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Haematopoietic System Flashcards

1
Q

Name the components of blood

A

~55% plasma
~1% buffy coat
~45% erythrocytes/RBC (~42% for females)

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2
Q

What are the functions of blood?

A
  1. Transport nutrients and O2
  2. Transport waste to kidneys and liver
  3. Transport of WBCs and antibodies to fight infection
  4. Transport of platelets and clotting factors to form clot
  5. Regulation of body temperature
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3
Q

What is found in plasma?

A
  • Nutrients
  • Electrolytes
  • Albumin proteins: transport lipid and steroid hormones + contribute to osmotic pressure
  • Globulin proteins: haemoglobin, immunoglobin
  • Regulatory proteins: hormones, enzymes
  • Clotting factors
  • Antibodies
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4
Q

What is found in buffy coat?

A
  • Platelets/thrombocytes
  • Leukocytes: monocytes/macrophages, neutrophils, eosinophils, basophils, lymphocytes
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5
Q

Describe the morphological features of white blood cells/leukocytes

A

Neutrophils: multilobated nucleus
Eosinophils: bilobed nucleus; red cytoplasmic granules
Basophils: bilobed nucleus; purplish-black cytoplasmic granules
Lymphocytes: large spherical nucleus, thin rim of pale blue cytoplasm
Monocytes: kidney-shaped nucleus, abundant pale blue cytoplasm

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6
Q

What is the function of erythrocytes?

A

O2/CO2 transport for metabolic requirements
Hb as an acid-base buffer

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7
Q

How should a blood sample be taken?

A
  • Fill to the top, as too little blood alter the citrate:plasma ratio
  • Add citrate to keep blood uncoagulated
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8
Q

Define haematocrit

A

Proportion of blood volume consisting of RBCs expressed as % (normal range: 40-54%)

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9
Q

Define haematopoiesis

A

Haematopoiesis is the process of formation and differentiation of different elements in blood

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10
Q

Briefly outline the process of haematopoiesis

A
  1. Haematopoietic stem cell (HSC) undergoes long-term self-renewal
  2. With the appropriate growth factors/cytokines + fibroblasts, HSCs differentiate into multipotent progenitor
  3. Multipotent progenitor differentiate into lymphoid and myeloid stem cell depending on the differentiation factors it is exposed to
  4. For the myeloid stem cell, it further divides at medullary/extramedullary sites
    - Into leukocytes if granulocyte-colony stimulating factor is present
    - Into megakaryocytes → platelets if thrombopoietin is present
    - Into erythrocytes if erythropoietin is present
  5. For the lymphoid stem cell, it further divides into T and B lymphocytes in the thymus and bone marrow respectively
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11
Q

Describe the location of haematopoiesis throughout the course of life

A

Yolk sac: 3-8 weeks
Liver: 6 weeks-birth
Spleen: 8-28 weeks
Bone marrow: 18 weeks-adult

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12
Q

Define the process of erythropoiesis

A

The process of formation and development of erythrocytes

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13
Q

Outline the 14-day process of erythropoiesis

A
  1. Myeloid stem cells stimulated to differentiate into pro-erythroblast in the presence of erythropoietin growth factor
  2. Pro-erythroblast undergoes DNA synthesis, becoming erythroblast
  3. Nucleus of erythroblast condenses and is extruded; cytoplasm of erythroblast turns from blue to pink
  4. Filling of Hb containing heme into erythroblast, forming reticulocyte
  5. Reticulocyte undergoes diapedesis to capillaries by squeezing through tiny pores
  6. Reticulocytes maturing into erythrocytes that are released into the bloodstream where it circulates for 120 days
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14
Q

Describe how the process of erythropoiesis is regulated

A

Hypoxic conditions → hypoxia-induced factor 1alpha (HIF-1a) produced at kidney released into bloodstream → stimulate transcription and translation of erythropoietin growth factor → increase rate of erythropoiesis

Neoplasms → angiogenesis → formation of new capillaries → increased reticulocyte diapedesis → increase rate of erythropoiesis

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15
Q

Define polycythaemia/ erythrocytosis

A

Increased levels of erythrocytes

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16
Q

What are the signs and symptoms of erythrocytosis?

A
  • Plethoric appearance
  • Hyperviscosity with hypoxia and/or clotting
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17
Q

Define lymphopenia

A

Decreased lymphocyte count → increased susceptibility to viral infections

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18
Q

Define neutropenia

A

Decreased neutrophil count → increased susceptibility to bacterial/fungal infections

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19
Q

Define haemolysis

A

Destruction of RBCs

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20
Q

Describe the process of haemolysis

A

RBCs age → lose membrane elasticity → cannot squeeze through tiny pores of spleen → get trapped and burst → macrophages engulf and destroy it → release Hb → release heme

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21
Q

How is heme, Hb and erythrocytes related?

A

Heme is a prosthetic group of proteins

Haemoglobins are tetrameric proteins consisting of 4 polypeptide chains (2 alpha 2 beta), each with a heme group

Erythrocytes are packed with Hb

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22
Q

Describe how Hb is encoded for by genes

A

Hb is made up of 2 alpha globins and 2 beta globins

Each alpha globin is encoded for by one ζ (zeta) and two α (alpha) genes found on chromosome 16

Each beta globin is encoded for by one ε (epsilon), one γ (gamma), one δ (delta) and β (beta) genes found on chromosome 11

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23
Q

Classify the forms of Hb and their inheritance pattern

A

Different combination of genes on the two chromosomes (one from each parent) give rise to different forms of Hb

Initial embryonic development
HbGower = ζ2ε2

Fetal development
HbF = α2γ2

Adult development
1. HbA = α2β2 (90%)
2. HbA2 = α2δ2 (2-5%)
3. HbF = α2γ2 (<2%)

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24
Q

Describe how oxygen binding to Hb is regulated

A

Regulated by diff binding affinities of diff forms of Hb

At tissues, deoxy-Hb is mostly present
1. Position of heme shifts
2. Tense state
3. Binding affinity to O2 low
4. Hb release O2

At lungs, oxy-Hb is mostly present
1. Position of heme shifts
2. Relaxed state
3. Binding affinity to O2 high
4. Hb binds O2

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25
Q

Define haemoglobinopathy

A

Haemoglobin variant resulting from a genetic mutation

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26
Q

Define thalessemia

A

Inherited disorders caused by mutations that decrease the synthesis of alpha and beta globin chains → dysregulation of Hb synthesis

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27
Q

Describe the clinical presentation of thalessemia

A

Abnormal association of gene → abnormal Hb → precipitation of other globins → damage RBCs → haemolysis

  1. Excessive heme release → jaundice
  2. Haematopoiesis in bone marrow that does not usually produce RBCs (as compensation due to insufficient Hb production) → enlarged skull, chipmunk face
  3. Insufficient Hb → anaemia → liver compensation → hepatomegaly
  4. Destruction of RBCs → overworked spleen → splenomegaly
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28
Q

Describe the inheritance pattern of alpha-thalessemia

A

Autosomal recessive

Since there are 2 α (alpha) genes found on chromosome 16 coding for alpha protein, and 2 chromosomes from both parents, there are 4 possible combinations of mutations

1/4 mutated alpha gene: asymptomatic carrier
2/4 mutated alpha gene: mild symptoms
3/4 mutated alpha gene: HbH disease
4/4 mutated alpha gene: fatal

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29
Q

Describe the inheritance pattern of beta-thalessemia

A

Autosomal recessive

Since there is 1β (beta) gene found on chromosome 11 coding for beta protein, and 2 chromosomes from both parents, there are 2 possible combinations of mutations

1/2 mutated beta gene: mild symptoms → thalessemia minor
2/2 mutated beta gene: severe symptoms → thalessemia major

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30
Q

Discuss how thalessemia can be diagnosed

A
  1. History
  2. Clinical presentation
  3. Peripheral blood film shows microcytic hypochromic anaemia
  4. Peripheral blood film shows target cells (RBCs with central red area and peripheral ring of pallor due to abnormal Hb synthesis)
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31
Q

Describe the pathogenesis of sickle cell anaemia

A
  1. AR condition, point mutation of beta-globin gene where the glutamic acid is swapped for valine at the 6th aa position
  2. Formation of hydrophobic cleft in HbS
  3. Cells become sickle-shaped with decreased O2-carrying capacity
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32
Q

Why do carriers for sickle cell anaemia have selective advantage in malaria endemic countries?

A

Sickle cell has less O2-carrying capacity → less hospitable to parasites → inhibit parasitic growth and replication within RBCs

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33
Q

Describe the structure of heme

A

Heme is a prosthetic group (non-amino acid component) of proteins found in haemoglobin, myoglobin and cytochrome proteins

It has a porphyrin ring with Fe in the centre, and multiple side groups (methyl, vinyl and propionic acid) in the periphery

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34
Q

Where is heme synthesised?

A

All cells but mostly erythroid cells in marrow and liver, specifically in mitochondria and cytosol

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35
Q

Describe the synthesis of heme

A

(REF TO BIOCHEM BOOKLET)
*Just need to know that ALA synthase, ferrochelatase, coproporphyrinogen III oxidase and protoporphyrinogen IX are in mitochondria, the rest are in cytosol
**Last step: insertion of Fe2+ into protoporphyrin IX by ferrochelatase to form heme

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36
Q

Describe the regulation of heme synthesis

A

Drugs, toxins → body wants to deal with oxidative stress and wants more heme to bind to more O2 → upregulate the activity of ALA synthase 1

Hypoxia, erythropoietin → body wants to support erythropoiesis in erythroid organs and wants more heme to bind to more O2 → upregulate the activity of ALA synthase 2

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37
Q

Describe genetic dysregulations in the synthesis of heme

A

PORPHYRIA = body cannot convert porphyrins to heme

  1. Acute intermittent porphyria = mutated porphobilinogen deaminase
  2. Congenital erythropoietic porphyria = mutated uroporphyrinogen catalase
  3. Porphyria cutanea tarda = mutated uroporphyrinogen decarboxylase
  4. Hereditary coproporphyria = mutated coproporphyrinogen oxidase
  5. Variegate porphyria = mutated protoporphyrin oxidase
  6. Erythropoietic protoporphyria = mutated ferrochelatase
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38
Q

Describe the clinical presentations of porphyrias

A

Synthesis stops at 1 PBG (aka acute intermittent porphyria)
1. Abdominal pain
2. Neuropsychiatric symptoms
3. Urine darken on exposure

Synthesis stops at 4 PBG (aka the rest)
1. Photosensitivity with skin lesions
2. Red-coloured urine

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39
Q

Describe acquired dysregulations in the synthesis of heme

A

HEAVY METAL POISONING
1. Exposure to lead from industrial settings, old/unregulated products like paint and ceramics
2. Inhibit ALA dehydratase and ferrochelatase

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40
Q

Describe the clinical presentations of heavy metal poisoning

A
  1. Lead not used in heme synthesis → chronic lead deposition → Burton’s line (bluish colouration of gumline)
  2. Anaemia → pallor
  3. Abdominal pain and neuropathy
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41
Q

Where does heme breakdown occur?

A

Reticuloendothelial macrophages in liver, gut, kidneys

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42
Q

Describe the breakdown of heme

A

(REF TO BIOCHEM BOOKLET)
*Heme oxygenase breaks down ring and oxidises Fe2+ to Fe3+

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43
Q

Describe the locations involved in heme breakdown

A
  • Unconjugated bilirubin bound to albumin protein circulates in blood
  • When unconjugated bilirubin dissociates from albumin protein, it enters hepatocytes at the liver to be conjugated
  • Active transport of bilirubin diglucuronide out of liver into bile caniculi through MRP2 transporter
  • Bilirubin diglucuronide in bile travels through common bile duct → pancreatic duct to the gut
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44
Q

Describe the dysregulations in heme breakdown

A

Hyperbilirubinemia: total bilirubin > 1.2mg/dL
Jaundice: total bilirubin > 2.5-3mg/dL

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45
Q

Classify the different types of jaundice and their causes

A
  1. Pre-hepatic jaundice: excessive haemolysis
    - Haemolytic anaemia
    - G6PD deficiency → shortened RBC lifespan
    - Malaria infections
    - Transfusion reaction
  2. Hepatic jaundice: defective conjugation/ excretion of conjugated bilirubin at hepatocytes
    - Liver cirrhosis
    - Gilbert’s syndrome (AR): UGT has 30% conjugation activity
    - Crigler-Najjar (AR): mutated UGT1A1 gene, which encodes UDP-glucuronosyltransferase 1A1 (UGT1A1)
    - Neonatal immaturity
    - Dubin-Johnson syndrome: mutated MRP2 transporter
  3. Obstructive jaundice: block in bile duct
    - Bile duct stones
    - Carcinoma
    - Infection
    - Cyst formation
    - Biliary atresia: failure to form bile duct lumen
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46
Q

Describe the general clinical presentations of jaundice

A

Yellowing of skin, sclera, mucous membrane of mouth

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47
Q

Describe the clinical findings of pre-hepatic jaundice

A
  1. Increased unconjugated bilirubin in blood
  2. Normal conjugated bilirubin in blood
  3. Increased haptoglobin binding to free Hb → formation of Hp-Hb complexes removed by macrophages → decreased haptoglobin levels
  4. If severe, haemoglobinuria (excretion of free Hb in urine) → “kopi-o” urine
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48
Q

Describe the clinical findings of hepatic jaundice

A
  1. Increased unconjugated bilirubin in blood (if mostly conjugation problem)
  2. Increased conjugated bilirubin in blood (if mostly excretion problem)
  3. Urine/stool depends on bilirubin composition
  4. Increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes → indicate liver damage
  5. Decreased albumin/coagulation factor production → indicate non-functioning liver
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49
Q

Describe the clinical findings of post-hepatic jaundice

A
  1. Normal unconjugated bilirubin in blood
  2. Increased conjugated bilirubin in blood
  3. Increased conjugated bilirubin in urine → bilirubinemia → tea-coloured urine
  4. Decreased stercobilin → light stools
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50
Q

Discuss the risk factors for neonatal jaundice

A
  1. Blood group incompatibility
  2. G6PD deficiency
  3. Prematurity
  4. Low albumin levels
  5. Chinese: higher risk of UGT mutation
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51
Q

Describe the treatment of jaundice

A
  1. Blue-light phototherapy: convert insoluble Z,Z-isomer of bilirubin to more soluble E,E-isomer → excretion in urine → decrease unconjugated bilirubin in blood
  2. Exchange transfusion to decrease bilirubin quickly if severe
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52
Q

Describe iron metabolism in the body

A

Iron can come from heme and non-heme (dietary) sources
1. Dietary iron converted from Fe3+ to Fe2+ by ferric reductase
2. Divalent metal transporter (DMT-1) at the apical membrane transports Fe2+ into intestinal cells
3. Heme is absorbed into intestinal cells, iron from heme is also released as Fe2+
4. Within intestinal cells, a portion of the iron is used for cell metabolism and a portion is stored as ferritin
5. The remaining iron is transported out as Fe2+ at the basolateral membrane by ferroportin
6. Fe2+ converted to Fe3+ by hephastin
7. Fe3+ bind to transferrin in bloodstream to form Fe3+-transferrin complex
8. Complexes are transported in blood to liver and reticuloendothelial system
9. Complexes bind to transferrin receptor and enter cells via endocytosis
10. Acidification of endosomes releases Fe into cytoplasm for cell metabolism and storage as ferritin
11. Ferritin stores in liver are readily mobilisable and can be detected in plasma
12. Excess ferritin stored as hemosiderin in macrophages (less accessible)

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53
Q

Where is dietary iron absorbed?

A

Upper end of small intestine (duodenum + proximal jejunum)

54
Q

Assess the biochemical measurements used to understand iron metabolism

A

Total iron binding capacity = total transferrin (bound/unbound)

Transferrin saturation = plasma iron/TIBC

Unsaturated iron binding capacity = unbound transferrin

Plasma iron levels = bound transferrin

Plasma ferritin levels = cellular iron stores

55
Q

Describe the regulation of iron absorption and storage

A

LOW IRON STATE
1. Increase expression of DMT-1 → increase Fe2+ transport into intestinal cells
2. Increase expression of ferroportin → increase Fe2+ transport into circulation
3. Increase expression of transferrin receptor → increase uptake of Fe-transferrin complex by liver

HIGH IRON STATE
1. Decrease expression of DMT-1 → decrease Fe2+ transport into intestinal cells
2. Decrease expression of ferroportin → decrease Fe2+ transport into circulation
3. Decrease expression of transferrin receptor → decrease uptake of Fe-transferrin complex by liver
4. Synthesis of hepcidin → downregulate ferroportin → decrease Fe2+ transport into circulation

56
Q

Describe dysregulations in iron absorption and storage

A

IRON DEFICIENCY
Low dietary intake/increased blood loss/increased need for iron (e.g. pregnancy) → decreased heme and Hb synthesis → anaemia

IRON EXCESS
Increased haemolysis/increased dietary intake → increased ferritin storage → formation of hemosiderin

57
Q

How will the biochemical measurements change with the dysregulations?

A

IRON DEFICIENCY
1. Plasma ferritin levels <30microg/L → low cellular iron stores
2. High TIBC → increased number of iron binding sites on transferrin as compensation to absorb more iron

58
Q

Describe the clinical presentations of the dysregulations in iron absorption and storage

A

IRON DEFICIENCY = anaemia
IRON EXCESS
1. Iron deposit in skin → bronzing
2. Iron accumulate in organs increases reactive O2 species → oxidative damage

59
Q

Define anaemia

A

A condition whereby Hb is lower than the ref range for the individual (depends on age/gender)

60
Q

Describe the mechanisms of anaemia

A

Decreased production
- Haematinic/nutrient deficiencies
- Primary BM failure
- Secondary BM failure

Increased loss
- Haemolysis
- Bleeding
- Sequestration during splenomegaly

Dilutional/increased plasma vol
- Pregnancy
- Fluids, transfusion

61
Q

Describe the general clinical presentations of anaemia

A

SYMPTOMS from compromised O2 transport
1. Headache, dizziness
2. Dyspnoea
3. Fatigue
4. Increased HR, chest pain
*Symptoms depend on age, comorbidities, speed of onset, severity

SIGNS
1. Conjunctival pallor (Hb<9)
2. Skin crease pallor (Hb<7)
3. Cardiac compensation (Hb<8) → high output failure (Hb<5)

62
Q

Classify the different types of anaemia based on cell size and causes

A

Microcytic
- Iron deficiency
- Thalassemia
- Inflammatory anaemia
- Sideroblastic anaemia: cannot use iron in synthesis of RBCs → cannot extrude nucleus → accumulate in mitochondria of RBCs → ringed appearance in nucleus

Normocytic
- Increased destruction: sequestration, acute bleeding, haemolysis
- Decreased production: renal anaemia (decreased EPO synthesis), inflammatory anaemia, marrow disease, myeloma
- Dilutional

Macrocytic
- B12/folate deficiency
- Drugs
- Reticulocytosis
- Alcohol resulting in liver disease
- Pregnancy
- Hypothyroidism
- Myelodysplastic syndrome: cancer which prevents maturation of blood cells in the bone marrow

63
Q

Describe the characteristics of iron deficiency anaemia

A

Microcytic, hypochromic anaemia in peripheral blood film

64
Q

How to treat iron deficiency anaemia?

A

ORAL IRON SUPPLEMENTS
- Increase Hb by ~1g/dL every week → continue 3-6 months aft to restore iron stores
- Can only use if not absorption problem but intake problem
- Side effects: upset stomach, nausea, diarrhoea, flatulence, dark stools, constipation → non-compliance

65
Q

Describe the characteristics of folate/B12 deficiency anaemia

A

Macrocytic, normochromic/ hypochromic anaemia

Megaloblastic anaemia or pernicious anaemia (special subtype of megaloblastic, has to do with intrinsic factor specifically)

66
Q

What are the investigations to be done for suspected megaloblastic anaemia and hallmark findings?

A
  1. Blood film: macro-ovalocytes, hypersegmented neutrophils
  2. Haemolysis: increased lactate dehydrogenase, increased unconjugated bilirubin due to increased intramedullary haemolysis
  3. Serology: intrinsic factor antibodies (blocking/binding) which decreases B12/folate absorption from ileum
67
Q

Why do we need to exclude B12 deficiency as a cause for macrocytosis?

A

B12 deficiency can lead to permanent neurological damage

68
Q

Explain how inflammation can lead to anaemia

A

Shunting of haematopoiesis to myelopoiesis for generation of more leukocytes → decreased erythropoiesis

Pro-inflammatory cytokines stimulate hepcidin release from liver → inhibit ferroportin → inhibit release of iron into bloodstream (deprive pathogens of iron required for survival) → but also decrease iron for erythropoiesis → iron deficient anaemia

Increased haemolysis → anaemia

69
Q

Describe the biomarkers for anemia of inflammation

A
  1. Low percentage of hypochromic erythrocytes, serum transferrin
  2. High serum ferritin and hepcidin
  3. Normal MCV, MCH and reticulocyte count
70
Q

What are the evidences which point to haemolysis?

A

BIOCHEMICAL MARKERS
1. Increased lactate dehydrogenase
2. Increased unconjugated bilirubin
3. Decreased haptoglobin

MORPHOLOGICAL (from peripheral blood film)
1. Spherocytes → immune cause
2. Bite/blister cells → oxidative hemolysis
3. Fragments → microangiopathic haemolytic anaemia

71
Q

How to determine if haemolytic anaemia is immune related?

A

Use Direct Coombs Test (DCT)

Positive result if
1. Autoimmune haemolytic anaemia
2. Delayed haemolytic transfusion reaction
3. Cold agglutinin disease (involves IgM)

72
Q

Define haemostasis

A

The physiological mechanism that leads to cessation of bleeding from a blood vessel

73
Q

Discuss the importance of haemostasis

A
  1. Maintain blood fluidity to distribute heat and nutrients to body
  2. Limit clotting to local sites
  3. Maintain vascular integrity
74
Q

Classify the coagulopathies that can arise from haemostasis

A
  1. Pro-coagulation → thrombosis
  2. Anti-coagulation → excessive bleeding
  3. Dislodged clots float around in circulation → embolism
75
Q

Outline the process of thrombopoiesis and primary haemostasis

A
  1. Trauma/breached vascular barrier
  2. Vascular spasm to decrease blood flow to site of injury
  3. Von-Willebrand’s factor (VWF) on exposed collagen bind to glycoprotein receptor on circulating platelets
  4. Platelets activated, change conf and release granules containing platelet agonists
  5. ADP attract and activate more platelets
  6. TXA2 increase vasoconstriction + platelet aggregation
  7. Platelets aggregate to form plug = primary haemostasis
76
Q

Describe the role of Von Willebrand’s factor (VWF) in blood clotting

A
  1. Mediates platelet aggregation and adhesion to damaged endothelium
  2. Carrier for factor 8 in plasma, stabilising factor 8
77
Q

What are the types of Von Willebrand’s factor disease and what are the treatment options?

A

Type I: deficiency of VWF → desmopressin or cryoprecipitate

Type II: abnormal and dysfunctional VWF → factor 8 concentrate or cyroprecipitate

Type III: absent VWF → factor 8 concentrate or cyroprecipitate

Cryoprecipitate is a blood product that is prepared from fresh frozen plasma (FFP) and contains a concentrated mixture of certain clotting factors, fibrinogen, and other plasma proteins

78
Q

What is the mode of inheritance of VWF diseases?

A

Autosomal dominant

79
Q

Define thrombocytosis and thrombocytopenia

A

Thrombocytosis = high platelet count
Thrombocytopenia = low platelet count

80
Q

What are the signs and symptoms of thrombocytopenia?

A

Petechiae
Bleeding
Epistaxis

81
Q

How do we determine the type of thrombocytopenia?

A

Examine peripheral blood film

If isolated thrombocytopenia
- Drug-induced
- HIV/HBV/HCV
- DIC
- Immune thrombocytopenic purpura (ITP): body’s immune cells attack self-platelets

If anaemia + thrombocytopenia
- MAHA (DIC/TTP)
- Evan’s syndrome

If WBC + thrombocytopenia
- EBV
- Dengue

If pancytopenia (WBC + RBC + platelet all deficient)
- Leukaemia
- Bone marrow disorders
- Bone marrow metastasis
- MDS
- Sequestration

82
Q

Outline the process of secondary haemostasis via the coagulation cascade

A

INTRINSIC PATHWAY
1. In the presence of platelet phospholipids, factor 12 → factor 12a (conf change)
2. 12a cleave and activate 11 → 11a
3. 11a cleave and activate 9 → 9a
4. In the presence of factor 8a and Ca2+, 9a cleave and activate 10 → 10a

EXTRINSIC PATHWAY (primary activator)
1. Damaged tissues release tissue factors and thromboplastin
2. which cleave and activate 7 → 7a
3. In the presence of Ca2+, 7a cleave and activate 10 → 10a

COMMON PATHWAY
1. In the presence of 5a and Ca2+, 10a cleave and activate prothrombin → thrombin
2. Thrombin convert fibrinogen to fibrin monomers
3. Fibrin monomers polymerise to form fibrin strand
4. Thrombin also convert fibrin-stabilising factor 13 → 13a
5. Fibrin-stabilising factor 13a cross-link fibrin strands at D-domains, forming fibrin mesh with increased tensile strength
6. Fibrin mesh traps blood cells and clotting factors
7. Formation of blood clot

*anything with 10 require Ca2+

83
Q

Describe the role of thrombin in the coagulation cascade

A
  1. Activates upstream proteins, primarily factors 5, 8 and 11 → further thrombin generation
  2. Cleaves fibrinogen into fibrin monomers → polymerisation to form fibrin mesh
  3. Activates factor 13, a fibroligase → increased tensile strength → stabilising clot
  4. Platelet aggregation, stimulate cell proliferation, modulate smooth muscle contraction
84
Q

What are coagulation factors and where are they found?

A

12 coagulation factors (from 1 to 13 except 6)
- Mostly plasma protein except factor 3 thromboplastin and factor 4 Ca2+
- Mostly produced by liver except factor 3 by damaged tissues and factor 4 by plasma
- Factors 2,7,9,10 require Vitamin K

Coagulation factors are grouped on the cell surface in close proximity to localise injury reaction and protect from inhibitors

85
Q

Explain why so many steps are required in coagulation

A
  • Many points of regulation
  • Prevent unintentional activation of clotting
  • Ensure that clotting happens only when there is a real need
86
Q

What is the disadvantage of having so many steps in coagulation

A

Many bleeding disorders can arise as each of the factors are synthesised by a diff gene which can have a diff mutation

87
Q

Explain how blood clotting is limited to the site of injury (NO/PGI2, TFP1, AT, APC/S, TPA)

A
  1. Intact endothelial cells release nitric oxide and prostacyclins → vasodilation and platelet inhibition → prevention of platelet plug formation
  2. TFP1 pathway: Intact endothelial cells release tissue factor pathway inhibitor (TFP1) → inhibit tissue factors released by damaged tissues → inhibit extrinsic pathway of coagulation cascade
  3. AT pathway: Intact endothelial cells secrete anti-thrombin → sequesters and inhibits thrombin (factor 2) leaked from clots and floating factor 10a and 9a
  4. APC/S pathway: Intact endothelial cells have thrombomodulin and endothelial protein C receptors (EPCR) bound to protein C → thrombomodulin sequesters thrombin → protein C and thrombin brought tgt in close proximity → protein C cleaved and activated by thrombin-thrombomodulin complex to give activated protein C (APC) → activated protein C bind to circulating protein S to form APC-PS complex → APC-PS complex cleaves and inactivates factor 5a and 7a
  5. Intact endothelial cells release tissue plasminogen activator (TPA) in the presence of fibrin → convert plasminogen to plasmin → plasmin cleave fibrin strands at D-domains (FIBRINOLYSIS) → release fibrin-degradation products (FDP) aka D-dimers into circulation → degradation of fibrin mesh
88
Q

What does elevated circulatory D-dimer levels in a person tell us?

A
  1. Injury/fresh wounds requiring large clots
  2. Thrombotic event if no injury
89
Q

What else can be done to prevent blood clot formation?

A

Ca2+ chelators to remove Ca2+
Prothrombin cannot be activated to thrombin by factor 10a

90
Q

Define thrombosis and thrombus

A

Thrombosis is the process of thrombus formation; thrombus is an intravascular blood clot formed from blood constituents

91
Q

What are the predisposing factors that increase the risk of thrombus formation?

A

VIRCHOW’S TRIAD

  1. Endothelial injury
  2. Venous stasis
  3. Hypercoagulability of blood
92
Q

What are the common sites of venous thromboembolism?

A

Deep veins of legs (e.g. femoral, popliteal, iliac) → deep vein thrombosis
Lungs → pulmonary embolism

93
Q

Describe the transient risk factors for venous thromboembolism

A
  • Pro-coagulatory oestrogen therapy
  • Pregnancy
  • Leg injury with impaired mobility
  • Travel >8hrs
  • Immobilisation
  • Major surgery/trauma
  • Caesarean section
94
Q

Describe the prolonged risk factors for venous thromboembolism

A
  • Paraneoplastic syndrome → cancer cells secreting clotting factors
  • Family history (usually immediate family member)
  • Obesity
  • Congestive heart failure
  • Inflammatory bowel disease → endothelial injury
  • Lower extremity paralysis
  • Factor 5 Leiden: gene mutation rendering factor 5a resistant to protein C cleavage
  • Prothrombin gene mutation
95
Q

Describe the mechanism for cancer-associated thrombosis

A

Adhesion molecules on cancer cells cause adhesion to normal cells → activation of normal cells → stimulate procoagulant phenotype

Production of inflammatory cytokines and proangiogenic factors → endothelial cell activation → activate normal host cells → stimulate procoagulant phenotype

96
Q

What are the clinical presentations of venous thromboembolism?

A
  • Swollen, painful, red
  • Syncope, cough, shortness of breath and pleuritic chest pain
97
Q

What are the characteristics of venous thrombosis?

A
  1. Low shear flow → thrombosis mediated by RBCs and fibrin → red thrombus
  2. Triggered by area of stasis in blood → venous stasis
98
Q

What are the differential diagnoses for venous thromboembolism?

A

If swollen leg more prominent
1. Muscle cramp
2. Lymphoedema
3. Cellulitis
4. Chronic venous insufficiency
5. Haematoma

If chest pain, SOB more prominent
1. Pneumothorax
2. CVS issues
3. MSK issues: contrusion, inflammation, fracture

99
Q

What are the investigations for suspected venous thromboembolism?

A
  1. D-dimer blood test → indicative of previous clot
  2. Compression doppler ultrasound → pressure applied to compress vessel → assess blood flow through compressed vessel
  3. CT pulmonary angiogram → contrast dye injected into vein → evaluate blood flow in pulmonary arteries → to rule out pulmonary embolism
100
Q

Explain the nature of the D-dimer test

A

Sensitive → negative can help rule OUT DVT/PE
Non-specific → positive cannot rule IN venous thromboembolism

101
Q

What is the treatment for venous thrombosis?

A

ANTICOAGULANTS
1. Low molecular weight heparins (LMWH)
2. Regular/unfractionated heparins
3. Warfarin

102
Q

List the natural anticoagulants

A
  1. Heparan sulphate → potentiator of antithrombin
  2. Antithrombin → inactivate factor 10a and thrombin
  3. Protein c → inactivate factor 5a and 8a
  4. Protein s → cofactor for protein c
103
Q

Describe the MOA of LMWH

A

Bind and activate antithrombin three → inactivate coagulation factor 10a

104
Q

Describe the MOA of unfractionated heparins

A
  1. Bind and activate antithrombin three → conf change → expose active site → more rapid interaction, form more inactive complexes with coagulation factors 2a, 9a and 10a by 1000 folds
  2. Stimulate tissue factor pathway inhibitor release from endothelium → prevent activation of coagulation factor 10a
105
Q

Distinguish between LMWH and UH

A
  1. LMWH have better bioavailability and longer half life than UH
  2. UH have longer polysaccharide side chain → can envelope thrombin which is required for its inhibition → enhanced anti 10a and antithrombin/anti 2a activity
106
Q

What are the advantages of using LMWH over UH?

A
  1. UH is large and negatively charged → more non-specific binding
  2. Longer half life → can be given as subcutaneous injection
  3. Predictable anticoagulant effect, less risk of heparin-induced thrombocytopenia → no need for routine monitoring
  4. Less risk of osteoporosis → safer for prolonged administration
  5. Lower overall cost → can be given as outpatient
107
Q

Why can’t heparins be given IM?

A

Haematomas

108
Q

Describe the clinical uses of heparin

A
  1. Treatment of DVT, PE, AMI
  2. Combination with thrombolytics for revascularisation
  3. Combination with GP 2b/3a inhibitors during angioplasty and placement of coronary stents
  4. Treatment of VTE in pregnancy
109
Q

Describe the MOA of warfarin

A

Inhibition of vitamin K reductase → inhibition of vitamin K recycling → vit-dependent coagulation factors cannot be carboxylated to be functional (2,7,9,10)

110
Q

What are the precautions that must be taken when administering warfarin?

A

Warfarin should never be administered during pregnancy → crosses placenta readily → can cause haemorrhagic disorder in foetus

Foetal proteins with gamma-carboxyglutamate residues found in bone and blood may be affected by warfarin

111
Q

Why are direct oral anticoagulants preferred over warfarin?

A
  • Rapid onset of action → no need for bridging
  • Predictable anticoagulant effect → no need for routine coagulation monitoring
  • Specific coagulation enzyme target → low risk of off-target adverse effects
  • Low potential for food interactions → no dietary precautions
  • Low potential for drug interactions → few drug restrictions
112
Q

What are the characteristics of arterial thrombosis?

A
  1. Occurs with endothelial damage
  2. High laminar flow → thrombosis mediated by platelets instead of coagulation factors → white thrombus
  3. Triggered by rupture of atherosclerotic plaque → endothelial damage
113
Q

What are the complications for arterial thrombosis?

A

MI and stroke

114
Q

What is the treatment for arterial thrombosis?

A

ANTIPLATELETS
1. NSAIDs (aspirin)
2. Platelet GP2b/3a receptor blockers
3. ADP receptor blockers
4. PDE inhibitor

115
Q

Describe the MOA and clinical uses of aspirin

A

Irreversible, non-selective inhibition of COX enzymes → decreased production of prostanoids → PGI2 regenerate after few hours with new COX enzyme whereas TXA2 takes 1-2 weeks with new platelet formation → PGI2 effect&raquo_space; TXA2 → antiplatelet

Used for
1. Prophylaxis of transient cerebral ischaemia
2. Reduce incidence of recurrent MI

116
Q

Discuss the effectiveness of aspirin as an antiplatelet

A
  1. Irreversible inhibition
  2. Inhibitory effect is rapid and lasts for the entire life of the platelet (7-10 days)
117
Q

What is glycoprotein 2b/3a?

A

A platelet membrane surface protein that functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and VWF

Activation of this receptor complex is the final common pathway for platelet aggregation

118
Q

Describe the MOA of abciximab

A

Abciximab is a humanised monoclonal antibody that reversibly inhibits the binding of fibrinogen and other ligands to GP2b/3a

119
Q

Describe the MOA of tirofiban

A

A small molecule blocker of the GP2b/3a receptor

120
Q

Describe the MOA of eptifibatide

A

An analog of the sequence at the extreme carboxyl terminal of the delta chain of fibrinogen which mediates the binding of fibrinogen to the receptor

Pretends to be fibrinogen to prevent fibrinogen binding to receptor

121
Q

Describe the clinical uses of GP2b/3a receptor blockers

A

Prevent restenosis after coronary angioplasty
Used in acute coronary syndromes

122
Q

Describe the MOA of ADP receptor inhibitors

A

E.g. clopidogrel, ticlopidine
Prevent ADP from activating platelets

123
Q

Describe the MOA of dipyridamole

A

Prevent degradation of cAMP to 5’-AMP by phosphodiesterase → cAMP can inhibit release of granules containing platelet agonists

124
Q

Define antiphospholipid syndrome

A

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

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

125
Q

What are the first line investigations of bleeding disorders?

A
  1. Full blood count → assess platelet count
  2. Peripheral blood film (morphology, especially in congenital problems)
  3. Partial thromboplastin time (PTT) → extrinsic pathway
  4. Activated partial thromboplastin time (aPTT) → intrinsic pathway
  5. Fibrinogen → fibrinogen conversion
126
Q

What must be added to the blood sample for the different clotting assays performed?

A

PT → add tissue factor
APTT → add activator of factor 7 (silica/cephalin)
Fibrinogen → add thrombin
To all, add phospholipid and Ca2+

127
Q

What are the second line investigations of bleeding disorders?

A
  1. Mixing test (after obtaining results which shows prolongation of APTT)
    - Mix patient’s blood with normal plasma
    - If correction → factor deficiency
    - If no correction → inhibitor of specific coagulation factors
  2. Platelet function test
  3. Specific coagulation factor levels
  4. Specialised tests (e.g. factor inhibitors/lupus anticoagulants)
128
Q

From the investigations, how do we determine what coagulopathy?

A

CLOTTING ASSAYS

Increased APTT only → intrinsic pathway problem → factors 8,9,11,12

Increased PT only → extrinsic pathway problem → factor 7

Increased PT and APTT → common pathway problem → fibrinogen, prothrombin, factor 5,10

Decreased/increased fibrinogen → common pathway problem → fibrinogen

129
Q

What are the related causes to the corresponding abnormalities?

A

Increased APTT
- Congenital/acquired haemophilia (haemophilia A = factor 8 deficiency, haemophilia B = factor 9 deficiency)
- Heparin
- Lupus anticoagulant

Increased PT
- Liver disease
- Vit K deficiency
- Usually not an inhibitor-related deficiency

Increased PT and APTT
- Warfarin
- Liver disease
- Disseminated intravascular coagulation (DIC) → widespread activation of coagulation cascade even when unnecessary, using up coagulation factors

Decreased fibrinogen
- Disseminated intravascular coagulation (DIC)
- Hypofibrinogenaemia
- Dysfibrinogenaemia

Increased fibrinogen
- Acute phase reactant of inflammation

130
Q

What are the potential limitations of bleeding history and investigations?

A

HISTORY
1. Mild bleeding symptoms also reported in healthy persons (e.g. epistaxis, gum bleeding, menorrhagia)
2. Paediatric or young adults may not have had any haemostatic challenges

INVESTIGATIONS
1. Normal platelet, PT, APTT does not mean no bleeding disorder
2. No routine global test which incorporates vessel wall, endothelium and fresh whole blood
3. FBC: numbers only
4. APPT/PT: fibrin detection only
5. Cross-linking of fibrin is NOT studied
6. Abnormal results do NOT accurately predict bleeding

131
Q

Distinguish between platelet-type vs coagulation-type bleeding disorders

A
  1. Bleeding at skin, mucous membranes VS bleeding at deep soft tissues (e.g. joints, muscles)
  2. Petechiae vs no petechiae
  3. Small, superficial ecchymosis/bruises VS large, deep ecchymosis/bruises
  4. Extremely rare for haemarthrosis vs common haemarthrosis (muscle bleeding)
  5. Bleeding after surgery/trauma usually immediate but mild VS delayed but severe

Y1 (14 decks)

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