophilia A? what is its epidemiology?

A
  • genetic deficiency of factor VIII
  • inherited as an X-linked recessive
  • affects 1 in 5000 males
115
Q

how can haemophilia A be categorised?

A
  • levels < 1 IU/dL (severe disease)
  • levels 1-5 IU/dL
  • levels > 5 IU/dL
116
Q

what are the clinical features of haemophilia A with plasma levels of factor VIII <1 IU/dL?

A
  • severe disease

- associated with frequent spontaneous bleeding into muscles and joints that can lead to a crippling arthropathy.

117
Q

what are clinical features of haemophilia A with plasma levels of factor VIII 1-5 IU/dL?

A

associated with severe bleeding following injury and occasional apparently spontaneous episodes

118
Q

what are clinical features of haemophilia A with plasma levels of factor VIII >5 IU/dL?

A

produces mild disease with bleeding only with trauma or surgery

119
Q

what are the investigations of haemophilia A?

A
  • there is a prolonged APTT and reduced plasma level of factor VIII.
  • the PT, bleeding time and vWF are normal.
120
Q

what is the management of haemophilia A?

A
  • intravenous infusion of recombinant factor VIII concentrate is the treatment of choice and is used in preference to plasma-derived concentrates where possible. given as prophylaxis, e.g. before and after surgery, or to treat an acute bleeding episode. patients with severe haemophilia are given prophylaxis three times weekly from early childhood to prevent permanent joint damage. many patients also have a supply of factor VIII concentrate at home to inject at the first sign of bleeding.
  • synthetic vasopressin (desmopressin) – intravenous, subcutaneous or intranasal administration – raises the level of factor VIII and is used to treat some patients with mild haemophilia.
  • patients should be vaccinated against hepatitis A and B and encouraged to take part in exercise regimens that avoid contact sport.
121
Q

what are complications of haemophilia A?

A
  • recurrent bleeding into joints leads to deformity and arthritis.
  • the risk of infection (hepatitis C and HIV) from multiple transfusions of plasma-derived clotting factor concentrates has been virtually eliminated because of the exclusion of high-risk blood donors, screening of donors and heat treatment of factor VIII concentrates.
  • ten per cent of people with haemophilia develop antibodies to factor VIII, and may need massive doses to overcome this. recombinant factor VIIa is also used to ‘bypass’ the inhibitor.
122
Q

what is haemophilia B? what is its epidemiology and treatment?

A
  • this is the result of a deficiency of factor IX, and affects 1 in 30 000 males.
  • inheritance and clinical features are the same as for haemophilia A.
  • treatment is with factor IX concentrates. desmopressin is ineffective
123
Q

what does vWF deficiency lead to?

A

defective platelet function and factor VIII deficiency

124
Q

what are clinical features of vWF disease?

A
  • types 1 and 2 are mild forms, with autosomal dominant inheritance, and characterized by mucosal bleeding (nose bleeds and gastrointestinal bleeding) and prolonged bleeding after dental treatment or surgery.
  • type 3 patients (recessively inherited) have more severe bleeding, but rarely experience the joint and muscle bleeds seen in haemophilia A.
125
Q

what are investigations of vWF disease?

A
  • prolonged bleeding time reflects a defect in platelet adhesion.
  • there is a prolonged APTT, normal PT and decreased plasma levels of VIII : C and vWF.
126
Q

what is the management of vWF disease?

A

this depends on the severity of the bleeding, and includes treatment with desmopressin and factor VIII concentrates, which contain vWF.

127
Q

what are features of vitamin K deficiency? what is its clinical presentation and treatment?

A
  • vitamin K is needed for the formation of active factors II, VII, IX and X.
  • deficiency occurs with malnutrition, malabsorption and with warfarin treatment (an inhibitor of vitamin K synthesis).
  • there is an increase in PT and APTT.
  • treatment is with phytomenadione
128
Q

how does the clinical presentation of arterial and venous thrombosis vary? why?

A
  • arterial thrombosis results in a cold, pale, pulseless limb because the blood can’t get there
  • venous thrombosis results in a warm, swollen, red limb because blood can’t leave
129
Q

what are side effects of heparin therapy?

A
  • bleeding and thrombocytopenia

- platelet count should be measured in all patients receiving heparin for more than 5 days

130
Q

what is a target 2.5 INR associated with?

A

pulmonary embolism, deep vein thrombosis, symptomatic inherited thrombophilia, atrial fibrillation, cardioversion, mural thrombus, cardiomyopathy

131
Q

what is a target 3 INR associated with?

A

prevention of embolisation after insertion of mechanical prosthetic aortic valves

132
Q

what is a target 3.5 INR associated with?

A

recurrence of venous thromboembolism while on warfarin therapy, antiphospholipid syndrome, prevention of embolisation after insertion of mechanical prosthetic mitral valves, coronary artery graft thrombosis

133
Q

what are some other anticoagulant drugs?

A
  • fondaparinux
  • hirudins
  • dabigatran and rivaroxaban
134
Q

what is fondaparinux?

A

a synthetic pentasaccharide that inhibits factor X and is similar to the LMWHs

135
Q

what are hirudins? when are they used?

A
  • direct thrombin inhibitors.
  • bivalirudin is used in percutaneous coronary interventions and lepirudin is used for anticoagulation in patients with heparin-induced thrombocytopenia
136
Q

what is dabigatran?

A
  • direct thrombin inhibitor
  • given orally
  • prophylaxis of venous thromboembolism after total hip or knee replacement surgery
137
Q

what is rivaroxaban?

A
  • inhibitor of factor X
  • given orally
  • prophylaxis of venous thromboembolism after total hip or knee replacement surgery
138
Q

what are indications for oral iron therapy?

A
  • treatment of iron deficiency, prophylaxis in patients with risk factors for iron deficiency, e.g. malabsorption, menorrhagia, pregnancy and post-gastrectomy.
  • iron and folic acid combination preparations are used in pregnancy for women who are at risk of developing iron and folic acid deficiency.
139
Q

what are examples of oral iron?

A
  • ferrous sulphate (200mg)

- ferrous gluconate (300mg)

140
Q

what are side effects of oral iron?

A
  • constipation and diarrhoea.
  • nausea and epigastric pain are related to the amount of elemental iron ingested and are lower with preparations containing a low elemental iron content, e.g. ferrous gluconate.
141
Q

what are cautions/contraindications of oral iron?

A

avoid long-term use unless indicated; excretion of iron is fixed at 1–2 mg of iron per day through gastrointestinal loss, and prolonged use may result in iron overload.

142
Q

what are indications for folic acid tablets?

A
  • folate-deficient megaloblastic anaemia
  • prevention of folic acid deficiency in chronic haemolytic states
  • renal dialysis and pregnancy
  • prevention of neural tube defects.
143
Q

what are side effects and cautions/contraindications of folic acid?

A
  • very rarely, allergic reactions
  • folic acid should not be used in undiagnosed megaloblastic anaemia unless vitamin B12 is administered concurrently, otherwise neuropathy may be precipitated
144
Q

what are examples of vitamin B12 tablets?

A
  • hydroxocobalamin

- cyanocobalamin

145
Q

what are side effects of vitamin B12?

A
  • itching, fever, nausea, dizziness, anaphylaxis after injection.
  • hypokalaemia, sometimes fatal, is due to intracellular potassium shift on anaemia resolution after treatment of severe vitamin B12 deficiency.
146
Q

what are cautions/contraindications of vitamin B12?

A

contraindicated if hypersensitivity to hydroxocobalamin or any component of preparation.

147
Q

what are indications for vitamin K?

A
  • water-soluble form used to prevent deficiency in patients with fat malabsorption (especially biliary obstruction or hepatic disease)
  • intravenous form for excessive anticoagulation with warfarin and in patients with prolonged INR (due to fat malabsorption) prior to invasive procedures (e.g. endoscopic retrograde cholangiopancreatography or liver biopsy) or in whom there is bleeding.
148
Q

what are examples of vitamin K tablets?

A
  • phytomenadione

- menadiol sodium phosphate

149
Q

what are side effects of vitamin K?

A

anaphylaxis with IV preparation

150
Q

what are cautions/contraindications of vitamin K?

A

caution with menadiol in G6PD deficiency and vitamin E deficiency (risk of haemolysis).

151
Q

what are examples of antiplatelet agents?

A
  • aspirin, dipyridamole
  • clopidogrel, prasugrel, ticagrelor
  • glycoprotein GPIIb/IIIa inhibitor.
152
Q

what is the mechanism of action of aspirin?

A

aspirin irreversibly inhibits the enzyme cyclo-oxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation

153
Q

what is the mechanism of action of dipyridamole?

A

dipyridamole inhibits phosphodiesterase-mediated breakdown of cyclic adenosine monophosphate (AMP), which leads to impaired platelet activation by multiple mechanisms.

154
Q

what is the mechanism of action of clopidogrel? what is it metabolised by?

A
  • clopidogrel is a pro-drug that is metabolized by the liver, partly by cytochrome P450 2C19, before it is biologically active.
  • it blocks binding of ADP to platelet receptors and thus inhibits activation of the GpIIb/IIIa complex and platelet activation
155
Q

what is the mechanism of action of glycoprotein GpIIb/IIIa inhibitors?

A

Glycoprotein GpIIb/IIIa inhibitors (e.g. abciximab, eptifibatide, tirofiban) prevent platelet aggregation by blocking the binding of fibrinogen to receptors on platelets. They are used as an adjunct to percutaneous coronary intervention in selected patients with acute coronary syndromes

156
Q

what are the side effects of antiplatelet agents?

A
  • increased bleeding risk
  • aspirin causes peptic ulceration. patients with a past history of ulceration must be co-prescribed a proton pump inhibitor (PPI) with aspirin, to prevent recurrent ulceration.
  • in patients with a history of peptic ulcer bleeding while taking aspirin, co-administration of a PPI is associated with a reduced rate of re-bleeding compared with administration of clopidogrel alone.
157
Q

what are cautions/contraindications to antiplatelet agents?

A
  • active bleeding, haemophilia and other bleeding disorders are contraindications.
  • aspirin also causes bronchospasm and must be prescribed with caution to patients with asthma.
  • aspirin interacts with a number of other drugs, and its interaction with warfarin is a special hazard
  • drugs that inhibit CYP2C19 (fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol) reduce the efficacy of clopidogrel and should be avoided.
158
Q

what are some drugs that inhibit CYP2C19 and thus reduce efficacy of clopidogrel?

A

fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol

159
Q

what are examples of thrombin inhibitors?

A
  • heparin
  • fondaparinux
  • bivalirudin
160
Q

what is the mechanism of action of thrombin inhibitors (heparin, fondaparinux and bivalirudin)?

A
  • unfractionated heparin is not a single substance but a mixture of polysaccharides which binds to and activates antithrombin (AT), which inactivates thrombin and other proteases involved in blood clotting, particularly factor Xa.
  • usually, LMWH is used, due to its superior bioavailability and longer half-life.
  • fondaparinux binds to AT and inhibits only factor Xa.
  • bivalirudin is a direct thrombin inhibitor.
161
Q

what are indications for thrombin inhibitors?

A
  • LMWH, produced by the enzymatic or chemical breakdown of the heparin molecule, is almost always used for the prevention and treatment of DVT and pulmonary embolism, myocardial infarction and acute coronary syndromes.
  • for patients at high risk of bleeding, unfractionated heparin (which requires monitoring by measurement of APPT) is more suitable than LMWH because its effect can be terminated rapidly by stopping the infusion.
162
Q

what are side effects of thrombin inhibitors?

A
  • haemorrhage
  • thrombocytopenia, which is immune mediated and does not usually develop until after 5–14 days after first exposure; it may be complicated by thrombosis.
  • hyperkalaemia due to aldosterone secretion
  • osteoporosis after prolonged use
163
Q

what are cautions/contraindications of thrombin inhibitors?

A
  • active bleeding, acquired or inherited bleeding disorders
  • thrombocytopenia (platelets < 75 × 109/L)
  • recent cerebral haemorrhage
  • severe liver disease, severe untreated hypertension (> 230/120 mmHg)
  • recent surgery to eye or nervous system
  • history of heparin-induced thrombocytopenia
  • lumbar puncture/epidural within the past 4 hours or expected within the next 12 hours
  • acute stroke
164
Q

what is the mechanism of action of warfarin?

A

warfarin, a coumarin, inhibits vitamin K-dependent γ-carboxylation of coagulation factors II, VII, IX and X, thus leading to biologically inactive forms. monitoring is by measurement of the INR.

165
Q

what are indications for warfarin?

A
  • prophylaxis of embolization in atrial fibrillation, cardioversion, dilated cardiomyopathy and mechanical prosthetic aortic or mitral valve insertion
  • prophylaxis and treatment of venous thrombosis and pulmonary embolism.
  • advise to avoid cranberry juice (increases INR).
166
Q

what are side effects of warfarin?

A
  • skin necrosis in patients with protein C or protein S deficiency, occurs soon after starting treatment.
  • haemorrhage; management is based on the INR and whether there is major or minor bleeding
167
Q

what are contraindications to warfarin?

A
  • underlying abnormalities of haemostasis (e.g. haemophilia, thrombocytopenia)
  • hypersensitivity to warfarin or any of the excipients
  • after an ischaemic stroke for 2–14 days depending on the size of infarct and blood pressure
  • surgery – stop warfarin 3 days prior to surgery if there is a risk of severe bleeding
  • severe uncontrolled hypertension
  • active peptic ulceration
  • severe liver disease
  • pregnancy – teratogenic in first trimester and risk of placental or fetal haemorrhage in third trimester. warfarin can be used during breast-feeding.
168
Q

what are drugs that increase warfarin activity?

A

alcohol, allopurinol, amiodarone, aspirin and other NSAIDs, omeprazole, ciprofloxacin, clofibrate, co-trimoxazole, dipyridamole, macrolide antibiotics such as erythromycin, metronidazole, statins, tamoxifen and levothyroxine

169
Q

what are drugs that decrease warfarin activity?

A

carbamazepine, rifampicin, rifabutin, griseofulvin and some herbal remedies, e.g. St John’s wort

170
Q

what is the mechanism of action of NOACs?

A
  • these orally active drugs directly inhibit either thrombin (e.g. dabigatran) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban).
  • NOACs have a much broader therapeutic window than warfarin, have fewer drug interactions (aside from stronger inducers and inbitors of P-glycoprotein and CYP3A4) and offer fixed drug dosing without the need for regular monitoring.
171
Q

what are indications for NOACs?

A

prevention of stroke in atrial fibrillation, treatment of venous thromboembolism and prevention of thrombosis in hip and knee replacement surgery.

172
Q

what are examples of NOACs?

A

dagibatran, rivaroxaban, apixaban, edoxaban

173
Q

what are side effects of NOACs?

A

NOACs have higher rates of gastrointestinal haemorrhage but lower rates of intracranial haemorrhage than warfarin. Specific antidotes are now available. If bleeding occurs on these new agents that requires anticoagulant reversal, partially using prothrombin complex concentrates. All agents have relatively short half-lives (< 14 hours) and will wear out of the circulation relatively quickly.

174
Q

what are contraindications to NOACs?

A

having significant hepatic dysfunction or renal impairment, due to their hepatic and renal excretion.

175
Q

what is the mechanism of action of fibrinolytic drugs?

A

fibrinolytic drugs hydrolyse a peptide bond in plasminogen to yield the active enzyme, plasmin, which promotes clot lysis.

176
Q

what are indications for fibrinolytic drugs?

A
  • acute myocardial infarction within 12 hours of symptom onset
  • selected cases of venous thromboembolism
  • acute ischaemic stroke within 4.5 hours of symptom onset.
177
Q

what are examples of fibrinolytic drugs?

A

alteplase, streptokinase

178
Q

what are side effects of fibrinolytic drugs?

A
  • indiscriminate activation of plasminogen both in clots and in the circulation, leading to an increased risk of haemorrhage.
  • other side effects are cardiac arrhythmias during reperfusion of the myocardium, hypotension and allergic reactions (bronchospasm, urticaria) with streptokinase.
179
Q

what are contraindications to fibrinolytic drugs?

A

gastrointestinal or genitourinary bleeding (within the previous 21 days), aortic dissection, severe uncontrolled hypertension, intracranial aneurysm, recent major trauma/surgery/head injury or invasive diagnostic procedure, recent stroke, bleeding disorders, pregnancy or recent obstetric delivery, INR > 1.7 if on warfarin.

Phase 2A (28 decks)

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