Haemostasis and thrombosis

Question 1

what is haemostasis?

Answer 1

Functions to limit blood loss (haemorrhage) following vascular damage, yet without compromising the fluidity of the blood.

Question 2

what is thrombosis?

Answer 2

Occlusion of a blood vessel (venous or arterial) by an intravascular blood clot or platelet clump.

Question 3

what are platelets/thrombocytes?

Answer 3

Platelets are cell fragments (no nucleus) produced from megakaryocytes in bone marrow

Question 4

how many platelets are there per micolitre of blood?

Answer 4

Normally 150,000-350,000 per microlitre (ml) of blood

Question 5

what is the clinical cut off for platelet deficiency?

Answer 5

Deficiency (< 50,000/ml) → danger of haemorrhage

Question 6

How is intravascular blood coagulation and platelet activation suppressed naturally?

Answer 6

• Non-thrombogenic surface of endothelium
• Production by endothelium of prostacyclin (PGI) and nitric oxide which inhibit platelet aggregation; nitric oxide also inhibits adhesion of platelets to vascular wall
• Presence in plasma of natural anticoagulants e.g. antithrombin III

Question 7

how are platelets activated following vascular damage?

Answer 7

• Platelets tend to flow near the endothelium
• Platelets adhere to exposed sub-endothelial collagen and become
  activated
• Coagulation is initiated by exposure of blood to tissue factor (Factor
  III) and facilitated by exposure of pro-coagulant phospholipid on
  platelet surface
• Platelets release agents (granules) which promote vasoconstriction and platelet aggregation, i.e. thromboxane A2, 5-HT and ADP
• Fibrin strands enmesh the platelet aggregate to consolidate the
  haemostatic plug
• The haemostatic plug is dissolved by the fibrinolytic system to allow
  tissue repair

Question 8

what molecules are involved at each phase?

Answer 8

• Vessel is cut or atherosclerotic plaque ruptures, leading to activation
  of platelets by sub-endothelial collagen
• Platelet surface integrin (glycoprotein GPIb) permits adhesion to
  collagen in vessel wall via von Willebrand factor bridge
• Platelets change shape from discoid to spherical, with development of
  pseudopodia
• Activated platelets expose another cell-surface integrin (GPIIb/IIIa)
  Platelets aggregate (adhere to each other) - fibrinogen cross-links GPIIb/IIIa receptors on adjacent platelets
• Arachidonic acid metabolism initiated forming thromboxaneA2 activates adjacent platelets and promotes vasoconstriction
• Platelets degranulate releasing stored ADP and 5-HT activate
  adjacent platelets and promote vasoconstriction
• Exposure of pro-coagulant phospholipid on platelet surface activates
  the coagulation cascade (Intrinsic pathway)

Question 9

what is the coagulation cascade and what does it result in?

Answer 9

An enzyme cascade involving:

• Coagulation factors (plasma proteins – activated by proteolytic cleavage to become, in turn, active proteases (II → IIa))
• Phospholipid on surface of activated platelets
• Calcium ions

Lead to the generation of the enzyme thrombin which, in turn, converts soluble fibrinogen to gel-like fibrin. Fibrin provides the matrix or strength of a blood clot.

Question 10

what is the enzyme amplification pathway?

Answer 10

factor XII
factor XI
factor IX
factor VIII
factor X
prothrombin activator
thrombin
fibrin

Question 11

what is von willebrand disease?

Answer 11

(most common) – deficiency of von
Willebrand factor – binds to and stabilises factor VIII and binds
platelets to collagen

Question 12

what is haemophilia A?

Answer 12

• deficiency of factor VIII

Question 13

what is haemophilia B?

Answer 13

deficiency of factor IX

Question 14

what is haemophilia C?

Answer 14

deficiency of factor XI- “Rosenthal syndrome” - more common in Ashkenazi jews

Question 15

which haemophilias are restricted to males?

Answer 15

haemophilia A and B, single X chromosome

Question 16

which gene encoding factors for coagulation are located on the X chromosome?

Answer 16

VIII and IX

Question 17

what is the fibrinolytic system and its outcome?

Answer 17

The physiological repair system for removing blood clots - involves the generation of the enzyme plasmin which digests fibrin

Question 18

what is the steps of the fibrinolytic pathway?

Answer 18

plasminogen bound to fibrin
-> plasmin with the help of plasminogen activator (t-PA)
plasmin converts fibrin polymer to soluble degradation products

Question 19

what is venous thrombosis?

Answer 19

• Intravascular blood clot (red) forms in deep veins, particularly of the
  legs, when flow is sluggish (e.g. economy class syndrome, post-
  operative thrombosis)
• Fragment may bud off (embolus) and block blood vessel, often
  pulmonary artery
• Therapy: anticoagulant drugs, DOACs, warfarin

Question 20

what is arterial thrombosis?

Answer 20

• Platelet aggregate (white), usually at site of ruptured atherosclerotic
  plaque, then encapsulated by clot (red)
• common sites: - coronary artery → myocardial infarction
• cerebral artery → thrombotic stroke
• Therapy: immediate - dissolve existing clots with fibrinolytics
  long term - anti-platelet drugs (antithrombotics)

Question 21

what factor initiates coagulation?

Answer 21

tissue factor

Question 22

what is tissue factor?

Answer 22

factor III

Question 23

which molecule permits adhesion to collagen in vessel wall?

Answer 23

glycoprotein GPIb

Question 24

what shape change do platelets undergo?

Answer 24

discoid to spherical