PMID- 8938285
OWN - NLM
STAT- MEDLINE
DCOM- 19970108
LR  - 20190724
IS  - 0160-2446 (Print)
IS  - 0160-2446 (Linking)
VI  - 27 Suppl 1
DP  - 1996
TI  - Restoration of the normal coagulation process: advances in therapies to 
      antagonize heparin.
PG  - S58-62
AB  - A number of naturally occurring anticoagulants exist that preserve normal blood 
      fluidity and limit blood clot formation to vascular injury sites, thus acting as 
      regulators of hemostasis. The protein C/protein S pathway is one system that acts 
      to modulate thrombin formation. The activation of protein C by thrombin is 
      accelerated more than 1,000-fold at the endothelial surface by thrombomodulin 
      localized on the endothelial cell. Activated protein C then binds to its 
      co-factor, protein S, and the protein C/protein S complex exerts its 
      antithrombotic function by inactivating the coagulation factors Va and VIIIa. 
      Patients deficient in protein C and protein S may be particularly vulnerable to 
      thrombotic events after cardiac surgery. In addition, several studies suggest 
      that reductions in protein C and protein S concentrations, as well as 
      thrombomodulin, occur during cardiopulmonary bypass (CPB). The possibility of a 
      low anticoagulant potential when heparinization is reversed may be an important 
      factor in the subsequent morbidity associated with thrombotic complications. 
      Aprotinin is a serine protease inhibitor that in vitro binds competitively with 
      the serine protease-activated protein C. However, aprotinin in the clinical 
      setting has not been reported to alter levels of protein C in patients undergoing 
      CPB. Reversal of the heparinization needed for CPB is almost universally 
      performed with protamine. However, protamine has many deleterious effects. 
      Recombinant platelet factor 4 (rPF4) has been proposed as an alternative to 
      protamine. We investigated the effective heparin neutralization dose of rPF4 vs. 
      the standard agent protamine in human blood activated through exposure to the CPB 
      circuit. Activated clotting time (ACT) measurements suggested a 2:1 (w/w) 
      reversal ratio for rPF4 and protamine. The first human open-label phase 1 trial 
      of rPF4 reported no serious side effects and no important hemodynamic effects. 
      Doses of 2.5 and 5.0 mg/kg were uniformly effective in reversing the 
      anticoagulant effect of heparin and reducing the ACT to <200 s by 5 min after 
      administration. Repeated monitoring of the ACT did not detect a rebound effect of 
      heparin.
FAU - D'Ambra, M
AU  - D'Ambra M
AD  - Cardiac Anesthesia Group, Massachusetts General Hospital, Boston, USA.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - J Cardiovasc Pharmacol
JT  - Journal of cardiovascular pharmacology
JID - 7902492
RN  - 0 (Heparin Antagonists)
RN  - 37270-94-3 (Platelet Factor 4)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Blood Coagulation/*drug effects/*physiology
MH  - Cardiopulmonary Bypass/*adverse effects
MH  - Heparin/therapeutic use
MH  - Heparin Antagonists/*therapeutic use
MH  - Humans
MH  - Platelet Factor 4/therapeutic use
RF  - 40
EDAT- 1996/01/01 00:00
MHDA- 1996/01/01 00:01
CRDT- 1996/01/01 00:00
PHST- 1996/01/01 00:00 [pubmed]
PHST- 1996/01/01 00:01 [medline]
PHST- 1996/01/01 00:00 [entrez]
AID - 10.1097/00005344-199600001-00012 [doi]
PST - ppublish
SO  - J Cardiovasc Pharmacol. 1996;27 Suppl 1:S58-62. doi: 
      10.1097/00005344-199600001-00012.