Coagulation and Dissolution of a Blood Clot Flashcards
1
Q
normal hemostasis
A
balance between generation of hemostatic clots and uncontrolled thrombus formation; anticoagulants dominate
2
Q
extrinsic pathway
A
- plasma mediated, initiation of hemostasis
- primary hemostasis
- key –> tissue factor
- activated when blood contacts cells outside the vascular endothelium
- nonvascular cells express a membrane protein called tissue factor III which initiates this pathway
3
Q
intrinsic pathway
A
- amplifies and propagates hemostasis
- secondary hemostasis
- key –> thrombin
- triggered when blood contacts a negatively charged surface (exposed sub-endothelial collagen)
4
Q
common pathway
A
- results in an insoluble fibrin clot; starts at Xa
- where intrinsic and extrinsic pathways converge with activation of factor X
5
Q
How do you decide whether or not to get preoperative coagulation testing?
A
- based on patient’s history and planned surgery
- balance between risk of surgical bleeding and risk of developing postoperative thromboembolism
6
Q
mechanism of normal hemostasis
A
- vasoconstriction
- platelet plug
- clot formation
- clot dissolution
7
Q
vasoconstriction in normal hemostasis
A
- vascular endothelium provides nonthrombotic or antiplatelet surface (basically makes it so the blood doesn’t stick to the surface and clot)
- damage to the endothelium exposes the underlying extracellular matrix and elicits contraction (vasoconstriction)
8
Q
what other things can induce prothrombotic endothelial changes?
A
- thrombin
- hypoxia
- high fluid sheer stress
9
Q
formation of platelet plug in normal hemostasis
A
when platelets are exposed to the extracellular matrix in damaged endothelium they undergo a series of biochemical and physical alterations
10
Q
3 major phases of platelet plug
A
- adhesion
- activation
- aggregation
11
Q
platelet normal concentration
A
150,000-400,000 per microliter
spontaneous bleeding can occur at <50,000
lethal is <10,000
12
Q
what is the life of a platelet?
A
8-12 days
13
Q
platelet adhesion
A
exposure to the subendothelial matrix proteins allows platelets to undergo a conformational change to adhere to the vascular wall; basically conformational change makes them more sticky
14
Q
platelet activation
A
- after platelets adhere to damaged endothelial cell wall, several intracellular signaling pathways are activated when ligands bind to platelet receptors and a series of physical and biochemical changes occur
- platelets develop pseudopod-like membrane extensions to increase platelet surface area
15
Q
platelet aggregation
A
- plt recruitment
- release granular contents resulting in recruitment and activation of additional platelets
- completes the formation of a platelet plug
- activators released during the activation phase recruit and amplify the response of additional platelets to the site of injury
- newly activated GPIIb/IIIa receptors on the platelet surface bind fibrinogen to provide for cross-linking with adjacent platelets
16
Q
Von Willebrand Factor (vWF)
A
- produced in endothelium and platelets
- released by endothelial cell and by activated plts
- primary function is to bind other proteins
17
Q
vWF primary function
A
- important bridging molecule between subendothelial matrix and platelets forming cross links
- Glycoprotein IIb/IIIa –> platelet to platelet
- Glycoprotein Ib/factor IX/factor V receptor complex –> plt to endothelium
18
Q
glycoprotein Ib-factor V-factor IX complex (GPIb-V-IX)
A
- binds vWF allowing platelet adhesion and platelet plug formation at sites of vascular injury
- absence of this complex = Bernard-Soulier syndrome
19
Q
Von Willebrand Disease (vWD)
A
- mainly activated in conditions of high blood flow and shear stress
- 1 in 100 individuals, but clinically significant cases are 1 in 10,000
- deficiency of vWF therefore show primarily in organs with small vessels such as skin, GI, and uterus
20
Q
vWD common presentation
A
woman with heavy periods, bleeding when flossing or brushing teeth
21
Q
vWD diagnosis
A
measure amount of vWF in a vWF antigen assay and the functionality of vWF with biding assays
22
Q
type 1 vWD
A
- 60-80% of cases
- failure to secrete vWF into circulation or vWF being cleared more quickly than normal
- mild, often goes undiagnosed until bleeding following surgery, easy bruising, or menorrhagia
23
Q
type 2 vWD
A
- 15-30%
- qualitative defect and bleeding varies (4 subtypes)
- decreased ability to bind to GPIb
- decreased ability to bind to VIII
24
Q
type 3 vWD
A
- most severe, homozygous defective gene, complete absence of production of vWF
- leads to extremely low levels of factor VIII since it does not exist to protect VIII from proteolytic degradation
25
platelet type or pseudo-vWD
- defect of the platelets GPIb receptor
| - vWF is normal but the platelet receptor GPIb is abnormal
26
what medications do we use that are a GPIIb/IIIa inhibitor?
- GPIIb/IIIa inhibitors (class of antiplatelet)
- abcizimab (ReoPro)
- eptifibatide (Integrilin)
- tirofiban (Aggrastat)
- blocks ability of fibrinogen to form around aggregated platelets
27
which medications do we use that are a thromboxane A2 inhibitor?
- aspirin - inhibits the ability of COX enzyme to synthesize the precursors of thromboxane within platelets
- naproxen - nonselective COX inhibitor
28
P2Y12 receptor
further amplify the response to ADP and draw the forth of the completion of aggregation
29
formation of blood clot
- follows platelet plug
- fibrinogen breaks down to produce fibrin, which becomes cross-linked into a stable mesh
- coagulation factors activated and initiate coagulation cascade
- soluble fibrinogen converted to insoluble fibrin
- converted by thrombin (IIa)
30
what is the key step in blood clotting?
conversion of fibrinogen (I) to fibrin (Ia) by thrombin (IIa)
31
coagulation factors
- identified with roman numerals
- most are glycoproteins
- most synthesized in liver
- circulate in an inactive state
- lower case "a" indicates active enzyme
32
which coagulation factors are not enzymes?
- vWF
- Tissue factor (III)
- glycoprotein
33
which coagulation factors are not synthesized in the liver?
- calcium (from diet)
| - vWF (synthesized in endothelial cells)
34
Which factors are dependent on vitamin K for utilization?
factors II, VII, IX and X
35
intrinsic pathway of coagulation
- contact activation system
- begins with damage to blood vessels
- formation of primary complex on collagen and thrombin generation by way of factor XII and ultimately merges to the common pathway to activate factor X
36
extrinsic pathway of coagulation
- tissue factor pathway
- initial step in plasma-mediated hemostasis
- following damage to the blood vessel, factor VII comes into contact with tissue factor (which is prevalent in the sub-endothelial tissues surrounding vasculature) and forms an activated TF-VIIa complex
- the TF-VIIa circulating the plasma activates factor X to promote the conversation of X to Xa
37
common pathway of coagulation
- common to both extrinsic and intrinsic
- prothrombin (II) is cleaved by activated factor X to produce thrombin (IIa)
- signal amplification
38
blood clot
- prothrombin gets activated to thrombin
- thrombin activates fibrinogen to form fibrin
- fibrin --> covalent bonds and cross-linking of fibers create a meshwork in all directions of blood cells, platelets and plasma which adhere to the surface of damaged blood vessel
- after clot is formed, actin/myosin of platelets trapped in fibrin mesh and interact in a manner like that in muscle contraction
39
dissolution of blood clot
- clot lysis occurs when plasminogen is activated to plasmin
- activation occurs by tissue plasminogen activator (t-PA) released from the tissue, vascular endothelium, plasma, and urine
- plasmin is an enzyme which digests fibrin fibers, fibrinogen, Factor V, Factor VIII, prothrombin, and Factor XII
40
prothrombin time (PT)
- evaluation of extrinsic pathway
- sample blood plasma incubated with tissue factor in the presence of excess Ca2+
- particularly sensitive to three of the four vitamin K factors (II, VII, and X)
- commercial prothrombin reagents vary markedly in their responsiveness to warfarin-induced decreases in clotting factors and are not interchangeable between laboratories
41
partial thromboplastin time (PTT)
- indicates performance of intrinsic pathway
| - a sample of blood triggered by adding an activator surface plus phospholipid and Ca2+
42
ACT
- performed by mixing whole blood with an activated substance to initiate activation of the clotting cascade
- widely used and is reliable for high heparin concentrations
- influenced by hypothermia, thrombocytopenia, coagulation deficiencies
43
viscoelastic testing
- thromboelastometry (TEG)
- rotational thromboelastometry (ROTEM)
- global assay for whole blood clotting including coagulation factors, inhibitors, anticoagulant drugs, platelets, and fibrinolysis
44
bleeding time
- sensitive test of platelet function
| - small incision made in underside of forearm and the amount of time it takes for bleeding to stop is recorded
45
heparin concentration measurements
- increasing concentrations of protamine added to samples of heparin containing blood
- time to clot measured by the sample in which heparin and protamine are most closely matched will clot first
46
platelet function tests
-classic method involves centrifugation of patient blood to obtain platelet rich plasma, which then analyzed in a cuvette at 37 degrees placed between light source and photocell
47
ACT
80-150 seconds
