Hemostasis

Dr Alok TripathiDepartment of Biotechnology

Hemostsis & Thrombosis: Definition

•Hemostasis is result from well regulated process that maintain blood in a fluid clot free state in a normal vessel while inducing a rapid formation of localized hemostatic plug at the site of vascular injury.•haemostasis—the rapid arrest of blood loss upon vascular damage, in order to maintain a relatively constant blood volume.•The process by which blood is maintained in a fluid state and confined to the circulatory system

Hemostasis

•The formation of blood clot (Thrombus) in uninjured vessel. Or•Thrombotic occlusion of a vessel after a relatively minor injury.

Thrombosis

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Main processes of hemostasis

1. Platelets adhesion and aggregation, formation of the platelet plug

2. Vasoconstriction

3. Blood clotting

4. Final repair by connective tissue

NB! The phases are not separated but rather manyfold interconnected

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Hemostasis

http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2

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Classics of blood clotting

Alexander Schmidt and Paul Morawitz discovered the enzymatic cascade nature of blood clotting

1st phase – activation (of thrombokinase which converts prothrombin to thrombin)

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Adhesion of platelets, white thrombus

http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2

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Thrombocytes

Production from megakaryocytes, 1.5-3.0 x 1011 in 1L

blood

Reservoirs of bioactive

substances

Serotonin (5-HT) and thromboxan

A2 potent vasoconstrictors

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Factors influencing platelets adhesion

Collageen and plasma von Willebrand factor (vWf) iniate adhesion.

Adhesion is blocked by negative surface charge of platelets, certain biochemical regulators (e.g. NO, prostacyclin etc), and endothelial barrier between collagen and blood.

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Platelets in “normal” state

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The activated platelets

Thrombin and collagen are the two most important platelet activators. ADP is considered a weak agonist; it causes aggregation but not granule release. (GP, glycoprotein; R1–R5, various receptors; AC, adenylyl cyclase; PLA2, phospholipase A2; PL, phospholipids; PLCβ,phospholipase Cβ; PIP2, phosphatidylinositol 4,5-bisphosphate; cAMP, cyclic AMP; PKC, protein kinase C; TxA2, thromboxane A2; IP3, inositol 1,4,5-trisphosphate; DAG, 1,2-diacylglycerol. The G proteins that are involved are not shown.

Diagrammatic representation of platelet activation.The external environment, the plasma membrane, and the inside of a platelet are depicted from top to bottom

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Intergrine: A cell surface receptors

•Cell-cell adhesion•Cell to matrix adhesion•Signal Transduction•Spreading •Apoptosis•Migration •Proliferation

Role of integrine

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Blood clots. “red thrombus”

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•inflammation, •epithelialization, •angiogenesis•and matrix deposition.

Fig. 1. Wound healing is a complex process encompassing a number of overlapping phases, including

•the formation of a blood clot re-establishes hemostasis and provides a provisional matrix for cell migration. •CK play significant role in the evolution of granulation tissue through• recruitment of inflammatory leukocytes•and stimulation of fibroblasts and epithelial cells.

During inflammation,

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Conversion of prothrombin to thrombin

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Fibrinogen

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Conversion of fibrin from fibrinogen

2nA+2nB

n(A)2 (B) 2 2 n222(2222)n

Fibrin Monomer Fibrin Clot

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Fibrinogen structure

The disulfide rings are region containing 3 di-sulfide bonds cyclic linking homologous segment of , and chains. N-linked polysaccharides are represented by filled hexagons. The Arg-Gly bonds that are cleaved by thrombin in fibrin activation are indicated

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Fibrin network

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Initiation of coagulation

The extrinsic pathway is critical in initiating of blood clotting.

The intrinsic pathway plays an important role in maintenance of coagulation.

There is no bleeding disorders in case of lack XII

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Regulation of coagulationSerine protease

inhibitors (antithrombin III)

The protein C system activated

by thrombin

The regulatory influences of

intact endothelial and blood cells

The fibrinolytic

system

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Serine protease inhibitors

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Protein C system

Proteiin C destroys factors V and VIII

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Fibrinolysis

Endothelium

Modulate several aspect of anti-cougulating properties

It may activated by infectious agents, hemodynamic factors plasma mediators &

CK

Anti-platelet ,Anti-couagulent & fibrinolytic

Exerts pro-couagulent functions

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Endothelium and coagulation

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Blood cells and coagulation

Platelets contain procoagulant anticoagulant substances

Polymorphonuclear leukocytes and monocytes produce tissue factor, factor V and present phospholipids, which all support blood coagulation

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Disturbances of blood coagulation

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Hypocoagulation

Thrombocytopenia

Deficiency of

coagulation factors

Deficiency of vitamiin

K

Vitamiin K is important to add gamma-

carboxyglutamate (gla) to

factors II, VII, IX ja X.

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Blood coagulation and blood cells

Platelets contain both substances which activate or inhibit blood clotting

Neutrophilic granulocytes and monocytes produce the tissue factor, the factor V, and phospholipids which all support blood clotting processes.

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Endothelium and blood clotting

In case of intact endothelium there is no clotting

Endothelial cells produce plasminogen activators.

A good overview and illustrations: http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html