Thrombophilic states

TThhromborombophphililicic sta statete

is is characharaccterizterizeded by a shift in the cby a shift in the coagulaoagulationtion balancebalance in in favour of hypercoagulabilitfavour of hypercoagulability – y – i.e. easier and oftener i.e. easier and oftener formation of the blood coagulumformation of the blood coagulum

inborn (genetically determined)inborn (genetically determined) acquired acquired

Acquired thrombophilic state

Thrombophilic reaction is a part of the complex Thrombophilic reaction is a part of the complex inflammatory and stress response of the organism, and inflammatory and stress response of the organism, and a part of the phylogenetic adaptation in order to deal a part of the phylogenetic adaptation in order to deal with presumed damage of the organism. with presumed damage of the organism.

The inflammatory states are accompanied by the The inflammatory states are accompanied by the following phenomena:following phenomena:

increased expression of increased expression of seleselecctintinss ( (sseleelecctin Etin E on endothelial on endothelial cellscells, , selectin L on leukocytes, sselectin L on leukocytes, seleelecctin Ptin P on platelets and on platelets and endothelial cellsendothelial cells) )

increased expression of increased expression of integrinintegrinss (ICAM (ICAM--11 and and VCAMVCAM--11 on on endothelial cellsendothelial cells, LFA, LFA--11 on leukocytes on leukocytes) )

mutual mutual interacinteractionstions of adhesion molecules induce aof adhesion molecules induce adhedhesionsion a andnd aacctivativation of endothelial and inflammatory cells that are tion of endothelial and inflammatory cells that are stimulated to stimulated to producproducee PAF ( PAF (platelet activating fplatelet activating faacctor) tor) with a with a subsequent subsequent adheadhesionsion of plateletsof platelets to to endotendothhelelium,ium, releasing releasing vWfvWf. .

Virchow`s triad

11// Changes in the pattern of blood flow (flow volume)Changes in the pattern of blood flow (flow volume)permanentpermanent dilution of cdilution of coagulaoagulationtion a andnd fibrinolytic fa fibrinolytic facctortorss

2/2/ Changes in the vessel wallChanges in the vessel wallintaintacct endott endothhelelium hasium has antit antithhrombotic arombotic andnd anti anticcoagulaoagulation effectstion effects (endot(endothhelelialial dysfunc dysfunction causestion causes t thhromborombophiliaphilia))

3/3/ Changes in the constituents of bloodChanges in the constituents of blood (hypercoagulability)(hypercoagulability) inflammatory rinflammatory reaeactionsctions, , inborn thinborn thromborombophphililicic sta statestes

Clinical situations accompanied by thrombophilia:Clinical situations accompanied by thrombophilia:

•• infeinfectionsctions

•• tumours, incl. haematological malignanciestumours, incl. haematological malignancies ( (often theoften the

first sign of the tumourfirst sign of the tumour))

•• operationsoperations

•• hormonal contraceptionhormonal contraception

* routine examinations: serum levels of * routine examinations: serum levels of CRP, fibrinogen, CRP, fibrinogen, platelet count, platelet count, D-dimD-dimersers

* special examinations: * special examinations: sseerrum levels of um levels of seleselecctintins s aand nd iintegrintegrinsns – – not available in common laboratoriesnot available in common laboratories

Laboratory diagnostics:

Types of the thrombi

white white tthhrombus rombus

arteriarteriaal (l (plateletsplatelets – leukocyt – leukocyteses – fibrinogen) – fibrinogen) with smallwith smallparticipation of participation of plaplassma ma ccoagulaoagulationtion fa facctortors (blood flows (blood flowwashes and dissolves them)washes and dissolves them)

- can be also formed on the can be also formed on the intaintacct endott endothheleliiuumm atat „ „shearshear stressstress“, “, that leads to its activationthat leads to its activation (platelets being activated (platelets being activated

as well)as well) a andnd expres expresssiion ofon of adhe adhesionsion mole moleccululeses with a with a subsequent cascade of subsequent cascade of tthhromborombophphililicic reac reactionstions

Clinical situations caused by the white thrombus:Clinical situations caused by the white thrombus:

acute coronary syndromesacute coronary syndromes arteriarteriaal tl thhromborombosesses ischischaaemic emic brain strokesbrain strokes

red thrombusred thrombus venousvenous (fibrin – eryt (fibrin – erythhrocytrocytes)es)

- often caused by slowing down of the blood flowoften caused by slowing down of the blood flow

CCliniclinical situations caused by the red thrombus:al situations caused by the red thrombus:

deep venous deep venous tthhromborombosis (DVT) of the lower extremitiessis (DVT) of the lower extremities pulmonary embolization (PE)pulmonary embolization (PE)

Clinically important thrombophilic states

APC resistance

inborn diseaseinborn disease mutation of the mutation of the Leiden faLeiden facctor V tor V Cambridge mutaCambridge mutationtion of the of the fafacctor Vtor V decreased level of the decreased level of the fafacctor Vtor V

ExaminationsExaminations: : ccoagulaoagulationtion – – aPTT aPTT PCR – PCR – mutation of the Leiden factormutation of the Leiden factor

Hyperhomocysteinaemia

inborninborn acquiredacquired

HomocysteinHomocysteinee is an is an intermediintermediateate productproduct of the of the metabolism metabolism of the of the eesssesentialntial amino acid mamino acid methioninethionine.e.

- risk factor for the development ofrisk factor for the development of arteri arteriaal l and venous and venous tthhromborombosissis

TThheraperapyy:: ffololates ates ++ vitaminvitamin B B

Antiphospholipid syndrome (Hughes syndrome)

- acquiredacquired- multiple different antibodies associated with both arterial and multiple different antibodies associated with both arterial and

venous thrombosis venous thrombosis

- primary primary –– three primary classes of antibodiesthree primary classes of antibodies:: 1) anticardiolipin antibodies1) anticardiolipin antibodies (ACLA) (ACLA) 2) lupus anticoagulant 2) lupus anticoagulant (LA)(LA) 33) antibodies directed against specific molecules) antibodies directed against specific molecules,, inclincl.. a molecule known as beta-2-glycoprotein 1 a molecule known as beta-2-glycoprotein 1 - sseecocondndary ary – – accompanying diseases, such asaccompanying diseases, such as SSLELE or other or other

autoimautoimmmununee diseasesdiseases, leuk, leukaaemiemiasas, lym, lymphphomomasas

Other inborn thrombophilic states

ddeficit eficit of the of the protein Cprotein C ddeficit eficit of the of the protein S protein S  ddeficit eficit of antithrombinof antithrombin III III increased levelincreased level of of protprothhrombin rombin ddeficit eficit of of tthhrombomodulinrombomodulin increased level ofincreased level of fa facctortorss VIII, IX, XI, fibrinogen VIII, IX, XI, fibrinogen

Antithrombogenic mutations

mutation of Annexin Vmutation of Annexin V

antithrombogenic mutation may counterbalance thrombophilic mutation in antithrombogenic mutation may counterbalance thrombophilic mutation in clinical practice and neutralize its thrombophilic effects.clinical practice and neutralize its thrombophilic effects.