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Biochemistry Theory Semester 1 > Blood Coagulation > Flashcards

Blood Coagulation Flashcards

1
Q

Front

A

Back

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2
Q

What is the primary source of haem for catabolism?

A

Haemoglobin from senescent red blood cells removed by the reticuloendothelial system.

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3
Q

Name two other sources of haem apart from haemoglobin.

A

Cytochrome P450 enzymes and other haem proteins.

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4
Q

What enzyme catalyzes the first step in haem breakdown?

A

Haem oxygenase.

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5
Q

Which bond does haem oxygenase cleave?

A

The α‑methine bridge between the two pyrrole rings containing vinyl substituents.

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6
Q

What gas is uniquely released during haem catabolism?

A

Carbon monoxide (CO).

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7
Q

What are the immediate products of haem breakdown by haem oxygenase?

A

Biliverdin, carbon monoxide, and Fe³⁺.

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8
Q

Which enzyme converts biliverdin to bilirubin?

A

Biliverdin reductase.

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9
Q

What cofactor does biliverdin reductase use?

A

NADPH.

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10
Q

In what form is bilirubin transported to the liver?

A

Bound to albumin (and α‑globulins).

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11
Q

How is bilirubin rendered water‑soluble in the liver?

A

It is conjugated with two glucuronic acid moieties to form bilirubin diglucuronide.

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12
Q

Which enzyme catalyzes bilirubin conjugation?

A

UDP‑glucuronosyltransferase (bilirubin UGT1A1).

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13
Q

What is the reaction forming bilirubin diglucuronide?

A

Bilirubin + 2 UDP‑glucuronate → Bilirubin diglucuronide + 2 UDP.

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14
Q

Where is bilirubin diglucuronide excreted?

A

Into bile via the canalicular MRP2 transporter.

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15
Q

What happens to bilirubin diglucuronide in the intestine?

A

Bacterial β‑glucuronidases remove glucuronides, producing free bilirubin which is reduced to urobilinogens.

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16
Q

What are urobilinogens converted into?

A

Urobilins (stercobilins) by oxidation in the colon—these give stool its brown color.

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17
Q

What causes prehepatic jaundice?

A

Excess haemolysis or ineffective erythropoiesis leading to high unconjugated bilirubin.

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18
Q

What are examples of prehepatic jaundice?

A

G6PD deficiency, sickle cell anemia, thalassemias, and neonatal physiologic jaundice.

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19
Q

What causes hepatic jaundice?

A

Liver cell damage from viral hepatitis, drugs/toxins, or genetic defects in uptake/conjugation (e.g. Gilbert’s, Crigler‑Najjar).

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20
Q

Name two syndromes causing defective bilirubin conjugation.

A

Gilbert’s syndrome (mild) and Crigler‑Najjar syndrome (severe).

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21
Q

What causes Dubin‑Johnson and Rotor’s syndromes?

A

Dubin‑Johnson: MRP2 defect (canalicular excretion); Rotor: impaired hepatic storage/uptake of conjugates.

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22
Q

What is a posthepatic cause of jaundice?

A

Obstruction of bile flow by gallstones, tumors (e.g. cholangiocarcinoma), or strictures.

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23
Q

How does phototherapy help in neonatal jaundice?

A

Blue light (460–490nm) photo‑isomerizes bilirubin to water‑soluble forms that can be excreted without conjugation.

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24
Q

What is kernicterus?

A

Bilirubin‑induced neurological damage in neonates due to high free unconjugated bilirubin crossing the blood‑brain barrier.

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25
What is the major pigment in stool derived from bilirubin?
Stercobilin.
26
How much bilirubin is produced daily in adults?
Approximately 250–300 mg from all heme sources.
27
Describe the structural difference between biliverdin and bilirubin.
Biliverdin retains a double bond at the α‑bridge; bilirubin is the reduced (methylene) form at that bridge.
28
Why is haem oxygenase considered a rate‑limiting enzyme?
HO‑1 is substrate‑inducible and its expression controls the overall rate of heme catabolism.
29
Which isoform of haem oxygenase is constitutive and which is inducible?
HO‑2 is constitutive; HO‑1 is inducible by stress and heme.
30
How is HO‑1 expression regulated?
Upregulated by heme, oxidative stress, heavy metals, cytokines, and hypoxia via promoter elements.
31
What additional roles does biliverdin reductase have beyond converting biliverdin?
It acts as a kinase and transcription regulator, modulating antioxidant responses.
32
What physiological signaling role does carbon monoxide play?
CO functions as a vasodilator and anti‑inflammatory signaling molecule.
33
How does bilirubin binding to albumin prevent toxicity?
Albumin sequesters free unconjugated bilirubin, reducing its ability to cross cell membranes.
34
What happens if bilirubin uptake into hepatocytes is impaired?
Unconjugated hyperbilirubinemia and jaundice due to reduced clearance.
35
Which transport proteins mediate bilirubin uptake at the sinusoidal membrane?
OATP1B1 and OATP1B3 (organic anion‑transporting polypeptides).
36
How is bilirubin diglucuronide transported into bile?
Via the canalicular efflux pump MRP2 (ABCC2).
37
What effect does rifampicin have on bilirubin metabolism?
It induces MRP2 and UGT1A1, increasing bilirubin clearance.
38
Why does Dubin‑Johnson syndrome cause conjugated bilirubin buildup?
A mutation in MRP2 prevents excretion of conjugates into bile, causing regurgitation into blood.
39
How does Rotor syndrome differ from Dubin‑Johnson?
Rotor has defective hepatic storage/uptake but normal MRP2—no dark liver pigment deposition.
40
Describe the enterohepatic circulation of bilirubin.
A portion of intestinal urobilinogen is reabsorbed, taken up by the liver, and re‑secreted in bile.
41
What laboratory test measures liver clearance of bilirubin?
Indocyanine green (ICG) clearance test.
42
What is the normal ratio of direct to indirect bilirubin in serum?
Direct (conjugated) is less than 20 % of total bilirubin.
43
How does Gilbert’s syndrome affect bilirubin levels?
Reduced UGT1A1 activity causes mild, intermittent unconjugated hyperbilirubinemia.
44
How does phenobarbital therapy help in Crigler‑Najjar type II?
It induces UGT1A1, improving bilirubin conjugation and lowering levels.
45
What causes the color change from biliverdin to bilirubin in a bruise?
Biliverdin (green) is reduced to bilirubin (yellow) during heme catabolism in macrophages.
46
What happens to bilirubin monoglucuronide vs. diglucuronide in neonatal cholestasis?
Monoglucuronide accumulates more due to incomplete conjugation capacity.
47
What is the function of ligandin in hepatocytes?
A cytosolic binding protein that sequesters bilirubin and other organic anions, reducing reflux.
48
Why might albumin‑binding displacement cause bilirubin encephalopathy?
Drugs that displace bilirubin from albumin raise free bilirubin, increasing neurotoxicity risk.
49
Explain the enzymatic mechanism of haem oxygenase cleavage.
HO binds heme‐Fe, introduces two oxygen atoms at the α‑bridge via NADPH‑P450 reductase, forming verdoheme before biliverdin release.
50
Outline the electron donors and steps in the haem oxygenase reaction.
Electrons flow from NADPH → cytochrome P450 reductase → HO, incorporating O₂ to cleave heme.
51
Describe kinetic differences between HO‑1 and HO‑2 (Km, Vmax).
HO‑1: Km ~0.5–1 μM (high affinity), inducible high Vmax; HO‑2: Km ~3–5 μM, constitutive lower Vmax.
52
How does nitric oxide (NO) interact with haem oxygenase?
NO can bind heme and inhibit HO activity, modulating CO production.
53
Discuss the role of biliverdin reductase in cellular redox homeostasis.
It generates NADP⁺ and regulates antioxidant gene expression via kinase activity.
54
How do UGT1A1 mutations lead to Crigler‑Najjar type I vs. II?
Type I: null mutation (no activity); Type II: missense (partial activity ~10 %).
55
Why is high bilirubin neurotoxic?
Free bilirubin disrupts neuronal membranes and induces oxidative stress in the CNS.
56
How does bilirubin’s amphipathic structure facilitate membrane interaction?
Hydrophobic rings insert into lipid layers; propionate side chains interact with aqueous environment.
57
Analyze the structural basis for bilirubin’s antioxidant properties.
Its conjugated double bonds and central methine bridge scavenge lipid peroxyl radicals.
58
What role do gut bacteria play in bilirubin metabolism?
They deconjugate bilirubin and reduce it to urobilinogens for excretion.
59
Propose a mechanism for cholestasis‑induced hyperbilirubinemia.
Blocked bile flow raises conjugated bilirubin in blood via impaired canalicular excretion.
60
How might OATP transporter mutations contribute to Rotor syndrome?
Reduced OATP1B1/1B3 uptake of conjugates elevates plasma bilirubin without dark pigment.
61
Compare bilirubin metabolism in humans vs. rodents.
Rodents form bilirubin glucuronides but also sulfate conjugates; they handle bilirubin differently due to UGT isoforms.
62
Explain the clinical significance of increased urinary urobilinogen.
Sign of hemolysis or hepatic dysfunction leading to excess bilirubin conversion.
63
How would a biliverdin reductase inhibitor affect heme catabolism?
Biliverdin would accumulate; bilirubin production and CO release would decrease.
64
Describe the interplay between heme synthesis and catabolism in porphyria.
Accumulated porphyrin intermediates inhibit HO regulation and feedback on ALA synthase.
65
How is heme catabolism linked to iron homeostasis?
Released Fe³⁺ is sequestered by ferritin or transported by transferrin for reuse.
66
What is the significance of HO‑1 induction in inflammatory diseases?
HO‑1 products (CO, biliverdin) exert anti‑inflammatory and cytoprotective effects.
67
Elaborate on regulation of the UGT1A1 gene.
Controlled by nuclear receptors (CAR, PXR) and transcription factors responding to xenobiotics and bilirubin.
68
Discuss fasting’s effect on bilirubin levels.
Increased lipolysis releases fatty acids that compete for UGT1A1, raising unconjugated bilirubin.
69
How does sepsis affect bilirubin transport and conjugation?
Pro-inflammatory cytokines downregulate OATP and MRP2, causing mixed hyperbilirubinemia.
70
Evaluate biliverdin’s hepatoprotective role in ischemia‑reperfusion injury.
Biliverdin activates antioxidant pathways and reduces neutrophil infiltration.
71
Explain how photoisomerization of bilirubin alters its solubility.
Forms configurational/cis‑trans isomers that are more polar and excretable without conjugation.
72
Discuss enterohepatic circulation’s role in gallstone formation.
High bilirubin load and bacterial deconjugation increase calcium bilirubinate precipitation.
73
Propose a gene therapy strategy for Crigler‑Najjar syndrome.
Deliver functional UGT1A1 gene via AAV vector targeted to hepatocytes to restore conjugation.

Biochemistry Theory Semester 1 (12 decks)

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