Clinica Chimica Acta 504 (2020) 73–80

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Clinica Chimica Acta

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Review

Pathogenesis and management of heparin-induced thrombocytopenia and T

thrombosis
Pan Zhoua,1, Jia-Xin Yinb,1, Hua-Lin Taoa, , Hong-wei Zhangc,
⁎ ⁎

a
Department of Clinical Laboratory, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
b
Class 1, Degree 2016, Department of Medical Laboratory, Southwest Medical University, Luzhou, Sichuan, China
c
Department of Blood Transfusion, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

ARTICLE INFO ABSTRACT

Keywords: Heparin-induced thrombocytopenia and thrombosis is a severe immune-mediated adverse drug effect caused by
Heparin the IgG antibodies to platelet factor4/heparin complexes. Activated platelets, vascular endothelium, and
Heparin-induced thrombocytopenia and monocytes generate the life-threatening thrombocytopenia and thrombosis. In this review, we will update the
thrombosis reader on recent findings on the pathogenesis and clinical management of heparin-induced thrombocytopenia
Platelet factor 4
and thrombosis. Firstly, PF4/heparin complexes make IgM mediate complement activation by classical pathway.
Pathogenesis
Secondly, Marginal zoneB cells play a crucial role in producing anti-PF4/heparin complex IgG antibody. Thirdly,
Management
two activation signals of platelets (protease-activated receptor 1/Fc gamma IIA receptor) were confirmed. Based
on these findings, we present a potential laboratory test of HITT (receptor glycoprotein Ⅳ) and two possible
treatments by using receptor inhibitors (vorapaxar/atopaxar) and IgG-degrading enzyme (streptococcus pyo-
genes/glutamyl endopeptidase V8/matrix metalloproteinases).

1. Introduction
Despite the clinical introduction of a few new drugs, heparin has
remained to be a widely used anticoagulant in clinical practice since
1970s because of its low cost, satisfactory efficacy, and accessibility.
However, heparin can also cause some adverse reactions including skin
lesions, thrombocytopenia, massive hemorrhage, and osteoporosis,
among which thrombocytopenia is the most severe one [1–4].
Studies on mechanism have revealed that HITT is caused by im-
mune antibodies to complexes between unfractionated heparin (UFH)
and platelet factor 4 (PF4). This iatrogenic disease usually occurs after
surgeries like knee joint replacement, hip joint replacement, cardiac
surgery and extracorporeal circulation [5–8] and there is a 50% chance
to lead to thrombosis complications of microarteries, microveins and
even systemic circulation [9–11]. Therefore, there is a need to increase
research on the pathogenesis and management of HITT.
There are two types of heparin-induced thrombocytopenia (HIT).
The first type, nonimmune heparin-associated thrombocytopenia or
HIT type 1, usually occurs when patients are exposed to UFH or high
doses of heparin for the first time. The major mechanism is that heparin
binds to surface-bound PF4 of platelets to form the PF4/heparin ultra-
large complexes (ULCs), triggering platelet activation and low platelet
counts [12]. Another mechanism is that high doses of heparin cause
platelets to bind to fibrinogen, resulting in a mild form of thrombocy-
topenia [13]. When HIT type 1 occurs, the platelet counts normalize
about four days after or even without any treatments [12,14,15]. Thus,
HIT type 1 isn’t significant in clinical practice.
The second type of HIT, HITT or HIT type 2 is more severe caused by
the ULCs-targeted IgG antibody in vivo, and patients with this type will
progress to life-threatening thrombosis and thrombocytopenia, ampu-
tation or even death. HITT usually occurs 5–10 days after treatment
with heparin [16]. The platelet counts could not recover unless UFH is
discontinued [15,17]. This paper will update the reader on recent de-
velopments on the pathogenesis and clinical management of HITT and
present a potential laboratory test and some possible treatments.
2. Heparin
A common anticoagulant drug in clinical treatment [18,19] fol-
lowing its discovery in 1916 and application in 1940s, heparin is a
linear polysaccharide highly sulfated, and most heparin contains acet-
ylation groups and sulfate groups often found in organs rich in mast

Corresponding authors at: Department of Clinical Laboratory, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China (H.-L. Tao).
⁎

Department of Blood Transfusion, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China (H.-W. Zhang).
E-mail addresses: lzyxyjyx@163.com (H.-L. Tao), wangchong8210@163.com (H.-w. Zhang).
1
The first two authors contributed equally to this paper.

https://doi.org/10.1016/j.cca.2020.02.002
Received 16 August 2019; Received in revised form 30 January 2020; Accepted 3 February 2020
Available online 04 February 2020
0009-8981/ © 2020 Elsevier B.V. All rights reserved.
P. Zhou, et al.
cells (i.e., intestine, liver, and lung cells) [20,21]. Heparin has been
extracted from pigs, cows, or other animals by various chemical or
physical means, and commercial heparin has many types such as he-
parin, low molecular weight heparin (LMWH), and ultra low molecular
weight heparin (ULMWH). The resources of heparin are related to the
risk of HITT. Some studies have shown that bovine heparin may be
more likely to cause HITT than porcine heparin [22,23].
The anticoagulant effect of heparin depends on the antithrombin in
the plasma and the structure of heparin would allow the heparin mo-
lecule to act as an intermediate binding thrombin and antithrombin at
two ends respectively [24]. Once banded to heparin molecules, the
structure of antithrombin would be changed so that it moves to the
other side of the heparin molecule to conjugate with thrombin to de-
activate the thrombin [25,26]. Subsequent reactions will inactivate
more thrombin and serine proteases [27,28]. Moreover, heparin can
bind to heparin cofactor Ⅱ to further inhibit plasma coagulation
[20,29–31].
Various types of heparin can induce thrombocytopenia.
Experiments have shown that UFH is more likely to interact with the
platelets to induce thrombocytopenia for its higher molecular weight,
and it is more likely to bind to endothelial cells and macrophages than
fractionated heparin is [21,32]. This corresponds to the fact that pa-
tients treated with LMWH suffer lower incidence of HITT [33,34].
3. Pathogenesis of HITT
Recent studies have shown that the key step of HITT is B cells ac-
tivation by the ULCs. The activated B cells generate IgG1-based immune
antibody (ULCs-targeted IgG antibody) which will conjugate with ULCs
to form PF4-H-IgG complex [35,36].
PF4-H-IgG complex would mainly bind to the Fc gamma IIA re-
ceptors (FcγRIIa receptors) on the platelets to activate the platelets and
release PF4 [2,37,38]. Moreover, the complex would bind to the
FcγRIIa receptors on monocytes to produce tissue factor (TF) and in-
flammatory mediators [39,40]. The activated platelets and monocytes
are involved in promoting thrombosis. The TF and inflammatory
mediators may be associated with inflammation [39].
3.1. PF4 and formation of ULCs
PF4, a tetramer molecule with a large amount of positive charge, is
a member of CXC catabolic factor and is also known as CXCL4. It is
produced by megakaryocytes and stored in the platelet alpha-granules.
When platelets are stimulated and activated, a large quantity of PF4
will be released into the peripheral blood [41–43] to bind to the ne-
gatively charged glycosaminoglycan (GAG) chains in the platelets [44]
(Fig. 1a). Then, negatively charged heparin binds to the free positive
charge PF4, resulting in the changes of the configuration of the tetramer
PF4 [45]. As a result, more ULCs will be formed and immune reactions
will be triggered eventually [46].
Studies have demonstrated that the path of ULCs formed by PF4 and
heparin is a bell curve [44,47]. The formation of ULCs reaches its peak
when the molar ratio of heparin and PF4 is 1:1. Otherwise, the for-
mation of ULCs will be inhibited [2,44,47,48]. The schematic diagram
of the formation of ULCs is shown in Fig. 1.
3.2. Production of ULCs-targeted IgG antibody
More pathogenetic studies have shown that free form of ULCs can
bind to free form of IgM or to the IgM on the membranes of B cells
[9,49] (Fig. 2a). The IgM activates the classical pathway to produce
complement fragments C3d that binds to the complexes to form com-
plement complexes [50,51] (Fig. 2b). Furthermore, the IgM makes the
complex bind to the complement receptor (CD21), and the combination
will activate the downstream singling pathways [49]. As research in-
dicates, the combination of C3d and CD21 can increase the immune
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Clinica Chimica Acta 504 (2020) 73–80
antigenicity of C3a up to 10,000-folds [52]. In addition, the CD21 on B
cells can bind to T cells to differentiate B cells into subtypes and gen-
erate ULCs-targeted IgG antibody [51] (Fig. 2d). Recent studies have
demonstrated ULCs-targeted IgG antibody is mainly composed of type 1
IgG (IgG1) and a small amount of type 2 IgG (IgG2) [45,51]. These
antibodies are mainly produced by MZ B cells [53–55]. Additionally,
MZ B cells can also produce IgM antibodies in T cell-independent im-
mune responses [53]. The mechanism of antibody production is illu-
strated in Fig. 2.
3.3. Binding of antibodies and participation of cells
3.3.1. FcγRIIa receptor and ULCs-targeted IgG antibody
MZ B cells, which are differentiated from B cells, can release ULCs-
targeted IgG antibody into the systemic circulation. When the complex
ULCs are formed from heparin and PF4, PF4 is changed to exhibit a new
binding motif. Therefore, the free form of ULCs-targeted IgG antibody
can bind to the new motif to form PF4-H-IgG complex that can bind
with the FcγRIIa receptor to transmit the signals and promotes cell
activation.
FcγRIIa receptor (CD32a), a type I transmembrane glycoprotein of
40KDa, is composed of two extracellular Ig domains, namely a trans-
membrane domain and an intracellular domain (ITAM) [37,56,57], and
it exists not only on the membrane surface of platelets, but also on the
surface of monocytes, endothelial cells and other types of cell mem-
branes [56,58,59]. Moreover, FcγRIIa receptor is a low-affinity receptor
of IgG. When this receptor binds to the ULCs-targeted IgG antibody, the
ITAM in the cytoplasm of FcγRIIa receptor will be activated, and then
the ITAM-dependent signaling pathway, such as phosphatidylinositol-3
kinase (PI3- kinase) and spleen tyrosine kinase (syk) pathway, will be
consequentially activated to transmit signals. All these are related to
cell activation [37,60–62].
It is reported that FcγRIIa receptor is encoded by FCGR2 gene and
polymorphism of FCGR2 [37,63]. One genotype is that the arginine (R)
on the position 131 is replaced by histidine (H) in the second Ig domain,
leading to different binding affinity of FcγRIIa receptor to IgG. Studies
have shown that the FcγRIIa-131H homozygous cells are easier to bind
to IgG 1[64,65].
The receptor glycoprotein IV (GPIV) is related to FcγRIIa receptor.
GPIV doesn’t contain ITAM but contains two Ig domains outside the
membrane. When FcγRIIa receptor binds to the PF4-H-IgG complex, it
detaches GPIV on the platelet membrane by mediating metalloprotei-
nase and releases into plasma the fragment of 55 kDa which is also
known as soluble GPIV(sGPIV) [66]. GPIV is a specific receptor of
platelet, and Qiao J’s study shows that HITT patients’ plasma level of
sGPIV is higher than that of the healthy ones [37]. Since FcγRIIa re-
ceptor can activate the platelets to release GPIV into the plasma [37], it
is possible to develop plasma G PIV as a biomarker of platelets acti-
vation and use this biomarker as a potential laboratory test of HITT.
More investigations are needed to test this hypothesis.
It is indicated that ULCs-targeted IgG antibody can be cleaved by
Streptococcus pyogenes (IdeS) [145]. The fragments of ULCs-targeted
IgG antibodies still have the ability to bind to ULCs. When the ULCs-
targeted IgG antibodies are cleaved, the binding affinity of PF4-H-IgG
complexes to FcγRIIa receptors is vastly reduced [145,146]. Corre-
spondingly, the ability of platelets to obtain the first activation signal
from FcγRIIa receptor is also greatly reduced, and the risk of thrombosis
in HITT is reduced in turn. Therefore, injection of IdeS could be a po-
tential management of severe HITT [145]. There are many enzymes
sharing the similar function to cleave the IgG antibody, such as human
proteases (matrix metalloproteinases) and glutamyl endopeptidase V8
(GluV8) [146–148]. More studies are needed to demonstrate the effi-
cacy of these enzymes in treating HITT.
3.3.2. Monocyte
In the pathogenesis of HITT, monocytes, platelets and endothelial
P. Zhou, et al.
Fig. 1. (a) Heparin binds to platelet-bound PF4, exposes PF4 new antigen, and forms platelet-bound ULCs. (b) Heparin binds to free PF4, exposing PF4 new antigen,
forming free ULCs.
cells may also be activated and could interact with one other to pro-
mote HITT [44,67,68]. It has been shown that monocytes have three
functions in the pathogenesis of the disease [5,45]. Firstly, monocytes
can phagocytize and clearly activate platelets with antibody complexes
[5], reducing the risk of thrombosis and decreasing the amount of
platelets. Secondly, after the activation of monocytes, a large amount of
TF and mononuclear particles are released, which promotes the acti-
vation of other cells and is associated with inflammation. It has also
been shown that activation would promote the expression of MHC class
II molecules and CD83 in monocytes [53,57,69] (Fig. 3a). Thirdly,
monocytes provide a second activation signal to platelets. When
monocytes are activated by PF4-H-IgG complexes, the cells can release
thrombin. Monocytes with bounding thrombin on the cell surface pass a
second activation signal to the platelets through protease-activated
receptor 1(PAR-1) (Fig. 3b), causing platelets to express phosphati-
dylserine and form prethrombus platelets [55,68].
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Clinica Chimica Acta 504 (2020) 73–80
PAR-1, on the cell surface transmitting a second activation signal to
platelets, is a G protein coupling protein receptor, which is mainly
expressed on the platelet membrane. Apart from PAR-1, there is also a
PAR-4 expression on the platelet membrane. These two receptors are
related to platelet activation [70–72], of which PAR-1 is the main
binding receptor of thrombin [73].
Studies have shown that there is a thrombin cleavage site at the N-
terminus in the structure of PAR-1. Thrombin binds to the N-terminus
of PAR-1 via the hirudin sequence [74–76], and the N-terminus is
cleaved to form a new N-terminus [71].The new N-terminus is activated
by being bound with other parts of extracellular PAR-1, which acts as a
guanine nucleotide exchange factor, allowing GTP to react with other G
protein subunits in the cell [77–79]. Then a series of related signaling
generate IP3 (inositol triphosphate). Then calcium, ADP, adrenaline,
serotonin will be released into the cytosol to activate other signal
pathways in the platelet [77,80,81], inducing platelets activation.
Fig. 2. (a) Free IgM binds to ULCs to form a
complex. (b) IgM activates complement by
the classical pathway, binding complement
fragment C3d. (c) A complex that binds to B
cells transmits an activation signal to B cells.
(d) T cells bind to the complex bind to CD21
on B cells, and transmit an activation signal.
(e) B cells differentiate into MZB cells, pro-
ducing a complex antibody mainly of IgG1.
P. Zhou, et al.
PAR-1 transmits the second activation signal to the platelets in the
pathogenesis of HITT, and it can be developed as a target for the
treatment of HITT. Currently a few PAR-1 inhibitors have been ap-
proved by the FDA. For example, vorapaxar (SCH-530348), atopaxar
(E5555) [82–84], and volapasha have been approved in 2014 to pre-
vent and treat thrombosis. The mechanism of these drugs is that the
PAR-1 inhibitors can competitively bind to PAR-1 to inhibit platelet
activation [73]. Although PAR-1 inhibitors are used for treating
thrombosis, it is not clear whether such drugs can be used for treating
HITT. This will probably become a new direction in HITT research.
3.3.3. Platelet
In the pathogenesis of HITT, the platelet-membrane receptors either
bind to the PF4-H-IgG complex or the PF4-H-IgG complex on the GAG
side chain of other platelets (Fig. 3c) to obtain the first activation signal.
When the platelets receive the first activation signal, the P-selectins
[85] will be up-regulated in the platelets, contributing to the formation
of thrombus and prethrombus state.
It has been reported that the second activation signal (transmitted
by PAR-1) will enhance the effect of the first activation signal [57].
Platelet agglutination occurs when the platelets are activated. Mean-
while, the microparticles secreted by the platelets through micro-
vesicles will further the formation of thrombus. The released PF4 by
activated platelets will counteractively accelerate the development of
HITT [5,86] (Fig. 3d). Platelet activation, thrombus formation, and
clearance of PF4-H-IgG complex lead to the decrease of platelet counts.
3.3.4. Endothelial cells
PF4-H-IgG complex binds to FcγRIIa receptor on vascular en-
dothelial cells to stimulate injury to vascular endothelial cells [5]. The
combination of platelet activation, thrombin tissue factors, mono-
nuclear particles, and other factors will cause thrombocytopenia and
vascular thrombosis (Fig. 3e).
Fig. 3
4. Management of HIT
In clinical practice, the 4Ts scoring system proposed by Warkentin is
often used to assess the risk of HITT in patients [87–89].The scoring
system includes four parameters: thrombocytopenia, timing of platelet
count fall, thrombosis or other clinical sequelae, and other causes of
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Clinica Chimica Acta 504 (2020) 73–80
Fig. 3. (a) Monocyte phagocytose the anti-
body complex and be activated, and release
thrombin, and express MHC class II mole-
cules and CD83 on membrane. (b) Surface
thrombin on activated-monocytes binds to
PAR-1, transmitting the second signal of
activation. (c) FcγRIIa bind to PF4-H-IgG
complex on platelet, transmitting the first
signal of activation. (d) Activated-platelets
release a large amount of PF4, and PF4 have
positive feedback on the HIT. (e)
Endothelial cells are injured after bind to
the antibody complexes, and combine with
activated-platelets to form thrombus.
thrombocytopenia [11,89]. Each parameter has three grades 0, 1 and 2
and the total score is used to determine the risk, with the score 0 to 3
corresponding to a low risk, 4 to 5 moderate risk, and 6 to 8 high risk
[87,90,91].
The diagnosis of HITT requires stronger evidence for laboratory
tests (platelet activation assays/immunoassays). Available tests vary
considerably in their specificity and sensitivity. The platelet activation
assays including 14C-serotonin release assay (SRA), platelet aggrega-
tion assay (PAA), and flow cytometric assay (FCA) have high specificity
(> 95%) but lower sensitivity (56–100%) [48,92], while immunoassays
including enzyme linked immunosorbent (ELISA), immunoturbidi-
metric and the like, have high sensitivity (> 99%) but lower specificity
(30–70%) [48]. Given the deficiencies of current tests, multiple diag-
nosis methods should be used to improve the specificity and accuracy. It
has been indicated by some studies that the use of 14c-5-hydro-
xtryptamine release test and heparin-induced platelet activation test
(HIPA) could contribute to the diagnosis of HITT [93]. In addition,
improved scoring methods, such as Hep scoring system [88] suggest the
possibility to standardize the diagnosis and detection of HITT in the
future studies.
On the other hand, as FcγRIIa receptor will produce sGPVI and re-
lease it to the plasma when the receptor is activated in HITT patient,
there might be possibility that the plasma level of GPVI can be seen as a
biomarker of potential laboratory test of HITT and more studies are
needed to test this hypothesis.
Once HITT is confirmed, heparin should be stopped immediately.
Moreover, the heparin coated catheter should be replaced, the extra-
corporeal circulation should be discontinued, and other types of an-
ticoagulants should be used [61,93,94]. There are a few novel drugs to
treat HITT, but they have not been widely used in clinical practice.
Overall, three types of drugs, including commercial heparin, thrombin
inhibitors, and oral anticoagulants, are used for treating HITT.
4.1. Commercial heparin
4.1.1. LMWH
LMWH is an anticoagulant extracted from UFH [21,95,96] by way
of oxidation, beta elimination, and deamination. The risk of HITT with
LMWH is between 0.2% and 0.6% [97,98], therefore, LMWH has been a
replacement to UFH for several decades [21,99].
The structure of LMWH contains pentaccharide binding with
P. Zhou, et al.
thrombin and antithrombin, thus inactivating thrombin and Xa factor
and leading to anticoagulation. It was also reported that LMWH has a
low affinity with macrophages, endothelial cells, monocytes, and PF4,
therefore it contributes to a lower risk of HITT compared with UFH
[24,100,101].
The length of LMWH is between UFH and ultra-low molecular
weight heparin (ULMWH), which enables it to be injected sub-
cutaneously rather than intravenously like heparin [93] so it is a
commonly used replacement for UFH [21].
4.1.2. ULMWH
ULMWH is an analogue of heparin synthesized by chemical means
[102] and it has the unique pentaccharide structure of heparin
[21,103,104] to ensure its same function as heparin. The molecular
weight of ULMWH is usually about 2,000 Da, which is lower than those
of LMWH (5,000 Da) and UFH (13,000 Da) [102].
Pharmacological studies have demonstrated that ULMWH has a
longer half-life in the plasma compared with LMWH and UFH. In ad-
dition, the efficacy of ULMWH is usually better than those of UFH and
LMWH and the HITT risk is lower [103,105,106]. ULMWH has many
types such as sodium sulfodar-heparin, AVE5026 (semuloparin), and ro-
14 (a derivative of bemiparin) [107,108]. ULMWH can also be injected
subcutaneously and can be used to replace UFH [21].
4.2. Direct thrombin inhibitors
4.2.1. Bivalirudin
Bivalirudin, a synthetic peptide containing 20 amino acids residues,
is a thrombin inhibitor [94,109,110]. It is often used as an antic-
oagulant in cardiovascular surgery, extracorporeal membrane oxyge-
nation (ECMO) and an alternative for treating HITT [109,111]. Dif-
ferent from UFH, bivalirudin can directly bind to thrombin to prevent
coagulation without any necessary help from any components in the
plasma. Bivalirudin’s mechanism of action is that it directly inhibits the
catalytic activity site of thrombin and disturbs the binding site between
thrombin and fibrin [109,112].The half-life of bivalirudin is only
25 min, shorter than that of UFH. Most bivalirudin can be hydrolyzed
by protease, and only 20% is excreted through the kidney [113–115].
As some studies demonstrate, bivalirudin can replace UFH to treat
or prevent anticoagulant, by virtue of its less risk of HITT. However, it
could increase the incidence of cardiovascular stent thrombosis
[116,117]. In addition, the cost of bivalirudin is significantly higher
than that of UFH [118,119], so it can not replace heparin to teat HITT.
4.2.2. Agatreban
Agatreban, a synthetic arginine derivative, is a thrombin inhibitor
[94,120,121]. Pharmacological studies show that agatreban can rapidly
bind to the active center of thrombin to prevent the formation of fibrin,
which would achieve anticoagulant effect [122,123].
Studies have indicated that agatreban has low antigenicity and a
low risk of producing antibodies, that the efficacy of agatreban does not
rely on other components in the plasma [112,124] and that it can be
used in the treamtment of HITT, or as an anticoagulant in cardiac
surgery and hemodialysis [108,125,126]. Agatreban has a half-life of
40–50 min, which is mainly metabolized by the liver and finally ex-
creted with feces [127] and it is not a burden to the kidney, so it can be
used in patients with renal insufficiency [112,128].
4.3. Direct oral anticoagulants (DOACs)
Direct oral anticoagulant (DOAC) is a group of anticoagulants that
exert anticoagulant effects through intestinal absorption [129,130].
There are five types of FDA-approved DOACs: apixaban, rivaroxaban,
edoxaban, betrixaban, and dabigatran, which are direct inhibitors of
factor Xa with the exception of dabigatran as an enzyme inhibitor
[131–134]. Usually, when HITT occurs, heparin should be stopped
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Clinica Chimica Acta 504 (2020) 73–80
immediately and replacement drugs should be used. After the platelets
counts increase to the normal level, vitamin K antagonist (e.g., war-
farin) can be used temporarily as an anticoagulant [135–137]. How-
ever, this process may increase the risk of thrombosis [135].
It has been shown that DOACs can be used as the primary or sec-
ondary drugs for treating HITT [138,139]. Compared with VKA, DOACs
act on a single coagulation factor, with similar efficacy and a lower risk
of thrombosis. DOACs do not react to PF4, PF4 complex, or HIT anti-
bodies [140,141], and have the advantages of rapid onset, easy use, and
short half-life. Since DOCAs are usually eliminated through kidney, the
deficiency in renal function or hypofunction can affect the efficacy of
DOACs [142–144].
5. Conclusion
HITT is a severe side effect in patients treated with heparin, the
primary anticoagulant in medical practice, therefore the prevention,
diagnosis, and management of HITT are of great significance. In the
future, more attention should be paid to the understanding of HITT
pathogenesis to better diagnose and manage HITT. Future studies could
test the role of the plasma level of GPVI as a biomarker in the laboratory
test of HITT. Also, ULCs-targeted IgG antibody, FcγRIIa, and PAR-1
could be the three major targets for HITT management, the efficacy of
the first of which has been shown above, and more efforts should be
made on those of FcγRIIa and PAR-1 receptors. Currently, FcγRIIa and
PAR-1 receptor inhibitors like vorapaxar (sch-530348) and atopaxar
(E5555) are available, but they are used for treating other diseases
(cardiovascular death/coronary artery disease) [149,150] and it re-
mains unclear whether these receptor inhibitors and other IgG antibody
enzymes (GluV8, matrix metalloproteinases) can be used as a potential
alternative treatment of HITT. Future studies are needed to shed light
on it.
Acknowledgments
This study was supported by Medical Science Innovation Project for
Youth of Sichuan Province (Grant Number: Q14031).
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