Encephalomalacia/gliosis, deep venous thrombosis, and cancer in Arg393His antithrombin Hanoi and the potential impact of the β-amyloid precursor protein (APP) on thrombosis and cancer

Khue Vu Nguyen; Khue Vu Nguyen

doi:10.3934/Neuroscience.2022010

AIMS Neuroscience

2022, Volume 9, Issue 2: 175-215. doi: 10.3934/Neuroscience.2022010

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Review

Encephalomalacia/gliosis, deep venous thrombosis, and cancer in Arg393His antithrombin Hanoi and the potential impact of the β-amyloid precursor protein (APP) on thrombosis and cancer

Khue Vu Nguyen ^{1,2
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Former Institution Attended:
1.
Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California, San Diego, Building CTF, Room C-103, 214 Dickinson Street, San Diego, CA 92103-8467, USA
2.
Department of Pediatrics, University of California, San Diego, School of Medicine, San Diego, La Jolla, CA 92093-0830, USA

Received: 25 October 2021 Revised: 15 April 2022 Accepted: 18 April 2022 Published: 21 April 2022

A heterozygous Arg393His point mutation at the reactive site of antithrombin (AT) gene causing thrombosis in a Vietnamese patient is reported and named as Arg393His in AT-Hanoi. The present variant is characterized by a severe reduction of functionally active AT plasma concentration to 42% of normal resulting in multiple severe thrombotic events such as cerebral venous thrombosis (CVT) (encephalomalacia/gliosis), recurrent deep venous thrombosis (DVT) and the development of kidney cancer. Today the complexity of thrombophilia has grown with appreciation that multiple inherited and acquired risk factors may interact to result in a clinically thrombotic phenotype. This article focuses on the following issues: (1) pathophysiology and clinical conditions of Arg393His in AT-Hanoi; (2) “two way association” between cancer and thrombosis in which venous thromboembolism (VTE) can be both a presenting sign and a complication of cancer; (3) efficacy of anticoagulants used for the prevention of cancer-related thrombosis; (4) conditions of acquired risk factors such as cancer or genetic disorders via epigenetic modifications in gene-gene (epistasis) and/or gene-environment interactions such as in Lesch-Nyhan disease (LND), in which the β-amyloid precursor protein (APP) that may interact to predispose a patient to thrombosis and cancer. It is also necessary to study the hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme, AT, and APP using expression vectors for exploring their impact on LND, thrombosis as well as other human diseases, especially the ones related to APP such as Alzheimer's disease (AD) and cancer. For such a purpose, the construction of expression vectors for HGprt and APP, with or without the glycosyl-phosphatidylinositol (GPI) anchor, was performed as described in Ref. #148 (Nguyen, K. V., Naviaux, R. K., Nyhan, W. L. Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). Nucleosides Nucleotides Nucleic Acids 2020, 39: 905–922). In the same manner, the construction of expression vectors for AT and APP can be performed as shown in Figure 6. These expressions vectors, with or without GPI anchor, could be used as tools for (a) studying the effects of Arg393His mutation in AT; (b) studying the emerging role of Arg393His mutation in AT and cancer; (c) studying intermolecular interactions between APP and AT.

Furthermore, the construction of expression vectors as described in Ref. #148, especially the one with GPI, can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) [155],[156], for example).
Citation: Khue Vu Nguyen. Encephalomalacia/gliosis, deep venous thrombosis, and cancer in Arg393His antithrombin Hanoi and the potential impact of the β-amyloid precursor protein (APP) on thrombosis and cancer[J]. AIMS Neuroscience, 2022, 9(2): 175-215. doi: 10.3934/Neuroscience.2022010

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Abstract

A heterozygous Arg393His point mutation at the reactive site of antithrombin (AT) gene causing thrombosis in a Vietnamese patient is reported and named as Arg393His in AT-Hanoi. The present variant is characterized by a severe reduction of functionally active AT plasma concentration to 42% of normal resulting in multiple severe thrombotic events such as cerebral venous thrombosis (CVT) (encephalomalacia/gliosis), recurrent deep venous thrombosis (DVT) and the development of kidney cancer. Today the complexity of thrombophilia has grown with appreciation that multiple inherited and acquired risk factors may interact to result in a clinically thrombotic phenotype. This article focuses on the following issues: (1) pathophysiology and clinical conditions of Arg393His in AT-Hanoi; (2) “two way association” between cancer and thrombosis in which venous thromboembolism (VTE) can be both a presenting sign and a complication of cancer; (3) efficacy of anticoagulants used for the prevention of cancer-related thrombosis; (4) conditions of acquired risk factors such as cancer or genetic disorders via epigenetic modifications in gene-gene (epistasis) and/or gene-environment interactions such as in Lesch-Nyhan disease (LND), in which the β-amyloid precursor protein (APP) that may interact to predispose a patient to thrombosis and cancer. It is also necessary to study the hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme, AT, and APP using expression vectors for exploring their impact on LND, thrombosis as well as other human diseases, especially the ones related to APP such as Alzheimer's disease (AD) and cancer. For such a purpose, the construction of expression vectors for HGprt and APP, with or without the glycosyl-phosphatidylinositol (GPI) anchor, was performed as described in Ref. #148 (Nguyen, K. V., Naviaux, R. K., Nyhan, W. L. Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). Nucleosides Nucleotides Nucleic Acids 2020, 39: 905–922). In the same manner, the construction of expression vectors for AT and APP can be performed as shown in Figure 6. These expressions vectors, with or without GPI anchor, could be used as tools for (a) studying the effects of Arg393His mutation in AT; (b) studying the emerging role of Arg393His mutation in AT and cancer; (c) studying intermolecular interactions between APP and AT.

Furthermore, the construction of expression vectors as described in Ref. #148, especially the one with GPI, can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) [155],[156], for example).

Abbreviations

Aβ

β-amyloid peptide

ACE2

angiotensin-converting enzyme 2

ACT

activated clotting time

Alzheimer's disease

APC

activated protein C

aPL

antiphospholipid

APLP1

β-amyloid precursor-like protein 1

APLP2

β-amyloid precursor-like protein 2

APP

β-amyloid precursor protein

APP-mRNA

β-amyloid precursor protein messenger RNA

APPsα

soluble APP fragment released from APP following the cleavage by α-secretase

aPTT or APTT

activated partial thromboplastin time

alternative splicing

ASCO

American society of clinical oncology

anthithrombin

AT I

antithrombin I

AT II

antithrombin II

AT III

antithrombin III

AT IV

antithrombin IV

ATP

adenosine-5′-triphosphate

CAPS

catastrophic antiphospholipid syndrome

cdk2

cyclin-dependent kinase 2

COVID-19

coronavirus disease 2019

CNS

central nervous system

computed tomography

CTA

computed tomography angiography

CUS

compression ultrasound

CVT

cerebral venous thrombosis

DVT

deep venous thrombosis

EGFR-R776H

epidermal growth factor receptor-Arg776His

FFP

fresh frozen plasma

GPI

glycosyl-phosphatidylinositol

GTP

guanosine-5′-triphosphate

HBS

heparin binding site

HDM2

human homologue of the murine double minute 2 protein

HGprt

hypoxanthine-guanine phosphoribosyltransferase

HIT

heparin-induced thrombocytopenia

HIV

human immunodeficiency virus

HND

HGprt-related neurological dysfunction

HPRT1

hypoxanthine phosphoribosyltransferase 1

HPRT1-mRNA

hypoxanthine phosphoryltransferase 1 messenger RNA

HRH

HGprt-related hyperuricemia

INDELS

deletion followed by an insertion

INR

international normalized ratio

KPI

Kunitz protease inhibitor

LMWH

low-molecular-weight heparin

LND

Lesch-Nyhan disease

LNV

Lesch-Nyhan variant

MIM

Mendelian inheritance in man

mRNA

messenger RNA

NET

neutrophil extracellular trap

NOAC

non-vitamin K antagonist oral anticoagulant

NSAID

nonsteroidal anti-inflammatory drug

P21/WAF1

also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting; protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable; of inhibiting all cyclin/CDK complexes, and thus function as a regulator; of cell cycle progression at G1 and S phase

PCR

polymerase chain reaction

pharmacodynamics

pulmonary embolism

pHi

pH intracellular

pharmacokinetics

PN-2

protease nexin-2

prothrombin time

PTT

partial thromboplastin time

reactive site

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

siRNA

small interfering RNA

TAD

trans-activation domain

tissue factor

TFPI

tissue factor pathway inhibitor

TK1

thymidine kinase 1

TP53

tumor suppressor protein 53

UFH

unfractionated heparin

VKA

vitamin K antagonist

VTE

venous thromboembolism

WARF

Wisconsin alumni research foundation

WNV

West Nile virus

Conflict of interest

The authors declare no conflict of interest.

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