Coagulao Sangunea Blood Clotting

Consideraes gerais
Davie e col; MacFarlane e col em 1964 descrevem o modelo da coagulao por via intrnseca e extrnseca. Cada fator de coagulao constitui uma glicoprotena cuja biossntese, na maior parte das vezes, ocorre no fgado, endotlio e megacaricito. So designados por nmeros romanos: I XIII. Ativados em uma cascata de ativao de Zimognios. Os fatores II, VII, IX, X, protena C e protena S so dependentes da vitamina K.

Inicia 20 segundos aps a injria.

Sinal
Ativao
Enzima 1

Enzima 2

Enzima 2

Enzima 2

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Enzima 3

Rpida Resposta ao Trauma

Cascatas enzimticas esto envolvidas em respostas Rpidas; Um sinal dispara uma srie de etapas, cada qual catalisada por uma enzima;Em cada etapa o sinal amplificado, podendo alcanar milhares de vezes.

Enzima 3

Sinal
N-C

Proenzima 1

Enzima Ativa 1

Proenzima 2

Enzima Ativa 2

Proenzima 3

Enzima Ativa 3

Proenzima 4

Enzima Ativa 4

VI

Nome atribudo ao Fator Va

Fatores de Coagulao
Zimgeno (ou pr-enzima) Protena madura

igure 1. Design of a ribonuclease zymogen. a, Scheme for creating a zymogen in which a circular permutation creates a steric block of the active site. b, Structural model of the unactivated ribonuclease A zymogen with 88/89 termini, 14-residue linker and six disulfide bonds. The conformational energy of the nonwild type residues was minimized with the program SYBYL (Tripos). Atoms of the linker and cystines are shown explicitly, and the two non-native cystines are labeled. c, Scheme of the primary sequence of ribonuclease A zymogens. The location of -helices (cylinders) and -strands (arrows) are indicated. The nine new termini (black triangles), 14-residue linker (boxed) and four native and one nonnative (Cys4Cys118) cystine are indicated.

Blood-Clotting Cascade
A fibrin clot is formed by the interplay of the intrinsic, extrinsic, and final common pathways. The intrinsic pathway begins with the activation of factor XII (Hageman factor) by contact with abnormal surfaces produced by injury. The extrinsic pathway is triggered by trauma, which activates factor VII and releases a lipoprotein, called tissue factor, from blood vessels. Inactive forms of clotting factors are shown in red; their activated counterparts (indicated by the subscript a) are in yellow. Stimulatory proteins that are not themselves enzymes are shown in blue. A striking feature of this process is that the activated form of one clotting factor catalyzes the activation of the next factor.

Via comum

Modular Structure of Prothrombin Cleavage of two peptide bonds yields thrombin. All the -carboxyglutamate residues are in the gla domain.

Via comum

Kringle domains

Kringle domains, named for Scandinavian pastries, are conserved sequences that fold into large loops (stabilized by 3 disulfide linkages) the conformation of which is defined by hydrogen bonds and small pieces of anti-parallel -sheet. Plasminogen-like kringles display affinity for free lysine and for lysine-containing peptides.

Protrombina Fator II ativado

Via comum

Fibrinognio
(also called factor I) is a 340 kDa glycoprotein

Via comum

A) A ribbon diagram. The two rod regions are -helical coiled coils, connected to a globular region at each end. (B) A schematic representation showing the positions of the fibrinopeptides A and B.

Via comum

Formation of a Fibrin Clot

(1) Thrombin cleaves fibrinopeptides A and B from the central globule of fibrinogen. (2) Globular domains at the carboxyl-terminal ends of the and chains interact with knobs exposed at the amino-terminal ends of the and chains to form clots.

Fibrina

Via comum

The 23-nm period along the fiber axis is half the length of a fibrinogen molecule. [Courtesy of Dr. Henry Slayter.]

Via comum

Fator XIIIa

This cross-linking reaction is catalyzed by transglutaminase (factor XIIIa), which itself is activated from the protransglutaminase form by thrombin.

Via comum

Via comum

Via comum

Leso exposio de superfcies aninicas

Aumento da atividade do FXII em 104 a 105 vezes

Converso de Pr-Calicrena em Calicrena

Calicrena converte FXII em FXIIa

Via Extrnseca

Tissue Factor - TF

Via extrnseca

also called platelet tissue factor, factor III, thrombokinase, or CD142

TF is the cell surface receptor for the serine protease Factor VIIa.

Via extrnseca

Tissue factor, also called platelet tissue factor, factor III, thrombokinase, or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. The best known function of tissue factor is its role in blood coagulation.

The complex of TF with factor VIIa catalyzes the conversion of the inactive protease factor X into the active protease factor Xa.
Together with factor VII, tissue factor forms the tissue factor or extrinsic pathway of coagulation. This is opposed to the intrinsic (amplification) pathway which involves both activated factor IX and factor VIII. Both pathways lead to the activation of factor X (the common pathway) which combines with activated factor V in the presence of calcium and phospholipid to produce thrombin (thromboplastin activity)

Via Intrnseca

Via Intrnseca

Contact activation pathway (intrinsic)

The contact activation pathway begins with formation of the primary complex on Collagen by:
High-molecular-weight kininogen (HMWK); Prekallikrein (PK) and; FXII (Hageman factor). Comea quando a PK, o HWHK, factor XI e XII so expostos a cargas negativas do vaso lesado, isso chamado de "fase de contacto". Collagen Cargas negativas

A pr-calicrena ento converte-se em calicrena e esta activa o fator XII. O fator XII activado acaba convertendo mais prekalicrena em calicrena e activando o factor XI. Na presena de os clcio, o fator XI ativado ativa o IX. Por sua vez o factor IX activado junto com o factor VIII activado, levam activao do factor X. Deste modo, o complexo enzimtico constitudo pelo factor X activado, juntamente com o factor V activado e Ca++, denomina-se de Protrombinase.

Adeso Plaquetria:
Inicia-se quando as plaquetas se aderem ao endotlio vascular.

Essa aderncia acontece com uma ligao entre a glicoprotena Ib/IX/V na superfcie das plaquetas e colgeno exposto durante a leso do endotlio.
Essa ligao mediada pelo fator de von Willebrand que funciona como uma "ponte" entre a superfcie da plaqueta e o colgeno.

Via Intrnseca

Consideraes gerais: Plaquetas

Via Intrnseca

Plaquetas: 150000-450000 plaquetas/mm3 Valores < 50000 = ditese hemorrgica. Valores < 20000 = Risco de sangramento fatal (SNC) ou hemorragia GI intensa. So fragmentos celulares derivados dos megacaricitos, produzidos pela medula ssea. Distribuio: 70-80% circulantes e 20-30% presentes no bao. Vida mdia: 10-14 dias. Remoo: SRE (fgado e bao).

Via Intrnseca

Fig 1. Eventos aps a ativao plaquetria. A plaqueta secreta vrias substncias ativas: vWF (fator de von Willebrand) ; ADP (adenosina di-fosfato) ; PDGF (fator de crescimento derivado da plaqueta). O processo culmina com a adeso e agregao plaquetria.

Via Intrnseca

Via Intrnseca

Fig.2 - A adeso plaquetria ao sub-endotlio facilitada pelo FvW , que forma uma ponte entre os receptores GpIb-IX das plaquetas e o colgeno sub-endotelial. Aadeso entre as plaquetas feita atravs dos receptores GpIIb-IIIa , intermediado pelo fibrinognio.

Via intrnseca

von Willebrand factor (vWF)

vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively in endothelium (in the Weibel-Palade bodies), megakaryocytes (granules of platelets), and subendothelial connective tissue

Via intrnseca

Funo
vWF is not an enzyme and therefore has no catalytic activity. Its primary function is binding to other proteins, particularly Factor VIII and it is important in platelet adhesion to wound sites.
vWF binds to a number of cells and molecules. The most important ones are: - Factor VIII is bound to vWF while inactive in circulation; Factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin. -vWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel.

vWF binds to platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stress (i.e., rapid blood flow in narrow blood vessels).

Via intrnseca

vWF binds to other platelet receptors when they are activated, e.g., by thrombin (i.e., when coagulation has been stimulated).

Schematic diagram of thrombin and GpIb-IX complexes in the region between platelets. GpIb and thrombin molecules are arranged as an adhesive ribbon structure, as observed in the crystals. The region between the last residue observed in GpIb and the stalk region is depicted as green dotted lines.

Leso exposio de superfcies aninicas

Aumento da atividade do FXII em 104 a 105 vezes

Converso de Pr-Calicrena em Calicrena

Calicrena converte FXII em FXIIa

Tenase complex

prothrombinase complex

Protena C ativa

Protena C

Vitamina K

Vitamin K1 is also known as phylloquinone or phytomenadione (also called phytonadione)

Vitamin K2 (menaquinone, menatetrenone) is normally produced by bacteria in the large intestine

Via comum Possui este nome por causa que essencial a Koagulation (escandinavo). utilizada na converso dos 10 primeiros glutamatos N-ternimais da protrombina em gama-carboxiglutamato. Permitindo a ligao do Ca++. Permitindo o ancoramento da protrombina a membranas fosfolipdicas de plaquetas aps uma leso.

Anticoagulante utilizado para prevenir trombose

Veneno de rato

Structures of Vitamin K and Two Antagonists, Dicoumarol and Warfarin

Via comum The Calcium-Binding Region of Prothrombin

Prothrombin binds calcium ions with the modified amino acid -carboxyglutamate (red).

Clulas endoteliais possuem caractersticas anticoagulantes e pr-coagulantes especializadas.

EDTA
EthyleneDiamineTetraacetic Acid

Aspirina
acetylsalicylic acid

Altera o stio cataltico da Cicloxigenase plaquetria (COX-1) impedindo a converso do cido araquidnico em prostaglandinas - irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. Acetilao irreversvel do resduo de serina 530 do stio ativo.

Heparina - glicosaminoglicano sulfatado.

A heparina um ativador da enzima sanguinea antitrombina III. Esta inibe vrios fatores da coagulao (II, IX e X) e mais significativamente a trombina, que forma o trombo de fibrina. A heparina, ou fragmentos dela, aumentam em muito (1000x) a atividade intrnseca da antitrombina. Ela no consumida durante a sua ao. O seu efeito pode apenas ser revertido em emergncias com injeo de protamina, que a inibe ao complexar-se com ela. Os fragmentos de heparina (heparina de baixo peso molecular) parecem ter a mesma funo e so mais seguros.

Varfarina ou Warfarina

A varfarina um inibidor da carboxilao-gama de vrios factores necessrios coagulao sanguinea (protrombina, e factores VII, IX e X). A reverso dos seus efeitos atravs de administrao de vitamina k.

Protena C Reativa

Inativa Fatores V e VIII

Protein S
is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b

Protein Z The main role of protein Z appears to be the degradation of factor Xa. This is done by protein Z-related protease inhibitor (ZPI), but the reaction is accelerated 1000-fold by the presence of protein Z.

Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases (serine protease inhibitors). The first members of the serpin superfamily to be extensively studied were the human plasma proteins antithrombin and antitrypsin, which play key roles in controlling blood coagulation

Plasmin is a serine protease that is released as plasminogen from the liver into the circulation and activated by tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), and factor XII (Hageman factor). The main function of plasmin is to dissolve fibrin blood clots.

Hemofilia
A Deficincia do Fator VIII

B Deficincia do Fator IX

C Deficincia do Fator XI
Autossmica no relacionada ao sexo.

Leso exposio de superfcies aninicas

Aumento da atividade do FXII em 104 a 105 vezes

Converso de Pr-Calicrena em Calicrena

C B A
Calicrena converte FXII em FXIIa