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Describe regulation of platelet production.
Thrombopoiesis senses mass, not #, of circulating platelets. Regulated by thrombopoietin TPO.
What disease is associated with giant platelets?
Bernard-Soulier Syndrome
What disease is associated with small platelets?
Wiscott-Aldrich Syndrome
What is scrambalase?
Causes relocation of platelet phospholipids(-) to outer leaflet during release reaction.
Name 2 types of secretory granules found in platelets.
1. Dense bodies (Ca, Mg, 5H-T, ADP, ATP).
"Storage pool diseases"

2. alpha-granules (larger molecules: IgG, fibrinogen)
3 functions of platelets.
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.
What deficiency is seen in von Willebrand's disease?
Factor 13 (b/c smaller polymers of vWF protect FActor 13 from degradation.)
Where is vWF made?
1. Megakaryocytes
2. Endothelial cells (in Weibel-Palade body)
What is a megakaryocyte.
Sources of platelets. Found in bone marrow.
Cytoplasm is packed with membranes which cover platelets as the leave the surface.
What is the strongest agonist of platelet agglutination?
Describe a test of platelet quality.
Aggregometry - determination of released adenine nucleotides. With clumping, have increased light transmission.
How does spleen size/presence relate to platelet #?
Enlarge spleen = thrombocytopenia and low platelet count.
Removal of spleen = increase platelet count.
What receptor does TPO bind to on megakaryocytes and platelets?
c-Mpl receptor.
Contents (5) of alpha particles of platelets. (Keep this question)
1. Factor 5 and 13
2. Protein S
3. vWF
4. IgG
5. Fibrinogen
What does a "gray" platelet suggest?
Absence of alpha particles.
List 3 organelles that are unique to platelets and what they do.
1. alpha granules (protein secretion)
2. dense bodies (agonist secretion)
3. dense tubular system (Ca++ storage).
List 9 consequences of platelet activation by agonists.
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.
What is arachidonate converted to when platelets are activated?
Thromboxanes (strong platelet agonist) and leukotrienes.
List 4 strong platelet agonists.
1. Thrombin (most potent.)
2. Subendothelial collagen.
3. Ruptured atherosclerotic plaque.
4. Thromboxanes (form of prostaglandins).
Why is thrombin such a potent platelet agonist?
It byasses some of the steps required by other agonists. No 2nd wave seen.
List 3 moderate platelet agonists.
1. Arachidonic acid.
2. Particulate collagens.
3. ADP.
Aspirin preents the conversion of arachidonic acid to?
1. Prostaglandins.
2. Thromboxanes.
What is source of arachidonic acid?
Describe 2 gene products involved in the vWF receptor.
1. GPIb-alpha
2. GPIb-beta
When does vWF receptor bind vWF?
At high shear.
What is Bernard-Soulier syndrome?
Absence of vWF receptor.
What is the main integrin receptor and what does it bind?
alphaIIb/Beta3 (AKA GP2b/3a)
Bids fibrinogen
List 2 adhesive glycoproteins containing RGD[S} aa sequence.
1. vWF
2. Fibrinogen
What is the Weibel-Palade body?
a storage organelle for vWF in endothelial cells.
Endothelial vWF (smaller and less sticky) is a chaperone for which clotting factor.
FActor 8.
What is relationship between platelet count and plasma concenc of thrombopoietin?
If platelet count low, less thrombopoietin bound to receptor on platelet, so higher conc in blood. This signals megakaryocyte to make more platelets.
What color do granules in platelets stain?
What is PFA-100?
An automated platelet function analyzer that works by filgtration. Measures adhesion of platelets to a filter.
List 3 weak platelet agonists.
1. ADP
2. Epi
3. 5H-T
List 2 agonists of unknown strength.
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.
What steps in platelet activation are Ca++ dependent?
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.
Describe 2 products of arachidonic acid breakdown.
a. TXA-2 (thromboxane A2)- potent platelet agonist.

b. PGI2 - platelet antagonist. which competes with thromboxane at the eicosanoid receptor.
What is the significance of myosin in platelets?
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.
In the resting platelet membrane what molecules are most abundant on outside? on inside?
outside: phophatidylcholine & cholesterol
inside: phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol
At rest, are platelets negatively charged on the outside?
Yes, though to less of a degree. Glycoproteins with sialic acid (-) cause negative charge. - charge causes platelet to repel each other
What change happens to platelet membrane when it is activated?
negatively-charged phospholipids move to outside.
Describe the 4 families of platelet receptor proteins and give example of each.
1. 7 Transmembrane (AKA response receptors).Protease-Activated Receptor,a thrombin receptor.
2. Integrin (alpha2b/beta3: fibrinogen receptor)
3. vWF
4. ?
Describe mechanism of protease-activated receptor: thrombin receptor.
Thrombin cleaves off extracellular end of PAR-1 receptor. TRAP is then released. Thrombin can then bind.
Describe mechanism of integrin receptors.
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.
What is the significance of integrin receptors and autoimmune disorders?
Antigens on surface of platelets (Pl-A1 & Bak)can induce autoimmune disorder such as Immune Thromobcytopenic Purpura
Describe 4 characteristics of sticky proteins (integrin and leucin-rich receptors).
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.
Describe characteristics of stimulus response receptors (7 transmembrane).
1. Very few.
2. Act quickly.
3. Act via 2nd messengers.
4. Extremely specific via way kinases are activated.
Why adhesive glycoproteins contain RGD?
1. vWF
2. Fibrinogen
3. Fibronectin.
4. Laminin
What is a zymogen?
Precursor to the active protelyic enzymes.
Describe the 2 ways that clotting can be initiated.
1. Contact activation. (12a, Prekallikrein, HMW-kininogen).

2. Normal pathway.(TF, 7a)
Describe steps in normal clotting pathway.
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.
Where is Tissue factor found?
Fibroblasts and smooth muscle cells.
What activates 5 to 5a?
thrombin. (+ feedback loop)
Note: Factor 5 is released when platelets are activated.
What is cleaved to convert Fibrinogen to Fibrin?
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.
What is required to activate Factor 9 and 10?
Factor 7a:TF complex
Which factors require interaction with negative phospholipids in a Vit-K dependent matter for activation?
Factors 7, 9, 10 & prothrombin.
How is localization of coagulation controlled?
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)
What is role of vit K in coagulation?
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.
How does coumarin work?
Anticoagulant by competing with vitamin K on the liver carboxylase enzyme.
List 2 plasma inhibitors of coagulation.
1. Antithrombin III. Binds thrombin and FActor 10a & disables them. Slow.
2. Tissue Factor Pathway Inhibitor (TFPI) released from alpha granules.
Describe how TFPI inhibits clotting.
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.
Describe 4 positive feedback coagulation controls.
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.
How to heparins work?
Increase rate of inhibition via Antithrombin III.
Describe 2 negative feedback coagulation controls.
1. TFPI: TFPI-10a switches off TF:7a.

2. Activated protein C. (VitK dependent). Inactivates 8a and 5a.
What is the role of thrombomodulin?
1. Switches off thrmobin's action of fibrinogen.
2. Thrombin bound to thrombomodulin attacks protein C, making APC.APC inactvates 8a and 5a.
Deficiency associated with Factor 5.
Factor 5 Leiden.
Due to change from Arg to Glu at single site. APC can no longer inactivate 5.
High degree of thrombosis.
Deficiency in Factor 11.
11a converts 9 to 9a normally.
Ashkenazi Jewish affected.
(AKA Hemophilia C)
Mild bleedin.
Deficiency in Factor 8 and 9.,
Hemophilia A and B.
If above 10% of normal, OK.
Antithrombin III deficiency,
Very high risk of thrombosis.
Homozygous - fetal in utero.
Protein C and S deficiency cause:
High risk of thrombosis.
Deficiency is associated with No clot formation.
Any of Factor 7, 10, 5, prothrombin, fibrinogen.
What does prothrombin time test for (PT)?
7,10,5,Prothrombin, Fibrinogen.
You get direct activation of 10a, so neither 8 nor 9 are involved.
What does partial thromboplastin time (PTT) measure?
12,11,9,8,10,5,Prothrombin, Fibrinogen.

Activates the contact system.
(doesn't involve 7 or 13)
Where is platelet clotting more like to occur - vein or artery?
How do arterial and venous thrombi differ?
Artery - consists of platelets and looks white.

Vein = consits mostly of fibrin which traps RBCs due to slower moving blood. Red clot.
List 3 function of fibrinogen.
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.
Describe the structure of fibrinogen.
*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.
Describe steps in fibrin clot formation.l
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).
What converts Factor 13 to 13a?
Describe steps in breakdown of fibrinogen.
1. Plasmin removes much of C termini, producing fragment X.
2. Fragment X breakdown into Fragment D,and Y then E.
What does presence of fragment D and Y in blood indicate?
Blood is able to clot because these products are produced by Fibrinogen breaking down into Fragment X, then D, Y, E.
Which breakdown product of fibrinogen can still make clots?
Fragment X.
What is a Kringle?
The repeating structural motif.. There are 5 Kringle domains and they carry (-)charge aa that bind to lysine residues in the clot.
What activates plasminogen to plasmin?
urokinase and tPA.
Plasmin shows positive feedback on plasminogen, making it more active.
Describe role of urokinase.
Released by macrophages and monocytes in response to inflmmatory mediatory and cytokines. and activates plasminogen.
Describe negative feedback on urokinase.
1. Plasmin accumulation leads to degradation of urokinase.
(Note:other form of regulation is that upreg of gene transcription is required).
What is plasmin's link to the immune response?
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.
What is the most active plaminogen activator in the blood?
Tissue Plasminogen Activator (tPA).
Describe 3 locations of proteinase activity, the proteinase, and its inhibitor.
1. Endothelium - tPA - PAI-1.
2. Monocyte - uPA - PAI-2
3. Plasma - plasmin -alpha2PI
What are lines of Zahn?
light and dark layering indicating the sequential formation of a thrombus.
How can you differentiate the head and the tail of the thrombus?
Head is white (facing oncoming blood)
Tail is red (slower moving stream of blood)
Where does a clot occur?
Extravascularly or (intravascularly post-mortem).
How does the appearance of clot differ from thombus?
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.
Name 6 causes of thrombus formation.
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.
What is a mural thrombus?
Attached to wall of heart.
3 things that can ultimately happen to a thrombus.
1. Persist, expand, propogate.
2. Resolution.
3. Emobolisis.
What is the hallmark of recanalization?
Small lumina traversing what used to be a blocked lumina.
List 9 types of emboli.
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 -
What is infarction?
Ischemic tissue death & necrosis.
Where does infarcation generally first start in the heart?
The endocardium b/c it is furtherest away from the vessels on the epicardial surface.
Where are pale infarcts seen?
In a solid organ with a single blood supply.
Tend to be wedge-shaped.
Where are red infarcts seen?
Spongy organs with dual blood supply.

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