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TEST FOR THE DIAGNOSIS OF SYMPTOMS OF HYPOXIA/HYPOPERFUSION, HYPERCOAGULABILITY AND MICROCLOTS (HHM) - HHM TEST.

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Abstract

TEST FOR THE DIAGNOSIS OF HYPOPERFUSION, HYPERCOAGULABILITY AND MICROCLOTS (HHM) SYMPTOMS - HHM TEST. This Test is useful for patients with Post-Acute COVID Syndrome (PACS) or Long COVID, Post-Vaccine COVID Syndrome (PVACS), ME/CFS (Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome), Fibromyalgia (FM), Multiple Chemical Sensitivity (MCS), Electrohypersensitivity (EHS), MCTD, Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS) or Spondyloarthritis, Sjögren's Syndrome (SS), Antiphospholipid Syndrome (APS), Lupus (SLE), Myositis, Scleroderma, Ehlers-Danlos Syndrome (EDS), POTS, Restless Legs Syndrome (RLS), Cramp-Fasciculation Syndrome, Pediatric Acute Onset Neuropsychiatric Syndrome (PANS), Stiff Person Syndrome (SPS), Small Fiber Neuropathy (SFN), FDN, Adrenal Insufficiency, Adrenal Fatigue, Thyroid Disorders, Diabetes, EBV, HHV-6, CMV, Lyme, Bartonella, Mycoplasma, Toxoplasma, Babesia, Rickettsiae, Dysbiosis, IBD, Vitamin D Deficiency, B Complex Vitamin Deficiency, Cancer and others diseases that present chronic fatigue and/or pain. It is also recommended in apparently healthy people, as they may have these symptoms and have not taken them into account. With this test, the patient himself, his relatives or treating doctors, can quickly identify these symptoms at home at no cost. If you score 10 or more points on the HHM Test, a clinical diagnosis of Hypoperfusion, Hypercoagulability and Microclots Syndrome (HHMS) would be made, which is due to chronic endothelitis, and the score of this Test is correlated with the amount of Microclots and the level of Viral and/or Microbial Load. We have stated that in PACS or Long COVID, PVACS, CFS/ME, FM, Rheumatoid Arthritis (RA), SLE, SS, Myositis, Scleroderma, Adrenal Insufficiency, Adrenal Fatigue, Diabetes, Thyroid Disorders, EBV infection, HHV-6, Chronic Lyme, IBD, POTS and other diseases that present chronic fatigue and/or pain. and other diseases with chronic fatigue and/or pain, different Subgroups of patients are included, grouped according to their pathophysiology and causes that originate the symptoms, being the main ones, to which most of the patients belong, the Subgroups associated with hypoperfusion and hypercoagulability due to chronic endotheliitis, in which there is hypoperfusion towards the tissues due to a persistent inflammation of the cells of the vascular walls accompanied by the presence of clots with a high content of fibrin amyloid, due to fulfill a function similar to Biofilms, we have proposed that they be called BioClots [1 to 7]. The main cause of this chronic endotheliitis is persistent intracellular infections [3 to 9]. In addition, as part of the evaluations to be carried out on patients with CFS/ME, FM, PACS, RA, SLE, SS and other chronic diseases with fatigue or pain, the Therapeutic Test to assist the diagnosis of Persistent Microclots and Hypoperfusion should be applied, which is described in the attached sheet.
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TEST FOR THE DIAGNOSIS OF SYMPTOMS OF HYPOXIA/HYPOPERFUSION,
HYPERCOAGULABILITY AND MICROCLOTS (HHM) HHM TEST v1.5
Aguirre-Chang, Gustavo and Trujillo F., Aurora. ResearchGate. August 11, 2022.
This Test is useful for patients with Long COVID or Post-Acute COVID Syndrome (PACS), Post-
Vaccine COVID Syndrome (PVACS), MIS-C, ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue
Syndrome), Fibromyalgia (FM), Hypersensitivity (HS) or Allergies, Multiple Chemical Sensitivity
(MCS), EHS, MCTD, Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS) or Spondyloarthritis,
Sjögren's Syndrome (SS), Antiphospholipid Syndrome (APS), Lupus (SLE), Myositis, Scleroderma,
Autoimmune diseases, POTS, Ehlers-Danlos Syndrome (EDS), Restless Legs Syndrome (RLS),
Cramp-Fasciculation Syndrome, BFS (Benigne Fasciculation Syndrome), Pediatric Acute Onset
Neuropsychiatric Syndrome (PANS), Stiff Person Syndrome (SPS), Small Fiber Neuropathy (SFN),
FDN, Adrenal Insufficiency or Fatigue, Thyroid Disorders, Diabetes, EBV, HHV-6, CMV, Lyme,
Bartonella, Mycoplasma, Toxoplasma, Babesia, Rickettsiae, Dysbiosis, IBD, Vitamin D Deficiency,
B Complex Vitamin Deficiency, Cancer and others diseases that present chronic fatigue and/or pain.
It is also recommended in apparently healthy people, as they may have these symptoms and have
not taken them into account. With this test, the patient himself, his relatives or treating doctors, can
quickly identify these symptoms at home at no cost. If you score 10 or more points on the HHM Test,
a clinical diagnosis of Hypoxia/Hypoperfusion, Hypercoagulability and Microclots Syndrome (HHMS)
would be made, which is due to chronic endothelitis, and the score of this Test is correlated with the
amount of Microclots and the level of Viral and/or Microbial Load.
Name:………….….…………….………… Age:…… Sex: M( ), F( ) Weight:….… Date:……...….
1. SIGNS OF HYPOXIA/HYPOPERFUSION AND HYPERCOAGULABILITY IN HANDS AND
FEET. In the last 6 months, have you had any of the following signs in your hands or feet:
Bluish or grayish color under the nails (due to cyanosis) or the skin of the hands and feet,
or mottled skin with bluish areas and pale or whitish areas, or Raynaud's phenomenon.
Dark red or violaceous skin lesions located in the distant areas of the fingers, or “COVID
toes”, which are similar to Erythema pernio, Perniosis or Chilblains.
Please mark with X only one of the following 3 alternatives, as appropriate:
No, in the last 6 months I have not had any of the 2 signs mentioned……….……….( ) -1
Yes, I have had one or both of the signs mentioned but currently they are only mild..( ) 1
Yes, every or almost every day I have one or both of the signs mentioned…….….( ) 3
2. SYMPTOMS ASSOCIATED WITH STAGNATION OR STASIS OF BLOOD FLOW, WHICH
INCREASES WITH IMMOBILITY THAT OCCURS DURING HOURS OF SLEEP.
In the last 3 months, have you had any of the following symptoms, especially when you
wake up in the morning after sleeping:
Stiffness, lack of flexibility, numbness, rigidity or hardening of the fingers of the hands,
with greater pain or discomfort when moving them in the first minutes after waking up,
and which usually increases with the cold and longer rest/immobility periods.
Numbness, paresthesia, tingling or feeling that one or both hands "have fallen asleep"
with a sensation of small punctures or stabs as if made with pins or needles.
Pain or discomfort in the fingers when making a fist with the hands in the morning.
Pleased mark with X only one of the following 3 alternatives, as appropriate:
No, in the last 3 months I have not had any of the 3 symptoms mentioned….... ( ) -2
Yes, I frequently have one of the 3 symptoms, but it is not every day…………..... ( ) 1
Yes, Yes, every day I have one or more of the 3 symptoms mentioned…………….. ( ) 2
2
3. OTHER SYMPTOMS ASSOCIATED WITH HHM, ENDOTHELIITIS AND BLOOD STASIS.
SINCE BECOMING ILL, I SUFFERS FROM (please mark an X as appropriate) :
Dilated/bulging/protruding veins in arms or legs (not due to previous varicose veins)... ( ) 4
Dilated vein in a finger, with discomfort or pain when touched, pressed or hit……..….. ( ) 3
Livedo reticularis or racemosa: dilation of small blood vessels in the form of a network
that resembles marble or in the form of clusters, they aresmore visible on both thighs.... ( ) 6
Mottled, purple or bluish color of the skin that covers the knee and extends to the thigh.. ( ) 4
Bulging nails with disappearance of the angle formed by the root of the nail with the finger.( ) 3
Excessive cold in the hands and feet, accompanied by paleness or whitish areas….…... ( ) 3
Slow capillary refill: pressed for 15 sec. and the time it takes for the pink color to return should
not be > 2 sec. on the pad of the middle finger nor > 4 sec. at the level of the kneecap... ( ) 4
Sensation of heaviness in the legs and feet, and swelling in the calves………….………..( ) 1
Pain or discomfort in the legs when walking , with greater intensity after resting……….... ( ) 3
The discomfort or pain in the legs improves with the use of compression stockings…..... ( ) 3
Restless legs and/or involuntary movements when resting, more at night........................ ( ) 2
Fasciculations, myoclonus, twitches, spasms, contractions, jerks, tremor; involuntary…. ( ) 2
Difficulty concentrating, understanding what you read, forgetfulness, which i did not have. ( ) 1
Dizziness and/or headache when standing up, walking or exertion in < 65 years old…... ( ) 1
Tinnitus, Ringing and/or sensation of blocked ears or greater sensitivity to noises……... ( ) 1
Blurry or double vision, trouble focusing, or eye pain or photophobia………………….. ( ) 1
Dry lips or throat upon awakening and increased thirst (which I did not have before)…… ( ) 2
Non-Restorative Sleep: wakes up with discomfort, tiredness, stiffness and/or pain…...... ( ) 1
In women of childbearing age: significant decrease in menstruation, or its absence……. ( ) 2
Varicose veins or dilation of the veins at the base of the tongue: In under 50 years old. ( ) 6
(which I didn't have before getting sick) In people between 50 and 65 years old... ( ) 3
Heart Rate (HR) of more than 120 bpm, 3 or more times a week, without effort/exertion.. ( ) 2
In Long COVID or Post-Vaccine Syndrome: has shortness of breath and his Saturation Oxigen:
is between 92 to 94% and/or its Perfusion Index (PI) is less than 1.3 (in adults)... ( ) 3
(in this question mark only one of the 2 alternatives) your Sat O2 is less than 92… ( ) 5
4. CLINICAL AND PATHOLOGICAL BACKGROUND:
Most of the symptoms that have been reported improve with the use of Anticoagulants,
Fibrinolytics (SP, NT, LK, Bromelain, others), Antiplatelets or with HELP Apheresis... ( ) 4
Has a disease that causes thrombosis, such as Factor V Leiden, Prothrombin mutation,
PAI-1 mutation, MTHFR, protein C or S deficiency, Hypofibrinogenemia, other…………… ( ) 2
Has had Acute COVID and Oxygen saturation dropped to less than 95%………..…...... ( ) 1
Fever, low-grade fever, chills, or night sweats for more than 3 days in the last month ....... ( ) 1
The patient has: Allergies, MCAS, histaminosis, trytasemia, or itching or burning skin…... ( ) -3
IN THE LAST 12 MONTHS:
Have you ever had (without being in the Acute stage of COVID):
Wound, ulcer or area on the fingers, with a black background, due to ischemia or gangrene ( ) 4
Temporary loss of vision in one eye, for seconds or minutes (Amaurosis fugax)…….….... ( ) 5
Trigger finger on awakening: finger gets stuck or locks in a bent or flexed position.….... ( ) 4
Has had any test results that indicate the presence of HHM (you can mark several answers) :
SPECT (Single Photon Emission CT), PET Scan, V/Q Scan, DLCO, Dual-energy CT (DECT),
Hyperpolarized gases MRI, Optical Coherence Tomography (OCT), LDI (Laser Doppler), Vascular
Doopler, PAT (Peripheral Arterial Tonometry), Correlated Diffusion Imaging (CDI), others...( ) 2
Blood Viscosity, Antiphospholipid antibodies, Fibrinogen, Plasminogen Activator Inhibitor 1 (PAI-1),
α-2AP, von Willebrand Factor (VWF), ADAMTS13, VEGF: Vascular Endothelial Growth Factor... ( ) 2
Venous Blood Gas with Venous O2 Saturation, Lactate, Microscopy or Peripheral Blood Smear,
Flow Cytometry, Thromboelastography (TEG), ROTEM, Near-Infrared Spectroscopy (NIRS).... ( ) 3
D-DIMER, with a result (check only 1 alternative): Above 0.9 ug/ml.............. ( ) 6
Between 0.5 and 0.9 ug….... ( ) 3
3
ADD THE POINTS OBTAINED IN THE TOTALITY HHM TEST = _____
Points
INTERPRETATION OF THE HHM TEST - CLINICAL DIAGNOSTICS
- 6 to 0
No HHM symptoms (it is necessary to investigate other causes: Histaminosis, MCAS; Low Cortisol;
Low Taurine; deficiency of iron, magnesium, Selenium, K; Hypovitaminosis, Hypothyroidism).
1 to 5
Without HHMS (investigate other causes, but it may be an oligosymptomatic case. And keep
in mind that there are many asymptomatic carriers of microclots)
6 to 9
Some HHM symptoms (requires further evaluations for HHM and for Hypersensitivity: HS,
allergies and mast cell activation and for other causes).
10 to
15
Mild to Moderate HHM Syndrome (associated with the presence of chronic endotheliitis and
Microclots).
16 to
21
Moderate HHM Syndrome (due to chronic endotheliitis, with Microclots/Bioclots and
Biofilms), with viral and/or microbial load that affects blood vessels.
22 to
27
Severe HHM Syndrome (with Microclots/Bioclots and Biofilms, with a disseminated viral
and microbial load that affects the blood vessels and with the existence of reservoirs).
28 to +
Very Severe HHMS (with Microclots/Bioclots and Biofilms, with disseminated high viral and
microbial load that affects the blood vessels and with the existence of reservoirs).
APPENDIX: INITIAL ASSESSMENTS TO BE PERFORMED ON PATIENTS WITH CHRONIC
FATIGUE AND/OR PAIN AND OTHER SYMPTOMS ASSOCIATED WITH
HYPOXIA/HYPOPERFUSION AND MICROCLOTS
We have stated that in Long COVID or PACS, PVACS, MIS-C, ME/CFS, FM, HS or Allergies,
MCS, EHS, MCTD, RA, AS, SS, APS, Lupus, Myositis, Scleroderma, Autoimmune Diseases,
POTS, Ehlers-Danlos Syndrome (EDS), Restless Legs Syndrome (RLS), Cramp-Fasciculation
Syndrome, BFS, PANS, Stiff Person Syndrome (SPS), SFN, FDN, Adrenal Insufficiency or Fatigue,
Thyroid Disorders, Diabetes, EBV, HHV-6, Lyme, Bartonella, Babesia, Dysbiosis, IBD, Vitamin D
Deficiency, Cancer, others diseases with chronic fatigue and/or pain, different Subgroups are
included according to the causes that originate the symptoms, the main ones being the Subgroups
associated with HHM, due to chronic endotheliitis, which causes the formation of microclots which
because they fulfill a function similar to Biofilms, we call them Bioclots [1-12]. In this context, the
initial evaluations to be carried out on those patients with chronic fatigue and/or pain would be:
1) Apply the Test for the Diagnosis of hypoxia/hypoperfusion, hypercoagulability and microclots
(HHM) symptoms. Which is the HHM Test described in this document.
2) Ask if they have symptoms or a history of HS, allergies, asthma, rhinitis, dermatitis,
histaminosis, HαT, MCAS and other diseases with the presence of HS or hyperreactivity.
3) Ask about the presence of recurrent or persistent rhinopharyngitis, tonsillitis or sinusitis.
4) Evaluate the presence of oral biofilm, and since what date has he not been to the dentist.
5) Ask about a history of infections, if there is a sick family member, if an infection predominates
in the place where they live. Review analyses and tests carried out.
6) Ask for a history of bleeding. Assess the risk of bleeding.
7) Apply the Therapeutic Test to help the Diagnosis of Persistent Microclots and Hypoperfusion
[6]. In summary, the Test it consists of taking 1 Antiplatelet or Anticoagulant, 1 Fibrinolytic and
Famotidine for 6 days, and on the 7th day the improvement in HHM symptoms is evaluated
and, if possible a D-Dimer and SvO2 (Venous Blood Gases) analysis should be performed.
Table 1 lists several supplements that do not require a prescription and that there is no increased
risk of taking during the 6 days of this Test. But if they are to continue taking them for more days,
the patient should be evaluated to investigate the presence of bleeding risk.
In reference number 6 is the link to the document detailing alternative medications and
supplements that can be taken to break down persistent microclots.
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Table 1
THERAPEUTIC TEST AND FIRST TREATMENT REGIME FOR
PATIENTS WITH CHRONIC FATIGUE AND/OR PAIN TO ASSIST THE
DIAGNOSIS OF PERSISTENT MICROCLOTS AND TISSUE HYPOXIA/HYPOPERFUSION
1. ACETYLSALICYLIC ACID (ASA) or LYSINE ACETYLSALICYLATE (LASA).
Alternatives that do not require a prescription: Ginger, Garlic, Taxifolin or Quercetin.
Alternatives that require a prescription: Clopidogrel, Dipyridamole, Apixaban or LMWH.
2. SERRAPEPTASE and/or NATTOKINASE and/or LYSINE (no prescription required).
Alternatives: LUMBROKINASE, Bromelain, Seaprose S, Pentoxifylline, Superpeptase.
3. FAMOTIDINE.
Alternatives that do not require a prescription: Baking Soda (Sodium Bicarbonate),
Potassium Bicarbonate, Andrews Salt or similar.
ADDITIONAL INDICATIONS:
- If the person has Hypersensitivity (HS) or allergy, they should avoid Natokinase, AAS, LASA
and others that can raise Histamine. It is recommended that you take in section 1: Quercetin
and Vitamin C, this plus 2 H1 type Antihistamines (Cetirizine or Levocetirizine and,
Diphenhydramine or Fexofenadine or Rupatadine), and Famotidine can also be included.
- Follow a diet low in Histamine and Nickel and high in Lysine and Vitamin D. Avoid coffee.
- If there is a Herx type reaction that cannot be tolerated, it is recommended: a) Discontinue the
medications in sections 1 and 2. b) Take 2 of the H1 Antihistamines mentioned, Famotidine,
Quercetin, Vitamin C and D. c) If the allergic reaction is severe, hydrocortisone or prednisone
would be indicated. d) Once the reaction is over, re-evaluate the case. Drugs against Microbial
Load and/or High dose Ozone, HBOT, Help Apheresis or EBOO-F may be indicated.
The HHM Test is also useful for patients who have side effects from the vaccine characterized by
the presence of persistent symptoms after the COVID vaccine and that we call it Post-Vaccine
COVID Syndrome or PVACS [13,14,15].
With the application of the HHM Test described in this document, the Clinical Diagnosis of the
presence of HHM Symptoms and of HHMS is made. With the application of the Therapeutic Test
of numeral 6, the Diagnosis is made by therapeutic response of Persistent Microclots and tissue
Hypoxia and Hypoperfusion [6]. And if the D-dimer analysis is performed, the Laboratory Diagnosis
of persistent clots and hypercoagulability would be obtained.
Other tests that we recommend performing are: Venous Blood Gases (VBG, this analysis includes
venous oxygen saturation: SvO2), Cortisol at 8 am, Complete Blood Count (CBC) with peripheral
Blood Smear, Blood Viscosity, Lactate, Fibrinogen and Antiphospholipid Antibodies.
If the patient scores 10 or more points in this Test and/or if his symptoms improve after taking the
3 supplements or medications included in the Therapeutic Test to break down Microclots [6], we
recommend following the Therapeutic Plan for ME/CFS, FM, RA, SS, Lupus, Myositis, Autoimmune
Diseases (AD) and others diseases with chronic fatigue and/or or pain [16]. The alternatives of
medications, supplements and procedures are described in the document on the Therapeutic Plan
for PACS or Long COVID and for Chronic COVID [17].
PUBLISHED STUDIES SUPPORTING THE HHM TEST.
There are several studies in which we support this test, most of which have been reviewed by
peers. These studies show the presence of a decrease in blood flow, hypoxia, hypoperfusion,
endothelial dysfunction, hypercoagulability, thrombophilia or alteration in hematological indices in
the aforementioned diseases and syndromes with fatigue and/or chronic pain. These alterations
do not occur in all cases, but they do occur in most.
In ME/CFS these alterations occur in 60 to 80% of cases [1 to 8].
In the case of FM, there are also several publications that associate it with a prothrombotic state
[1,18,19], with endothelial dysfunction, blood vessel stiffness [20,21,22], and alterations in some
5
hematological indices, such as the Mean Platelet Volume [23]. And it has been identified that
patients with FM more frequently present a vitamin D deficiency [8,24], which by itself is associated
with an increased risk of thrombosis [25,26].
In Rheumatoid Arthritis (RA) multiple studies show a higher frequency of thrombotic events,
hypercoagulability, endothelial dysfunction and platelet hyperactivity [27 to 31].
Antiphospholipid Syndrome (APS) deserves special attention, as it is present in several of the
diseases that we have mentioned and in 3 to 5% of the population [32].
And in addition, the presence of hereditary diseases must be taken into account, highlighting Factor
V Leiden, present in around 5% of the Caucasian population [32].
More references can be found in the Therapeutic Plan document for ME/CFS, FM, RA, SS, Lupus,
Myositis, Autoimmune Diseases and others diseases with chronic fatigue and/or pain [16] and in
other documents that we have made available free of charge to the entire population, including the
scientific community, patients and their families [33].
If this document was helpful to you, please donate to continue our scientific activities:
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REFERENCES.
1) Berg D, Berg LH, et al. Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid
antibody syndrome: an explanatory model and approach to laboratory diagnosis. Blood Coagul Fibrinolysis.
1999 Oct;10(7):435-8. PMID: 10695770. DOI: https://doi.org/10.1097/00001721-199910000-00006
2) Brewer J.H. and Berg D. Hypercoagulable state associated with active human herpesvirus-6 (HHV-6)
viremia in patients with Chronic Fatigue Syndrome. J. Chron. Fatigue Syndr. 8, 111-116. 2011.
DOI: https://doi.org/10.1300/J092v08n03_10
3) Nunes JM, Kruger A, et al. The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Pharmaceuticals. 2022; 15(8):931.
DOI: https://doi.org/10.3390/ph15080931
4) Scherbakov N, Szklarski M, Hartwig J, Sotzny F, Lorenz S, Meyer A, Grabowski P, Doehner W,
Scheibenbogen C. Peripheral endothelial dysfunction in Myalgic Encephalomyelitis/ Chronic Fatigue
Syndrome. ESC Heart Fail. 2020 Jun;7(3):1064-1071. Epub 2020 Mar 10. PMID: 32154656; PMCID:
PMC7261521. DOI: https://doi.org/10.1002/ehf2.12633
5) van Campen CLMC, Rowe PC, Visser FC. Cerebral blood flow remains reduced after tilt testing in myalgic
Encephalomyelitis/Chronic Fatigue Syndrome patients. Clin Neurophysiol Pract. 2021 Sep 23;6:245-255.
PMID: 34667909. DOI: https://doi.org/10.1016/j.cnp.2021.09.001
6) Aguirre-Chang, Gustavo and Trujillo F., Aurora. ME/CFS, FM, RA, SS, POTS, PVACS, Lyme: Therapeutic
Test and First Treatment Regime with Fibrinolytics and Famotidine for patients with Chronic Fatigue and/or
Pain to assist the diagnosis of Persistent Microclots and Hypoperfusion. October 2021.
https://www.researchgate.net/publication/355757939
7) Aguirre-Chang G. and Trujillo Aurora. The SARS CoV-2 Virus and other microorganisms use clots as a
refuge to protect and persist. ResearchGate. July, 2021.
https://www.researchgate.net/publication/353523795
8) Aguirre-Chang G. and Trujillo A. Non-Restorative Sleep or waking up tired, with Malaise or Pain in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Long COVID or PACS, Chronic Lyme,
Fibromyalgia, Rheumatoid Arthritis and Ankylosing Spondylitis or Spondyloarthritis is associated with
Immobility during sleep causing blood stagnation or stasis and tissue hypoperfusion and hypoxia.
ResearchGate. July, 2022.
https://www.researchgate.net/publication/362293402
9) Aguirre-Chang, Gustavo and Trujillo F., Aurora. Chronic Fatigue Syndrome and Brain Fog are associated
with Hypoxia, Hypoperfusion and persistent Microclots or Bioclots. ResearchGate. September, 2021.
https://www.researchgate.net/publication/354969152
10) Aguirre-Chang G. and Trujillo Aurora. COVID-19: The appearance of clots and the decrease or absence of
menstruation are associated with the presence of microclots in the blood. ResearchGate. August, 2021.
https://www.researchgate.net/publication/353909766
11) Aguirre-Chang, Gustavo. The use of platelets and clots for persistent intracellular infections including SARS
CoV-2 infection and neoplasms. ResearchGate. December 2020.
https://www.researchgate.net/publication/348080280
12) Aguirre-Chang G. and Trujillo Aurora. Chronic COVID (PACS or Long COVID) it is an infectious disease
which mainly affect the blood vessels. ResearchGate. November 2021.
https://www.researchgate.net/publication/355949081
13) Said KB, Al-Otaibi A, Aljaloud L, Al-Anazi B, Alsolami A, Alreshidi FS, On Behalf Of The Ha'il Com Research
Unit Group. The Frequency and Patterns of Post-COVID-19 Vaccination Syndrome Reveal Initially Mild and
Potentially Immunocytopenic Signs in Primarily Young Saudi Women. Vaccines (Basel). 2022 Jun
24;10(7):1015. PMID: 35891179; PMCID: PMC9323608.
6
DOI: https://doi.org/10.3390/vaccines10071015
14) AlMutairi LT, Alalayet WY, Ata SI, Alenzi KA, AlRuthia Y. Self-Reported COVID-19 Vaccines' Side Effects
among Patients Treated with Biological Therapies in Saudi Arabia: A Multicenter Cross-Sectional Study.
Vaccines (Basel). 2022 Jun 20;10(6):977. PMID: 35746586; PMCID: PMC9231333.
DOI: https://doi.org/10.3390/vaccines10060977
15) Aguirre-Chang, Gustavo and Trujillo F, Aurora. Post-Vaccine COVID Syndrome (PVACS) is a adverse
event or side effect of vaccines that causes the Enhancement/Potentiation or Activation of Persistent or
Latent Infections by SARS CoV-2, Herpesvirus and/or other microorganisms. ResearchGate. March 2022.
https://www.researchgate.net/publication/359427025
16) Aguirre-Chang, Gustavo and Trujillo F, Aurora. Therapeutic Plan for patients with Chronic Fatigue
Syndrome/ Myalgic Encephalomyelitis, Fibromyalgia, Rheumatoid Arthritis, Sjögren Syndrome, Lupus,
Myositis, Autoimmune Diseases and others diseases with chronic fatigue and/or pain. ResearchGate. July
2022. https://www.researchgate.net/publication/362405138
17) Aguirre-Chang, Gustavo and Trujillo F., Aurora. Sub-Acute and Chronic COVID: Therapeutic Plan for
patients with Post Acute COVID Syndrome (PACS) or Long COVID. ResearchGate. April 2021.
https://www.researchgate.net/publication/351274265
18) Molina F, Del Moral ML, La Rubia M, Blanco S, Carmona R, Rus A. Are patients with Fibromyalgia in a
Prothrombotic State? Biol Res Nurs. 2019 Mar;21(2):224-230. Epub 2019 Jan 17. PMID: 30654628.
DOI: https://doi.org/10.1177/1099800418824716
19) Karlibel İA, Demirci H, Kasapoğlu M, Türe DA, & Altan, L. The relationship between vitamin 25 (OH) D level
and hematological parameters in newly diagnosed women with fibromyalgia syndrome. Journal of Surgery
and Medicine, 5(1), 61-65. 2021. DOI: https://doi.org/10.28982/josam.746743
20) Mertoglu C, Gunay M, Yerligok O. Could Endocan, a Marker of Inflammation and Endothelial Dysfunction,
be a New Diagnostic Marker for Fibromyalgia? Clin Lab. 2018 Mar 1;64(3):405-410. PMID: 29739097.
DOI: https://doi.org/10.7754/Clin.Lab.2017.171024
21) Ghoneim FM, Abo-Elkhair SM, Elsamanoudy AZ, Shabaan DA. Evaluation of Endothelial Dysfunction and
Autophagy in Fibromyalgia-Related Vascular and Cerebral Cortical Changes and the Ameliorative Effect of
Fisetin. Cells. 2021 Dec 24;11(1):48. PMID: 35011610; PMCID: PMC8750434.
DOI: https://doi.org/10.3390/cells11010048
22) Chen WT, Yu CH, Sun CW. Altered near-infrared spectroscopy response to breath-holding in patients with
fibromyalgia. J Biophotonics. 2019 Jan;12(1):e201800142. Epub 2018 Sep 3. PMID: 29952139.
DOI: https://doi.org/10.1002/jbio.201800142
23) Rajaram Jayakrishnan AK, Easwar SV, Thattil J, Vignesh M, Rath S, et al. Studying the Relation Between
Fibromyalgia Severity and Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Mean
Platelet Volume. Cureus. 2022 May 9;14(5):e24847. PMID: 35702479; PMCID: PMC9177217.
DOI: https://doi.org/10.7759/cureus.24847
24) Lombardo M, Feraco A, Ottaviani M, Rizzo G, Camajani E, Caprio M, Armani A. The Efficacy of Vitamin D
Supplementation in the Treatment of Fibromyalgia Syndrome and Chronic Musculoskeletal Pain. Nutrients.
2022 Jul 22;14(15):3010. PMID: 35893864; PMCID: PMC9330000.
DOI: https://doi.org/10.3390/nu14153010
25) Farooqui MW, Chavis Y, Ghouse N, Bank J, Chan M, Bhan A, Lancaster N, Ghouse M. Role of Vitamin D
Levels in Venous Thrombosis. Blood, vol. 138, (Supl 1): p. 4255. 2021.
DOI: https://doi.org/10.1182/blood-2021-148146
26) Tao J, Lou F, Liu Y. The Role of Vitamin D in the Relationship Between Gender and Deep Vein Thrombosis
Among Stroke Patients. Front Nutr. 2021 Dec 2;8:755883. PMID: 34926545; PMCID: PMC8674815.
DOI: https://doi.org/10.3389/fnut.2021.755883
27) Fukui S, Gutch S, Fukui S, Chu L, Wagner DD. Anti-inflammatory protective effect of ADAMTS-13 in murine
arthritis models. J Thromb Haemost. 2022 Jul 25. Epub ahead of print. PMID: 35875933.
DOI: https://doi.org/10.1111/jth.15828
28) Stojanovic A, Veselinovic M, Zong Y, Jakovljevic V, Pruner I, Antovic A. Increased expression of
Extracellular Vesicles is associated with the procoagulant state in patients with established Rheumatoid
Arthritis. Front Immunol. 2021 Jul 29;12:718845. PMID: 34394126; PMCID: PMC8358654.
DOI: https://doi.org/10.3389/fimmu.2021.718845
29) Hu LJ, Ji B, Fan HX. Venous thromboembolism risk in Rheumatoid Arthritis patients: a systematic review
and updated meta-analysis. Eur Rev Med Pharmacol Sci. 2021 Nov;25(22):7005-7013. PMID: 34859863.
DOI: https://doi.org/10.26355/eurrev_202111_27249
30) Xue L, Tao L, Li X, Wang Y, Wang B, et al. Plasma fibrinogen, D-dimer, and fibrin degradation product as
biomarkers of Rheumatoid Arthritis. Sci Rep. 2021 Aug 19;11(1):16903. PMID: 34413382; PMCID:
PMC8377052. DOI: https://doi.org/10.1038/s41598-021-96349-w
31) Molander V, Bower H, Frisell T, Askling J. Risk of venous thromboembolism in Rheumatoid Arthritis, and
its association with disease activity: a nationwide cohort study from Sweden. Ann Rheum Dis. 2021
Feb;80(2):169-175. Epub 2020 Oct 8. PMID: 33032998.
DOI: https://doi.org/10.1136/annrheumdis-2020-218419
32) Senst B, Tadi P, Basit H, Jan A. Hypercoagulability. 2022 Sep 26. In: StatPearls [Internet]. Treasure Island
(FL): StatPearls Publishing; 2022 Jan-. PMID: 30855839.
https://www.ncbi.nlm.nih.gov/books/NBK538251/
33) Other publications are available at: https://www.researchgate.net/profile/Gustavo-Aguirre-Chang
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Introduction: Accumulating evidence had demonstrated that females had a higher risk of deep vein thrombosis (DVT) than males, but the mechanism was still unknown. Vitamin D was found to play an essential role in DVT, and gender may influence the serum vitamin D levels. This study aimed to explore whether vitamin D played a role in the gender difference in DVT. Materials and Methods: A total of 444 patients with acute stroke were recruited, which were divided into the DVT group (n = 222) and the non-DVT group (n = 222). Serum vitamin D levels were measured after admission and were split into three categories, including deficiency (<50 nmol/L), insufficiency (52.5–72.5 nmol/L), and sufficiency (more than 75 nmol/L). Hierarchical regression analysis was adopted to analyze the relationship between gender and DVT, controlling the confounding factors. Results: Females showed a higher proportion of DVT than males (60.7 vs. 42.5%, p < 0.001), and lower serum vitamin D levels than males (53.44 ± 16.45 vs. 69.43 ± 23.14, p < 0.001). Moreover, serum vitamin D levels were lower in the DVT group than in the non-DVT group (59.44 ± 19.61 vs. 66.24 ± 23.86, p < 0.001). Besides, the DVT group showed a lower proportion of vitamin D sufficiency than the non-DVT group (21.2 vs. 32.9%, p < 0.05). Hierarchical regression analysis showed that females had 2.083-fold (p < 0.001, unadjusted model) and 1.413-fold (p = 0.155, adjusted model) risk to develop DVT. In addition, the sufficiency status of vitamin D showed an independent protective effect on DVT (unadjusted model OR, 0.504, p = 0.004; adjusted model OR, 0.686, p = 0.011). Conclusion: Females had a higher risk of DVT than males, and vitamin D may play an essential role in this relationship. Further studies are needed to explore whether vitamin D supplementation could reduce DVT risk in stroke patients, especially females.