Aula de Coagulao-Medicina1

8/2/2019 Aula de Coagulao-Medicina1

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Coagulao Sangunea Blood Clotting


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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 cujabiossntese, 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 sodependentes da vitamina K.

Inicia 20 segundos aps a injria.

Consideraes gerais


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

Sinal

Enzima 1

Enzima 2Enzima 2 Enzima 2

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Enzim

a3

Rpida Resposta ao Trauma

Ativao


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Sinal

Proenzima 1 Enzima Ativa 1




N- -C


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VI Nome atribudo ao Fator Va


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Fatores de CoagulaoZimgeno (ou pr-enzima)

Protena madura


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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 zymogenwith 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. Thelocation of -helices (cylinders) and -strands (arrows) are indicated. The nine new termini (black triangles), 14-residue linker (boxed) and four native and one non-native (Cys4Cys118) cystine are indicated.


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Blood-Clotting CascadeA fibrin clot is formed by the interplay of theintrinsic, extrinsic, and final commonpathways. The intrinsic pathway begins withthe activation of factor XII (Hageman factor)by contact with abnormal surfaces producedby injury. The extrinsic pathway is triggered bytrauma, which activates factor VII andreleases a lipoprotein, called tissue factor,from blood vessels. Inactive forms of clottingfactors are shown in red; their activatedcounterparts (indicated by the subscript a)

are in yellow. Stimulatory proteins that are notthemselves enzymes are shown in blue. A

striking feature of this process is that theactivated form of one clotting factor catalyzesthe activation of the next factor.


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Modular Structure of ProthrombinCleavage of two peptide bonds yields thrombin. All the -carboxyglutamate

residues are in the gla domain.

Via comum


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Kringle domains

Kringle domains, named for Scandinavian pastries, are conserved sequences that fold into large loops (stabilized by 3disulfide 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.

Via comum


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Protrombina Fator II ativadoVia comum


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

of the fibrinopeptides A and B.

Via comumFibrinognio

(also called factor I) is a 340 kDa glycoprotein


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(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 interactwith knobs exposed at the amino-terminal ends of the and chains to form

clots.

Via comum

Formation of a Fibrin Clot


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

Via comumFibrina

Vi


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

Via comum

Fator XIIIa

Vi


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Via comum

Vi


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Via comum

Vi


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Via comum

L i d f i i i


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Aumento da atividade do FXIIem 104 a 105 vezes

Leso exposio de superfcies aninicas

Converso de Pr-Calicrena

em Calicrena

Calicrena converte FXII em FXIIa


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Via Extrnseca

Ti F t TF Via extrnseca


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Tissue Factor - TFalso called platelet tissue factor, factor III, thrombokinase, or CD142

Via extrnseca


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TF is the cell surfacereceptor for theserine proteaseFactor VIIa.

Via extrnseca


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Tissue factor, also called platelet tissue factor, factor III,thrombokinase, or CD142 is a protein present in subendothelialtissue, 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 orextrinsic pathway of coagulation.

This is opposed to the intrinsic (amplification) pathway which involvesboth activated factor IX and factor VIII. Both pathways lead to theactivation of factor X (the common pathway) which combines withactivated factor V in the presence of calcium and phospholipid toproduce thrombin (thromboplastin activity)

Via extrnseca


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Via Intrnseca

Via Intrnseca


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Contact activation pathway (intrinsic)

The contact activation pathway begins withformation of the primary complex on Collagenby:

High-molecular-weight kininogen (HMWK);Prekallikrein (PK) and;

FXII (Hageman factor).

Comea quando a PK, o HWHK, factor XI e XIIso expostos a cargas negativas do vasolesado, isso chamado de "fase de contacto".

Via Intrnseca

CollagenCargas negativas


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A pr-calicrena ento converte-se em calicrena e esta activa ofator XII.

O fator XII activado acaba convertendo mais prekalicrena emcalicrena 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 Xactivado, juntamente com o factor V activado e Ca++,denomina-se de Protrombinase.


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Adeso Plaquetria:

Inicia-se quando as plaquetas se aderem ao endotlio vascular.

Essa aderncia acontece com uma ligao entre a glicoprotena Ib/IX/V nasuperfcie 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


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Via Intrnseca

Via Intrnseca


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Plaquetas: 150000-450000 plaquetas/mm3

Valores < 50000 = ditese hemorrgica.Valores < 20000 = Risco de sangramento fatal

(SNC) ou hemorragia GI intensa.

So fragmentos celulares derivados dosmegacaricitos, produzidos pela medula ssea.

Distribuio: 70-80% circulantes e 20-30%presentes no bao.

Vida mdia: 10-14 dias.

Remoo: SRE (fgado e bao).

Consideraes gerais: PlaquetasVia Intrnseca

Via Intrnseca


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

plaquetria.

Via Intrnseca

Via Intrnseca


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Via Intrnseca

Via Intrnseca


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Fig.2 - A adeso plaquetria ao sub-endotlio facilitada pelo FvW , que forma umaponte 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

Via intrnseca


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a t seca

von Willebrand factor (vWF)

vWF is a large multimeric glycoprotein present in blood plasma and producedconstitutively in endothelium (in the Weibel-Palade bodies), megakaryocytes (-

granules of platelets), and subendothelial connective tissue

Via intrnseca


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Funo

vWF is not an enzyme and therefore has no catalytic activity. Itsprimary function is binding to other proteins, particularly Factor VIII andit 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 VIIIdegrades rapidly when not bound to vWF. Factor VIII is released fromvWF by the action of thrombin.

-vWF binds to collagen, e.g., when it is exposed in endothelial cells dueto damage occurring to the blood vessel.

vWF binds to platelet gpIb when it forms a complex with gpIX and Via intrnseca


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

Schematic diagram ofthrombin and GpIb-IXcomplexes in the regionbetween platelets. GpIb

and thrombin molecules arearranged as an adhesiveribbon structure, asobserved in the crystals.The region between the lastresidue observed in GpIb

and the stalk region isdepicted as green dottedlines.

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



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Converso de Pr-Calicrenaem Calicrena


Tenase complex

prothrombinase complex

Protena C

Protena C ativa


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Vitamina K

Vitamin K1

is also known as phylloquinone orphytomenadione (also called phytonadione)

Vitamin K2

(menaquinone, menatetrenone)is normally produced by bacteria

in the large intestine

Via comum


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Structures of Vitamin K and Two Antagonists, Dicoumarol and Warfarin

Veneno de rato

Anticoagulante utilizado para prevenirtrombose

Possui este nome por causa que essencial a Koagulation (escandinavo). utilizada na converso dos 10 primeirosglutamatos N-ternimais da protrombina

em gama-carboxiglutamato.Permitindo a ligao do Ca++. Permitindo oancoramento da protrombina amembranas fosfolipdicas de plaquetasaps uma leso.

Via comum


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

The Calcium-Binding Region of Prothrombin


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Clulas endoteliais possuem caractersticas


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Clulas endoteliais possuem caractersticasanticoagulantes e pr-coagulantes especializadas.


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EDTAEthyleneDiamineTetraacetic Acid


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Aspirina

acetylsalicylic acid

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

Heparina glicosaminoglicano sulfatado


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A heparina um ativador da enzima sanguinea antitrombina III. Esta inibe vrios fatores dacoagulao (II, IX e X) e mais significativamente a trombina, que forma o trombo de fibrina. Aheparina, 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 emergnciascom 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.

Heparina - glicosaminoglicano sulfatado.


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Varfarina ou Warfarina


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Varfarina ou Warfarina

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


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Protena C Reativa


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Protena C Reativa

Inativa Fatores V e VIII


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Protein S

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


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The main role of protein Z appears to be the degradation of factor Xa. This isdone by protein Z-related protease inhibitor (ZPI), but the reaction is accelerated1000-fold by the presence of protein Z.

Protein Z


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Serpinsare a group of proteins with similar structures that were first identified as a set ofproteins able to inhibit proteases. The acronym serpin was originally coinedbecause many serpins inhibit chymotrypsin-like serine proteases (serine proteaseinhibitors). The first members of the serpin superfamily to be extensively studiedwere the human plasma proteins antithrombin and antitrypsin, which play key rolesin controlling blood coagulation


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Plasmin

is a serine protease that is released as plasminogen from the liver into thecirculation and activated by tissue plasminogen activator (tPA), urokinaseplasminogen activator (uPA), and factor XII (Hageman factor). The main function of

plasmin is to dissolve fibrin blood clots.

Hemofilia


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Hemofilia

A Deficincia do Fator VIII

B Deficincia do Fator IX

C Deficincia do Fator XIAutossmica no relacionada ao sexo.



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Converso de Pr-Calicrenaem Calicrena


AB

C

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