Anticoagulant and Nonanticoagulant Actions of Heparin
Anticoagulant and Nonanticoagulant Actions of Heparin
The fascinating multifactorial faces of the polysulfated glycosaminoglycan heparin
were reported first by Doyon in 1912. He revealed heparin's nonanticoagulant action
when he investigated the effect of peptone on blood coagulation in canine livers.
McLean and his mentor Howel observed an anticoagulant effect in the liver when they
purified a thromboplastic component from various organs and named it heparin, according
the Greek name of its origin (ηπαρ = hepar). These contradictory actions of heparin
are still observed until today such as they can have disastrous thrombotic side effects
in the form of heparin-induced thrombocytopenia.[1]
The chemical composition of heparin was discovered by Chargaff and Olson in 1937.
They found that the negatively charged heparin binding to positively charged protamine
sulfate antagonized the anticoagulant property of heparin. Jorpes and Bergström identified
a polysulfated glucosamine/glucopyranose and uronic acid of the heparin polysaccharide.
The function of heparin still remains under investigation because the sulfated saccharides
have a three-dimensional structure for several reasons such as it changes upon binding
to proteins and cell surfaces.[2]
Heparin's Multifaceted Structure
Heparin's Multifaceted Structure
In this issue, Beurskens et al from the cardiovascular institute in Maastricht published
a review on the pleiotropic anticoagulant and nonanticoagulant effects of heparin.[3] They describe in detail the structure of heparin as a glycosaminoglycan. The chemical
structure of heparin is commonly known by its anticoagulant activity toward factor
Xa and thrombin, which is mostly related to its high affinity binding to antithrombin
(AT). Low affinity binding of heparin to AT mediates anticoagulant as well as nonanticoagulant
action. Furthermore, the structural composition of heparin varies between species
and even tissues; commercially available forms of heparin are typically derived from
porcine intestinal mucosa and rarely from bovine intestinal mucosa; from bovine lung
it is not extracted any more for clinical use. The growing demand for heparins has
pushed us to consider other sources, such as from the ovine intestinal mucosa, and
bioengineered heparin.
Some additional structural aspects of heparin compared with Beurskens et al[3] include a relationship between different disaccharide components and how these relationships
can identify the origin of a heparin sample obtained by industrial extraction processes.[4]
-
Different structures for as many as five pentasaccharide sequences for the AT binding
(ATB) region of mucosal bovine and porcine heparins were identified.[5]
-
Two molecules of trisulfated disaccharides of an 18-unit oligomer containing ATB at
reducing end are required to maximize the effect of AT on the anionic charge density
of thrombin.[6]
-
The conformational flexibility of the iduronic acid chain components induces heparin's
pleiotropic properties.
-
Shorter chains than 18 monomers containing AT sites are devoid of anticoagulant activity
but have antithrombotic activity.
It is astonishing that heparin's structure continues to surprise us today despite
its use as a cornerstone therapy for thromboembolism for more than 50 years. This
structural variation may be explained by heparin's glycosylic structure; a synthetic
full-length active polyanionic oligosaccharide sequence is not yet commercially available,
unlike proteins consisting of amino acids. Furthermore, improving physico-chemical
methods can now better detect three-dimensional peculiarities after binding to proteins.[4]
Heparin's Anticoagulant and Nonanticoagulant Actions
Heparin's Anticoagulant and Nonanticoagulant Actions
Beurskens et al[3] have precisely described the many antithrombotic and anticoagulant actions of heparin.
Antithrombotic actions include release of tissue factor pathway inhibitor, modulation
of fibrinolytic activity, binding of chemokines and cytokines, and activation of growth
factors. Nonanticoagulant actions include inhibition of tumor growth, metastasis,
inflammation, and neutrophil extracellular traps ([Fig. 1]). The authors conclude that the clinical benefits of heparin outweigh its many and
potentially life-threatening side effects.
Fig. 1 Interplay of anticoagulant and nonanticoagulant actions of heparin and heparin-like
compounds on biological functions.
The multiple actions of heparin comprise the following processes:
-
Heparin and other polyanions such as dermatan sulfate (located in the vessel wall)
potentiate the antithrombotic activity of heparin cofactor II.
-
Heparin inhibits protein Z (PZ) by potentiating a PZ inhibitor and thereby inhibiting
blood coagulation.
-
Heparin potentiates C1-esterase inhibitor action on the contact system by inhibiting
kallikrein and factor XIIa.[2]
-
Heparin inhibits the naturally occurring inhibitor of heparanase.[7]
Anticoagulant Actions of Heparin in COVID-19
Anticoagulant Actions of Heparin in COVID-19
Beurskens et al reviewed heparin's actions before the coronavirus disease (COVID-19)
pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).[8] The most severely ill patients initially present with respiratory insufficiency
that progresses to multiple organ dysfunction, involving septic-induced coagulopathy
and eventually disseminated intravascular coagulation.[9] The treatments of choice for disseminated intravascular coagulation are unfractionated
heparin, low molecular weight heparin (LMWH), and fondaparinux.[10] These reduce mortality and normalize coagulation marker levels, prothrombin time,
activated partial thromboplastin time, fibrinogen levels, platelet count, and D-dimer
levels.[11] Twice daily administration of LMWH appears to have a more protective effect in COVID-19
patients than once daily dose, probably because of better nychthemeral coverage.[12]
Heparin's Nonanticoagulant Antiviral Actions
Heparin's Nonanticoagulant Antiviral Actions
Unfractionated nonanticoagulant heparins are obtained by desulfation processes that
modify the anionic charge of the AT domain, or by glycol split of heparin. Glycol
split does not change the number and distribution of anionic charges and introduces
flexible joints to the polymer chain, which increases the freedom of charge orientation
toward the target proteins' cationic sites. Another therapeutic application of heparin
is its use as an inhibitor of viral adhesion.[13] This is also supported by the observation that heparin disrupts the interaction
of the SARS-CoV-2 surface protein Spike with its host cell receptors of various organs
via its S1 receptor[14] as follows:
-
Angiotensin-converting enzyme 2, a metallopeptidase, was identified as one of the
functional binding receptors allowing SARS-CoV to enter host cells.[15]
-
The immune changes associated with coagulation in COVID-19 patients may resemble the
NETosis process observed during bacterial, fungal, and some viral infections.[16]
-
Lesions of the endothelium destroy the glycocalyx leading to microthrombotic reactions
and extravascular fluid leaks. Heparin can enter the glycocalyx[17] to mobilize syndecan pools[18] and partly take over syndecan 1 function.[19] This restores glycocalyx function in the vascular endothelium to prevent inflammation[20] and reduce septic shock.[18]
-
Autopsies of patients who died of COVID-19 revealed microvascular thrombosis in many
organs such as lung, liver, and heart,[21]
[22] as well as neurological effects such as severe acute hearing loss which indicate
viral sepsis.[23]
Heparins achieve their multiple nonanticoagulant actions by inhibiting heparanase,
which is elevated in malignancies, chronic inflammation, atherosclerosis, and Alzheimer's
disease[7] ([Fig. 2]). Advances in the field are presented at annual symposia[24]
[25]; the 28th symposium will be postponed until 2021 because of the COVID-19 pandemic.
The anticoagulant and nonanticoagulant actions of heparin make it a promising candidate
for the treatment of COVID-19.
Fig. 2 Actions of heparin classified as beneficial that could have implication for medical
care of COVID-19 patients.
Extended Anticoagulation and COVID-19
Extended Anticoagulation and COVID-19
Ideally, heparins should be administered to COVID-19 patients as early as possible.
Before hospital admittance, anticoagulation therapy should be in the form of indirect-acting
vitamin-K antagonists (VKA) or direct-acting oral anticoagulants (DOACs) in patients
with nonvalvular atrial fibrillation and thromboembolism.[26] Upon hospitalization, anticoagulation therapy should be switched as soon as possible
to heparin/LMWH to ensure beneficial effects and to reduce interactions of VKA and
DOACs during polypharmaceutical treatment of COVID-19. The presence of VKA and DOACs
needs to be determined by rapid and accurate point of care methods.
Before recovered patients are discharged from hospital, therapy should be switched
from heparin/LMWH to VKA or DOACs after the anticoagulant effects of treatment have
been specifically tested.[29]
What the Future May Offer
What the Future May Offer
Our understanding of the chemical structure of heparin and its derivatives and their
mode of action is increasing. In parallel, our knowledge of heparin's biological functions
in plasma and on cell surfaces and receptors is also increasing. This in turn increases
the spectrum of medical therapies and therapeutic indications that heparin can offer.
Specific efforts are being undertaken to modify heparin to improve its safety and
decrease the risk of bleeding complications. Promising approaches for treatment of
COVID-19 and other nonthrombotic diseases may focus on heparin's nonanticoagulant
effects and the inhibition of heparin by heparanases.
