HH M2 Content__CA2__Systemic Pathology__Blood Patho

Question 1

what are the functions of blood

Answer 1

<ol><li>transport nutrients and O2</li><li>transport waste to kidneys and liver</li><li>transport of WBCs and antibodies to fight infection</li><li>transport of platelets and clotting factors to form clot&nbsp;</li><li>regulation of body temperature</li></ol>

Question 2

5 types of white blood cells & their morphologies 

Answer 2

<ul><li>granulocytes&nbsp;</li><ul><li>neutrophils: multilobed nucleus, pale red and blue cytoplasmic granules&nbsp;</li><li>eosinophils: bilobed nucleus, red cytoplasmic granules</li><li>basophils: bilobed nucleus, purplish-black cytoplasmic granules&nbsp;</li></ul><li>agranulocytes&nbsp;</li><ul><li>lymphocytes: large spherical nucleus, thin rim of pale blue cytoplasm&nbsp;</li><li>monocytes: kidney shaped nucleus, abundant pale blue cytoplasm&nbsp;</li></ul></ul>

<div><img></img><br></br></div>

Question 3

what are the main growth factors which regulate hematopoiesis

Answer 3

<ul><li>erythropoietin (RBCs)</li><li>thrombopoietin (platelets)</li><li>granulocyte colony stimulating factor (granulocytes)&nbsp;</li></ul>

<div><img></img><br></br></div>

Question 4

what are the causes of reduced production of blood cells

Answer 4

<ul><li><b>primary bone marrow failure (congenital/acquired)</b></li><ul><li>stem cells are not developing properly (eg in megaloblastic anaemia there is ineffective thrombopoiesis due to defective precursor)&nbsp;</li><li>no GFs to produce (eg in kidney failure there is reduced erythropoietin; in chemotherapy there is reduced GCSF)</li></ul><li><b>bone marrow infiltration</b></li><ul><li>congenital: storage disorders&nbsp;</li><li>acquired: heme malignancies, solid tumours&nbsp;</li></ul><li>hematinic/hormone deficiency</li><li>infection</li><li>autoimmune</li><li>drugs</li></ul>

Question 5

what are the causes of increased destruction of blood cells/blood loss

Answer 5

<ul><li>congenital</li><li>acquired&nbsp;</li><ul><li>immune: autoimmune neutropenia (destroys neutrophils), immune thrombocytopenia (destroys platelets)</li><li>non-immune: <b>hemolytic anaemia</b> (destroys RBCs)</li></ul><li><b>acute bleeding</b></li><li>sequestration</li></ul>

Question 6

what are the signs and symptoms of anaemia

Answer 6

fatigue, pallor, dyspnea

Question 7

what are the signs and symptoms of erythrocytosis

Answer 7

plethoric appearance, hyperviscosity with hypoxia and/or clotting

Question 8

what are the signs and symptoms of thrombocytopenia

Answer 8

petechiae, bleeding

Question 9

what are the signs and symptoms of thrombocytosis

Answer 9

bleeding (due to defective platelet function) or clotting

Question 10

what are the signs and symptoms of neutropenia 

Answer 10

increased susceptibility to fungal/bacterial infection

Question 11

what are the signs and symptoms of lymphopenia

Answer 11

susceptibility to viral infections

Question 12

what to look for in FBC

Answer 12

<ul><li>hemoglobin</li><ul><li>if anaemia is present, look for MCV (size) and MCH (colour) to determine the type of haemoglobin&nbsp;</li></ul><li>white cell&nbsp;</li><li>platelet&nbsp;</li><li>peripheral blood film</li></ul>

Question 13

what is anaemia

Answer 13

defined as haemoglobin which is lower than the reference range for the individual, which depends on the age/gender of the patient

Question 14

what do the symptoms of anaemia depend on

Answer 14

<ul><li>age</li><li>comorbidities</li><li>speed of onset (acute/chronic)</li><li>severity&nbsp;</li></ul>

Question 15

what are the general symptoms and signs of anaemia

Answer 15

usually result from <u>hypoperfusion</u> due to compromised O2 transport<div><ul><li>symptoms</li><ul><li>fatigue and low energy</li><li>increased heart rate </li><li>shortness of breath </li><li>headache </li><li>dizziness</li><li>chest pain </li></ul><li>signs</li><ul><li>conjunctival pallor (Hb <9)</li><li>skin crease pallor (Hb <7)</li><li>cardiac compensation (Hb <8) → high output failure (Hb <5) <br></br></li></ul></ul></div>

Question 16

classification of anaemia based on cell size + causes

Answer 16

look at <span>MCV</span> <div><ul><li>microcytic</li><ul><li><b>iron deficiency</b></li><li><b>thalassaemia</b></li><li>inflammatory anaemia</li><li>sideroblastic anaemia (cannot use iron in synthesis of RBCs → cannot extrude nucleus →  accumulate in mitochondria in RBCs → <u>ringed appearance in the nucleus</u>) <br></br></li></ul><li>normocytic (classified according to <u>mechanism</u>)</li><ul><li>increased destruction: sequestration, <b>acute bleeding, haemolysis </b></li><li>decreased production: renal anaemia (decreased EPO synthesis), inflammatory anaemia, marrow disease, myeloma</li><li>dilutional</li></ul><li>macrocytic</li><ul><li><b>B12/folate deficiency</b></li><li>drugs</li><li>reticulocytosis</li><li>alcohol resulting in liver disease</li><li>pregnancy</li><li>hypothyroidism</li><li>myelodysplastic syndrome (cancer which prevents maturation of blood cells in the bone marrow)</li></ul></ul></div>

Question 17

how to classify anaemia based on mechanism 

Answer 17

use <span>reticulocyte count</span> in peripheral blood film<div>increased reticulocyte count indicates increased bone marrow activity</div>

Question 18

what are the different mechanisms of anaemia

Answer 18

<ul><li>decreased production</li><ul><li>haematinic (nutrient) deficiencies: iron, B12/folate</li><li>primary bone marrow failure (stem cell/GF deficiency)</li><li>secondary bone marrow failure (infiltration with malignancies)</li></ul><li>increased production</li><ul><li>increased destruction (haemolysis, can be due to immune/non-immune causes)</li><li>increased loss due to bleeding&nbsp;</li><li>sequestration (splenomegaly)</li></ul><li>dilutional (increased plasma volume)</li><ul><li>pregnancy</li><li>fluids</li><li>transfusion</li></ul></ul>

Question 19

characteristics of iron deficiency anaemia in FBC

Answer 19

<span>microcytic, hypochromic anaemia</span> <div><ul><li>low RBC count </li><li>smaller than normal (in peripheral blood film, a normal RBC = lymphocyte nucleus)</li><li>pale cell (in normal RBC, the pale central disk should only be 1/3 of RBC size)</li><li>different shape </li></ul></div>

Question 20

what are the hallmark investigations of iron deficiency anaemia 

Answer 20

<ul><li><b>ferritin &lt; 30microg/L&nbsp;</b></li><ul><li>main iron storage protein</li><li>low levels indicate low iron stores&nbsp;</li></ul><li><b>TIBC increased&nbsp;</b></li><ul><li>transferrin is the iron transport protein, which <u>increases</u>&nbsp;in iron deficiency to help absorb iron</li><li>TIBC reflects the number of iron binding sites on transferrin, therefore increase in transferrin = increase in TIBC&nbsp;</li></ul></ul>

Question 21

what are the causes of iron deficiency anaemia

Answer 21

<ul><li><b>increased iron loss</b></li><ul><li>GI bleeding (ulcerations)</li><li>regular blood donation</li><li>menstruation</li><li>iron loss through sweating</li><li>drugs (eg NSAIDs, aspirin, blood thinners)</li></ul><li><b>increased iron requirements</b></li><ul><li>children aged 0-5</li><li>adolescent girls</li><li>pregnancy</li><li>women of childbearing age</li></ul><li><b>decreased intake and malabsorption</b></li><ul><li>vegetarianism</li><li>drugs which reduce stomach acidity</li><li>lack of balanced diet&nbsp;</li><li>GI ulcers/infections</li><li>Removal of duodenum (Dude Is Just Feeling Ill Bro)</li></ul></ul>

Question 22

solution to iron deficiency anaemia 

Answer 22

<span>oral iron supplementation</span><div><ul><li>if it is NOT an absorption problem</li><li>aims to increase Hb by ~1g/dL every week</li><li>continue 3-6 months after Hb normalises to restore iron stores</li><li>for non-responders, consider looking for ongoing loss or try IV iron</li></ul></div>

Question 23

possible side effects of iron supplements

Answer 23

note: common reasons for non-compliance <div><ul><li>upset stomach</li><li>nausea</li><li>diarrhoea</li><li>faintness</li><li>vomiting </li><li>dark stools</li><li>constipation</li></ul></div>

Question 24

what is thalassaemia

Answer 24

inherited disorders caused by mutations that <b>decrease the synthesis</b> of alpha/beta globin chains<b> </b>(e.g alpha and beta thalassaemia)

Question 25

what is haemoglobinopathy

Answer 25

haemoglobin <b>variant </b>resulting from a genetic mutation (e.g haemoglobin S in sickle cell anaemia)

Question 26

inheritance pattern of thalassemia 

Answer 26

both alpha and beta thalassemia are <b>autosomal recessive</b><div><br></br></div><div><img></img><img></img><br></br></div>

Question 27

pathogenesis of alpha thalassemia

Answer 27

different clinical presentations arise due to the different number of deletions of alpha genes <div>encoded by 2 gene loci, 4 alleles preset<br></br><div><ul><li>0-1 mutations: asymptomatic</li>

<li>2 mutations: mild symptoms</li>

<li>3-4 symptoms: severe (insufficient α globin proteins → insufficient haemoglobin → incompatible with life)</li>

</ul><div><img></img><br></br></div></div></div>

Question 28

pathogenesis of beta thalassemia 

Answer 28

<div>encoded by 1 gene loci, 2 alleles present<br></br></div>

<ul>
<li>0 mutations: asymptomatic</li>
<li>1 mutation: mild anaemia</li>
<li>2 mutations: severe anaemia but compatible with life</li></ul>

<div><img></img><br></br></div>

Question 29

peripheral blood film appearance of thalassemia RBCs 

Answer 29

<b>microcytic hypochromic + target cells </b><div><br></br></div><div>just think of thal RBCs as small, sad and targeted? LOL</div>

Question 30

clinical features of thalassemia

Answer 30

<div>abnormal association of gene → abnormal haemoglobin → hemolysis</div>

<ul>
<li><b>jaundice</b> (due to excessive release of heme)</li>
<li><b>enlarged skull</b> (hemaropoiesis in bone marrow in areas which do not usually produce RBCs)</li>
<li><b>hepatomegaly</b> (compensation due to anaemia, hematopoiesis in liver)</li>
<li><b>splenomegaly </b>(destruction in RBCs)</li></ul>

Question 31

pathogenesis of sickle cell anaemia

Answer 31

point mutation of beta globulin gene, leading to cells becoming sickle shaped (structural abnormalities) <div>autosomal recessive condition, carrier has a selective advantage in malaria endemic countries </div>

Question 32

what are the investigations to be done for suspected megaloblastic anaemia & hallmark findings

Answer 32

<ul><li><b>blood film</b>: macro-ovalocytes, hypersegmented neutrophils</li><li><b>haemolysis</b>: increased lactate dehydrogenase, increased unconjugated bilirubin due to increased intramedullary hemolysis&nbsp;</li><li><b>serology</b>: intrinsic factor antibodies (blocking/binding) which decreases B12/folate absorption from the gut (ileum) (Dude Is Just Feeling<b> Ill Bro</b>)</li><ul><li>note: need to exclude B12 deficiency as cause of macrocytosis as <b><font>B12 deficiency can lead to permanent neurological damage</font></b></li></ul></ul>

Question 33

how to approach haemolysis

Answer 33

<ol><li>is patient hemolysing</li><li>is it immune related</li><li>history taking</li></ol>

Question 34

what are the evidences which point to hemolysis

Answer 34

<ul><li><b>biochemical markers&nbsp;</b></li><ul><li><b>increased lactate dehydrogenase&nbsp;</b></li><li><b>increased unconjugated bilirubin</b></li><li><b>decreased haptoglobin</b> (which binds<b> free haemoglobin</b> in the blood, which is released from RBC during haemolysis) (haptoglobin-hb complex will then be removed by the spleen)</li></ul><li><b>morphological</b> (from peripheral blood film)</li><ul><li>spherocytes, usually hinting at immune cause</li><li>bite/blister cells, usually hinting at oxidative hemolysis</li><li>fragments, usually hinting at microangiopathic hemolytic anaemia&nbsp;</li></ul></ul>

Question 35

how to determine if haemolytic anaemia is immune related

Answer 35

use <b>Direct Coombs Test (DCT)</b><div>will test <u>positive</u> in </div><div><ul><li>autoimmune haemolytic anaemia</li><li>delayed haemolytic transfusion reaction</li><li>cold agglutinin disease (involves IgM)</li></ul></div>

Question 36

link between inflammation and anaemia

Answer 36

<ol><li><b>drives haematopoiesis towards myelopoiesis</b> → <b>decreases erythropoietin</b> →&nbsp; decreased erythropoiesis&nbsp;</li><li>hepcidin release from the liver is increased → reduces iron available for erythropoiesis as it inhibits iron release from reticuloendothelial system</li><li>increased phagocytosis of RBCs&nbsp;</li></ol>

Question 37

biomarkers for anemia of inflammation

Answer 37

LOW percentage of hypochromic erythrocytes, serum transferrin<div>HIGH serum ferritin and hepcidin </div><div>NORMAL MCV, MCH and reticulocyte count </div>

Question 38

platelet-type vs coagulation-type bleeding disorder symptoms 

Answer 38

<img></img>

Question 39

what are the first line investigations of bleeding disorders (and what it checks for)

Answer 39

<ul><li><b>full blood count</b> (assess platelet count)</li><li><b>peripheral blood film</b> (morphology, especially in congenital problems)&nbsp;</li><li><b>PT</b> (extrinsic pathway, add tissue factor to test)</li><li><b>APTT</b> (intrinsic pathway, add activator of XII)</li><li><b>fibrinogen</b> (fibrinogen conversion, add in thrombin)</li></ul>

Question 40

how should a blood sample be taken

Answer 40

<ul><li><b>fill to the top</b>, as too little blood alter the citrate:plasma ratio</li><li><b>add citrate to keep blood uncoagulated</b></li></ul>

Question 41

what are the different clotting assays performed, and what is added to the blood sample

Answer 41

add<b> phospholipid and calcium to all samples</b><div><ul><li>PT: add tissue factor</li><li>APTT: add silica/cephalin</li><li>fibrinogen: add thrombin</li></ul></div>

Question 42

what are the second line bleeding tests 

Answer 42

<ul><li><b>mixing test</b> (after obtaining results which shows prolongation of APTT)&nbsp;</li><ul><li>mix patient's blood with normal plasma&nbsp;</li><li>if there is<b> correction </b>of the APTT, means that there is<b> <u>factor deficiency</u></b></li><li>if there is <b>no correction</b> of the APTT, means that there is an <b><u>inhibitor of specific coagulation factors</u></b></li></ul><li>platelet function test</li><li>specific coagulation factor levels&nbsp;</li><li>specialised tests eg factor inhibitors/lupus anticoagulants</li></ul>

Question 43

what are the potential limitations of bleeding history and investigations 

Answer 43

<u>history</u><div><ul><li>mild bleeding symptoms are also reported in healthy persons (eg epistaxis, gum bleeding, menorrhagia) </li><li><b>pediatric or young adults may not have had any hemostatic challenges </b></li></ul><div><u>investigations</u></div></div><div><ul><li>normal platelet, PT, APTT does not mean no bleeding disorder </li><ul><li>there is no routine global test which incorporates <u>vessel wall, endothelium and fresh whole blood</u></li><li>FBC: numbers only</li><li>APPT/PT: fibrin detection only </li><li>cross-linking of fibrin is NOT studied</li></ul><li>abnormal results do NOT accurately predict bleeding </li></ul></div>

Question 44

how to classify bleeding disorders

Answer 44

<img></img>

Question 45

how to determine the type of thrombocytopenia 

Answer 45

<img></img>

Question 46

how to determine if its a coagulopathy<div>and what are the related causes to the corresponding abnormalities </div>

Answer 46

<div>clotting assays&nbsp;</div>

<img></img>

Question 47

what are the effects of anticoagulants on coagulation tests

Answer 47

<img></img>

Question 48

mode of inheritance of von willebrands disease

Answer 48

autosomal dominant

Question 49

function of von willebrands factor 

Answer 49

<ul><li>carrier protein for factor VIII in plasma&nbsp;</li><li>helps with&nbsp;platelet aggregation and adhesion to damaged endothelium&nbsp;</li></ul>

Question 50

what are the types of von willebrands disease and what are the treatment options

Answer 50

<ul><li>type I: deficiency of VWF → desmopressin or<b>&nbsp;cryoprecipitate</b></li><li>type II: abnormal and dysfunctional VWF → factor VIII concentrate or <b>cyroprecipitate&nbsp;</b></li><li>type III: absent VWF → factor VIII concentrate or <b>cyroprecipitate&nbsp;</b></li></ul>

Question 51

what are the natural anticoagulants 

Answer 51

<ul><li>heparan sulphate (potentiator of antithrombin)</li><li>antithrombin (inactivates factor Xa and thrombin)</li><li>protein c (inactivates factor Va and VIIIa)&nbsp;</li><li>protein s (cofactor for protein c)&nbsp;</li></ul>

Question 52

what are the characteristics of arterial thrombosis 

Answer 52

<ul><li>occurs with endothelial damage&nbsp;</li><li><b>white thrombus (platelet rich)</b></li><li>triggered by rupture of atherosclerotic plaque</li></ul>

<div>Due to high laminar flow, arterial thrombosis is mostly mediated by platelets instead of coagulation factors!</div>

Question 53

what are the complications and treatment for arterial thrombosis 

Answer 53

<ul><li>complications: MI and stroke</li><li>treatment: <b>antiplatelets</b></li></ul>

Question 54

what are the characteristics of venous thrombosis

Answer 54

<ul><li><b>red thrombus </b>(mainly composed of RBCs and fibrin due to <u>low shear flow</u>)</li><li>triggered by area of stasis in the blood</li></ul>

Question 55

what are the complications and treatment of venous thrombosis

Answer 55

<ul><li>complications: DVT and PE</li><li>treatment: <b>anticoagulants</b></li></ul>

Question 56

where is a common site for DVT

Answer 56

deep veins of the legs (popliteal, femoral, iliac)<div><br></br></div><div>Need to name examples of deep veins in exam!!</div>

Question 57

what are the risk factors for thrombosis 

Answer 57

acquired:<b> immobility</b>, <b>surgery</b>, cancer, connective tissue disease, age, catheters <div>inherited: family history (first degree relatives only) </div><div>past history: thrombotic challenges in pregnancy and delivery </div><div><br></br></div><div>Apply virchow’s triad. Endothelial injury, hypercoagulable state, altered blood flow. </div>

Question 58

what is virchow’s triad 

Answer 58

<b>Stasis/Altered blood flow </b><br></br><div><b>Hypercoaguable state</b></div><div><b>Endothelial damage</b></div><div><br></br></div><div><img></img><br></br></div>

Question 59

what are the minor and major <b>transient </b>provoking risk factors for venous thromboembolism

Answer 59

<u>minor</u><div><ul><li>immobilisation</li><li>travel > 8h</li><li>use of estrogen therapy</li><li>pregnancy or puerperium</li><li>leg injury with impaired mobility </li></ul><div><u>major</u></div></div><div><ul><li>major surgery/trauma</li><li>caesarean section</li></ul></div>

Question 60

what are the minor and major <b>persistent</b> provoking factors for venous thromboembolism 

Answer 60

<u>minor</u><div><ul><li>inflammatory bowel disease</li><li>lower extremity paralysis/paresis </li><li>congestive heart failure </li><li>obesity </li><li>family history</li></ul><div><u>major</u></div></div><div><ul><li>active cancer excluding basal/squamous cell skin cancer </li></ul></div>

Question 61

what is antiphospholipid syndrome 

Answer 61

autoimmune disease which can cause frequent clotting in arteries and veins and/or miscarriages<div>results from the presence of proteins in the blood called anti-phospholipid autoantibodies (commonly called aPL) formed against the person’s own tissues</div>

Question 62

what is the mechanism of action of cancer associated thrombosis 

Answer 62

<ul><li>adhesion molecules on cancer cells which cause adhesion to host cells → activate normal host cells → stimulate procoagulant phenotype&nbsp;</li><li>production of inflammatory cytokines &amp; proangiogenic factors → endothelial cell activation → activate normal host cells → stimulate procoagulant phenotype</li></ul>

Question 63

what are the clinical presentations of venous thromboembolism

Answer 63

symptoms and signs of DVT and PE <br></br><ul><li>swollen, painful, red <br></br></li><li>syncope, cough, shortness of breath and pleuretic chest pain </li></ul>

Question 64

what are the differential diagnoses from the symptoms and signs of VTE

Answer 64

<b>swollen leg</b><div><ul><li>muscle cramp/spasm, cellulitis, baker’s cyst </li><li>lymphoedema, chronic venous insufficiency, hematoma </li></ul><div><b>chest pain, SOB </b></div></div><div><ul><li>chest infection, pneumothorax</li><li>heart failure, MI, aortic dissection, pericarditis </li><li>musculoskeletal disorders: contusion, inflammation and fracture </li></ul></div>

Question 65

investigations of suspected venous thromboembolism 

Answer 65

<ul><li><b>d-dimer blood test</b> (formed when fibrin is broken down, indicating presence of previous clot)&nbsp;</li><ul><li><b>sensitive test</b> (negative can help to rule out DVT/PE)</li><li>not specific test (positive does not rule in VTE)&nbsp;</li></ul><li>compression doppler ultrasound</li><li>ct pulmonary angiogram&nbsp;</li></ul>

Question 66

how to use risk stratification on population to screen for DVT/PE

Answer 66

<ol><li>assessment of clinical pretest probability&nbsp;</li><li>d-dimer/imaging with compression ultrasound/CTPA</li></ol>

Question 67

what are the different types of anticoagulants 

Answer 67

<img></img>

Question 68

mode of action of low molecular weight heparin

Answer 68

<b>- binds and activates plasma protease inhibitor antithrombin III </b>→ inactivates coagulation factor Xa<br></br>

Question 69

mode of action of unfractionated hepatin, and the difference from low molecular weight heparin 

Answer 69

<div><div><b>- binds and activates plasma protease inhibitor antithrombin III&nbsp;</b>→ conformational change → exposes its active site --&gt;&nbsp;<b>forms more inactive complexes with coagulation factor IIa, IXa &amp; Xa by 1000 folds</b></div><div>-<b>&nbsp;stimulates tissue factor pathway inhibitor (TFPI) release&nbsp;</b>from endothelium to<b>&nbsp;prevent activation of coagulation factor Xa</b><br></br></div><div><br></br></div>it has a longer polysaccharide side chain that can envelope thrombin, therefore giving <u>enhanced anti Xa and IIa activity</u></div>

Question 70

advantages of using low molecular weight heparin over unfractionated heparin 

Answer 70

UFH is <u>large and negatively charged</u>, therefore leading to more non-specific binding <div><img></img><br></br></div>

Question 71

what is the mode of action of warfarin

Answer 71

inhibition vitamin K reductase leading to inhibition of of vitamin K recycling <div><ul><li>vitamin K-dependent clotting factors (2, 7, 9, 10) have to be carboxylated to become functional</li><li>this process depends on vitamin K</li></ul></div>

Question 72

why are direct oral anticoagulants preferred over warfarin

Answer 72

<div><img></img><br></br></div>