disorders of blood coagulation

Question 1

Why is a blood clot important?

Answer 1

• keeps blood in
• keeps pathogens out
• tightly regulated process that stops bleeding at the site of an injury
• must remain localised - if blood clot gets transported to the brain = stroke

Question 2

what is hemostasis?

Answer 2

• platelets and fibrinogen circulate ready to go
• damage in vessel wall triggers clotting
• aggregated platelets + fibrin mesh
• blood loss is stopped by formation of a plug composed of platelets and fibrin.
• fibrinolysis breaks down blood clots preventing clots from growing and detaching.
• the balance between these two processes is called hemostasis.

Question 3

How is clotting normally prevented when there is no trauma/injury?

Answer 3

=> endothelium in blood vessels normally maintains anticoagulant surface
=> injury exposes sub endothelial surface collagen to come into contact with blood component to activate clotting

Question 4

outline the process of primary haemostasis

Answer 4

Primary hemostasis involves adhesion, aggregation and activation.

1. The endothelium continuously releases small amounts of von williebrand Factor in weibel-palade bodies for release when approximately stimulated.
2. if collagen becomes exposed to blood (because the endothelium is damaged), Von Willebrand factor binds to it.
3. Platelets express receptors for both collagen and von willebrand Factor and become activated when these proteins bind to them. Activated platelets express functional fibrogen receptors , which are required for aggregation.

Question 5

Outline secondary haemostasis.

Answer 5

Secondary hemostasis causes activation of fibrin formation through clotting cascade.

1. activated platelets
2. tissue factor (TF) , expressed by nearly all subendothelial cells activates the coagulation cascade to initiate minor burst of thrombin. Factor FVIIa binds to Tissue Factor, which ultimately leads to conversion of prothrombin to thrombin.
3. Thrombin activates receptors on platelets as well as endothelium, amplifying platelets aggregation and initiating release of stored von Willebrand Factor from endothelial cells.
4. thrombin will activate 2 cofactors : factor Va and Factor VIIIa which subsequently form calcium ion- dependent complexes on the surface of platelets with factor IX a ((tense complex) and Factor Xa (the prothrombinase complex). These complexes greatly accelerate production of Factor Xa and thrombin, respectively.
   This is the amplification stage of the coaggulation cascade.
5. The greatly increased production of thrombin via tenase and prothrombinase contribute considerably more to the process. Thrombin will convert fibrinogen to fibrin mesh.

Question 6

Define antithrombin.

Answer 6

• thrombin inhibitor
• its a serpin (serine protease inhibitor)
• activity of antothrombin in greatly enhanced by binding sites on endothelial cells
• major checkpoint to inhibit coaggulation(thrombin, IXa and Xa)

Question 7

What is another fibrinolytic system/plasminogen activation system?

Answer 7

• plasminogen (circulating in blood) => plasmin (proteolytic enzyme)
• it breaks fibrin into fragments called fibrin degradation products, one of these products is called D-dimer.

Question 8

Why is D- dimer significant?

Answer 8

-D - dimer can be used to identify the stages of clotting cascade.

Question 9

What is the difference between heparan and heparin?

Answer 9

1. Heparan = natural binding site on endothelial cell

2. heparin = anticoaggulant, mimics effects of antithrombin.

Question 10

How do protein C and protein S function to inhibit coaggulation?

Answer 10

• protein C and protein S are natural anticoaggultant plasma protein.
• protein C is activated when thrombin binds to thrombomodulin (TM) on endothelial cell.
• Protein C is converted to active protein C (APC)
• protein S is an APC co factor which helps binding to cell surfaces Protein S degrades co factors FVa and FVIIIa( mutation in this co factor leads to hemophilia)

Question 11

Define haemophilia

Answer 11

-failure to clot leading to haemorrhage

Question 12

What defects lead to haemophilia A and B?

Answer 12

• mutations in coagulation factors
• platelet abnormalities
• collagen abnormalities

A = mutation in factor 8 (80%) 
B= mutation on co factor 9 (20%)

Question 13

What is Von willebrand disease?

Answer 13

• inherited defect/deficiency in vWF
• without vWF platelets can’t bind to endothelial cells so no clotting.
• platelet disorders
• type of haemophilia

Question 14

what is thrombophilia?

Answer 14

• excessive clotting leading to thrombosis
  1. inherited : mutations in coagulation factors (DVT)
  2. acquired: malignancy increases clotting factor (DVT)

Question 15

What is disseminated intravascular coagulation (DIC) - whole body clots?

Answer 15

• infection

- depletion of clotting factors and platelets leads to bleeding.

Question 16

What cofactor mutation occurs in heamophilia A?

Answer 16

• FVIII (factor 8)

- 80% of mutations

Question 17

What cofactor mutation occurs in haemophilia B?

Answer 17

• FIXa (facto 9)

- 20% mutation

Question 18

Where is bleeding in hemophilia and von willebrand disease localised to?

Answer 18

1. hemophilia = bleeding into joints

2. Von willebrand disease: affects mucous membranes, mostly mild but bleeding can vary in severity

Question 19

Explain resistance to activated protein C and how it leads to increased risk of DVT.

Answer 19

• factor V leiden mutation causes FVa to be resistance to APC so FVa is not inactivated so clot gets bigger and increases risk of DVT.

Question 20

Explain how antithrombin deficiency leads to excessive clotting.

Answer 20

1. antithrombin deficiency means inhibition of FXa and FIXa and thrombin doesn’t occur.
2. clotting continues, leading to excessive clotting
3. increased risk of DVT

Question 21

What is the Virchow’s triad of thrombosis made up of?

Answer 21

1. hypercoagulability
2. Vessel wall injury
3. stasis

Question 22

What does development of a venous thrombus depend on?

Answer 22

• alterations in the constituents of blood
• changes in normal blood flow
• damage to the endothelial layer

Question 23

What are symptoms of deep vein thrombosis?

Answer 23

• swelling
  -pain and tenderness of veins
  -superficial venous distension
  -increased skin temperature
• skin discolouration
  All reflect obstruction to the venous drainage increased risk of pulmonary embolism.

Question 24

What is disseminated intravascular coagulation (DIC)?

Answer 24

• As sepsis (body’s response to an infection injures its own tissues and organs.
• depletion of clotting factors and platelets leads to bleeding.

Question 25

What are examples of anti-coagulants?

Answer 25

• eg: Warfarin, heparin, direct oral anticoagulants (DOACs)

- prevent clotting

Question 26

What are examples of direct oral anticoaggulants?

Answer 26

• Rivaroxaban, apixaban (FXa inhibitors)

- Dabigatran (thrombin, FIIa inhibitor)

Question 27

What do thrombolytic/fibrinolytics do?

Answer 27

• break down clots

- eg: plaminogen activators, tPA, streptokinase(bacterial)

Question 28

What are investigation for venous thrombin embolism (VTE)?

Answer 28

1. clotting screen :
   - prothrombin time
   - partial thromboplastin time
   - thrombin time
2. full blood count
3. Renal screen
4. Liver function tests
   - if clinical suspicion of liver disease.

Question 29

What are treatments of venous thrombin embolism (VTE)?

Answer 29

1. DVT: anticoagulate
   - immediate anticoagulant effect
   -heparin or warfarin
   -DOACs = rivaroxaban, apixaban (FXa inhibitor)
   Dabigatran (thrombin FIIa inhibitor)
2. PE : thrombolysis
   - alteplase (tissue plasminogen activator
   - streptokinase
   - followed by anticoagulant to prevent recurrence.

Question 30

What are bleeding complications from anticoagulants?

Answer 30

• intracerbral bleed