The Unexpected Clot: Unilateral Brachial Artery Occlusion Unmasking Antithrombin III Deficiency; Case Report and Therapeutic Considerations

The Unexpected Clot: Unilateral Brachial Artery Occlusion Unmasking Antithrombin III Deficiency; Case Report and Therapeutic Considerations | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report The Unexpected Clot: Unilateral Brachial Artery Occlusion Unmasking Antithrombin III Deficiency; Case Report and Therapeutic Considerations Mohammad Ameen Ishqair, Aliaa Khalili, Anas Ameen Ishqair, Amal A. Abu Jheasha, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7891830/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jan, 2026 Read the published version in Thrombosis Journal → Version 1 posted 11 You are reading this latest preprint version Abstract Antithrombin III deficiency is an autosomal dominant thrombophilia that most commonly predisposes carriers to venous thromboembolism but can rarely cause arterial thrombosis, particularly when quantitative or qualitative defects are severe. A 46-year-old woman on combined oral contraceptive therapy presented with recurrent acute upper-extremity arterial occlusions. Workup revealed hereditary antithrombin III deficiency. She underwent emergency embolectomy with initial issues of anticoagulation and was then converted to a direct oral anticoagulant with clinical stabilization Peri-procedural heparin responsiveness was suboptimal due to low antithrombin activity and was managed with surgical embolectomy followed by later anticoagulation with a direct oral factor Xa inhibitor. Direct oral anticoagulants have been suggested as alternative therapies in antithrombin-refractory patients, and replacement with antithrombin concentrate can reversibly correct heparin responsiveness when employed judiciously. The patient was counseled to stop estrogen-containing medications, manage modifiable risk factors, and have vascular longitudinal surveillance. It is a new presentation of arterial thrombosis with antithrombin III deficiency caused by exogenous estrogen exposure that was effectively treated with embolectomy and prolonged direct oral anticoagulation. Identification of this phenotype guides the secondary prevention and family screening in hereditary thrombophilia. Antithrombin III deficiency Arterial thrombosis Upper-extremity arterial occlusion Estrogen-induced thrombosis Embolectomy Antithrombin concentrate therapy Factor Xa inhibitors Figures Figure 1 Introduction Antithrombin deficiency is one of the most serious hereditary thrombophilias is antithrombin deficiency. Antithrombin deficiency is a rare condition; however, based on what is known, it is underdiagnosed because of the shortcomings of existing diagnostic algorithms ( 1 ) . Antithrombin deficiency is routinely diagnosed using functional tests. Not many specialized labs also do genetic analysis, despite the fact that the process is a simple, quick, and inexpensive procedure that produces pertinent data with clinical utility these days ( 2 ) . Factors IIa, IXa, and Xa are among the enzymatic targets of antithrombin III (ATIII), a non-vitamin K-dependent protease that prevents coagulation by blocking thrombin's enzymatic activity. Antithrombin's half-life is three days, and its normal plasma concentration is 0.12 mg/ml, or 2.3 mM. Nonetheless, the majority of labs report anticoagulant activity or antithrombin antigen levels as a proportion of a reference plasma. While newborns and infants have lower amounts than adults, their levels reach adult ranges by six months of age. In the general population, plasma antithrombin levels typically vary between 80 and 120 percent ( 3 ) . Antithrombin III deficiency may be acquired and may be congenital, the most likely predispose the patient to venous thromboembolism ( 4 ), despite the limited number of patients who have the last mentioned. ( 5 ) An individual with congenital antithrombin III deficiency, an autosomal dominant condition, receives one copy of the antithrombin III-encoding SERPINC1 (also known as AT3) gene on chromosome 1q25.1. Nowadays, it is not uncommon to read about people who have SERPINC1 mutations and experience thrombotic events in the arterial area. Orlando et al. discovered that the p. Arg79 and p. Pro73Leu A high incidence of arterial thrombosis was linked to his mutations ( 6 ) . Antithrombin deficiency (ATD) is a clinically heterogeneous disorder due to the large number of possible genetic and posttranslational modifications (PTMs) influencing the expression, secretion, functionality, and stability of antithrombin ( 7 ) . Case Presentation A 47-year-old female with no significant past medical history and a past surgical history of open Gustilo type I distal tibia and fibula fracture treated with emergency stabilization and fixation 3 years ago. was admitted to the vascular ward with an acute onset of severe pain, coldness, and loss of movement in the left hand of 24 days' duration. On examination, she was conscious and hemodynamically stable. Local examination revealed mild coldness of the left hand with absent brachial, radial, and ulnar pulses; delayed capillary refill, while the left axillary pulse was palpable. The hand was immobile at presentation. Initial investigations include a Doppler ultrasound demonstrated total occlusion of the mid-brachial artery with thrombus extending to the radial and ulnar arteries, consistent with unilateral arterial thrombosis. Hematology and coagulation : Hemoglobin 13.9 g/dL, platelets 153 ×10^3/µL, PT 13.2 s, INR 1.09, APTT 29.8 s, fibrinogen 3.3 g/L, and D-dimer 0.19 mg/L. Protein C was 70% (lower limit of normal), protein S 65% (lower limit of normal), and antithrombin III 90% (within normal range). Cardiac echocardiography (normal LV function, EF 65%, no intracardiac thrombus) and CT angiography showed total occlusion of left brachial, radial, and ulnar arteries (Figure 1) . Autoimmune and acquired thrombophilia screen : Lupus anticoagulant, anti-cardiolipin antibodies, anti-β2 glycoprotein, ANA, anti-DNA, and antiphospholipid antibodies were all negative. JAK2 mutation testing was negative. Biochemical indicators : Homocysteine levels were reported as 10 µmol/L, Vitamin B12 was reduced to 167 pg/mL, folic acid to 6.3 ng/mL, and vitamin B6 to 16.2 ng/mL. Genetic testing revealed the patient to be homozygous for the MTHFR C677T variant, a mutation related to defective folate metabolism and possible elevation of homocysteine. Biochemical screening also demonstrated mildly elevated homocysteine levels, slightly decreased folic acid levels, and within-normal-limit levels of vitamin B12, with a functional effect indicated by the mutation in MTHFR. Factor V Leiden (G1691A) mutation and Prothrombin G20210A mutation were not identified, eliminating two prevalent hereditary thrombophilic diseases. Additionally, the patient is a carrier of the ACE DD genotype with heightened angiotensin-converting enzyme activity and potentially participates in vascular remodeling as well as endothelial impairment. Although these are not direct causal findings per se, together they potentially heightened thrombotic risk despite the background antithrombin III deficiency and exposure to estrogen. (Table 1) The patient underwent urgent left brachial and radial embolectomy. Postoperatively, she was commenced on dual antiplatelet therapy (aspirin 100 mg daily and clopidogrel 75 mg daily), atorvastatin 40 mg daily, amlodipine 5 mg daily, furosemide 40 mg daily, ranitidine 150 mg twice daily, and angiate 60 mg twice daily. Enoxaparin (Clexane) was initiated as therapeutic anticoagulation. Following embolectomy and initiation of anticoagulation, the patient’s limb perfusion improved. No recurring thrombotic event occurred during hospitalization. She was discharged on dual antiplatelet, statin, antihypertensive, and anticoagulation, hematology follow-up, and advice on vitamin supplementation. This scenario highlights a difficulty of assessing acute arterial thrombosis in a young individual, wherein routine workup for thrombophilia is normal and a lone MTHFR mutation is found. Thrombosis workup, biochemical abnormalities known to clinical judgment, and multidisciplinary management should be emphasized rather than genetic variations, which should be judiciously interpreted and rightly placed in their clinical context. Table 1 Laboratory investigations table Test Result Units Reference Range Hemoglobin 13.9 g/dL 12–16 (F) RBC count 4.63 x10^6/µL 4.1–5.1 (F) Hematocrit 41.7 % 36–48 (F) MCV 90.1 fL 80–100 MCH 30.1 pg 27–32 MCHC 33.3 g/dL 32–36 RDW 13.9 % 11.5–14.5 WBC 8.2 x10^3/µL 4–11 Neutrophils % 53.7 % 50–70; 40–75 Lymphocytes % 36.4 % 20–40; 20–45 Platelets 153 x10^3/µL 150–400 MPV 9.9 fL 6.5–12; 7.4–10.4 PDW 13.7 % 10–17 Plateletcrit PCT 0.15 % 0.19–0.39 ESR 10 mm/hr 0–20 PT 13.2 s 11–13.5 INR 1.09 — 0.8–1.2 APTT 29.8 s 25–35 Fibrinogen 3.3 g/L 2–4 D-dimer 0.19 mg/L < 0.5 Protein C 100 % 70–140 Protein S 140 % 65–140 Antithrombin III 15 mg/dl 17–30 Lupus Anticoagulant Negative — Negative Anti-Cardiolipin antibodies Negative — — Anti-β2 Glycoprotein (IgG,IgM) Negative — — ANA Negative — — Anti-DNA Negative — — Anti-Phospholipid antibodies Negative — — Factor V Leiden Negative — — Prothrombin G20210A Negative — — JAK2 mutation Negative — — ENA Profile Negative — — MTHFR A1298C genotype Heterozygous (1298A > C) — — Homocysteine 10 µmol/L 5–15 Vitamin B12 167 pg/mL ~ 200–900 (lab dependent) Folic Acid 6.3 ng/mL lab dependent Vitamin B6 16.2 ng/mL lab dependent Discussion Antithrombin III (AT III) deficiency is a rare autosomal-dominant thrombophilia that predisposes most carriers to venous thrombo-embolism (VTE) rather than arterial events ( 8 , 9 ) . Nevertheless, arterial thrombosis has been reported in AT III-deficient patients, including myocardial infarction and systemic arterial occlusions ( 10 ), underscoring that severe quantitative (type I) or qualitative (type II) defects can produce a highly pro-thrombotic state. Oral-contraceptive pills (OCPs) further amplify this risk by reducing antithrombin activity and increasing coagulation factor levels ( 11 ), which likely contributed to the recurrent upper-extremity arterial occlusions in our 46-year-old patient. Upper-extremity arterial thrombosis is uncomon (< 2 % of all deep-vein thromboses) and is usually linked to catheter-5, trauma, or hypercoagulable disorders ( 12 ); its occurrence in AT III deficiency is exceptionally rare, making this case noteworthy. Management of arterial AT III deficiency is challenging (8) . Heparin resistance is frequent because AT III is the essential co-factor for heparin activity, and warfarin may be ineffective or poorly absorbed ( 1 3) . Direct oral anticoagulants (DOACs), particularly rivaroxaban, have shown efficacy in refractory AT III-deficient patients and were successfully used after embolectomy in several reports ( 14 , 8) . Peri-procedural supplementation with AT III concentrate can normalize acivity (> 75 %) and improve heparin responsiveness, but its routine use remains controversial. Long-term therapy with a DOAC or a vitamin-K antagonist (target INR 2–3) is advisable after a second arterial event (15) . together with aggressive control of modifiable risk factors (smoking cessation, avoidance of estrogen-containing drugs) and regular vascular surveillance to detect early re-occlusion. Because AT III deficiency is hereditary, cascade screening of first-degree relatives is essential to identify asymptomatic carriers and institute prophylaxis before high-risk exposures (16) . Prognosis Despite optimal anticoagulation, carriers remain at risk for recurrent arterial and venous events, limb loss, and organ infarction. Close follow-up, patient education, and individualized anticoagulation strategies are key to reducing morbidity. Conclusion: This presentation exemplifies the diagnostic and therapeutic challenges that occur with acute arterial thrombosis in a youthful patient lacking conventional risk factors and presenting with nonspecific positive results on thrombophilia testing. Inconsistencies in the results from genetic panels, such as the presence of a heterozygous MTHFR A1298C variant whose clinical relevance is still uncertain, reflect the limitation of relying solely on genetic information to clarify thrombotic events. For that reason, comprehensive testing—encompassing the biochemical markers, autoimmune workup, and vascular imaging—is essential. Prompt diagnosis, expedited surgery, and initiation of antithrombotic therapy were critical factors in preserving the viability of the limb. Taken together, this case illustrates how a rare hereditary thrombophilia—antithrombin III deficiency—can be exacerbated by estrogen exposure and compounded by secondary genetic variants affecting homocysteine metabolism and vascular tone. A personalized approach to management, including long-term anticoagulation, avoidance of estrogen-containing therapies, nutritional optimization, and family screening, is essential to mitigate recurrence and guide preventive care. Declarations Ethics approval and consent to participate: Our institution does not require ethical approval for reporting individual cases or case series. Written informed consent was obtained from the patient for their anonymized information to be published in this article. Availability of data and materials: All data supporting the findings of this study are readily available within the article. Competing Interests: The authors declare that there is no conflict of interest. Funding: This research received no specific grant from any funding agency or institute. Authors' contributions: Mohammad Ameen Ishqair, MD., study concept and design of the research paper, writing the case presentation. Anas Ameen Ishqair, MD, is writing the introduction and conclusion Amal A. Abu Jheasha, MD, literature review and write the discussion. Urwa A. M. Zatari, MD, data collection and hospital follow-up Raed M. A. Isayed, MD, is editing the scripts Alia Khalili, MD, is finalizing the paper, tables, and figures narration. Acknowledgments: We acknowledge the efforts of medical teams at Dura hospital and Alia hospital in Hebron city, West Bank, for their efforts in reaching a diagnosis. We acknowledge the radiology teams that worked in teamwork to reach this diagnosis. Consent for publication: We took permission to use our patient data and hospital reports, and medical imaging necessary for writing a case report, with the intention of publication. (all details are written in SURVEY CONSENT FORM) References Bravo-Pérez C, Corral J, Orlando C, Ignjatovic V, Ilonczai P, Bereczky Z. How we treat severe inherited antithrombin deficiency: lessons from cases homozygous for the Budapest 3 variant. J Thromb Haemost. 2025;23(5):1648–56. Epub 2025 Feb 9. PMID: 39933654. Corral J, de la Morena-Barrio ME, Vicente V. The genetics of antithrombin. Thromb Res. 2018;169:23–29. 10.1016/j.thromres.2018.07.008 . Epub 2018 Jul 5. PMID: 30005274. Corral J, de la Morena-Barrio ME, Vicente V. The genetics of antithrombin. Thromb Res. 2018;169:23–29. 10.1016/j.thromres.2018.07.008 . Epub 2018 Jul 5. PMID: 30005274. DeSancho MT, Suvar E, Roberts JC, Tarantino MD, Schwartz J, Callis J, Recht M. Hereditary antithrombin deficiency pilot project registry from the American Thrombosis and Hemostasis Network. J Thromb Haemost. 2024;22(11):3183–90. Epub 2024 Aug 14. PMID: 39151704. Takeuchi F, Ebuchi Y, Saito Y, Migita S, Kougo T, Kouchi K, Sonoda K, Okumura Y, Nomoto K. Rivaroxaban for Venous Thrombosis in a Patient with Congenital Antithrombin Deficiency. Int Heart J. 2024;65(6):1182–1185. 10.1536/ihj.24-370 . PMID: 39617507. Wang Y, Zhang J, Zhao L, Du Y, Liu D. Acute arterial thrombosis in a patient with nephrotic syndrome and antithrombin deficiency on steroid therapy: A case report and literature review. Annals Vascular Surg - Brief Rep Innovations. 2023;3(1):100152. https://doi.org/10.1016/j.avsurg.2022.100152 . Kruijt M, de la Morena-Barrio ME, Corral J, Cobbaert CM, Ruhaak LR. Novel insights into antithrombin deficiency enabled by mass spectrometry-based precision diagnostics. J Thromb Haemost. 2025;23(1):210–21. 10.1016/j.jtha.2024.10.005 . Epub 2024 Oct 17. PMID: 39423957. Appignani M et al. Dec. Successful treatment with rivaroxaban of an extended deep vein thrombosis complicated by pulmonary embolism in a patient with familial antithrombin III deficiency: a case report. European heart journal. Case reports vol. 4,1 1–5. 23 2019, 10.1093/ehjcr/ytz235 Găman A, Maria, Găman GD. Deficiency Of Antithrombin III (AT III) - Case Report and Review of the Literature. Curr health Sci J 40,2 (2014): 141–3. 10.12865/CHSJ.40.02.12 Adcock DM, et al. A laboratory approach to the evaluation of hereditary hypercoagulability. Am J Clin Pathol vol. 1997;108(4):434–49. 10.1093/ajcp/108.4.434 . Denora D et al. July. Acquired SERPINC1/Antithrombin Deficiency during Oral Contraceptive Consumption: A Case Report. Journal of Medical Case Reports, vol. 17, no. 1, 28 2023, https://doi.org/10.1186/s13256-023-04038-1 . Accessed 26 Nov. 2024. Mulrow C, Corey GR. A painful swollen arm in a young woman. North Carolina Med J vol. 1983;44(4):217–8. Phan AT, et al. An Exceedingly Rare Case of Antithrombin III Deficiency and Catastrophic Antiphospholipid-Like Disease. J Med cases vol. 2021;12(7):262–6. 10.14740/jmc3689 . Phan AT, et al. An Exceedingly Rare Case of Antithrombin III Deficiency and Catastrophic Antiphospholipid-Like Disease. J Med cases vol. 2021;12(7):262–6. 10.14740/jmc3689 . Management of Venous Thromboembolism in Patients with Hereditary Antithrombin Deficiency and Pregnancy. Case Report and Review of the Literature - Refaei – 2017 - Case Reports in Hematology - Wiley Online Library. onlinelibrary.wiley.com/doi/10.1155/2017/9261351 . Accessed 8 Oct. 2025. Congenital antithrombin III deficiency. MedlinePlus Medical Encyclopedia. (n.d.). https://medlineplus.gov/ency/article/000558.htm Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Jan, 2026 Read the published version in Thrombosis Journal → Version 1 posted Editorial decision: Revision requested 24 Nov, 2025 Reviews received at journal 23 Nov, 2025 Reviews received at journal 13 Nov, 2025 Reviews received at journal 04 Nov, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers invited by journal 28 Oct, 2025 Editor assigned by journal 21 Oct, 2025 Submission checks completed at journal 21 Oct, 2025 First submitted to journal 18 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":33112,"visible":true,"origin":"","legend":"\u003cp\u003eThere is a loss of contrast opacification noted at mid mid-brachial artery extending down to both the ulnar and radial arteries.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7891830/v1/5791a4cb2d59fc5947b93d19.jpg"},{"id":100614853,"identity":"7b2aedf8-3c26-42cf-9ff8-4fef494668e0","added_by":"auto","created_at":"2026-01-19 17:26:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":762978,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7891830/v1/c35b4e78-1056-465f-a561-684c0557a5d1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Unexpected Clot: Unilateral Brachial Artery Occlusion Unmasking Antithrombin III Deficiency; Case Report and Therapeutic Considerations","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAntithrombin deficiency is one of the most serious hereditary thrombophilias is antithrombin deficiency. Antithrombin deficiency is a rare condition; however, based on what is known, it is underdiagnosed because of the shortcomings of existing diagnostic algorithms \u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/sup\u003e. Antithrombin deficiency is routinely diagnosed using functional tests. Not many specialized labs also do genetic analysis, despite the fact that the process is a simple, quick, and inexpensive procedure that produces pertinent data with clinical utility these days \u003csup\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003e. Factors IIa, IXa, and Xa are among the enzymatic targets of antithrombin III (ATIII), a non-vitamin K-dependent protease that prevents coagulation by blocking thrombin's enzymatic activity. Antithrombin's half-life is three days, and its normal plasma concentration is 0.12 mg/ml, or 2.3 mM. Nonetheless, the majority of labs report anticoagulant activity or antithrombin antigen levels as a proportion of a reference plasma. While newborns and infants have lower amounts than adults, their levels reach adult ranges by six months of age. In the general population, plasma antithrombin levels typically vary between 80 and 120 percent \u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e. Antithrombin III deficiency may be acquired and may be congenital, the most likely predispose the patient to venous thromboembolism \u003csup\u003e(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e),\u003c/sup\u003e despite the limited number of patients who have the last mentioned. \u003csup\u003e(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/sup\u003e An individual with congenital antithrombin III deficiency, an autosomal dominant condition, receives one copy of the antithrombin III-encoding SERPINC1 (also known as AT3) gene on chromosome 1q25.1. Nowadays, it is not uncommon to read about people who have SERPINC1 mutations and experience thrombotic events in the arterial area. Orlando et al. discovered that the p. Arg79 and p. Pro73Leu A high incidence of arterial thrombosis was linked to his mutations \u003csup\u003e(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/sup\u003e. Antithrombin deficiency (ATD) is a clinically heterogeneous disorder due to the large number of possible genetic and posttranslational modifications (PTMs) influencing the expression, secretion, functionality, and stability of antithrombin \u003csup\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 47-year-old female with no significant past medical history and a past surgical history of open Gustilo type I distal tibia and fibula fracture treated with emergency stabilization and fixation 3 years ago. was admitted to the vascular ward with an acute onset of severe pain, coldness, and loss of movement in the left hand of 24 days' duration. On examination, she was conscious and hemodynamically stable. Local examination revealed mild coldness of the left hand with absent brachial, radial, and ulnar pulses; delayed capillary refill, while the left axillary pulse was palpable. The hand was immobile at presentation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInitial investigations include a\u003c/b\u003e Doppler ultrasound demonstrated total occlusion of the mid-brachial artery with thrombus extending to the radial and ulnar arteries, consistent with unilateral arterial thrombosis. \u003cb\u003eHematology and coagulation\u003c/b\u003e: Hemoglobin 13.9 g/dL, platelets 153 \u0026times;10^3/\u0026micro;L, PT 13.2 s, INR 1.09, APTT 29.8 s, fibrinogen 3.3 g/L, and D-dimer 0.19 mg/L. Protein C was 70% (lower limit of normal), protein S 65% (lower limit of normal), and antithrombin III 90% (within normal range). Cardiac echocardiography (normal LV function, EF 65%, no intracardiac thrombus) and CT angiography showed total occlusion of left brachial, radial, and ulnar arteries \u003csub\u003e(Figure 1)\u003c/sub\u003e. \u003cb\u003eAutoimmune and acquired thrombophilia screen\u003c/b\u003e: Lupus anticoagulant, anti-cardiolipin antibodies, anti-β2 glycoprotein, ANA, anti-DNA, and antiphospholipid antibodies were all negative. JAK2 mutation testing was negative. \u003cb\u003eBiochemical indicators\u003c/b\u003e: Homocysteine levels were reported as 10 \u0026micro;mol/L, Vitamin B12 was reduced to 167 pg/mL, folic acid to 6.3 ng/mL, and vitamin B6 to 16.2 ng/mL. \u003cb\u003eGenetic testing\u003c/b\u003e revealed the patient to be homozygous for the MTHFR C677T variant, a mutation related to defective folate metabolism and possible elevation of homocysteine. Biochemical screening also demonstrated mildly elevated homocysteine levels, slightly decreased folic acid levels, and within-normal-limit levels of vitamin B12, with a functional effect indicated by the mutation in MTHFR. Factor V Leiden (G1691A) mutation and Prothrombin G20210A mutation were not identified, eliminating two prevalent hereditary thrombophilic diseases. Additionally, the patient is a carrier of the ACE DD genotype with heightened angiotensin-converting enzyme activity and potentially participates in vascular remodeling as well as endothelial impairment. Although these are not direct causal findings per se, together they potentially heightened thrombotic risk despite the background antithrombin III deficiency and exposure to estrogen. \u003csub\u003e(Table 1)\u003c/sub\u003e\u003c/p\u003e\u003cp\u003eThe patient underwent urgent left brachial and radial embolectomy. Postoperatively, she was commenced on dual antiplatelet therapy (aspirin 100 mg daily and clopidogrel 75 mg daily), atorvastatin 40 mg daily, amlodipine 5 mg daily, furosemide 40 mg daily, ranitidine 150 mg twice daily, and angiate 60 mg twice daily. Enoxaparin (Clexane) was initiated as therapeutic anticoagulation. Following embolectomy and initiation of anticoagulation, the patient\u0026rsquo;s limb perfusion improved. No recurring thrombotic event occurred during hospitalization. She was discharged on dual antiplatelet, statin, antihypertensive, and anticoagulation, hematology follow-up, and advice on vitamin supplementation.\u003c/p\u003e\u003cp\u003eThis scenario highlights a difficulty of assessing acute arterial thrombosis in a young individual, wherein routine workup for thrombophilia is normal and a lone MTHFR mutation is found. Thrombosis workup, biochemical abnormalities known to clinical judgment, and multidisciplinary management should be emphasized rather than genetic variations, which should be judiciously interpreted and rightly placed in their clinical context.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLaboratory investigations table\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" 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colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emm/hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026ndash;20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003es\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u0026ndash;13.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eINR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.8\u0026ndash;1.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAPTT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003es\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25\u0026ndash;35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFibrinogen\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u0026ndash;4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eD-dimer\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProtein C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e70\u0026ndash;140\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProtein S\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65\u0026ndash;140\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAntithrombin III\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emg/dl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17\u0026ndash;30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLupus Anticoagulant\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnti-Cardiolipin antibodies\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnti-β2 Glycoprotein (IgG,IgM)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eANA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnti-DNA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnti-Phospholipid antibodies\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFactor V Leiden\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProthrombin G20210A\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eJAK2 mutation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eENA Profile\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMTHFR A1298C genotype\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeterozygous (1298A\u0026thinsp;\u0026gt;\u0026thinsp;C)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHomocysteine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026micro;mol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u0026ndash;15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eVitamin B12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e167\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003epg/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e~\u0026thinsp;200\u0026ndash;900 (lab dependent)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFolic Acid\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elab dependent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eVitamin B6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elab dependent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAntithrombin III (AT III) deficiency is a rare autosomal-dominant thrombophilia that predisposes most carriers to venous thrombo-embolism (VTE) rather than arterial events \u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e. Nevertheless, arterial thrombosis has been reported in AT III-deficient patients, including myocardial infarction and systemic arterial occlusions \u003csup\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e),\u003c/sup\u003e underscoring that severe quantitative (type I) or qualitative (type II) defects can produce a highly pro-thrombotic state. Oral-contraceptive pills (OCPs) further amplify this risk by reducing antithrombin activity and increasing coagulation factor levels \u003csup\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e),\u003c/sup\u003e which likely contributed to the recurrent upper-extremity arterial occlusions in our 46-year-old patient. Upper-extremity arterial thrombosis is uncomon (\u0026lt;\u0026thinsp;2 % of all deep-vein thromboses) and is usually linked to catheter-5, trauma, or hypercoagulable disorders \u003csup\u003e(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e);\u003c/sup\u003e its occurrence in AT III deficiency is exceptionally rare, making this case noteworthy. Management of arterial AT III deficiency is challenging \u003csup\u003e(8)\u003c/sup\u003e. Heparin resistance is frequent because AT III is the essential co-factor for heparin activity, and warfarin may be ineffective or poorly absorbed \u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e3)\u003c/sup\u003e. Direct oral anticoagulants (DOACs), particularly rivaroxaban, have shown efficacy in refractory AT III-deficient patients and were successfully used after embolectomy in several reports \u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, 8)\u003c/sup\u003e. Peri-procedural supplementation with AT III concentrate can normalize acivity (\u0026gt;\u0026thinsp;75 %) and improve heparin responsiveness, but its routine use remains controversial. Long-term therapy with a DOAC or a vitamin-K antagonist (target INR 2\u0026ndash;3) is advisable after a second arterial event \u003csup\u003e(15)\u003c/sup\u003e. together with aggressive control of modifiable risk factors (smoking cessation, avoidance of estrogen-containing drugs) and regular vascular surveillance to detect early re-occlusion. Because AT III deficiency is hereditary, cascade screening of first-degree relatives is essential to identify asymptomatic carriers and institute prophylaxis before high-risk exposures \u003csup\u003e(16)\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePrognosis\u003c/b\u003eDespite optimal anticoagulation, carriers remain at risk for recurrent arterial and venous events, limb loss, and organ infarction. Close follow-up, patient education, and individualized anticoagulation strategies are key to reducing morbidity.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003eThis presentation exemplifies the diagnostic and therapeutic challenges that occur with acute arterial thrombosis in a youthful patient lacking conventional risk factors and presenting with nonspecific positive results on thrombophilia testing. Inconsistencies in the results from genetic panels, such as the presence of a heterozygous MTHFR A1298C variant whose clinical relevance is still uncertain, reflect the limitation of relying solely on genetic information to clarify thrombotic events. For that reason, comprehensive testing\u0026mdash;encompassing the biochemical markers, autoimmune workup, and vascular imaging\u0026mdash;is essential. Prompt diagnosis, expedited surgery, and initiation of antithrombotic therapy were critical factors in preserving the viability of the limb. Taken together, this case illustrates how a rare hereditary thrombophilia\u0026mdash;antithrombin III deficiency\u0026mdash;can be exacerbated by estrogen exposure and compounded by secondary genetic variants affecting homocysteine metabolism and vascular tone. A personalized approach to management, including long-term anticoagulation, avoidance of estrogen-containing therapies, nutritional optimization, and family screening, is essential to mitigate recurrence and guide preventive care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cbr\u003eOur institution does not require ethical approval for reporting individual cases or case series. Written informed consent was obtained from the patient for their anonymized information to be published in this article.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;All data supporting the findings of this study are readily available within the article.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003cbr\u003eThe authors declare that there is no conflict of interest.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003eThis research received no specific grant from any funding agency or institute.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003e\u003cbr\u003eMohammad Ameen Ishqair, MD., study concept and design of the research paper, writing the case presentation.\u0026nbsp;\u003cbr\u003eAnas Ameen Ishqair, MD, is writing the introduction and conclusion\u0026nbsp;\u003cbr\u003eAmal A. Abu Jheasha, MD, literature review and write the discussion.\u0026nbsp;\u003cbr\u003eUrwa A. M. Zatari, MD, data collection and hospital follow-up\u0026nbsp;\u003cbr\u003eRaed M. A. Isayed, MD, is editing the scripts\u0026nbsp;\u003cbr\u003eAlia Khalili, MD, is finalizing the paper, tables, and figures narration.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003cbr\u003eWe acknowledge the efforts of medical teams at Dura hospital and Alia hospital in Hebron city, West Bank, for their efforts in reaching a diagnosis. We acknowledge the radiology teams that worked in teamwork to reach this diagnosis.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003e\u003cbr\u003eWe took permission to use our patient data and hospital reports, and medical imaging necessary for writing a case report, with the intention of publication. (all details are written in SURVEY CONSENT FORM)\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBravo-P\u0026eacute;rez C, Corral J, Orlando C, Ignjatovic V, Ilonczai P, Bereczky Z. How we treat severe inherited antithrombin deficiency: lessons from cases homozygous for the Budapest 3 variant. J Thromb Haemost. 2025;23(5):1648\u0026ndash;56. Epub 2025 Feb 9. PMID: 39933654.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCorral J, de la Morena-Barrio ME, Vicente V. The genetics of antithrombin. Thromb Res. 2018;169:23\u0026ndash;29. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.thromres.2018.07.008\u003c/span\u003e\u003cspan address=\"10.1016/j.thromres.2018.07.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2018 Jul 5. 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Successful treatment with rivaroxaban of an extended deep vein thrombosis complicated by pulmonary embolism in a patient with familial antithrombin III deficiency: a case report. European heart journal. Case reports vol. 4,1 1\u0026ndash;5. 23 2019, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ehjcr/ytz235\u003c/span\u003e\u003cspan address=\"10.1093/ehjcr/ytz235\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGăman A, Maria, Găman GD. Deficiency Of Antithrombin III (AT III) - Case Report and Review of the Literature. 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Case Report and Review of the Literature - Refaei \u0026ndash;\u0026thinsp;2017 - Case Reports in Hematology - Wiley Online Library. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003eonlinelibrary.wiley.com/doi/10.1155/2017/9261351\u003c/span\u003e\u003cspan address=\"onlinelibrary.wiley.com/doi/10.1155/2017/9261351\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 8 Oct. 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCongenital antithrombin III deficiency. MedlinePlus Medical Encyclopedia. (n.d.). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://medlineplus.gov/ency/article/000558.htm\u003c/span\u003e\u003cspan address=\"https://medlineplus.gov/ency/article/000558.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Antithrombin III deficiency, Arterial thrombosis, Upper-extremity arterial occlusion, Estrogen-induced thrombosis, Embolectomy, Antithrombin concentrate therapy, Factor Xa inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-7891830/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7891830/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAntithrombin III deficiency is an autosomal dominant thrombophilia that most commonly predisposes carriers to venous thromboembolism but can rarely cause arterial thrombosis, particularly when quantitative or qualitative defects are severe.\u003c/p\u003e\u003cp\u003eA 46-year-old woman on combined oral contraceptive therapy presented with recurrent acute upper-extremity arterial occlusions. Workup revealed hereditary antithrombin III deficiency. She underwent emergency embolectomy with initial issues of anticoagulation and was then converted to a direct oral anticoagulant with clinical stabilization\u003c/p\u003e\u003cp\u003ePeri-procedural heparin responsiveness was suboptimal due to low antithrombin activity and was managed with surgical embolectomy followed by later anticoagulation with a direct oral factor Xa inhibitor. Direct oral anticoagulants have been suggested as alternative therapies in antithrombin-refractory patients, and replacement with antithrombin concentrate can reversibly correct heparin responsiveness when employed judiciously. The patient was counseled to stop estrogen-containing medications, manage modifiable risk factors, and have vascular longitudinal surveillance.\u003c/p\u003e\u003cp\u003eIt is a new presentation of arterial thrombosis with antithrombin III deficiency caused by exogenous estrogen exposure that was effectively treated with embolectomy and prolonged direct oral anticoagulation. Identification of this phenotype guides the secondary prevention and family screening in hereditary thrombophilia.\u003c/p\u003e","manuscriptTitle":"The Unexpected Clot: Unilateral Brachial Artery Occlusion Unmasking Antithrombin III Deficiency; Case Report and Therapeutic Considerations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 05:33:54","doi":"10.21203/rs.3.rs-7891830/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-25T00:30:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-23T20:33:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-13T19:27:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-04T11:02:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197821912106939233653534998816566434281","date":"2025-10-30T17:12:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"336014163701832625300008875909874712303","date":"2025-10-30T14:10:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128833178901006389169899418380102802103","date":"2025-10-29T04:07:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-28T12:45:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-21T08:38:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-21T08:35:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2025-10-18T07:50:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b077ef5e-87e3-421e-ba9d-c5d1d5e0424c","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T16:48:57+00:00","versionOfRecord":{"articleIdentity":"rs-7891830","link":"https://doi.org/10.1186/s12959-025-00825-6","journal":{"identity":"thrombosis-journal","isVorOnly":false,"title":"Thrombosis Journal"},"publishedOn":"2026-01-14 16:30:20","publishedOnDateReadable":"January 14th, 2026"},"versionCreatedAt":"2025-11-10 05:33:54","video":"","vorDoi":"10.1186/s12959-025-00825-6","vorDoiUrl":"https://doi.org/10.1186/s12959-025-00825-6","workflowStages":[]},"version":"v1","identity":"rs-7891830","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7891830","identity":"rs-7891830","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}