Exam 2: Platelets and Coagulation Flashcards

Question

Common Pathway

Answer 1

**Factor Xa to Fibrin:** 1. **Factor Xa** from both _intrinsic_ and _extrinsic_ paths associates with **Factor Va**_{(accessory protein}₎ forming **Xa-Va** ⇒ **Prothrombinase complex** * Binding of Va ⇒ 20x ↑ in Xa activity 2. Binding of Ca²⁺ to Gla residue on **Prothrombin** (_Factor II_) facilitates binding of Prothrombin to membrane and to Xa-Va complex 3. Xa-Va complex cleaves **Prothrombin** (II) **→ Thrombin** (IIa) * Excises Gla region releasing Thrombin from the membrane * Only time Gla excised * Gla-peptide remains bound to membrane surface * Taken up by the liver 4. **Thrombin_plasma** cleaves **Fibrinogen** (Factor I) → **Fibrin** (Ia) 5. Fibrin forms the **fibrin soft clot** 6. **Thrombin_plasma** activates **Factor** **XIII** → **XIIIa** 7. **Factor XIIIa** (transglutaminase) cross-links Gln from one fibrin with Lys of another ⇒ _isopeptide bond_ * Converts soft clot into an **insoluble** **hard clot**

Answer 2

* **Fibrinogen** * Soluble glycoprotein made by the liver * Dimers of three different polypeptides held together at N-termini by disulfide bonds * N-termini of the chains form "**tufts**" on the central three globular domains (D, E, D) * **Thrombin** _cleaves the negatively charged tufts_ producing **fibrinopeptides**: * Fibrinogen → fibrin monomers * Solubility decreases * Fibrin monomers associate laterally * **Soft fibrin clot** **formed**

Answer 3

_Pathway Interconnections:_ * **Factor VIIa** of extrinsic path activates **factor IX** of intrinsic path * **Factor XIIa** of intrinsic path activates **factor VII** of extrinsic path * **Thrombin (IIa)** of common path activates factors of intrinsic and extrinsic paths * Factors 7, 12, 11, 8, and 5

Answer 4

primary hemostasis

Answer 5

secondary hemostasis

Answer 6

1. **vWF** _binds exposed collagen_ on endothelial surface 2. **Platelets** bind: * _To vWF_ via **GP1b** * Part of the membrane receptor complex (**GP1b/V/IX**) * vWF made by endothelial cells and megakaryocytes * _Directly to collagen_ via **GPVI** 3. Binding stops forward movement of platelets causing **adherence** 4. Platelet activation causes **degranulation** * Thrombin is the most potent activator * Required for platelet activation and fibrin formation * Also **exposes anionic PL** which allows _formation of tenase complex_ on surface of platelets 5. Conformational Δ following activation leads to **platelet** **aggregation** * Forms the **platelet plug** ⇒ _primary hemostasis_ 6. Conformational Δ in **GPIIb/IIIa** receptor exposes fibrinogen binding sites 7. Fibrinogen _binds & links_ activated platelets to one another * Fibrinogen → Fibrin by **Thrombin (IIa)** * Cross linkage by **Factor XIIIa** from plasma and platelets * **Fibrin net** strengthens platelet plug to resist shear forces * Achieves _secondary hemostasis_

Answer 7

1. **Thrombin** binds to and activates protease-activated receptors (**PARs**) on the surface of platelets & endothelial cells * Type of G_q receptor 2. Receptor activates **PLC** which cleaves PIP₂→ **DAG** and **IP₃** 3. **DAG** activates **PKC** leading to **degranulation** 4. **IP₃** causes release of **Ca²⁺** from _delta granules_ 5. **Calcium** causes: * **Shape changes in platelet** * Ca²⁺ activates MLCK which phosphorylates MLC * Favors association with actin * **Activation of PLA₂** * Synthesis of **TXA₂** * Platelet degranulation * Vasoconstriction * Via serotonin * Activation of additional platelets * By binding to GPCR on platelet membrane

Answer 8

* Vascular wall is **separated from blood** by endothelial cells * Components like collagen and laminin are not exposed * Endothelial cells synthesize the **vasodilators** **PGI₂** and **NO** * Endothelial cells have a cell **surface ADPase** that converts ADP → AMP

Answer 9

Degranulation releases: * Delta granules * **Serotonin**: causes vasocontriction * **ADP**: activates additional platelets * **Plavix** blocks ADP receptors preventing ability to activate platelets * Alpha granules: * **PDGF**: helps in wound healing * **Factor** **Va** * **vWF** * **Fibrinogen** * Many more

Answer 10

* **Deficiency of von Willebrand's factor** * Results in _abnormal platelet adhesion_ * Most common inherited coagulopathy * AR

Answer 11

* **Deficiency of platelet receptor for von Willebrand's factor** * GP1b receptor * Results in _abnormal platelet adhesion_

Answer 12

* **Deficiency of platelet receptor for fibrinogen** * GPIIb/IIIa complex * Results in _decreased platelet aggregation_

Answer 13

Autoimmune disorder caused by autoantibodies to platelet receptor for fibrinogen.

Answer 14

* **TF—VIIa** of extrinsic path activates **IX** of intrinsic path * **XIIa** of intrinsic path activates **VII** of extrinsic path * **Thrombin (IIa)** of common path activates components of both the intrinsic and extrinsic paths and also activates platelets * **Tenase complex** of intrinsic path forms on the surface of activated platelets and damaged endothelium * **One fifth of total Va** is released by activated platelets * **XIIIa** and **vWF** present in both plasma and platelets

Answer 15

* Made by the liver * **Serine protease inhibitor (serpin)** * _ATIII binds to and inactivates:_ * **Thrombin** (most important) * Binding makes catalytic domain of thrombin inaccessible * **Factor IXa through XIIa** * Inactivation of **X** is key * **Factor VIIa-TF complex** * Complexes removed by liver * AT-III : Thrombin binding is greatly increased by **heparin** * Sulfated GAG released by mast cells in response to injury

Answer 16

* Therapeutically used to **↓ clot formation** * IV administration * Rapid-onset * Short half-life

Answer 17

**Protein C-Protein S complex inactivates Va and VIIIa by proteolysis.** * **Protein C**_(Gla) activated by **thrombin-thrombomodulin** complex * **Thrombomodulin** expressed on the surface of undamaged endothelial cells * Binds thrombin * ↓ thrombin's affinity for fibrinogen * ↑ thrombin's affinity for Protein C * **Protein C** complexes with **Protein S**_(Gla) ⇒ **activated Protein C complex (APC)** * **APC cleaves Va and VIIIa** * Protein S helps achor Protein C to the clot

Answer 18

Protein that inhibits the extrinsic pathway shortly after its activation. Intrinsic path becomes dominant.

Answer 19

* **Plasminogen** binds to fibrin & _incorporated into clots_ during formation * Physiological activators of plasminogen bind and cleave **plasminogen** → **plasmin** * **Tissue plasminogen activator (t-PA or TPA)** * Made by endothelial cells * Secreted in inactive form in response to thrombin * Becomes active when bound to fibrin-plasminogen * **Urokinase (u-PA)** * Made in the kidney * **Plasmin** _hydrolyzes fibrin clot_ * Bound plasmin and TPA protected from inhibitors * When fibrin clot is dissolved, they are exposed and inactivated * **α-2 antiplasmin** ⇒ ⊗ plasmin * **PAI (plasminogen activator inhibitor)** ⇒ ⊗ TPA

Answer 20

* Serine protease which degrades fibrin * Plasminogen made by the liver & released into the blood * Binds to fibrin and is incorportated into clots as they are formed * Activated by TPA or u-PA

Answer 21

Treat patients with TPA or u-PA

Answer 22

**"Hypercoagulability"** _Caused by:_ * **Factor V Leiden** * **G20210A prothrombin gene mutation** * ↑ factor II activity * Most prevalent genetic risk factor for venous thrombosis in Spanish populations * **Deficiencies of proteins C, S, and ATIII** * **Excess lipoprotein A** * **Hyperhomocysteinemia** * **Anti-phospholipid Ab** ⇒ referred to as Lupus anticoagulant

Answer 23

* **Mutant form of factor V ⇒ resistant to APC cleavage** * Most commonly inherited thrombophilic condition * Esp. Caucasians, specifically Scandinavians * Heterozygotes have a 7x increased risk of forming clots * Homozygotes have 80x increased risk

Answer 24

Three broad categories thought to contribute to thrombophilia:

Answer 25

* Tissue injury ⇒ blood vessel damage ⇒ collagen exposure * Platelets bind collagen * Mediated by vWF * Platelet activation * Thrombin is key * Platelet degranulation and synthesis of arachidonic acid products * Vasoconstriction * Platelet recruitment * Support the clotting cascade * Factors of intrinsic, extrinsic, and common paths of clotting cascade + Ca²⁺ + anionic surface ⇒ fibrin clot formation * Initial platelet plug ⇒ primary hemostasis * Fibrin mesh ⇒ secondary hemostasis * Clotting limited to injured site * Proteins that inactivate thrombin ⇒ AT-III, heparin * Proteins that degrade V & VIII ⇒ APC * After wound is healed, fibrin clot degraded by plasmin * Plasmin inactivated by α-2 antiplasmin * TPA inactivated by PAI

Answer 26

Disorders of vessels, platelets, and coagulation proteins ⇒ deviations in ability to clot. * Vessels * Scurvy * Plaque formation * Hyper-Hcy * ↑ Lp(a) * Platelets * ↓ number ⇒ thrombocytopenia * ↓ function * Deficiency of vWF ⇒ VW disease * Deficiency of GP1b ⇒ Bernard-Soulier syndrome * Deficiency of CPIIb/IIIa ⇒ Glanzmann thrombasthenia * Coagulation proteins * VIII ⇒ Hemophilia A * IX ⇒ Hemophilia B * XI ⇒ Hemophilia C * Factor V Leiden

Answer 27

* _Platelets_ * Platelet counts * Platelet function tests * _Extrinsic through common path_ * **Prothrombin time (PT)** * Uses thromboplastin * Combination of PL + TF * Expressed as INR (international normalized ratio) * _Intrinsic through common path_ * **Activated partial thromoplastin time (aPTT)** * Uses partial thromboplastin * Just the PL portion b/c TF isn't needed to activate intrinsic path