BIOC520: Medical Biochemistry			
L-59: BLOOD COAGULATION 

Objectives: 
1.	Know the intrinsic and extrinsic pathways
2.	What triggers clotting?
3.	How is a clot dissolved?
4.	Where is vitamin K involved?
5.	Appreciate the balance in hemostasis

Clinical Correlations: 
	von Willebrand's disease
	Hemophilia A  (Marks, p. 100) and B
	Protein C and S deficiencies

Lecture
I. Hemostasis-limits blood loss by precisely regulated interactions
between components of the vessel wall, circulating blood platelets,
and plasma protein

	A. Problems occur with hemorrhage, intravascular thrombosis,
embolism, and inherited disorders
		1. Patients at risk for thrombosis and embolism
			a. Immobilized after surgery
			b. Chronic congestive heart failure
			c. Atherosclerotic vascular disease
			d. Malignancy
			e. Pregnancy
			f. Inherited hypercoaguable or prethrombotic state

	B. Normal hemostasis: Occurs when trauma, surgery, or disease
disrupt the vascular endothelial lining and blood is exposed to
subendothelial connective tissue
		1. Primary: platelet plug formation at sites of injury,
occurring within seconds, stopping loss of blood 	from capillaries,
small arterioles, and venules
			a. Platelet adhesion: collagen fibrils via
glycoprotein Ib; this is stabilized by von Willebrand's factor (Marks,
Fig. 9-35)
			b. Granule release: all kinds of factors and
signals
			c. Platelet aggregation: mediated by fibrinogen
and 				glycoproteins Iib and IIIa












		2. Secondary: reactions of the plasma coagulation system,
resulting in fibrin formation, occurring within minutes; fibrin
strands strengthen platelet plug; prevents recurring bleeding hours or
days after injury (Table 34-1, Fig. 34-1))
			a. Intrinsic Pathway: started by Hageman factor
(XII), High Molecular Weight Kininogen (HMK), and prekallikrein, which
form a complex on 	vascular subendothelial collagen, e.g. CONTACT
PHASE
			b. Extrinsic Pathway: started by Factor VII, Ca2+,
and tissue factor (III)(a ubiquitous lipoprotein present in cellular
membranes which is exposed following cellular injury)
			c. Convergence at Factor X (requirement for Ca2+
and phospholipid)
			d. Activation of thrombin (IIa)
			e. Fibrinogen to fibrin (Fig. 34-3 to 34-7); SOFT
CLOT
			f. Crosslinking of fibrin with XIIIa (Fig. 34-8);
transglutaminase links e-amino group of Lys with amide of Gln; HARD
CLOT 
		3. Vitamin K dependent factors and g-carboxyGlu = Gla
(Fig. 34-9, p. 1201)
			a. II, VII, IX, X, protein C, and protein S
			b. Mechanism (Fig. 34-12)
			c. Antagonists: coumarin derivatives (Fig. 34-10)
			d. Vitamin K deficiencies: inadequate intake,
intestinal malabsorption, and loss of storage due to liver disease
		4. Anticoagulants
			a. Proteins: antithrombin III (forms a complex
with all serine proteases except VIIa); heparin (promotes antithrombin
action); protein C (inactivates Va and VIIIa); and protein S (assists
protein C)


















				b. Vitamin K antagonists
				c. Calcium chelators: oxalate, fluoride,
citrate, EDTA

II. Clot dissolution
	A. Plasmin
		1. Major activators: Hageman factor fragments, urokinase,
and tissue plasminogen activator























		2. a2-Plasmin inhibitor binds any plasmin which escapes
the clot
		3. Plasminogen activator inhibitor-is released from
vascular endothelium and activated platelets

	B. Tight local control: there is enough clotting potential in 1.0
ml of blood to clot all the fibrinogen in the body in 10-15 seconds

III. Diseases
	A. Inherited
		1. von Willebrand's disease (1 in 800-1000); autosomal
dominant; decreased platelet adhesion; also carries Factor VIII in plasma
		2. Factor VIII or Hemophilia A (1 in 10,000 males);
X-linked; bleeding into soft tissues, muscles, and weight bearing joints;
circulates complexed with vWF
		3. Factor IX or Hemophilia B (1 in 100,000 males);
X-linked; also called Christmas disease
		4. Afibrinogenemia and dysfibrinogenemia-severe bleeding
after surgery
		5. Antithrombin III
		6. Protein C (thromboembolisms)
		7. Protein S (thromboembolisms)

	B. Acquired
		1. Vitamin K deficiency
		2. Disseminated intravascular coagulation (DIC);
obstetrical catastrophes, metastatic malignancy, massive trauma, and
bacterial sepsis; materials resembling tissue factor are released















IV. Therapy
	A. Clinical dispute over use of tPA, urokinase, streptokinase
		1. Recombinant tPA
		2. Pro-urokinase (melanoma cell cultures)
		3. Urokinase (renal tubular cell cultures)
		4. Streptokinase (b-hemolytic streptococci)