02/23d Thrombosis I Flashcards
What happens during primary hemostasis?
Platelets adhere to and activate at sites of injury
What happens during secondary hemostasis?
Coagulation proteins act on platelet surfaces to form fibrin, which stabilizes the platelet plug
What are the two steps of the initially proposed 1904 model of coagulation?
1) Prothrombin is converted to thrombin by thrombokinase + calcium
2) Thrombin converts fibrinogen to fibrin
What are the two pathways of the clotting cascade?
Intrinsic pathway
Extrinsic pathway
What pathway is assessed by the prothrombin time test? What is involved in the test?
Extrinsic pathway
Tissue factor, phospholipid, and calcium are added to a blood sample, and clot time is measured
How do you assess the intrinsic pathway?
Activated partial thromboplastin time
A charged surface is added to a blood sample - this activates factor XII
Calcium and phospholipid are then added and clot time is measured
What are the vitamin K-dependent coagulation factors? What are their relevant characteristics?
Serine proteases that circulate as inactive zymogens, and are activated by proteolysis
Work best in complex with a protein cofactor on a phospholipid surface
Activity is calcium-dependent
What processes and factors are necessary for coagulation protease activity?
Post-translational modification to produce negatively charged amino acid residues (vitamin K dependent)
Calcium cofactor
Phospholipid surface
How does warfarin work?
Vitamin K is a required cofactor for the activity of coagulation proteases
When coagulation proteases are activated, Vitamin K is oxidized
In order to maintain activity, Vitamin K must be re-reduced
Warfarin blocks the enzyme that reduces Vitamin K to the usable state
Which coagulation factors are affected by warfarin? Why?
Factors II, VII, IX, and X
They are vitamin K dependent
On what cell surfaces does hemostasis occur in the body?
Tissue factor-bearing cells
Platelets
Which factor is the precursor of thrombin?
Factor II
Which factor is the precursor of fibrin?
Factor I
What will occur during the PT and aPTT tests if a patient is deficient in a coagulation factor?
Time to clot will be prolonged
What is a major drawback of the PT and aPTT tests?
They cannot predict bleeding tendency in the patient
What are the three steps of hemostasis in the body?
1) Initiation
2) Amplification
3) Propagation
What is involved in initiation of hemostasis?
Tissue factor-bearing cell activates factors X and IX, which generates a small amount of thrombin
What is involved in amplification during hemostasis?
Initial small amount of thrombin, plus other coagulation factors, activate platelets
What is involved in propagation during hemostasis?
Activated platelets generate lots of thrombin through the intrinsic pathway
Thrombin converts fibrinogen to fibrin
What is the structure of the fibrin clot?
Fibrin form polymers that are cross-linked and stabilized by factor XIII
What are the major steps and components of fibrinolysis?
Plasminogen is activated to plasmin
Plasmin dissolves the fibrin clot into many fibrin fragments
What sorts of things can activate plasminogen, and where are they found?
Tissue plasminogen activator (tPA) - found on endothelial cells
Streptokinase - comes from bacteria
Urokinase - found in urine, produced by WBCs
Factors XIIa and kallikrein
What are Amicar and Aprotinin? How do they work?
Anti-fibrinolysis treatments
Amicar blocks activation of plasminogen by tPA
Aprotinin inhibits breakdown of fibrin clots by plasmin
How is clot formation controlled in the body? List three ways
Separation of initiation and propagation steps by blood vessel walls
Presence of plasma coagulation inhibitors such as antithrombin (AT) and tissue factor pathway inhibitor (TFPI)
Anti-thrombotic mechanisms on healthy vascular endothelial cells
What are the symptoms of a platelet-related bleeding problem?
Petechiae and purpura
Mucocutaneous bleeding
What are the symptoms of a coagulation factor-related bleeding problem?
Bruises (ecchymoses)
Soft tissue hemorrhage
How does thrombocytopenia (lack of platelets) cause petechiae and purpura?
Causes endothelial changes that causes RBCs to extravasate
What does von Willebrand’s factor do?
Mediates platelet adhesion under high shear and acts as a carrier for factor VIII
What are the symptoms of von Willebrand’s disease?
Most commonly inherited bleeding disorder
Bleeding, petechiae, excessive menstrual bleeding in women
Reduced level of factor VIII
Prolonged aPTT
What is hemophilia, at the cellular/molecular level? What does this mean for the clotting cascade?
A failure of platelet surface thrombin generation
A platelet plug may form initially, but the rest of clotting cascade is deficient, and thus the wound will rebleed
What factors are deficient in Hemophilia A and B?
Factors VIII or IX
What are the general symptoms of hemophilia A and B?
Prolonged aPTT
Spontaneous soft tissue and joint hemorrhage in the severely affected
What are the signs and characteristics of Factor XI deficiency?
Autosomal disorder, common in populations with lots of consanguinity
Bleeding is usually mild except with trauma or surgery
