Platelet And Coagulation Phase Hemostasis

Front 1

Platelets are derived from __________ that when mature, are polyploid (4N to 6N) and the largest hematopoietic cells.

Back 1

megakaryocytes

Front 2

What is the major regulator of megakaryocytes, and thus platelet, development?

Back 2

Thrombopoietin , produced in the liver.

Thrombopoietin stimulates CFU-meg division and megakaryocyte development. The time interval from differentiation of the stem cell to paltelet productionis on average 7-10 days. Additional factors that support megakaryocyte development include IL-3 and IL-11.

Front 3

Along with thrombopoietin, what two additional factors are involved in megakaryocyte development?

Back 3

IL-3 and IL-11

Front 4

What are GATA-1, FOG1 and miRNA150 responsible for in terms of Common myeloid committed progenitor cells and its differentiation?

Back 4

Levels of GATA1, FOG1 and high levels of miRNA150 influences the common myeloid progenitor to progress towards CFU-Mega.

Levels of GATA1 and FOG1, coupled with low levels of miRNA150, influences progression towards CFU-E.

Front 5

What three things are needed to have CFU-Mega progress towards a megakaryocyte differentiation?

Back 5

Thrombopoeitin, IL-3 and IL-11

Front 6

Thrombopoietin is produced at a pretty constant rate by the liver. What is its receptor on the platelet surface?

Back 6

c-MPL

Front 7

Platelet count and mean platelet volume are inversely related. What does that infer about how the body maintains platelets?

Back 7

Body cares about maintaining a consistent total platelet mass.

Front 8

Where are platelets distributed in the body?

Back 8

These anuclear fragments are distributed 66% in the circulation and 34% in the spleen. The lifespan is 7-10 days.

Front 9

True or False:
The last stage of platelet development, fragmentation of the megakaryocyte, is NOT thromboietin dependent.

Back 9

True

Front 10

Platelet granules are platelet derived as well as plasma-derived. In the alpha granules, what is platelet derived and what is plasma derived?
A. Albumin
B. Fibrinogen
C. IgG
D. PF-4
E. PDGF
F. TGF beta
G. vWF

Back 10

Plasma-derived:
A. Albumin
B. Fibrinogen
C. IgG

Platelet derived:
D. PF-4
E. PDGF
F. TGF beta
******G. vWF***** <-- very important!

Front 11

In order for the platelet to make Thromboxane A2, needs cyclooxygenase to be functional! Why is Thromboxane A2 important?

Back 11

It influences the balance between the platelet derived thromboxane (promotes vasoconstriction, and platelet aggregation) and the endothelial derived prostacyclin (promotes vasodilation, inhibits platelet aggregation).

Front 12

vWF comes from two major sources. Name em.

Back 12

The endothelial cells and platelets' alpha granules.

Front 13

What three things can coax out a bit more vWF from endothelial cells than normal.

Back 13

Stress, hormones and vasopressin

Front 14

What is the enzyme that cleaves ultralarge vWF into smaller vWF forms?

Back 14

ADAMTS13 enzyme, the vWF cleaving enzyme

Front 15

What is the effect of Favtor VIII "riding" on vWF versus being free in plasma?

Back 15

Factor VIII is stabilized and its half life increased to ~12 hours when it is with vWF. When it is by itself, Factor VIII has a half life of just minutes!

Front 16

True or False:
Factor VIII is produced from the endothelium when the endothelium is injured.

Back 16

True

Front 17

When endothelium is injured, collagen is exposed. What then ensures in this platelet adhesion stage of the platelet phase?

Back 17

vWF binds to the exposed collagen and GP Ib-IX platelet surface receptor binds to vWF. Thus, vWF acts as abridge between the subendothelium and platelets.

Front 18

After the platelet adhesion stage of the platelet phase of hemostasis, what occurs next?

Back 18

platelet activation, where the surface-connected canalicular system is exposed. (It sends out extensions.) GP IIb/IIIa is exposed.

Front 19

In the platelet secretion phase, what things are secreted?

Back 19

vWF, PF4, Thromboxane A2, Fibrinogen, ADP

Front 20

After platelet activation, when the surface-connected canalicular system is exposed, GP IIb/IIIa is exposed. What does GP IIb/IIIa do?

Back 20

GP IIa/IIIb binds fibrinogen when platelet is activated. Fibrinogen acts as bridge between activated platelets.

Front 21

Detail the whole process of platelet phase hemostasis.

Back 21

When endothelium is injured, collagen is exposed. vWF binds to the exposed collagen and GP Ib-IX platelet surface receptor binds to vWF. Thus, vWF acts as a bridge between the subendothelium and platelets. Then platelet activation occurs where the surface-connected canalicular system is exposed, also exposing GP IIb/IIIa. Platelet secretion then occurs where vWF, thromboxane A2, fibrinogen, ADP, PF4 are released. Platelet aggregation then occurs as GPIIb/IIIa binds fibrinogen and fibrinogen acts as a bridge between activated platelets.

Front 22

What acts as a "bridge" from:
A. the subendothelium with exposed collagen to the GP Ib/IX receptor.
B. from one activated platelet to another via GP IIb/IIIa

Back 22

B. vWF
C. fibrinogen

Front 23

Explain how aspirin inhibits platelet adhesion/ aggregation.

Back 23

Aspirin inhibits cyclooxygenase IRREVERSIBLY. The downstream results is a decrease in Thromboxane A2 which, remember promotes vasoconstriction, and platelet aggregation in a delicate balance with the endothelial derived prostacyclin which promotes vasodilation and inhibits platelet aggregation.

Front 24

Explain how Clopidogrel (plavix) inhibits platelet adhesion/ aggregation.

Back 24

Clopidogrel IRREVERSABLY inhibits the platelet ADP receptor on a platelet. Blocking the ADP receptor leads to decrease in ADP mediated activation of GPIIb/IIIa and decrease in platelet AGGREGATION.

Front 25

Clopidogrel decreases:
A. platelet adhesion
B. platelet activation
C. platelets secretion
D. platelet aggregation

Back 25

D. platelet aggregation

Front 26

What is NOT true of abciximab?
A. is a monoclonal antibody
B. irreversibly inhibits GPIIa/IIIb receptor
C. is used to prevent clotting at stent sites and for catheterizations
D. is in a drug class that includes tirofiban and epifibatide which, are not monoclonal antibodies like abciximab

Back 26

B. irreversibly inhibits GPIIa/IIIb receptor

abciximab is REVERSIBLE. within 2-5 days.

Front 27

What is the deficiency in:
A. Bernard- Soulier syndrome
B. Glanzmann disease

Back 27

A. Bernard- Soulier syndrome: deficiency of GPIb/IX --> adhesion problem . Associated with thrombocytopenia and large platelets. Is an autosomal recessive disorder.
B. Glanzmann disease: deficiency in GP IIb/IIIa --> platelet aggregation problem. Platelets have normal numbers and morphology. Autosomal recessive.

Bernard Soulier syndrome has normal aggregation response to agonists requiring fibrinogen and abnormal aggregation response to ristocetin whereas Glanzmann thrombastenia has abnormal aggregation response to agonists requiring fibrinogen and normal aggregation response to ristocetin.

Front 28

What are the aggregation responses to a) ristocetin b) agonists requiring fibrinogen
for Bernard-Soulier syndrome and Glanzmann Thrombastenia?

Back 28

Bernard Soulier syndrome (problem of adhesion):
- abnormal aggregation response to ristocetin
- normal aggregation response to agonists requiring fibrinogen

Glanzmann thrombastenia (problem of aggregation):
- normal aggregation response to ristocetin
- abnormal aggregation response to agonists requiring fibrinogen

Front 29

What Vitamin is necessary for the conversion of Factor IX, VII, X, II and protein C and S into active forms?

Back 29

Vitamin K

Front 30

Why is the traditional model of coagulation NOT valid? (2 reasons, both having to do with certain factors)

Back 30

1. Factor XII deficiency not associated with any clinical bleeding disorder.
2. Factor VIII is needed to activate factor X, but Factor VIII is activated by thrombin (Factor II) which only comes later in the cascade!

Front 31

The current cascade model is broken down into the initiation phase and amplification phase. Describe em.

Back 31

The initiation phase is the classic extrinsic pathway. With cellular injury, tissue factor is release resulting in the complex formation with and activation of Factor VII.
Tissue factor bound Factor VIIa is joined on the phospholipid surface along with calcium to form the extrinsic pathway X-ase complex, i.e. the serine protease enzyme which activates factor X. A small amount of thrombin is generated, which feedbacks to activate factor XI and Factors V and VIII. Thus, that side of the cascade can occur to make the thrombin burst. Thrombin cleaves off fibrinopeptides to make em sticky and activates Factor XIII, which glues the clot together.

Front 32

What is the significance of Factor XIII? What activates it?

Back 32

Factor XIII is activated by thrombin. Factor XIII provides the glue that stabilizes the clot.

Front 33

With cellular injury, tissue factor is released resulting in the complex formation with and activation of _________.

Back 33

Factor VII

Front 34

In the absence of Factor _____ , Factor Xa is able to generate only a small amount of thrombin (aka Factor IIa).

Back 34

In absence of Factor Va

But that is enough to activate factors V and VIII as well as be fedback activation for factor XI.

Front 35

What things does thrombin activate at the end of the initiation phase/beginning of acceleration phase? (3) How about after the thrombin burst? (1)

Back 35

During initiation phase:
Factor V and Factor VIII,
Factor XI

After thrombin burst: Factor XIII to glue clot for stabilization.

Front 36

Tissue factor pathway inhibitor inactivates VIIa-tissue factor complex only after it....

Back 36

first binds to Xa-phopholipid. This allows system to be turned on before tissue factor pathway is turned off and prevents having to delay clotting until TFPI saturated by VIIa. TFPI controls the extrinsic pathway.

Front 37

Which is the primary anticoagulant?
A. Antithrombin
B. Tissue Factor Pathway Inhibitor
C. Protein C and S

Back 37

A. Antithrombin

Front 38

What does antithrombin inactivate? What does Protein C and S inactivate?

Back 38

Antithrombin does everything but Factors V and VIII. Protein C and S does those.

Front 39

What is heparin a cofactor for?
A. antithrombin
B. B. Tissue Factor Pathway Inhibitor
C. Protein C and S

Back 39

A. antithrombin

Antithrombin-Heparin complex inactivates UNBOUND thrombin (IIa) and Xa

Front 40

Which anticoagulants are Vitamin K dependent?

Back 40

Protein S and C. Both are activated by thrombin.

Front 41

Once formed, the clot must be removed via fibrinolysis. The primary enzyme which serves this role is __________ in its activated form, _________.

Back 41

plasminogen, plasmin

Front 42

Plasminogen activation to plasmin can be accomplished by a variety of means, including... (2)

Back 42

tissue plasminogen activator (tPA) and thrombin.

Front 43

What is each complex comprised of:
A. extrinsic Xase complex
B. intrinsic Xase complex
C. prothrombinase complex

Back 43

A. Extrinsic Xase complex = TF + Factor VIIa + Calcium
B. Intrinsic Xase complex = Factor IXa + Factor VIIIa + Calcium
C. Prothrombinase complex = Factor Xa + Factor Va + calcium

Front 44

Heparin is a cofactor to _______.

Back 44

Antithrombin. It helps degrade Factors XIIa, XIa, IXa, Xa, IIa. Heparin comes in an unfractionated (large MW) form and a low MW form. The large MW form has a smaller half life than the low MW form but the low MW form is slightly less effective at inactivating IIa from a physiological standpoint, though still works equally clinically.

Front 45

Warfarin is a vitamin K antagonist. Why does it work to make both various coagulation and anticoagulation factors inert?

Back 45

Vitamin K antagonist inhibits Vitamin K epoxide reductase, thus preventing Vitamin K to be available to post-translationally carboxylate the glutamic acid residues of various coagulation and anticoagulation factors like factors II, VII, IX, X, Protein C and Protein S. Thus, they are rendered inert since they are not activated into a functional form. Warfarin works slowly, then, since it only stops functional activation of newly synthesized factors.

Front 46

Why is a person more thrombogenic initially after starting Warfarin therapy?

Back 46

The half life of the Vitamin K dependent factors vary. Prothrombin, involved in coagulation, has a longer half life (3 days) whereas Protein C (anticoagulant), has a much shorter half life (6-10hours). Thus, upon administration, there is a slight tendency towards thrombogenisis. This is especially prominent and problematic for those who are Protein C deficient to begin with or who have a thrombus so often you will see Heparin started then Coumadin too.

Front 47

True or False:
Heparin is a drug that lacks easily predicted dosing and the potential along the way for diet and medications to alter even steady state dosing.

Back 47

FALSE, the description is of Warfarin.

Front 48

Vitamin K antagonist is Warfarin. What are the Vitamin K dependent factors?

Back 48

Factors II, X, VII and IX plus Protein C and Protein S

Front 49

This drug group activates plasminogen, thus actually dissolving the existing clot(s).
A. Heparin
B. Warfarin
C. Fibrinolytics
D. Direct thrombin inhibitors
E. Direct Ea inhibitors

Back 49

C. Fibrinolytics

ex. tPA, streptokinase, urokinase

Front 50

Which drug group actually dissolves existing clots?

Back 50

Fibrinolytics

ex. tPA, streptokinase, urokinase