6/17 - ICR Thrombosis and Bleeding Flashcards
Platelets are activated at the site of vascular injury to form a platelet plug that provides the initial hemostatic response to stop bleeding. The intact endothelium prevents the adherence of platelets.
How then does the adhesion process begin?
Intimal injury exposes subendothelial elements such as collagen. Platelets bind loosely to collagen via binding of the glycoprotein Ib/IX/V complex to von Willebrand factor which in turn binds to the subendothelial matrix, and firm adhesion of platelets requires binding of glycoprotein Ia/IIa complex to collagen
Problems with the initial binding complexes can lead to disorders. What are the two big ones that have to do with this beginning process?
Deficiency of any component of the GP Ib/IX/V complex or VWF leads to congenital bleeding disorders (Bernard-Soulier disease (rare – autosomal recessive) and von Willebrand disease (the most common inherited bleeding disorder – autosomal dominant))
The change induced by collagen on platelets and what this change results in
Collagen activates platelets which causes them to undergo a profound shape change from a disc shape into a “star” (extension of pseudopods) along with secretion of platelet granules.
This conformational change also activates GP IIb/IIIa which allows for binding of fibrinogen and von Willebrand factor and subsequent aggregation of platelets
Glanzmann thrombasthenia
GP IIb/IIIa is critical for formation of the platelet plug – Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a defect in GP IIb/IIIa
Where are procoagulants made?
All of the procoagulants are synthesized in the liver except VWF, which is synthesized in megakaryocytes and endothelial cells.
Outline the coagulation cascade.
Injured endothelium expresses tissue factor (TF) which serves as the cofactor required for the production of activated factor VII (FVIIa). The TF-FVIIa complex initiates coagulation by activating factors X and IX, which in turn generate a small amount of thrombin (from prothrombin). Thrombin converts fibrinogen to fibrin, which undergoes polymerization. Thrombin serves as a potent amplifier of the coagulation process through activator of additional platelets and activation of factors V, VIII, and XI.
The positive feedback mechanisms promoting and amplifying clotting helps to establish hemostasis, but if unchecked could lead to pathologic thrombosis beyond the site of injury. Coagulation is modulated by natural antithrombotic pathways which are anchored on intact endothelium.
Discuss the termination of clotting
The termination phase of the coagulation process involves antithrombin and a clottinginitiated inhibitory process, the protein C pathway. This termination phase is critical in mediating the extent of clot formation, as demonstrated by the thrombotic disorders present in individuals with deficiencies in antithrombin, protein C, and protein S (the cofactor for protein C).
Discuss how we break up the clot
To restore vessel patency following hemostasis, the clot must be organized and removed. Plasminogen binds fibrin and tissue plasminogen activator (tPA), and this complex leads to conversion of the plasminogen to plasmin.
Plasmin cleaves the polymerized fibrin strand at multiple sites and releases fibrin degradation products (FDPs). One of the major FDPs is D-dimer
How do we regulate plasmin activity
Plasmin activity is regulated by vascular endothelial cells that secrete plasminogen activators (e.g., tPA) and inhibitors (e.g., plasminogen activator inhibitor, PAI).
Prothrombin time measures what?
Prothrombin time (PT) — measures the function of factors VII, X, V, prothrombin, and fibrinogen.
(extrinsic pathway)
activated Partial Thromboplastin Time measures what?
Activated Partial Thromboplastin Time (aPTT) — measures the function of high weight molecular kininogen, kallekrein, factors XII, XI, IX, VIII, X, V, prothrombin, and fibrinogen.
What is the “Common Pathway?”
Note that both of these clotting times include measurement of function of X, V, prothrombin, and fibrinogen. This final portion of the pathway is also called the “Common Pathway.”
Discuss how we use a Correction Study.
The correction study is done by mixing, in equal proportions, the patient’s plasma with normal plasma (pooled from many normal volunteers) and then repeating, with the mixture of normal/patient plasma, the test that was abnormal. If the clotting test now results in a normal clotting time, then the patient is missing some clotting component from the plasma
If, however, the clotting test does not return to normal, then there is an inhibitor present in the patient’s plasma. (The inhibitor inhibits a component of the clotting test and even normal plasma cannot overcome this inhibitor)
When dealing with an isolated prolonged PT, we can deal solely with the extrinsic pathway of coagulation. Only a few abnormalities result in an ISOLATED prolongation of the PT (i.e., the aPTT is normal).
What inherited diseases would cause an isolated elevated Prothrombin time?
Factor 7 Deficiency is the only one.
When dealing with an isolated prolonged PT, we can deal solely with the extrinsic pathway of coagulation. Only a few abnormalities result in an ISOLATED prolongation of the PT (i.e., the aPTT is normal).
What acquired diseases would cause an isolated elevated Prothrombin time (5)?
Acquired Factor 7
Vitamin K Deficiency
Moderate Liver Disease
Inhibitor of Factor 7
Early DIC
