Q Haematology

Question 1

How does vascular endothelium prevent haemostasis?

Answer 1

Inhibition of platelet adhesion
-secretion of NO and prostacyclin (PCI2)
-enzyme adenosine phosphatase –> degrades ADP, essential for platelet activation

Anticoagulant effects
-heparin sulphate –> similar structure to heparin, activates plasma protein antithrombin iii, inactivates thrombin (IIa) and Xa

-Thrombomodulin directly binds thrombin. Also activated protein C. Together with cofactor protein S activated protein C is a potent anticoagulant, inactivating factor Va and VIIIa

Fibrinolytic Effects
-endothelial cells also secrete tissue plaminogen activator (t-Pa). Cleaves proenzyme plasminogen to form plasmin. Plasmin degrades fibrin clots from the endothelial cell surface in a process called fibrinolysis.

Question 2

Steps in Haemostasis

Answer 2

1. Vasoconstriction
2. Platelet Aggregation
3. Coagulation

Question 3

How is Haemostasis initiated?

Answer 3

Vessel damaged –> plasma becomes exposed to:
1. Von Willebrand Factor. Endothelial cells synthesise and store. Normally small amount secreted into lumen where it binds with factor 8. Damaged vessel releases large amount, then binds platelets to subendothelial collagen fibres.
2. Collagen Fibres. Exposed when vessel damaged. platelets bind through a vwbf bridging molecule and become activated.
3. Tissue Factor expressed by subendothelial cells but not normally endothelial unless damaged. TF activates plasma coagulation proteins through extrinsic pathway –> production of thrombin.

Question 4

Describe the steps involved in platelet activation

Answer 4

Serotonin and thromboxane A2 reduce blood flow.
Platelets attraxcted to site of injury.
Activated and bound via vWF to subendothelial collagen, exposed collagen coated in a layer of platelets. Next layer activated by ADP released by first cohort of platelets. Binding ADP causes platelets to change shape and release more chemicals from storage granules.
Activated platelets exhibit glycoprotein IIb/IIIa receptor on their surgace. Fibrinogen and vwF glue platelets together through this receptor. –> soft platelet plug.
Strands of fibrinogen –> fibrin by thrombin (the end point of coagulation cascade)/

Question 5

Intrinsic Pathway

Answer 5

12 –> 12a
11–> 11a
9–> 9a
9a + VIIIa + Ca2+ + PF3
Turns X to Xa

Question 6

Intrinsic Pathway

Question 7

Extrinsic Pathway

Answer 7

Blood vessel damage –> exposes circulating clotting factors to subendothelial tissue factor.
7 –> 7A
7A activates Factor 10

Question 8

Common Pathway

Answer 8

factor xa coverts prothrombin (II) to thrombin (iia)
Thrombin then works on the fibrinogen mesh within the platelet plug, hydrolysing the soluble fibrinogen to produce insoluble fibrin strands.
Activatino of factor XIIIa which forms covalent crossbridges between fibrin strants in the platelet plug.

Question 9

Tested by thrombin time

Answer 9

Common pathway

Question 10

Tested by prothrombin time

Answer 10

Extrinsic Pathway

Question 11

Tested by activated partial thromboplastin time

Answer 11

Intrinsic Pathway

Question 12

What is ROTEM

Answer 12

Thromboelastography
POC whole haemostatic process
Assesses platelet function, coagulation and fibrinolysis.
Better represent in vivo haemostasis.
Sample of whole blood added to a slowly rotating cuvette, mimicing sluggish venous flow.
plastic pin attached to a torsion wire lowered into the cuvette. As the blood clots, fibrin strands form between the cuvette and the pin and the torsion of the wire changes.
The speed and strength of the clot formation are calculated from the change in torsion of the wire, resulting in cigar shaped graph.

Question 13

Prothrombin Time

Answer 13

Extrinsic pathway
Adding TF to a sample of plasma, measuring the time of clot formation.
INR is ratio of patients PT compared to average PT of a control sample.
Assesses clotting factor VII, II, X, fibrinogen,

Prolonged by: decreased hepatic synthesis of vt K dependent clotting factors: II, VII, IX and X
(warfarin, vit K def, liver disease)
DIC due to consumption of clotting factors.

Question 14

APTT

Answer 14

Intrinsic Pathway
Adding phospholipid and an activator (silica) to a plasma sample, measuring the time taken to clot.
Assesses VIII, IX, XI and XII
II, X and fibrinogen
Prolonged by:
Unfractionated heparin therapy, activation of antithrombin III (inactivates factors Xa and thrombin),
Haemophilia, (8 def), Christmas disease (IX), amd von willebrand,
DIC due to consumption of clotting factors)/

Question 15

Thrombin Time

Answer 15

test of the final common pathway
Thrombin is added to plasma and the clotting time is measured.
TT tests the interaction between thrombin and fibrinogen and is prolonged in fibrinogen deficiency (eg DIC)

Question 16

Fibrinolysis Pathway

Answer 16

Plasminogen (B globulin, synthesised by liver), becomes interwoven into the fibrin clot as it is formed.
It gets converted to plasmin, a serum protease, mainly by t-PA.
Fibrin is cleaved by plasmin, producing fibrin degredation products (FDPs), eg D Dimer.
Slower process than clot formation to allow for healing.

Question 17

How can you manipulate the fibrinolysis pathway?

Answer 17

Thrombolysis –> promote conversion of plasminogen to plasmin, thus increasing fibrinolysis.
Inhibition of fibrinolysis- Antifibrinolytic drugs eg Tranexamic Acid, inhibit the activation of plasminogen.