PMID- 8883269
OWN - NLM
STAT- MEDLINE
DCOM- 19970205
LR  - 20061115
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 76
IP  - 3
DP  - 1996 Sep
TI  - Effect of heparin on the activation of factor XI by fibrin-bound thrombin.
PG  - 347-53
AB  - Fibrin-bound thrombin is protected from inactivation by antithrombin III, while 
      its coagulant potential is retained. In the presence of heparin, ternary 
      complexes between thrombin, fibrin and heparin are formed. In these complexes the 
      coagulant activity of thrombin is retained, whereas the anticoagulant activity of 
      fibrin-bound heparin is neutralized. The limited effectiveness of heparin in the 
      prevention of both venous thrombosis and coronary reocclusion is probably related 
      to the protective effect of fibrin on the inactivation of thrombin by 
      anti-thrombin III. Recently, it has been shown that factor XI can be activated by 
      thrombin, resulting in the generation of additional thrombin via the intrinsic 
      pathway. This additional thrombin is capable of stabilizing the clot by 
      protecting it from fibrinolysis. We studied the effect of heparin on the 
      activation of factor XI by fibrin-bound thrombin. First, we used fibrin monomers 
      coupled to Sepharose to which thrombin and unfractionated heparin (UFH) were 
      bound. Factor XI activation by thrombin was the same in the presence of 
      fibrin-Sepharose or control-Sepharose. The addition of heparin (0.1 U/ml) 
      resulted in a 91 and 15-fold enhancement in the presence of control-Sepharose and 
      fibrin-Sepharose, respectively. Next, we added complexes of heparin, thrombin and 
      fibrin monomer to factor XII and XI double-deficient plasma in the presence or 
      absence of a reconstituting amount of factor XI. In the presence of factor XI, 
      additional fibrin formation was observed indicating that factor XI activation by 
      thrombin in complex with fibrin and heparin can take place in plasma. We then 
      studied the effect of other heparin-like anticoagulants on the thrombin-mediated 
      factor XI activation. UFH enhanced thrombin-mediated factor XI activation 
      68-fold, LMWH (low molecular weight heparin, Fragmin) 12-fold, danaparoid 
      (Orgaran) 3-fold, while the pentasaccharide ORG 31540 did not result in an 
      enhancement. Binding studies of these anticoagulants to fibrin-Sepharose showed 
      that LMWH bound with approximately the same affinity as UFH, while danaparoid and 
      the pentasaccharide did not bind to fibrin. We conclude that fibrin-bound 
      thrombin is capable of factor XI activation. Furthermore, heparin bound in a 
      complex with fibrin can act as a cofactor for this activation. This factor XI 
      activation capacity may play a role in the limited effectiveness of heparin. 
      Provided that thrombin-mediated factor XI activation plays an important role in 
      vivo, danaparoid and especially the pentasaccharide may be better anticoagulants 
      than UFH and LMWH.
FAU - von dem Borne, P A
AU  - von dem Borne PA
AD  - Department of Haematology, University Hospital Utrecht, The Netherlands.
FAU - Meijers, J C
AU  - Meijers JC
FAU - Bouma, B N
AU  - Bouma BN
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 9001-31-4 (Fibrin)
RN  - 9005-49-6 (Heparin)
RN  - 9013-55-2 (Factor XI)
RN  - EC 3.4.21.27 (Factor XIa)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Blood Coagulation
MH  - Factor XI/drug effects/*metabolism
MH  - Factor XIa/*metabolism
MH  - Fibrin/*metabolism
MH  - Heparin/*metabolism/pharmacology
MH  - Humans
MH  - Protein Binding
MH  - Thrombin/*metabolism
EDAT- 1996/09/01 00:00
MHDA- 1996/09/01 00:01
CRDT- 1996/09/01 00:00
PHST- 1996/09/01 00:00 [pubmed]
PHST- 1996/09/01 00:01 [medline]
PHST- 1996/09/01 00:00 [entrez]
PST - ppublish
SO  - Thromb Haemost. 1996 Sep;76(3):347-53.