Bloot Clotting and Blood Groups Flashcards
1
Q
Whawt is hemostasis
A
balance between maintaining blood flwo under normal conditions and clotting blood to minimize its loss when vascular injry ruptures a blood vessel
2
Q
What does sealing a vascular rupture require?
A
requires responses on both the cellular and the molecular levels in teh form of aggregated PLATELETS and FIBRIN CLOTS respectively
3
Q
What is the MOLECULAR RESPONSE (coagulation cascade)
A
produces FIBRIN CLOTS
4
Q
What is the CELLULAR REPSONSE
A
Involves the role of PLATELETS
5
Q
What are hemorrhagic disorders
A
Uncontrolled bleeding
6
Q
What are THROMBOTIC disorders. What are examples?
A
produces THROMBOSIS (localized blodo clotting) that obstructs BF inside arterial and/or venous BV.
MI, stroke, Deep Vein Thrombosis
7
Q
What’s first, cellular (platelet) or molecular (fibrin)
A
Platelet!
- Platelets- cover the big whole
- Fibrin- stop/slow flow with clot
8
Q
What is the first response to vascular damage?
A
contraction of SM, which minimiezes flow via VASOCONSTRICTION
9
Q
What is produced with endothelial damage?
A
Endothelin
10
Q
What is endothelin
A
oligopeptide with powerful VASOCONSTRICTOR properties
11
Q
What is the cellular response triggered by?
A
- exposure to collagen
- von Willebrand factor (vWF)
this transproms the inactive and soluble platelets into platelets that adhere to rim of vascular tear
12
Q
What happens with platelets during cellular response
A
platelets become sticky (via activation) to promote aggregation that blocks rupture.
13
Q
What intitates moleuclar repsonse?
A
TF–> then produces FIBRIN CLOTS
fibrinogen –> fibrin clots
14
Q
what happens once sealed –>
A
repair process begins b/c circulating blood contains factors that inhibit cellular and molecular responses, adn promote FIBRINOLYSIS (process of dissovling fibrin clots) and vasodialtion
15
Q
Factor I
A
Fibrinogen
16
Q
Factor II
A
Prothrombin
17
Q
Factor III
A
Tissue Factor (TF or Thromboplastin
18
Q
Factor IV
A
Ca 2+
19
Q
HOw many serine proteases activate other factors?
A
7
20
Q
Which factors are zymogen?
A
prothrombin
prekallikrein
Factors VII, IX-XII (7, 9-12)
21
Q
Which factors are Activated forms?
A
Thrombin
kallikrein
Factors VIIa, IXa-XIIa
22
Q
Which factor is NOT a protease
A
Factor VIII
23
Q
Is there a factor VI?
A
No!
24
Q
Which factors have only ONE form ?
A
- TF
Phospholipids
Calcium ions
25
What factors have inactive (zymogen) and active (active) fors?
Prothrombin, prekallikrein, and
26
Wich factor ahve three forms?
Factors V and VIII.
1. inactive precursors (V and VIII)
2. Active form (VA and VIIIa)
3. Inactive degraded form (Vi and VIIIi)
27
what part is cleavage >
only activation
28
what vitamin is an imporant one in coag?
Vitamin K
29
what are the four variets of factors?
1. 6 serine proteases
2. 4 are cofactors
3. 1 forms the fibrin clot
4. 1 is the transglutaminase tha tcrosslinks the fibrin clot
30
What are teh 6 serine proteases (facotrs)
```
thrombin
VIIa
IXa
Xa
XIa
XIIa
```
31
what are the 4 cofactors
TF
Ca2"
Va
VIIIa (8a)
32
What forms the fibrin clot
Fibrin
| q
33
What is the translutaminase that crosslinks the fibrin clot
XIII (13)
34
what is the role of vWF
1. stabilize Factor VIII by forming 1:1 complex hen factor is circulating
2. role in platelet adhesion
35
What does the INTRINSIC pathway connect to and provide
It connects kallikrein-kinin pathway and provides cofactor HMWK and PK
36
What are the three pathways of the Molecular response
1. Extrinsic
2. Intrinsic
3. Common
37
How is the Intrinsic Pathway activated?
by the extrinsic pathway
38
What does the EXTRINSIC involve
PL,
Ca 2+
VII
TF
39
What doe INTRINSIC pathway involve
```
PL
Ca2+
VIII
IX
XI
XII
vWF, HMWK, and PK also conribute
```
40
What does the COMMON pathway involve
```
PL
Ca2+
V
X
XIII
Prothrombin
Fibrinogen
```
41
What is another name for TF?
Thromboplastin or Factor III
42
What happens when vascular inury
TF is exposed and as an integral membrane glycoprotein, it is tightly assocaited with membrane PL
43
What converts VII to VIIA?
Autoactivation produces some factor VIIa that is found circulating in the blood
This small amt participated
Cascade initates and then Factor Xa provides positive feedback by concerting more factor VII to VIIa
44
To fully activate VIIa, it must be assembled with
TF, Ca ions, PL, in a membrane assocaited cmpelx called EXTRINSIC TENASE
45
What is extrinsic tease
Complex with VIIa, TF, Ca ions, and PL that coverts Factor X to Xa
46
what factors are in the Common pathway?
V, X, XIII
| as well as prothrombin (II) and fibrinogen (I)
47
What needs to assemble with Xa to fully activate it
Va in teh presence of PL and Ca ions to form a mebrana ss. complex called PROTHROMBINASE
48
What is prothrombinase fnc
itconversts Prtothrombin to throbin, which in turn converts fibrinogen to fibrin
49
What does Thrombin activate?
converts Factor XIII to XIIIa which in turn cross-links fibrin to form hard clot
50
what can initiate Intrinsic Pathway
by extrinsic pathwy or by negatively charged surfaces such as PL on activated platelets
In vitro- pathway initiated by negatively charged surfaces such as powdered glass, kaolin, or dextran sulfate
51
What is Factor XII
Hageman Factor
binds to negatively charged surfaces and undergoes conformational change that increases its proteolytic activity to convert factor XI to XIa up to 100,000 fold
52
What factor in the intrinsic pathway does Extrinsic Tenase Activate
Factor IX
53
WHAT IS THE difference between hard clot and soft clot
soft clot- fibrin monomers no longer soluble and polymerize to form fibrin clot
hard clot- Thrombin converts facor 13-->13a--> then cross-links fibrin to form a hard clot
54
WHAT IS THE difference between hard clot and soft clot
soft clot- fibrin monomers no longer soluble and polymerize to form fibrin clot
hard clot- Thrombin converts facor 13-->13a--> then cross-links fibrin to form a hard clot
55
WHAT IS THE difference between hard clot and soft clot
soft clot- fibrin monomers no longer soluble and polymerize to form fibrin clot
hard clot- Thrombin converts facor 13-->13a--> then cross-links fibrin to form a hard clot
56
WHAT IS THE difference between hard clot and soft clot
soft clot- fibrin monomers no longer soluble and polymerize to form fibrin clot
hard clot- Thrombin converts facor 13-->13a--> then cross-links fibrin to form a hard clot
57
WHAT IS THE difference between hard clot and soft clot
soft clot- fibrin monomers no longer soluble and polymerize to form fibrin clot
hard clot- Thrombin converts facor 13-->13a--> then cross-links fibrin to form a hard clot
58
WHAT IS THE difference between hard clot and soft clot
soft clot- fibrin monomers no longer soluble and polymerize to form fibrin clot
hard clot- Thrombin converts facor 13-->13a--> then cross-links fibrin to form a hard clot
59
What does serine protease thrombin do?
converts solutible fibrinogen MONOMERS into FIBRIN POLYMERS
this is key step in clotting process- formation of soft fibrin clot
60
What does serine protease thrombin do?
converts solutible fibrinogen MONOMERS into FIBRIN POLYMERS
this is key step in clotting process- formation of soft fibrin clot
60
How dos TFPI inhibit thromboses?
It blocks EXTRINSIC TENASE .
It has NO effect on Factor VIIa alone
it only blocsk VIIa when it assembles with TF, factor Xa and Calcium ions on a PL surface
61
How does antithrombin inhibit thromboses?
Though Protein C Pathway: It inhibits the common and intrinsic pathways by forming a 1:1 complex with either thrombin of factor Xa to inactivate these serine proteases.
Antithrombin can also inactivate KALLIKREIN as well as Factor 9a, 11a, 12a in vitro
Only inhibition of Xa are fast enought to be physiologically significant
62
How does heparin contribute to the reaction between thrombin and antithrombin?
Reaction is markedly accelerated (2,000x faster) int eh presence of heparin.
63
What is heparin
It's a polysacchardie having numerous negative hcarges (carboxylates and sulfates).
Heparain in syntheized by cells linign the BC walls of many tissues. It is used therapeutically as an anticoagulant; it must be administered parentaerally and its efect only lasts a few hours
64
How long does the effect of heparin last?
only a few hours
65
What is the role of NO, PGI2 and ADPase
Inhibits platelet activation
66
What is the role of Throbmbin + Thrombomodulin?
Thorugh PRotein C pathway it inhibits INTRINSIC TENASE and PROTHROMBINASE
67
What does Antithrombin + heparin
Inhibits thrombin and Factor Xa
68
Wha tdoes Tsisue Factor Pathway Inhbitior (TFPI) do?
Inhibits EXTRINSIC TENASE
69
What deosplasminogen activators tPA and uPA do
release plasmin--> degrades fibrin clots
70
What is the general role of the protein C pathway
What two surfaces does this pathway occur on?
primarily prevents thrombosis in healthy capillaries and small BV
This pathway occurs on Endothelial CElls and ACTIVATEDPLATELETS
71
What is Protein C (PC)
inactive form of a serine protease.
72
Lumen side of the vascular endothelium that expresses teh surface glycoprotein thrombomodulin
Thrombomodulin modifies the substrate specificity of circulating throbin by forming a 1:1 cmplex with it
Thrombin is ineffective in clot formation
73
Describe the Protein C pathway on endothelial cell surface
TM + Thrombin --> covert PC to APC --> forms 1:1 complex with PS --> APC and PS ass. with PL via a bridging ions
74
What is the role of membrane assocaited comlex APC and PS (3)
1. degrads factor 8a to factor 8i in the intrinsic tenase compelx
2. degrades factor Va to factor Vi in teh Prothrombinase complex
3. Degradation of these essential cofactor proteins indirectly inhibits the actiity of hte respective serine proteases in both complexes, factor 9a and 10a
75
What is associated with deficiencies in eitehr PC or PS?
Increased thrombosis, demosnstrating these proteisn are improtant in hemostasis
76
What is Factor V Leiden?
Single Nucleotide mutation in the Factor V gene (Arg506-->Gln)
common muation in northern Europeans (heteroxygous incidence of 5-10%)
B/c APC-mediated inactivatino of Factor V-Leiden is lsower than normal the risk for venous thrombosis is increased for patients with this mutation
77
What is Plasmin
Serine protease that hydrolyzes peptide bonds in the rod-segment of fibrin to break up the fibrin clot (resulting chunks of protein are called fibrin split products)
78
Where does Plasmin come from?
proteolytic cleavage of an inactive precursor, PLASMINOGEN , be the serine protease tissue plasmimogen activator (tPA)
79
How is tPA used therapeutically?
produced by recombinatn DNA methods has found use as thrombolytic agent in early treatment of MI
80
What is Urokinase and its role?
also a serine protease. An activator of plasminogen which is produced in teh kidney and excreted into the urine; believed to dissolve fibrin clots in teh epithelila cell lining excretory ducts
81
What are the two ways to inhibit FIBRINOLYSIS?
1. Plasminogen Activator Inhibitor, PAI
inactivates tPA and urokinase, thereby inhibitng the conversion of plasminogento plasmin, which in turn ihhibits fibrinoylysis
2. alpha-2 Plasmin inhibitor (alpha-2-antiplasmin) rapidly inhibits plasmin by formation of a 1:1 complex.
It also preents plasminogen bindign to newly formed fibrin clot.
alpha 2 plasmin is linked to fibrin during coagulation by factor 13a, making fibrin more resistant to breakdown by plasmin
82
What is the role of APC (activated protein C)?
Stimulates Fibrinolysis by inactivating PAI01
Inhibiting the inhibitor leads to activation
83
What causes Hemophilia A?
Deficiency of Factor VIII
84
Describe Hem A
X liked
1/5,000 mean
Queen Victoria was a carreir who passed it on to royal families of PRussia, Russia, Spain
85
What causes Hemophilia B? What is aka
Christmas Disease
Deficieny in Factor IX
Defect to Intrinsic TEnase Complex
Tx: Facotr VIII purified from blood
86
Dx Hem B
X linked
1/ 30,000 men
Defect to INTRINSIC TENASE COMPLEX
IX purified from blood
87
vWF Disease
caused by absence of defect in vWF
Expereince bleeding disorders arising from reduced platelet adhesion,
Most common inherited, autosomal wild type,
88
What is the role of vWF? (2)
1. Prevents degradation of Factor 8
| 2. Acts as a mediator between collagen and GP Ib-V-IX
89
What is the Bournard-Soulier Syndrome?
Cause; Mutation in GP Ib-IX-V receptor that often decreases expression of collagen --> which binds vWF --> which in turn binds to GP IB-IX-V expressed on platelet surface.
Rare disease demsntrates improtance of platelet adhesion to blood clotting
rare (incidence is <1/1,000,000)
90
What is Glanzmann's Thrombasthenia
Mutation in genes that encode GP IIB or GP IIIa- cause qualitative or quantitative abnormalities
rare autosomal recessive bleeding disorder that is
severely reudced or absent platelet AGGREGATION in response to physiological agonists, such as ADP, Thrombin or collagen
91
What are physiological agonists to platelet AGGREGATION
1. ADP
2. Thrombin
3. Collagen
92
Antithrombin Deficeinces
predispose affected individuals to serious venous and arterial thrombotic disease.
An autosomal domiannt trait, inherited antithrombin deficeinty has a prevelence between 2 in 10,000 and 5 in 10,000 persons
93
What can Actute Arterial Thrombosis cause?
Platelet Rich
Most MI and Strokes:
Antiplatelet drugs and fibrinolysis activators are primary therapies
94
What can venous thromboembolism cause?
Fibrin Rich
3rd leading cause of CV-asocaited death
Therapy: anticoagulants
95
What is the primary tirgger for arterial thrombosis?
rupture of atherosclerotic plaque
| they are platelet rich.
96
What are the three possible stesp taht drugs could inhibit for arterial thrombosis?
Platelet adhesion
Platelet Activtion
Platelet Aggregation
97
What are ways you can inhibit Arterial Thrombosis (process and drug)
1. Irreversibly inhibit platelet ACTIVATION with ASPIRIN-
2. Irreversibly inhibit plaletet activation with CLOPIDOGREL (Plavix and Iclid)
3. Inhibit Platelet AGGREGATION with GPIIb/IIIa R antagonists (Eptifibatide , tirofiban, fab fragment abciximab
4. activation of fibrinolysis is also a therapy
98
HOw does Aspirin inhibit Platelet Activation?
It Acetylates one specific His o sterically hinder substrate entry into active site of COX-1, which is needed to produce Thromboxane A2 (act. platelet and is vasoconstrictor)
99
How does clopidogrel (Plavix) and ticlopidine (Ticlid) inhibit platelet activation?
blocks ADP R --> inhigibts platelet aggregation
100
How does eptifibatide (Integrilin) or Tirogiban (Aggrastat) or Fab Frabmetn abciximab (ReoPro) work to inhibt plaetl agregation?
They are GPIIb/IIIa R Atagonists
