Coagulation

Front 1

Describe regulation of platelet production.

Back 1

Thrombopoiesis senses mass, not #, of circulating platelets. Regulated by thrombopoietin TPO.

Front 2

What disease is associated with giant platelets?

Back 2

Bernard-Soulier Syndrome

Front 3

What disease is associated with small platelets?

Back 3

Wiscott-Aldrich Syndrome

Front 4

What is scrambalase?

Back 4

Causes relocation of platelet phospholipids(-) to outer leaflet during release reaction.

Front 5

Name 2 types of secretory granules found in platelets.

Back 5

1. Dense bodies (Ca, Mg, 5H-T, ADP, ATP).
"Storage pool diseases"

2. alpha-granules (larger molecules: IgG, fibrinogen)

Front 6

Describe regulation of platelet production.

Back 6

Thrombopoiesis senses mass, not #, of circulating platelets. Regulated by thrombopoietin TPO.

Front 7

What disease is associated with giant platelets?

Back 7

Bernard-Soulier Syndrome

Front 8

What disease is associated with small platelets?

Back 8

Wiscott-Aldrich Syndrome

Front 9

What is scrambalase?

Back 9

Causes relocation of platelet phospholipids(-) to outer leaflet during release reaction.

Front 10

Name 2 types of secretory granules found in platelets.

Back 10

1. Dense bodies (Ca, Mg, 5H-T, ADP, ATP).
"Storage pool diseases"

2. alpha-granules (larger molecules: IgG, fibrinogen)

Front 11

3 functions of platelets.

Back 11

1. Adhesion - bind to collagen via vWF.

2. Aggregation - Integrin (when activated)binds fibrinogen.

3. Act as agonists. Inducing influx of Ca from storage, shape change, protein phosphyrlation, liberation of arachidonic acid, release of secretory particles.

Front 12

What deficiency is seen in von Willebrand's disease?

Back 12

Factor 13 (b/c smaller polymers of vWF protect FActor 13 from degradation.)

Front 13

Where is vWF made?

Back 13

1. Megakaryocytes
2. Endothelial cells (in Weibel-Palade body)

Front 14

What is a megakaryocyte.

Back 14

Sources of platelets. Found in bone marrow.
Cytoplasm is packed with membranes which cover platelets as the leave the surface.

Front 15

What is the strongest agonist of platelet agglutination?

Back 15

Thrombin.

Front 16

Describe a test of platelet quality.

Back 16

Aggregometry - determination of released adenine nucleotides. With clumping, have increased light transmission.

Front 17

How does spleen size/presence relate to platelet #?

Back 17

Enlarge spleen = thrombocytopenia and low platelet count.
Removal of spleen = increase platelet count.

Front 18

What receptor does TPO bind to on megakaryocytes and platelets?

Back 18

c-Mpl receptor.

Front 19

Contents (5) of alpha particles of platelets. (Keep this question)

Back 19

1. Factor 5 and 13
2. Protein S
3. vWF
4. IgG
5. Fibrinogen

Front 20

What does a "gray" platelet suggest?

Back 20

Absence of alpha particles.

Front 21

List 3 organelles that are unique to platelets and what they do.

Back 21

1. alpha granules (protein secretion)
2. dense bodies (agonist secretion)
3. dense tubular system (Ca++ storage).

Front 22

List 9 consequences of platelet activation by agonists.

Back 22

1. Ca++ moves to cytoplasm from storage.
2. Discoid shape b/c spiny sphere.
3. Ca++ dependent integrin activation.
4. PIP2 breaks down to IP3 + DAG (requires PLC)
5. Protein kinases are phosphylated.
6. Arachidonate (via PPL A2) converted to thromoxanes and leuikotrienes.
7. Alpha granules released.
8. Dense body contents released.
9. Aggregation and plug formation.

Front 23

What is arachidonate converted to when platelets are activated?

Back 23

Thromboxanes (strong platelet agonist) and leukotrienes.

Front 24

List 4 strong platelet agonists.

Back 24

1. Thrombin (most potent.)
2. Subendothelial collagen.
3. Ruptured atherosclerotic plaque.
4. Thromboxanes (form of prostaglandins).

Front 25

Why is thrombin such a potent platelet agonist?

Back 25

It byasses some of the steps required by other agonists. No 2nd wave seen.

Front 26

List 3 moderate platelet agonists.

Back 26

1. Arachidonic acid.
2. Particulate collagens.
3. ADP.

Front 27

Aspirin preents the conversion of arachidonic acid to?

Back 27

1. Prostaglandins.
2. Thromboxanes.

Front 28

What is source of arachidonic acid?

Back 28

Phospholipids.

Front 29

Describe 2 gene products involved in the vWF receptor.

Back 29

1. GPIb-alpha
2. GPIb-beta

Front 30

When does vWF receptor bind vWF?

Back 30

At high shear.

Front 31

What is Bernard-Soulier syndrome?

Back 31

Absence of vWF receptor.

Front 32

What is the main integrin receptor and what does it bind?

Back 32

alphaIIb/Beta3 (AKA GP2b/3a)
Bids fibrinogen

Front 33

List 2 adhesive glycoproteins containing RGD[S} aa sequence.

Back 33

1. vWF
2. Fibrinogen

Front 34

What is the Weibel-Palade body?

Back 34

a storage organelle for vWF in endothelial cells.

Front 35

Endothelial vWF (smaller and less sticky) is a chaperone for which clotting factor.

Back 35

FActor 8.

Front 36

What is relationship between platelet count and plasma concenc of thrombopoietin?

Back 36

If platelet count low, less thrombopoietin bound to receptor on platelet, so higher conc in blood. This signals megakaryocyte to make more platelets.

Front 37

What color do granules in platelets stain?

Back 37

purplish.

Front 38

What is PFA-100?

Back 38

An automated platelet function analyzer that works by filgtration. Measures adhesion of platelets to a filter.

Front 39

List 3 weak platelet agonists.

Back 39

1. ADP
2. Epi
3. 5H-T

Front 40

List 2 agonists of unknown strength.

Back 40

1. IgG - platelets have IgG receptors.
2. Ristocetin - used in diagnostic tests for vWF b/c it can only clump platelets when vWf is present.

Front 41

What steps in platelet activation are Ca++ dependent?

Back 41

1. Movement of phosphatidyl serine to outer membrane so that clotting factors can find via calcium-dependent bridges.

2. Activation of integrin receptor.

3. Breakdown of PIP2 via Ca-generated PPL C.
3.

Front 42

Describe 2 products of arachidonic acid breakdown.

Back 42

a. TXA-2 (thromboxane A2)- potent platelet agonist.

b. PGI2 - platelet antagonist. which competes with thromboxane at the eicosanoid receptor.

Front 43

What is the significance of myosin in platelets?

Back 43

Myosin is made by a separate gene w/i the megakaryocytes. Platelet Myosin Light Chain Kinase phos and activates myosin. If gene mutation, very large platelets.

Front 44

In the resting platelet membrane what molecules are most abundant on outside? on inside?

Back 44

outside: phophatidylcholine & cholesterol
inside: phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol

Front 45

At rest, are platelets negatively charged on the outside?

Back 45

Yes, though to less of a degree. Glycoproteins with sialic acid (-) cause negative charge. - charge causes platelet to repel each other

Front 46

What change happens to platelet membrane when it is activated?

Back 46

negatively-charged phospholipids move to outside.

Front 47

Describe the 4 families of platelet receptor proteins and give example of each.

Back 47

1. 7 Transmembrane (AKA response receptors).Protease-Activated Receptor,a thrombin receptor.
2. Integrin (alpha2b/beta3: fibrinogen receptor)
3. vWF
4. ?

Front 48

Describe mechanism of protease-activated receptor: thrombin receptor.

Back 48

Thrombin cleaves off extracellular end of PAR-1 receptor. TRAP is then released. Thrombin can then bind.

Front 49

Describe mechanism of integrin receptors.

Back 49

IIb and IIIA subunits join when Ca++ is released. Fibrinogen is multivalent and binds to several different platelets. 2b/3a binds RGD with high affinity.

Front 50

What is the significance of integrin receptors and autoimmune disorders?

Back 50

Antigens on surface of platelets (Pl-A1 & Bak)can induce autoimmune disorder such as Immune Thromobcytopenic Purpura

Front 51

Describe 4 characteristics of sticky proteins (integrin and leucin-rich receptors).

Back 51

1. Abundant.
2. Require activation step before interact c ligand.
3. Considerable redundancy due to shared RGD comain.
4. Intracellular part joins to cytoskeleton under the membrane.

Front 52

Describe characteristics of stimulus response receptors (7 transmembrane).

Back 52

1. Very few.
2. Act quickly.
3. Act via 2nd messengers.
4. Extremely specific via way kinases are activated.

Front 53

Why adhesive glycoproteins contain RGD?

Back 53

1. vWF
2. Fibrinogen
3. Fibronectin.
4. Laminin

Front 54

What is a zymogen?

Back 54

Precursor to the active protelyic enzymes.

Front 55

Describe the 2 ways that clotting can be initiated.

Back 55

1. Contact activation. (12a, Prekallikrein, HMW-kininogen).

2. Normal pathway.(TF, 7a)

Front 56

Describe steps in normal clotting pathway.

Back 56

1. TF forms complex c 7.
2. TF:7 > TF:7a via 10a.
3. X > Xa via TF:7a
or 9-9a, then 9a-10 via 8a.
4. 10a & 5a converts Prothrombin to Thrombin.
5. Fibrinogen to Fibrin via Thrombin.
6. Fibrin to Fibrin x-linked via 13a.

Front 57

Where is Tissue factor found?

Back 57

Fibroblasts and smooth muscle cells.

Front 58

What activates 5 to 5a?

Back 58

thrombin. (+ feedback loop)
Note: Factor 5 is released when platelets are activated.

Front 59

What is cleaved to convert Fibrinogen to Fibrin?

Back 59

2 alpha chains, 2 beta chains. Gammas chains are not cleaved.
alpha must be cleaved before beta. Beta does not have to be released in order to form clot.

Front 60

What is required to activate Factor 9 and 10?

Back 60

Factor 7a:TF complex

Front 61

Which factors require interaction with negative phospholipids in a Vit-K dependent matter for activation?

Back 61

Factors 7, 9, 10 & prothrombin.

Front 62

How is localization of coagulation controlled?

Back 62

1. Tissue Factor-containing membranes (Factors 9 and 10).
2. Negative Phospholipid on membrane required for activation of Factors 7,9,10, prothrombin. (requires Ca++bridge)

Front 63

What is role of vit K in coagulation?

Back 63

In the liver, Factors 7,9,10, prothrombin, protein C and protein S are post-translationally carboxylated by Vit K at the Gla domain. Carboxylation is required for Ca++ binding.
Ca++ ions are bridge b/w factors (proteins) and negative phospholipids of activated platelets. THIS is primary way that coagulation is localized.
VitK= protin carboxylation = binding of Ca++ = Factors binding to - phospholipids on membrane.

Front 64

How does coumarin work?

Back 64

Anticoagulant by competing with vitamin K on the liver carboxylase enzyme.

Front 65

List 2 plasma inhibitors of coagulation.

Back 65

1. Antithrombin III. Binds thrombin and FActor 10a & disables them. Slow.
2. Tissue Factor Pathway Inhibitor (TFPI) released from alpha granules.

Front 66

Describe how TFPI inhibits clotting.

Back 66

2 stages.
1. TFPI binds & inhibits 10a.
2. TFPI:10a inhibits the TF:7a complex (which prevents further production of 10a).
10a normally converts prothrombin to thrombin.
Negative Feedback.

Front 67

Describe 4 positive feedback coagulation controls.

Back 67

1. Thrombin on FActor 5 and 8.
2. Thrombin on Factor 11.
3. Factor 10a on TF:7.
4. Thrombin activation of platelets.

Thrombin > +5, 8, 11, platelets.
FActor 10a>+TF:7.

Front 68

How to heparins work?

Back 68

Increase rate of inhibition via Antithrombin III.

Front 69

Describe 2 negative feedback coagulation controls.

Back 69

1. TFPI: TFPI-10a switches off TF:7a.

2. Activated protein C. (VitK dependent). Inactivates 8a and 5a.

Front 70

What is the role of thrombomodulin?

Back 70

1. Switches off thrmobin's action of fibrinogen.
2. Thrombin bound to thrombomodulin attacks protein C, making APC.APC inactvates 8a and 5a.

Front 71

Deficiency associated with Factor 5.

Back 71

Factor 5 Leiden.
Due to change from Arg to Glu at single site. APC can no longer inactivate 5.
High degree of thrombosis.

Front 72

Deficiency in Factor 11.

Back 72

11a converts 9 to 9a normally.
Ashkenazi Jewish affected.
(AKA Hemophilia C)
Mild bleedin.

Front 73

Deficiency in Factor 8 and 9.,

Back 73

Hemophilia A and B.
If above 10% of normal, OK.

Front 74

Antithrombin III deficiency,

Back 74

Very high risk of thrombosis.
Homozygous - fetal in utero.

Front 75

Protein C and S deficiency cause:

Back 75

High risk of thrombosis.

Front 76

Deficiency is associated with No clot formation.

Back 76

Any of Factor 7, 10, 5, prothrombin, fibrinogen.

Front 77

What does prothrombin time test for (PT)?

Back 77

7,10,5,Prothrombin, Fibrinogen.
You get direct activation of 10a, so neither 8 nor 9 are involved.

Front 78

What does partial thromboplastin time (PTT) measure?

Back 78

12,11,9,8,10,5,Prothrombin, Fibrinogen.

Activates the contact system.
(doesn't involve 7 or 13)

Front 79

Where is platelet clotting more like to occur - vein or artery?

Back 79

Artery.

Front 80

How do arterial and venous thrombi differ?

Back 80

Artery - consists of platelets and looks white.

Vein = consits mostly of fibrin which traps RBCs due to slower moving blood. Red clot.

Front 81

List 3 function of fibrinogen.

Back 81

1. Binds to integrin receptors & allows platelet aggregation.

2. Fibrinogen converts to fibrin which forms x-linkages.

3. Fibrin and fibrinogen can encapsulate infectious foci.

Front 82

Describe the structure of fibrinogen.

Back 82

*3 chains alpha (long), beta and gamma (small) held together via disulfide bonding.
* N-termni towards center (fragment E), C-termini at ends (fragment C which is digestable).
* Fibrinopeptides at cener are sites of cleavage by thrombin.
* Coiled coil macrostructure.
*

Front 83

Describe steps in fibrin clot formation.l

Back 83

1. Thombin removes A and B peptides, converting fibrinogen to fibrin.
2. Fibrins monomers associate reversibly by charge interactions (Fragment E).
3. Transglutaminase (Factor 13) forms irreversible sideways bonds between proteins (consolidation).

Front 84

What converts Factor 13 to 13a?

Back 84

Thrombin.

Front 85

Describe steps in breakdown of fibrinogen.

Back 85

1. Plasmin removes much of C termini, producing fragment X.
2. Fragment X breakdown into Fragment D,and Y then E.

Front 86

What does presence of fragment D and Y in blood indicate?

Back 86

Blood is able to clot because these products are produced by Fibrinogen breaking down into Fragment X, then D, Y, E.

Front 87

Which breakdown product of fibrinogen can still make clots?

Back 87

Fragment X.

Front 88

What is a Kringle?

Back 88

The repeating structural motif.. There are 5 Kringle domains and they carry (-)charge aa that bind to lysine residues in the clot.

Front 89

What activates plasminogen to plasmin?

Back 89

urokinase and tPA.
Plasmin shows positive feedback on plasminogen, making it more active.

Front 90

Describe role of urokinase.

Back 90

Released by macrophages and monocytes in response to inflmmatory mediatory and cytokines. and activates plasminogen.

Front 91

Describe negative feedback on urokinase.

Back 91

1. Plasmin accumulation leads to degradation of urokinase.
(Note:other form of regulation is that upreg of gene transcription is required).

Front 92

What is plasmin's link to the immune response?

Back 92

Macrophages release IL-1 and TNF-alpha which mediate innate immune response. Plasmin is needed to breakdown tissue to allow monocytes to get to site.

Front 93

What is the most active plaminogen activator in the blood?

Back 93

Tissue Plasminogen Activator (tPA).

Front 94

Describe 3 locations of proteinase activity, the proteinase, and its inhibitor.

Back 94

1. Endothelium - tPA - PAI-1.
2. Monocyte - uPA - PAI-2
3. Plasma - plasmin -alpha2PI

Front 95

What are lines of Zahn?

Back 95

light and dark layering indicating the sequential formation of a thrombus.

Front 96

How can you differentiate the head and the tail of the thrombus?

Back 96

Head is white (facing oncoming blood)
Tail is red (slower moving stream of blood)

Front 97

Where does a clot occur?

Back 97

Extravascularly or (intravascularly post-mortem).

Front 98

How does the appearance of clot differ from thombus?

Back 98

Clot is homogenous, currant jelly-like, no marbalization, layering only seen post-mortem.
Thrombus is marbalized,dull,takes shape of vessel, lines of Zahn, with head and tail.

Front 99

Name 6 causes of thrombus formation.

Back 99

1. Atherosclerotic plaque with a broken fibrous cap which initiates coagulation.
2. Turbulence flow.
3. foreign objects in contact with blood.
4. Problems with pre-formed elements in blood (Sickle cell & Rouleaux Formation)
5.Cancer. (forming glands)
6. Risk factors such as smoking & BCP.

Front 100

What is a mural thrombus?

Back 100

Attached to wall of heart.

Front 101

3 things that can ultimately happen to a thrombus.

Back 101

1. Persist, expand, propogate.
2. Resolution.
3. Emobolisis.

Front 102

What is the hallmark of recanalization?

Back 102

Small lumina traversing what used to be a blocked lumina.

Front 103

List 9 types of emboli.

Back 103

1. Venous (leg usually)
2. Arterial (often a mural in L ventricle)
3. Paradoxical (from leg vein into Left ventricle thru patent foramen ovale)
4. Saddle - straddles pulmonary artery at point of bifurcation and blocks both branches.
5. Bone
6. Air
7. Gas (decompression sickness)
8. Fat
9. Amniotic -

Front 104

What is infarction?

Back 104

Ischemic tissue death & necrosis.

Front 105

Where does infarcation generally first start in the heart?

Back 105

The endocardium b/c it is furtherest away from the vessels on the epicardial surface.

Front 106

Where are pale infarcts seen?

Back 106

In a solid organ with a single blood supply.
Tend to be wedge-shaped.

Front 107

Where are red infarcts seen?

Back 107

Spongy organs with dual blood supply.