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 variant 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 autosomal recessive

Question 27

pathogenesis of alpha thalassemia

Answer 27

different clinical presentations arise due to the different number of deletions of alpha genes 

encoded by 2 gene loci, 4 alleles preset

• 0-1 mutations: asymptomatic
• 2 mutations: mild symptoms
• 3-4 symptoms: severe (insufficient α globin proteins → insufficient haemoglobin → incompatible with life)

Question 28

pathogenesis of beta thalassemia 

Answer 28

encoded by 1 gene loci, 2 alleles present

• 0 mutations: asymptomatic
• 1 mutation: mild anaemia
• 2 mutations: severe anaemia but compatible with life

Question 29

peripheral blood film appearance of thalassemia RBCs 

Answer 29

microcytic hypochromic + target cells 

just think of thal RBCs as small, sad and targeted? LOL

Question 30

clinical features of thalassemia

Answer 30

abnormal association of gene → abnormal haemoglobin → hemolysis

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

Question 31

pathogenesis of sickle cell anaemia

Answer 31

point mutation of beta globulin gene, leading to cells becoming sickle shaped (structural abnormalities) 

autosomal recessive condition, carrier has a selective advantage in malaria endemic countries 

Question 32

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

Answer 32

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

Question 33

how to approach haemolysis

Answer 33

1. is patient hemolysing
2. is it immune related
3. history taking

Question 34

what are the evidences which point to hemolysis

Answer 34

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

Question 35

how to determine if haemolytic anaemia is immune related

Answer 35

use Direct Coombs Test (DCT)

will test positive in 

• autoimmune haemolytic anaemia
• delayed haemolytic transfusion reaction
• cold agglutinin disease (involves IgM)

Question 36

link between inflammation and anaemia

Answer 36

1. drives haematopoiesis towards myelopoiesis → decreases erythropoietin →  decreased erythropoiesis 
2. hepcidin release from the liver is increased → reduces iron available for erythropoiesis as it inhibits iron release from reticuloendothelial system
3. increased phagocytosis of RBCs 

Question 37

biomarkers for anemia of inflammation

Answer 37

LOW percentage of hypochromic erythrocytes, serum transferrin

HIGH serum ferritin and hepcidin 

NORMAL MCV, MCH and reticulocyte count 

Question 38

platelet-type vs coagulation-type bleeding disorder symptoms 

Answer 38

Question 39

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

Answer 39

• full blood count (assess platelet count)
• peripheral blood film (morphology, especially in congenital problems) 
• PT (extrinsic pathway, add tissue factor to test)
• APTT (intrinsic pathway, add activator of XII)
• fibrinogen (fibrinogen conversion, add in thrombin)

Question 40

how should a blood sample be taken

Answer 40

• fill to the top, as too little blood alter the citrate:plasma ratio
• add citrate to keep blood uncoagulated

Question 41

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

Answer 41

add phospholipid and calcium to all samples

• PT: add tissue factor
• APTT: add silica/cephalin
• fibrinogen: add thrombin

Question 42

what are the second line bleeding tests 

Answer 42

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

Question 43

what are the potential limitations of bleeding history and investigations 

Answer 43

history

• mild bleeding symptoms are also reported in healthy persons (eg epistaxis, gum bleeding, menorrhagia) 
• pediatric or young adults may not have had any hemostatic challenges 

investigations

• normal platelet, PT, APTT does not mean no bleeding disorder 
• there is no routine global test which incorporates vessel wall, endothelium and fresh whole blood
• FBC: numbers only
• APPT/PT: fibrin detection only 
• cross-linking of fibrin is NOT studied
• abnormal results do NOT accurately predict bleeding 

Question 44

how to classify bleeding disorders

Answer 44

Question 45

how to determine the type of thrombocytopenia 

Answer 45

Question 46

how to determine if its a coagulopathy

and what are the related causes to the corresponding abnormalities 

Answer 46

clotting assays 

Question 47

what are the effects of anticoagulants on coagulation tests

Answer 47

Question 48

mode of inheritance of von willebrands disease

Answer 48

autosomal dominant

Question 49

function of von willebrands factor 

Answer 49

• carrier protein for factor VIII in plasma 
• helps with platelet aggregation and adhesion to damaged endothelium 

Question 50

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

Answer 50

• type I: deficiency of VWF → desmopressin or cryoprecipitate
• type II: abnormal and dysfunctional VWF → factor VIII concentrate or cyroprecipitate 
• type III: absent VWF → factor VIII concentrate or cyroprecipitate 

Question 51

what are the natural anticoagulants 

Answer 51

• heparan sulphate (potentiator of antithrombin)
• antithrombin (inactivates factor Xa and thrombin)
• protein c (inactivates factor Va and VIIIa) 
• protein s (cofactor for protein c) 

Question 52

what are the characteristics of arterial thrombosis 

Answer 52

• occurs with endothelial damage 
• white thrombus (platelet rich)
• triggered by rupture of atherosclerotic plaque

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

Question 53

what are the complications and treatment for arterial thrombosis 

Answer 53

• complications: MI and stroke
• treatment: antiplatelets

Question 54

what are the characteristics of venous thrombosis

Answer 54

• red thrombus (mainly composed of RBCs and fibrin due to low shear flow)
• triggered by area of stasis in the blood

Question 55

what are the complications and treatment of venous thrombosis

Answer 55

• complications: DVT and PE
• treatment: anticoagulants

Question 56

where is a common site for DVT

Answer 56

deep veins of the legs (popliteal, femoral, iliac)

Need to name examples of deep veins in exam!!

Question 57

what are the risk factors for thrombosis 

Answer 57

acquired: immobility, surgery, cancer, connective tissue disease, age, catheters 

inherited: family history (first degree relatives only) 

past history: thrombotic challenges in pregnancy and delivery 

Apply virchow's triad. Endothelial injury, hypercoagulable state, altered blood flow. 

Question 58

what is virchow's triad 

Answer 58

Stasis/Altered blood flow 

Hypercoaguable state

Endothelial damage

Question 59

what are the minor and major transient provoking risk factors for venous thromboembolism

Answer 59

minor

• immobilisation
• travel > 8h
• use of estrogen therapy
• pregnancy or puerperium
• leg injury with impaired mobility 

major

• major surgery/trauma
• caesarean section

Question 60

what are the minor and major persistent provoking factors for venous thromboembolism 

Answer 60

minor

• inflammatory bowel disease
• lower extremity paralysis/paresis 
• congestive heart failure 
• obesity 
• family history

major

• active cancer excluding basal/squamous cell skin cancer 

Question 61

what is antiphospholipid syndrome 

Answer 61

autoimmune disease which can cause frequent clotting in arteries and veins and/or miscarriages

results from the presence of proteins in the blood called anti-phospholipid autoantibodies (commonly called aPL) formed against the person’s own tissues

Question 62

what is the mechanism of action of cancer associated thrombosis 

Answer 62

• adhesion molecules on cancer cells which cause adhesion to host cells → activate normal host cells → stimulate procoagulant phenotype 
• production of inflammatory cytokines & proangiogenic factors → endothelial cell activation → activate normal host cells → stimulate procoagulant phenotype

Question 63

what are the clinical presentations of venous thromboembolism

Answer 63

symptoms and signs of DVT and PE 

• swollen, painful, red 
  
• syncope, cough, shortness of breath and pleuretic chest pain 

Question 64

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

Answer 64

swollen leg

• muscle cramp/spasm, cellulitis, baker's cyst 
• lymphoedema, chronic venous insufficiency, hematoma 

chest pain, SOB 

• chest infection, pneumothorax
• heart failure, MI, aortic dissection, pericarditis 
• musculoskeletal disorders: contusion, inflammation and fracture 

Question 65

investigations of suspected venous thromboembolism 

Answer 65

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

Question 66

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

Answer 66

1. assessment of clinical pretest probability 
2. d-dimer/imaging with compression ultrasound/CTPA

Question 67

what are the different types of anticoagulants 

Answer 67

Question 68

mode of action of low molecular weight heparin

Answer 68

- binds and activates plasma protease inhibitor antithrombin III → inactivates coagulation factor Xa

Question 69

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

Answer 69

- binds and activates plasma protease inhibitor antithrombin III → conformational change → exposes its active site --> forms more inactive complexes with coagulation factor IIa, IXa & Xa by 1000 folds

- stimulates tissue factor pathway inhibitor (TFPI) release from endothelium to prevent activation of coagulation factor Xa

it has a longer polysaccharide side chain that can envelope thrombin, therefore giving enhanced anti Xa and IIa activity

Question 70

advantages of using low molecular weight heparin over unfractionated heparin 

Answer 70

UFH is large and negatively charged, therefore leading to more non-specific binding 

Question 71

what is the mode of action of warfarin

Answer 71

inhibition vitamin K reductase leading to inhibition of of vitamin K recycling 

• vitamin K-dependent clotting factors (2, 7, 9, 10) have to be carboxylated to become functional
• this process depends on vitamin K

Question 72

why are direct oral anticoagulants preferred over warfarin

Answer 72