XXXII Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia

Ponencias

Introduction

Hemostasis is a process in which a damaged blood vessel wall

is closed off by a fibrin-rich platelet plug to stop the loss of blood

into the extracellular space and initiate the repair of the damaged

endothelium. This process begins with the activation of coagulation

factors in the blood and is classically divided into two pathways

known as the intrinsic and the extrinsic pathways of coagulation,

which converge on the generation of thrombin and fibrin to form

a hemostatic plug or clot. The intrinsic pathway, also called the

contact pathway, can be activated

in vitro

when blood is exposed to

negatively charged substances or artificial surfaces, which causes the

conversion of factor XII (FXII) into activated FXII (FXIIa)

. FXIIa

cleaves the coagulation factor prekallikrein (PK) to generate active

kallikrein, which in turn feeds back to activate additional FXII. Acti-

vated FXII initiates the activation of factor XI (FXI) to FXIa, which

in turn activates factor IX (FIX) to FIXa. Activated FIX activates

factor X (FX) to FXa, after which the contact pathway leads into the

common or final pathway, resulting in the generation of thrombin

and fibrin formation. Meanwhile, the extrinsic pathway of coagu-

lation is initiated by the exposure of blood to tissue factor (TF) in

complex with activated FVII (FVIIa), which induces the activation

of FX and FIX and initiation of the common pathway leading to

thrombin and fibrin formation

. Blood platelets also become acti-

vated and play an important role in hemostasis, releasing additional

activating compounds, providing a surface to accelerate reactions,

and aggregating to form the bulk of the clot.

Deficiency in some coagulation factors is associated with bleed-

ing disorders. FIX deficiency is associated with the severe bleeding

disorder hemophilia B, and FVIII deficiency causes hemophilia A.

However, despite the ability of the contact activation pathway to

initiate coagulation

in vitro

, FXI appears to be the only contact factor

required for hemostasis. Deficiencies in FXII, PK or HK are not

associated with bleeding tendencies, while FXI-deficient patients

sometimes present with mild bleeding, suggesting that the role of

FXI in hemostasis is independent of contact activation

Role of FXI in the intrinsic and extrinsic pathway

The role of FXI in activating the extrinsic pathway involves

multiple mechanisms, due to the promiscuous interaction of FXI

with a number of enzymatic substrates. The previous understand-

ing that FXI only participated in the contact pathway was first

questioned upon the discovery that FXI can be activated by throm-

bin downstream of the extrinsic pathway

. Although FXIa’s pri-

mary substrate is the contact pathway factor FIX, more recently

FXI has also been shown to activate FX

in vitro

and to promote

thrombin generation by activating the cofactors FVIII and FV

FXIa is also known to shorten the clotting time of recalcified

FIX-depleted plasma, again revealing its pro-coagulant activity

independent of FIX

. We have also recently discovered that FXIa

promotes activation of the extrinsic pathway through proteolysis

of tissue factor pathway inhibitor (TFPI)

, a Kunitz-type protease

that is the primary inhibitor of the TF/FVIIa/FXa complex. This

inhibitory activity of FXI against TFPI may represent an important

new mechanism by which FXI promotes coagulation independent

of the contact pathway.

Additionally, it appears that the presence of platelets is

required for FXIa to support hemostasis through the extrinsic

pathway. Activated platelets release short-chain polyphosphates

(polyP; 70-85-mer), which are linear polymers of orthophosphate

linked by phosphoanhydride bonds. Platelet polyP can enhance the

feedback activation of FXI by thrombin by approximately three

thousand-fold

. Interestingly, platelet-derived polyP has been

shown to enhance the activation of FXI in a flow chamber model

independently of FXIIa, and this activation requires the participa-

tion of the extrinsic pathway

FXI and hemostasis

Hemophilia C, the congenital deficiency of coagulation FXI,

is associated with postoperative or posttraumatic bleeding, espe-

cially in tissues with robust fibrinolytic activity such as the nose,

oral cavity, and urinary tract

. However, current diagnostic tests

are unable to accurately predict bleeding tendencies in FXI-de-

ficient patients, as the symptoms are highly variable between

patients and poorly correlated with plasma FXI levels. As a result,

some FXI-deficient individuals may receive unnecessary FXI

replacement therapy, which has been shown to enhance the risk

of thrombosis or transfusion-related complications. Conversely,

FXI-deficient patients left untreated can be at increased risk of

life-threatening hemorrhage during surgery, presenting a serious

dilemma for clinicians and patients.

One common diagnostic test, the activated partial thrombo-

plastin time (aPTT) assay, which measures thrombin generation in

platelet-poor plasma (PPP) following contact pathway activation,

has not been found to accurately predict the bleeding phenotype

of FXI-deficient patients. In contrast, a recent study demonstrated

that a thrombin generation assay in platelet-rich plasma (PRP)

in which the contact pathway was inhibited while the extrinsic

pathway was activated via TF was able to successfully identify

which FXI-deficient patients demonstrated a bleeding pheno-

type

. This claim is supported by studies showing that patients

deficient in the contact activation initiators FXII, prekallikrein

The hemostatic role of factor XI

C. Puy, Owen, J.T. McCarty

Departments of Biomedical Engineering. Division of Hematology and Medical Oncology. School of Medicine. Oregon Health & Science University. Portland, OR,

EE.UU.