Chapter Summary, Questions Answers - Blood clotting

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Chapter: Biochemistry : Blood clotting

Blood clotting (coagulation) is designed to rapidly stop bleeding from a damaged blood vessel in order to maintain a constant blood volume (hemostasis).


Blood clotting (coagulation) is designed to rapidly stop bleeding from a damaged blood vessel in order to maintain a constant blood volume (hemostasis). Coagulation is accomplished through formation of a clot (thrombus) consisting of a plug of platelets (thrombocytes) and a meshwork of the protein fibrin (Figure 34.25). Wound to a tissue damages blood vessels and exposes collagen. Platelets adhere to the exposed collagen, get activated, and aggregate to form a platelet plug. Adhesion is mediated by von Willebrand Factor (VWF). VWF binds collagen, and platelets bind VWF via GPIb within a receptor complex on the platelet surface. Deficiency of VWF results in von Willebrand disease, the most common inherited coagulopathy. Once adhered, platelets get activated. Platelet activation involves changes in shape (discoidal to spherical with pseudopodia) and degranulation, the process by which platelets release the contents of their storage granules. Thrombin is the most potent activator of platelets. Thrombin binds to protease-activated G protein–coupled receptors on the surface of platelets. Activated platelets release substances that cause vasoconstriction (serotonin and thromboxane A2 [TXA2] ) , recruit and activate other platelets (adenosine diphosphate and TXA2) and support the formation of a fibrin clot (factor [F] V, FXIII, and fibrinogen). Activation causes changes in platelets that lead to their aggregation. Structural changes in a surface receptor (GPIIb/IIIa) expose binding sites for fibrinogen. Fibrinogen molecules link activated platelets to one another. The fibrinogen is activated to fibrin by thrombin and then cross-linked by FXIIIa, a transglutaminase coming both from the blood and from platelets. The initial loose plug of platelets (primary hemostasis) is strengthened by the fibrin meshwork (secondary hemostasis).

The formation of the fibrin meshwork involves the extrinsic and intrinsic pathways (and their associated protein factors) that converge at FXa to form the common pathway. Many of the protein factors are serine proteases with trypsin-like specificity. Ca 2+ binds the negatively charged γ-carboxyglutamate (Gla) residues present in certain of the clotting proteins (FII, FVII, FIX, and FX), facilitating the binding of these proteins to exposed phosphatidylserine at the site of injury and on the surface of platelets. γ-Glutamyl carboxylase and its coenzyme, the hydroquinone form of vitamin K, are required for formation of Gla residues. In the reaction, vitamin K gets oxidized to the nonfunctional epoxide form. Warfarin, a synthetic analog of vitamin K used clinically to reduce clotting, inhibits the enzyme vitamin K epoxide reductase that regenerates the functional reduced form. The extrinsic pathway is initiated by exposure of FIII (tissue factor [TF]), an accessory protein, in vascular subendothelium. Exposed TF binds a circulating Gla-containing protein, FVII, activating it through conformational change. The TF–FVIIa complex then binds and activates FX by proteolysis. The extrinsic pathway is rapidly inhibited by tissue factor pathway inhibitor. The intrinsic pathway is initiated by FXIIa. FXIIa activates FXI, and FXIa activates FIX. FIXa combines with FVIIIa (an accessory protein), and the complex activates FX. FVIII deficiency results in hemophilia A, whereas FIX deficiency results in the less common hemophilia B. FXa associates with FVa (an accessory protein), forming prothrombinase that cleaves prothrombin (FII) t o thrombin (FIIa) . Thrombin then cleaves fibrinogen to fibrin (FIa). Fibrin monomers associate, forming a soluble (soft) fibrin clot. The fibrin molecules get cross-linked by FXIIIa, forming an insoluble (hard) fibrin clot. Proteins synthesized by the liver and by blood vessels themselves balance coagulation with anticoagulation. Antithrombin III, a serine protease inhibitor, or serpin, binds to and removes thrombin from the blood. Its affinity for thrombin is increased by heparin, which is used therapeutically to limit clot formation. Protein C, a Gla-containing protein, is activated by the thrombin–thrombomodulin complex. Thrombomodulin decreases thrombin’s affinity for fibrinogen, converting it from a protein of coagulation to a protein of anticoagulation. Protein C in complex with protein S (a Gla-containing protein) forms the activated protein C (APC) complex that cleaves the accessory proteins FVa and FVIIIa. Factor V Leiden is resistant to APC. It is the most common inherited thrombophilic condition in the United States. The fibrin clot is cleaved (fibrinolysis) by the protein plasmin, a serine protease that is generated from plasminogen by plasminogen activators such as tissue plasminogen activator (TPA, t-PA). Recombinant TPA is used clinically. Disorders of platelets and coagulation proteins can result in deviations in the ability to clot. Prothrombin time and activated partial thromboplastin time are used to evalulate the clotting cascade.

Figure 34.25 Key concept map for blood clotting. a = active; F = factor.


Study Questions
Choose the ONE best answer.


For Questions 31.1–31.5, match the most appropriate protein of clotting to the description.












34.1 This factor activates components of the intrinsic, extrinsic, and common pathways.


34.2 This factor converts the soluble clot to an insoluble clot.


34.3 This factor initiates the common pathway.


34.4 This factor is an accessory protein that potentiates the activity of factor Xa.


34.5 This factor is a γ-carboxyglutamate–containing serine protease of the extrinsic pathway.


Correct answers = B, J, H, D, E. Thrombin (FII) is formed in the common pathway and activates components in each of the three pathways of the clotting cascade. Factor (F)XIII, a transglutaminase, covalently cross-links associated fibrin monomers, thereby converting a soluble clot to an insoluble one. The generation of FXa by the intrinsic and extrinsic pathways initiates the common pathway. FV increases the activity of FXa. It is one of three accessory (nonprotease) proteins. The others are FIII (tissue factor) and FVIII (complexes with FIX to activate FX). FVII is a γ-carboxyglutamate–containing serine protease that complexes with FIII in the extrinsic pathway.


34.6 In which patient would prothrombin time be unaffected and activated partial thromboplastin time be prolonged?

A. A patient on aspirin therapy

B. A patient with end-stage liver disease

C. A patient with hemophilia

D. A patient with thrombocytopenia

Correct answer = C. Prothrombin time (PT) measures the activity of the extrinsic through the common pathways, and activated partial thromboplastin time (aPTT) measures the activity of the intrinsic through the common pathways. Patients with hemophilia are deficient in either factor (F)VIII (hemophilia A) or FIX (hemophilia B), components of the common pathway. They have an intact extrinsic pathway. Therefore, the PT is unaffected, and the aPTT is prolonged. Patients on aspirin therapy and those with thrombocytopenia have alterations in platelet function and number, respectively, and not in the proteins of the clotting cascade. Therefore, both the PT and the aPTT are unaffected. Patients with end-stage liver disease have decreased ability to synthesize clotting proteins. They show prolonged PT and aPTT.


34.7 Which one of the following can be ruled out in a patient with thrombophilia?

A. A deficiency of antithrombin III

B. A deficiency of factor IX

C. A deficiency of protein C

D. An excess of prothrombin

E. Expression of factor V Leiden

Correct answer = B. Symptomatic deficiencies in clotting factors will present with a decreased ability to clot (coagulopathy). Thrombophilia, however, is characterized by an increased tendency to clot. Choices A, C, D, and E result in thrombophilia.


34.8 Current guidelines for the treatment of patients with acute ischemic stroke (a stroke caused by a blood clot obstructing a vessel that supplies blood to the brain) include the recommendation that tissue plasminogen activator (TPA) be used shortly after the onset of symptoms. The basis of the recommendation for TPA is that it activates:

A. antithrombin III.

B. the activated protein C complex.

C. the receptor for von Willebrand factor.

D. the serine protease that degrades fibrin.

E. thrombomodulin.

Correct answer = D. Tissue plasminogen activator (TPA) converts plasminogen to plasmin. Plasmin (a serine protease) degrades the fibrin meshwork, removing the obstruction to blood flow. Antithrombin III in association with heparin binds thrombin and carries it to the liver, decreasing thrombin’s availability in the blood. The activated protein C complex degrades the accessory proteins FV and FVIII. The platelet receptor for von Willebrand factor is not affected by TPA. Thrombomodulin binds thrombin and converts it from a protein of coagulation to one of anticoagulation by decreasing its activation of fibrinogen and increasing its activation of protein C.


34.9 The adhesion, activation, and aggregation of platelets provide the initial plug at the site of vessel injury. Which of the following statements concerning the formation of this platelet plug is correct?

A. Activated platelets undergo a shape change that decreases their surface area.

B. Formation of a platelet plug is prevented in intact vessels by the production of thromboxane A2 by endothelial cells.

C. The activation phase requires production of cyclic adenosine monophosphate.

D. The adhesion phase is mediated by the binding of platelets to von Willebrand factor via glycoprotein Ib.

E. Thrombin activates platelets by binding to a protease-activated G protein– coupled receptor and causing activation of protein kinase A.

Correct answer = D. The adhesion phase of platelet plug formation is initiated by the binding of von Willebrand factor to a receptor (glycoprotein Ib) on the surface of platelets. Shape change from discoidal to spherical with pseudopodia increases the surface area of platelets. Thromboxane A2 is made by platelets. It causes platelet activation and vasoconstriction. Adenosine diphosphate is released from activated platelets, and it itself activates platelets. Thrombin works primarily through receptors coupled to Gq proteins causing activation of phospholipase C.


34.10 Several days after having had their home treated for an infestation of rats, the parents of a 3-year-old girl become concerned that she might be ingesting the poison-containing pellets. After calling the Poison Hotline, they take her to the Emergency Department. Blood studies reveal a prolonged prothrombin and activated partial thromboplastin time and a decreased concentration of factor (F)II, FVII, FIX, and FX. Why might administration of vitamin K be a rational approach to the treatment of this patient?

Many rodent poisons are super warfarins, drugs that have a long half-life in the body. Warfarin inhibits γ-carboxylation (production of γ-carboxyglutamate, or Gla, residues), and the clotting proteins reported as decreased are the Gla-containing proteases of the clotting cascade. [Note: Proteins C and S of anticlotting are also Gla-containing proteins.] Because warfarin functions as a vitamin K antagonist, administration of vitamin K is a rational approach to treatment.

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