ILA Mr Crudus

Question 1

What is Haemostasis?

Answer 1

Haemostasis describes the process the body undergoes to counteract a haemorrhage.

Question 2

What is coagulation?

Answer 2

Coagulation is the process of forming a stable platelet plug at a site of haemorrhage to stop blood loss.

Question 3

List the cells, factors, enzymes, and pathways involved in haemostasis.

Answer 3

1. platelets - form the platelet plug and release ADP & Thromboxane A2.
2. Von Willebrand Factor - binds to exposed collagen allowing platelets to initiate the plug.
3. Factors I-XII (no factor VI) - form steps of the intrinsic and extrinsic cascade pathway.
4. Vitamin K - required to synthesise many of the above factors.
5. Thromboplastin - factor III, begins the extrinsic pathway.
6. Thrombin - converts fibrinogen to fibrin, activates factor XIII to stablise fibrin meshwork, enhances platelet aggregation.
7. Prostacyclin & nitric oxide - prevent the plug from growing past the limits of thesite of injury.
8. Thromboxane A2 & ADP - activates & recruits passing platelets for the plug.

Question 4

What are the platelets and how are they involved in clotting / haemostasis?

Answer 4

1. Platelets are cell fragments that arise from megakaryocytes, and have many roles in haemostasis.
2. Attach to vWF that is bound to exposed collagen in the site of injury, intiating a platelet plug.
3. release ADP & thromboxane A2, which activate other passing platelets.
4. Activated platelets have contractile filaments in their processes, allowing them to pull the edges of the wound site together.

Question 5

What is thrombin and how is it involved in clotting / haemostasis?

Answer 5

1. thrombin is an enzyme (protease), exists in the plasma as its inactive precursor prothrombin.
   Roles:
2. Stimulates / catalyses conversion from fibrinogen (large soluble plasma protein) to fibrin (insoluble protein, loose network).
3. activates factor XIII, which stabilises the fibrin network.
4. Through positive feedback, enhances its won formation from prothrombin.
5. enhances platelet aggregation.

Question 6

What is thromboxane and how is it involved in clotting / haemostasis?

Answer 6

Roles:
1. Role in the formation of the platelet plug: TXA2 stimulates nearby platelets to become activated -> they change shape from disc-shaped and smooth to irregular with spiky processes/pseudopods -> helps them adhere to collagen and other platelets
2. Induce platelet degranulation -> release more ADP -> promotes platelet aggregation and further TXA2 formation.
3. TXA2 is also a vasoconstrictor, plays a role in the vascular spasm (first step in haemostasis). Vascular spasm slows blood flow and minimises blood loss.

Question 7

What is prostaglandin and how is it involved in clotting / haemostasis?

Answer 7

Prostaglandin are hormone-like compounds
- Can activate (thromboxane A2) or inhibit platelet buildup (prostacyclin) for blood clot formation
- Cause vasoconstriction (thromboxane A2) or vasodilation (prostacyclin)

Question 8

What is thromboxane A2?

Answer 8

Thromboxane A2
- Released by activated platelets
- Promotes platelet aggregation and further enhances it indirectly by triggering the release of more ADP from the platelet granules (Sherwood, 2015)

Question 9

What is Fibrin and how is it involved in clotting process?

Answer 9

Fibrin is a fibrous protein that is converted from soluble fibrinogen to its insoluble fibrin to form a clot. Fibrinogen itself is responsible for the aggregation of platelets to form an initial plug at the site of injury, and once converted to the more insoluble form fibrin, it promotes adhesion and increases the stability of the clot.

Question 10

Use a flow chart to display the clotting process.

Answer 10

Question 11

What is the role of liver in haemostasis?

Answer 11

1. Production of clotting and anticoagulation factors
   - liver synthesises essential coagulation factors: I, II, V, VII, IX, X, XI, XII, and XIII.
   - produces anticoagulants, including protein C, protein S, and antithrombin, which regulate the clotting cascade.
   - activation of several factors (e.g., protein C&S) depends on liver-supplied Vitamin K.
2. Fibrinolysis
   - liver produces plasminogen, converted to plasmin, which degrades fibrin clots during fibrinolysis.
3. Clearance of coagulation factors
   - impaired liver function increases the risk of bleeding or thrombosis due to ineffective clearance and regulation of clotting factors.

Question 12

What is the role of bone marrow in haemostasis?

Answer 12

1. Haematopoiesis - bone marrow houses hematopoietic stem cells (HSCs), which differentiate into all blood cell types, including platelets crucial for haemostasis.
2. Thrombopoiesis (platelet production) 0 bone marrow produces megakaryocytes, which give rise to platelets. -> primary haemostasis by forming a weak platelet plug.
3. Primary haemostasis mechanism:
   a). platelet adhesion - platelets aggregate at the injury site via interactions with von Willebrand factor (vWF) and exposed collagen, forming a plug.
   b). platelet activation - activated paltelets release factors (e.g., ADP), changing shape to increase surface area and adhesion, leading to the formation of the parimy paltelet plug.

Question 13

What are the causes of prolonged bleeding?

Answer 13

1. blood disorders: haemophilia (deficiency in clotting factors), von Willebrand disease (enhance loss of factor VII -> limited activation of thrombin).
2. medication: blood thinners: Warfarin (inhibitng vitK clotting factors), Heparin (natural occuring glycosaminoglycan -> enhances activity of antithrombin III which main target is thrombin -> inhibits conversion of fibrinogen to fibrin and paltelet aggregation), Aspirin (inhibits COX-1 in platelets -> responsible for thromboxane A2 production which participate in paltelet aggregation….)
3. Liver disease
4. Vitamin deficiency
5. Trauma to blood vessels or organs
6. cancers

Question 14

How does intteruption to clotting cascade result in prolonged bleeding? (give 2 examples)

Answer 14

1. Hemophilia: Genetic disorder where certain clotting factors (Factor VIII in Hemophilia A, Factor IX in Hemophilia B) are absent or deficient. Without these factors, the normal sequence of chemical reactions in the clotting cascade cannot continue, hence prolonged bleeding occurs even from minor injuries.
2. Vitamin K Deficiency: Vitamin K is needed for the synthesis of clotting Factors II, VII, IX, and X. Deficiency in Vitamin K therefore interrupts the sequence of reactions in the clotting cascade. A vitamin K deficiency can occur due to inadequate dietary intake, certain medications (such as some antibiotics that affect Vitamin K metabolism), or malabsorption disorders.

Question 15

Discuss the effect of Aspirin on Haemostasis.

Answer 15

Aspirin acts as an anticoagulant by irreversibly inhibiting the enzyme cyclo-oxygenase-1 (COX-1), which blocks the synthesis of prostaglandins. Prostaglandins are essential for platelet activation, as they make platelets sticky and trigger thrombin release, necessary for converting fibrinogen to fibrin. By inhibiting COX-1, aspirin reduces the production of thromboxane A2, a compound that promotes platelet activation and aggregation. Since platelets cannot regenerate COX-1, this effect lasts for their lifespan (about 8 days), leading to impaired platelet function, slower clot formation, and prolonged bleeding time.

Question 16

How much aspirin needs to be given to cause an alteration in haemostasis?

Answer 16

325 mg and above, maximum 4 g per day.
Aspirin has a permanent effect on the cohesiveness of platelets for their entire lifetime if consumed daily. The impact on primary hemostasis that bleeding time is lengthened. Platelet count is not affected by aspirin.

Question 17

How long does it take for the effect of aspirin on haemostasis to go back to normal if a patient like Mr crudus stops taking it?

Answer 17

Aspirin inhibition of platelet function
1. Acetylate enzyme cyclooxygenase (COX) > produces thromboxane A2 (promotes platelet aggregation). The inhibition of the COX-1 enzyme by aspirin is irreversible.
2. Platelets (cell fragments) do not have nucleus > cannot synthesize new enzymes
3. Hence effect on platelets last its entire lifespan until it is turned over (occurs every 7-10 days).

Average lifespan of platelet: 7-10 days > typically will take about 5-10 days after stopping aspirin, consequently haemostasis return to normal > can vary on individual factors (dose of aspirin, duration of use, individual’s overall health)

Question 18

List the systemic homeostatic responses to prolonged bleeding/haemorrhage?

Answer 18

1. Baroreceptor Reflex
   - Haemorrhage depletes blood volume, thus, decreases BP
   - Decreased stretch results in decreased baroreceptor activity
   - Response of increased sympathetic drive and decreased parasympathetic drive
   - Tachycardia & vasoconstriction
   - maintains cardiac output ensuring perfusion of vital organs
2. RAAS & vasopressin

Question 19

How does the CVS work to restore BP after haemorrhage?

Answer 19

• Increase in HR to maintain cardiac output, as a result less time for diastole (less filling of chamber) and more time is systole (increased contraction)
• Vasoconstriction to increase TPR

Question 20

How does the renal system work to restore BP and normal fluid balance after haemorrhage?

Answer 20

After haemorrhage, the renal system helps restore blood pressure and fluid balance by promoting sodium reabsorption and water retention. Initially, baroreceptors detect low blood pressure, triggering autonomic responses like increased cardiac output, vasoconstriction, and reduced blood loss. Sodium is primarily reabsorbed in the proximal convoluted tubule, with water following due to osmotic gradients. In response to low blood pressure and sodium levels, renin is released, activating the renin-angiotensin-aldosterone system (RAAS), which increases sodium and water reabsorption and causes vasoconstriction. Additionally, vasopressin is released, enhancing water retention, helping restore blood volume and pressure.

Question 21

How does RAAS restore BP?

Answer 21

Angiotensin II activates several homeostatic mechanisms to restore blood volume and pressure, including an increase in sympathetic innervation, which boosts cardiac output, heart rate, venous return, and peripheral vasoconstriction by stimulating adrenergic receptors. It also upregulates the synthesis of vasopressin in the posterior pituitary, facilitating water retention, and promotes the synthesis and secretion of aldosterone, which increases sodium and chloride reabsorption in the distal convoluted tubule and collecting ducts. Additionally, it causes vasoconstriction of afferent arterioles, reducing glomerular filtration rate (GFR) and decreasing the excretion of sodium and water. These actions collectively restore blood pressure and volume to healthy levels.

Question 22

How does Vasopressin (ALD) restore BP?

Answer 22

Vasopressin acts on the principal cells of the distal convoluted tubule (DCT) and collecting duct by binding to V2 receptors on the apical membrane. This binding triggers a signal cascade that leads to the synthesis of aquaporins, specifically AQ2 channels, which allow water movement across the membrane into the principal cell. Water then diffuses through AQ1 receptors across the basolateral membrane into the interstitial space and peritubular capillaries, resulting in water retention and increased blood volume. Aldosterone, synthesized in the adrenal cortex, binds to intracellular receptors in principal cells of the DCT and collecting ducts, altering DNA transcription to produce epithelial sodium channels (ENaC), which facilitate sodium reabsorption from the nephron into peritubular capillaries. This sodium reabsorption creates an osmotic gradient, enabling concurrent water retention. Additional sodium channels, like the sodium/hydrogen ion antiporter, support sodium reabsorption while excreting hydrogen ions, crucial for countering metabolic acidosis caused by anaerobic glycolysis and lactic acid buildup during haemorrhage. This mechanism helps restore both blood volume and pH balance.

Question 23

What role does the ANS system have in the conpensations to maintain homeostasis when there is haemorrhage?

Answer 23

The autonomic nervous system (ANS) plays a key role in compensating for blood loss during haemorrhage by reducing parasympathetic activity in the heart, leading to an increase in heart rate, cardiac output, and arterial pressure to restore normal blood pressure. At the same time, sympathetic activity increases, enhancing heart contractility, stroke volume, and venous return through venous vasoconstriction, while arteriole vasoconstriction raises total peripheral resistance, all of which help restore blood pressure. Additionally, the RAAS system is activated by the SNS, leading to the release of renin, which converts angiotensinogen into angiotensin I, later transformed into angiotensin II, a potent vasoconstrictor that raises blood pressure and stimulates aldosterone secretion. Aldosterone promotes sodium and water reabsorption, increasing blood volume and pressure, while angiotensin II also triggers thirst and vasopressin (ADH) release, further aiding in water retention and blood pressure restoration.