CPR 04 & 07 - Blood Coagulation and Fibrinolysis (Hemostasis)

Question 1

List the primary steps of hemostasis

Answer 1

Question 2

List what occurs and why during the first step of hemostasis.

Answer 2

Question 3

What are the stages to the second step of hemostasis?

Answer 3

Question 4

What prevents platelet adherence to the endothelium of blood vessels?

Answer 4

The negative charges on both the platelets and endothelial cells repel each other.

Question 5

Describe the key events that take place during initial platelet adhesion.

Answer 5

Question 6

What is and what causes Bernard-Soulier syndrome?

Answer 6

A bleeding disorder caused by a defect in the platelet receptor Glycoprotein IB (GPIb)

Question 7

What are the two primary functions of vWF?

Answer 7

Question 8

What is vWF deficiency often associated with?

Answer 8

Question 9

What three things immediately follow the initial platelet adhesion?

Answer 9

1. Platelet activation = shape change
2. Release of platelet granule contents (ADP), which activates other platelets, promoting aggregation
3. Synthesis and release of thromboxane A2 (TXA2)

Question 10

What is the purpose of the ADP released by activated platelets?

Answer 10

Question 11

What stimulates a platelet cell to release TXA2? List the steps and important enzymes involved in this mechanism.

Answer 11

Question 12

What does TXA2 do once a platelet releases it into the plasma?

Answer 12

It induces platelet aggregation by activating other platelets. It also stimulates vasoconstriction

Question 13

What molecules bind aggregated platelets together?

Answer 13

Fibrinogen binds to the platelet receptors GPIIB/IIIA on different platelets.

Question 14

What is and what causes Glanzmann Thrombasthenia?

Answer 14

It is a bleeding disorder caused by a defect in GPIIB/IIIA

Question 15

List the steps to platelet plug formation.

Answer 15

Question 16

What is and what causes von willebrand disease?

Answer 16

A bleeding disorder caused by missing or defective von willebrand factor

Question 17

What is the purpose of the third step of hemostasis and what component is critical to this process?

Answer 17

To convert blood from a liquid state to a solid/gel like state in order to stabilize the platelet plug. This is done by converting soluble fibrinogen to insoluble fibrin threads. This conversion requires thrombin

Question 18

What are the three clotting pathways and what is the goal of each of them?

Answer 18

Intrinsic Pathway - Activate factor X to Xa

Extrinsic Pathway - Activate factor X to Xa

Common Pathway - Convert fibrinogen to cross-linked fibrin

Question 19

List the clotting factors that have several names? List those alternate names

Answer 19

Factor 1 is also called fibrinogen

Factor 1a is also called fibrin

Factor 2 is also called prothrombin

Factor 2a is also called thrombin

Factor 3 is also called tissue factor, platelet tissue factor, or thromboplastin

Factor 4 is calcium

Factor 12 is also called Hageman Factor

Factor 14 is Protein C

Question 20

Describe the importance of platelet phospholipids to the clotting cascades.

Answer 20

• The platelets that form the initial platelet plug undergo activation resulting in a drastic shape change and the exposure of phospholipids on their surfaces
• Factors VIIa, IXa, and Xa must bind to these phospholipids in order to carry out their functions (activation of X and II respectively)
• This ensures that clotting occurs only at the site of injury (since activated platelets are only at the site of injury)

Question 21

Describe the importance of Vitamin K to the clotting cascades.

Answer 21

• Factors II (prothrombin), VII, IX, X, and Proteins C (XIV) and S are all synthesized in the liver in an immature form and require the activity of γ-carboxylase to carboxylate certain glutamate residues, to become mature coltting factors.
• γ-carboxylase uses Vitamin K as a coenzyme
• Two adjacent negatively charged γ-carboxyglutamate groups present in these clotting factors is what allows them to bind Ca++.
• Being bound to calcium is what allows the clotting factors to bind to phospholipids on the platelet membrane.
• Without Vitamin K, none of this is possible

Question 22

Describe the importance of Ca++ to the clotting cascades.

Answer 22

Factors VII, IX, and X (all factors that require Vitamin K for synthesis) all need to bind Ca++ before being able to perform their various functions.

Question 23

Describe the extrinsic clotting pathway.

Answer 23

1. Tissue factor (Factor III) is a protein localized to the subendothelium of blood vessels. It is exposed to the blood when a vessel is injured where it will activate Factor VII to VIIa, thus starting the extrinsic pathway.
2. Factor VIIa will then bind to tissue factor, Ca++, and exposed activated platelet phospholipids before activating factor X to Xa

Question 24

What factor starts off the intrinsic clotting cascade? How and when?

Answer 24

Factor 12 (hageman factor) gets converted to factor 12a when exposed to concentrated negative charge. This occurs in the blood by coming into contact with rough endothelial surface (lightly damaged vessel wall), subendothelial collagen (lightly damaged vessel wall), or ADP released by already activated platelets

Question 25

Describe the intrinsic clotting pathway.

Answer 25

1. Exposure to rough endothelium, collagen, or ADP activates XII to XIIa 2. XIIa activates XI to XIa (thrombin can also activate XI) 3. XIa activates IX to IXa (thrombin can also activate IX) 4. IXa binds to VIIIa (activated from VIII by thrombin), Ca++, and exposed activated platelet phospholipids before activating X to Xa

Question 26

Describe the common clotting pathway

Answer 26

1. Xa binds to Va (activated from V by thrombin), Ca++, and exposed activated platelet phospholipid to form the _prothrombinase complex_ that splits II (prothrombin) into IIa (thrombin). 2. Thrombin will then cleave the fibrinopeptides off of fibrinogen (I), forming fibrin (Ia). It will also activate V, VIII, XI, and XIII into their active forms. 3. Fibrin monomers (Ia) will spontaneously aggregate with one another via hydrogen bonds forming a fibrin polymer (soft clot) 4. XIIIa is a highly specific transglutaminase that will then crosslink fibrin monomers by forming a covalent bond between the amino group of a lysine and the amide nitrogen of a glutamine. This forms the hard clot

Question 27

What makes the formation of thrombin such a critical step in the clotting cascade?

Answer 27

It catalyzes the key step to clot formation, fibrinogen to fibrin, and kicks the clotting cascades into high gear by also activating clotting factors V, VII, VIII, XI, and XIII

Question 28

Answer 28

Question 29

Draw out the clotting pathways. Be sure to include which factors require Vitamin K for synthesis, which factors activate other factors, and which reactions require Ca++, a phospholipid surface or both. Also indicate where the prothrombinase complex is.

Answer 29

Question 30

What is fibrinolysis?

Answer 30

Dissolution of the fibrin clot

Question 31

Describe how fibronolysis occurs and how it is regulated.

Answer 31

An inactive proteolytic enzyme called plasminogen is incorporated into a developing clot. When tissue plasminogen activator or urokinase is present, plasminogen is converted into active plasmin which then starts breaking down fibrin. Plasminogen activator inhibitors 1 & 2 will prevent plasminogen from being activated and antiplasmin will prevent plasmin form functioning. This process is very closely regulated.

Question 32

What drug can trigger fibrinolysis and how?

Answer 32

Streptokinase can activate plasminogen to plasmin

Question 33

What test can determine the extent of fibrinolysis being performed in the body? What is this useful for?

Answer 33

One of the products of fibrin degredation by plasmin is D-dimer. D-dimer levels can be checked via blood test. D-dimer levels are raised in patients with DVTs.

Question 34

Discuss the mechanisms that prevent a clot from spreading throughout the circulation.

Answer 34

* Factors VII, IX, & X have to bind to an activated platelet to perform function. * Normal endothelium cells release PGI2 (prostacyclin) and NO which prevent platelet aggregation. PGI2 increases intracellular cAMP levels in platelets, preventing activation and acting as a thromboxane antagonist * Normal endothelial cells also express thrombomodulin on their membranes which binds to thrombin and increases activation of protein C which, using protein S as a cofactor, will inactivate Va and VIIIa. * Antithrombin III (activated by heparin) binds and inhibits Xa, IIa, and other activated clotting factors * Coagulation automatically initiates fibrinolysis

Question 35

Answer 35

Question 36

What are the primary bleeding/clotting tests and what do they test for specifically? How reliable are these tests? What do their results indicate?

Answer 36

1. Bleeding time (BT) - times how long it takes for bleeding to stop which is an indicator of platelet plug formation. Prolonged bleeding time is an indicator of low platelet count, vWF deficiency, or platelet receptor defects. Not reliable 2. Coltting time - times how long it takes for stable fibrin formation. Prolonged clotting time indicates defects in the coagulation cascades. Not reliable 3. Prothrombin time (PT) or International normalized ratio (INR) - tests the extrinsic and common coagulation pathways. Measures defects in TF, I, II, V, VII, and X 4. Activated Partial Thromboplastin Time (APTT/aPTT/PTT) - tests the instrinsic and common coagulation pathways. Measures defects in I, II, V, VIII, IX, X, XI, and XII.

Question 37

What are the platelet function tests? What are they typically used for and how are they performed?

Answer 37

Question 38

How do patients with bleeding disorders usually present to the clinic?

Answer 38

Question 39

What are the most prevalent inherited disorders of the clotting pathway and plate plug formation defects?

Answer 39

Question 40

What is defective in Hemophilia A and B? How do these diseases inherit? How do you distinguish the two from one another?

Answer 40

Question 41

How would the bleeding/clotting tests come back for patients with hemophilia A and B?

Answer 41

Question 42

How would a patient with von willebrand disease present to the clinic?

Answer 42

Question 43

What are the lab findings on a von willebrand patient?

Answer 43

Question 44

What are the three platelet defect disorders we need to know and how are they diagnosed?

Answer 44

Question 45

Answer 45