PMID- 31471127
OWN - NLM
STAT- MEDLINE
DCOM- 20200923
LR  - 20200923
IS  - 1532-1681 (Electronic)
IS  - 0268-960X (Linking)
VI  - 39
DP  - 2020 Jan
TI  - From unfractionated heparin to pentasaccharide: Paradigm of rigorous science 
      growing in the understanding of the in vivo thrombin generation.
PG  - 100613
LID - S0268-960X(19)30017-7 [pii]
LID - 10.1016/j.blre.2019.100613 [doi]
AB  - Following a chance discovery made by a medical student who was searching for a 
      clot-promoting activity in tissue extracts, it took 15-20 years to attain the 
      therapeutic use of standard unfractionated heparin (UFH), due to problems with 
      the purification and extraction of the active material. Soon it was found that: 
      1) thrombin inactivation by UFH was associated with the formation of molecular 
      complexes between antithrombin and the activated forms of factor X (FXa) and 
      thrombin, 2) low-molecular-weight fractions of UFH lose their antithrombin 
      activity while still interacting with FXa, 3) a pentasaccharide sequence of UHF 
      increases FXa (but not thrombin) inactivation by antithrombin. 
      Low-molecular-weight heparins (LMWHs) with little effect on thrombin and strongly 
      active versus FXa were then developed. In patients, LMWHs (and the 
      pentasaccharide sequence) came up as a useful class of drugs to prevent and treat 
      thrombosis, their greatest advantage over UFH being the convenience of the 
      once/twice daily subcutaneous injections at a fixed dose without any laboratory 
      monitoring. In addition to providing major information on in vivo modulation of 
      thrombin generation, the heparin saga served as a paradigm to support an 
      alternative coagulation scheme that includes platelets and tissue factor as 
      integral parts of the model. Forthcoming work with this scheme - also supported 
      by studies in hemophilia and rare bleeding disorders - is expected to provide 
      major hints for understanding why some patients benefit more than others from the 
      small amount of thrombin they form and directions to tailor prevention and 
      treatment of thromboembolic disorders.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Spadarella, Gaia
AU  - Spadarella G
AD  - Postgraduation School in Radiodiagnostics, Universita degli studi di Milano, 
      Italy. Electronic address: gaia.spadarella@unimi.it.
FAU - Di Minno, Alessandro
AU  - Di Minno A
AD  - Dipartimento di Farmacia, Universita degli Studi di Napoli "Federico II, Naples, 
      Italy. Electronic address: a.diminno@hotmail.com.
FAU - Donati, Maria Benedetta
AU  - Donati MB
AD  - Department of Epidemiology and Prevention, IRCCS Istituto Neurologico 
      Mediterraneo Neuromed, Pozzilli, Italy. Electronic address: 
      mbdonati@moli-sani.org.
FAU - Mormile, Mauro
AU  - Mormile M
AD  - Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli 
      "Federico II", Naples, Italy. Electronic address: mormile@unina.it.
FAU - Ventre, Itala
AU  - Ventre I
AD  - Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli 
      "Federico II", Naples, Italy. Electronic address: italaventre@libero.it.
FAU - Di Minno, Giovanni
AU  - Di Minno G
AD  - Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli 
      "Federico II", Naples, Italy. Electronic address: diminno@unina.it.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20190823
PL  - England
TA  - Blood Rev
JT  - Blood reviews
JID - 8708558
RN  - 0 (Anticoagulants)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Oligosaccharides)
RN  - EC 3.4.21.5 (Thrombin)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
MH  - Anticoagulants/pharmacology
MH  - Blood Coagulation/drug effects
MH  - Fondaparinux/pharmacology/therapeutic use
MH  - Heparin, Low-Molecular-Weight/isolation & purification/pharmacology/*therapeutic 
      use
MH  - Humans
MH  - Oligosaccharides/pharmacology/*therapeutic use
MH  - Randomized Controlled Trials as Topic
MH  - Thrombin/*biosynthesis/metabolism
OTO - NOTNLM
OT  - Anticoagulation
OT  - Clinical trials
OT  - Deep venous thrombosis
OT  - Heparin history
OT  - Laboratory monitoring
OT  - Mechanism of action
OT  - Natural polysaccharides
OT  - New scheme of coagulation
OT  - Pentasaccharide
OT  - Translational medicine
EDAT- 2019/09/01 06:00
MHDA- 2020/09/24 06:00
CRDT- 2019/09/01 06:00
PHST- 2019/02/20 00:00 [received]
PHST- 2019/08/19 00:00 [revised]
PHST- 2019/08/22 00:00 [accepted]
PHST- 2019/09/01 06:00 [pubmed]
PHST- 2020/09/24 06:00 [medline]
PHST- 2019/09/01 06:00 [entrez]
AID - S0268-960X(19)30017-7 [pii]
AID - 10.1016/j.blre.2019.100613 [doi]
PST - ppublish
SO  - Blood Rev. 2020 Jan;39:100613. doi: 10.1016/j.blre.2019.100613. Epub 2019 Aug 23.