Unraveling a Clinical Coagulation Paradox: The Laboratory’s Investigative Role

A 44-year-old female with anemia showed an unusual occurrence of thrombotic events following a double gastrojejunal bypass surgery. Specifically, the patient experienced recurrent deep vein thrombosis (DVT), the most recent of which was complicated by pulmonary embolism. One month after the last thrombotic event, the patient was admitted for further diagnostic investigations. The workup included biochemical studies and a comprehensive thrombophilia screening panel; see Table 1 for details. Coagulation profile, thrombophilia testing, and vitamin K assessment.a aThis table summarizes routine coagulation screening (PT and aPTT ratios), 1-stage coagulation factor activities, LA testing, and natural anticoagulant activities (PC, PS, and AT) assessed after bariatric surgery. Antiphospholipid antibody results (anti–β2-glycoprotein I and anticardiolipin) are reported as immunoassays. Additional thrombophilia testing includes the APCR assay and genotyping for factor V Leiden (F5 G1691A) and the PAI-1 4G/5G polymorphism. Vitamin K was quantified in serum by LC-MS. Where multiple values are reported for PC, PS, AT, or APCR, they reflect independent measurements performed on separate occasions. Abbreviations: PT, prothrombin time; aPTT, activated partial thromboplastin time; dRVVT, dilute Russell viper venom time; IgG, immunoglobulin G; IgM, immunoglobulin M; LA, lupus anticoagulant; PTT, partial thromboplastin time; APCR, activated protein C resistance. The initial evaluation of the main coagulation parameters, prothrombin time ratio and activated partial thromboplastin time ratio, revealed limited variability in both values in the absence of anticoagulation therapy (Table 1), as reported by the referring clinicians. The alteration of both the extrinsic and intrinsic pathways was subsequently attributed to a widespread deficiency of coagulation factors (Table 1). Based on these laboratory results and the coexisting anemic state, a comprehensive diagnostic workup ruled out a bleeding diathesis. How could bariatric surgery affect clotting factor synthesis and the activity of natural anticoagulants such as PC and PS? In which clinical scenarios is thrombophilia testing essential to ensure timely diagnosis and effective patient management? What is the role of the laboratory in diagnosing thrombotic events in patients with multiple risk factors, and how can collaboration between laboratory and clinicians, along with preoperative thrombophilia screening, improve the management and prevention of thrombotic complications? What is the role of clinical–laboratory collaboration and preoperative thrombophilia screening in preventing thrombotic complications after bariatric surgery? Thrombophilia screening showed a mixing study that corrected the prolonged activated partial thromboplastin time, supporting the suspected factor deficiency (Table 1). In addition, reduced levels of the natural anticoagulants, protein C (PC), protein S (PS), and antithrombin (AT) were observed, representing an important laboratory finding potentially contributing to the thrombotic events (Table 1). Autoimmune testing for antiphospholipid antibodies, including anticardiolipin and anti-β-2 glycoprotein I antibodies, yielded negative results. Further molecular biology testing included factor V Leiden G1691A (FVL) mutation in association with activated protein C resistance, prothrombin G20210A, and methylene tetrahydrofolate reductase C677T/A1298C mutations together with homocysteine levels and plasminogen activator inhibitor-1. The results obtained revealed a heterozygous FVL mutation, which corresponded with the altered activated protein C resistance assay result, and a heterozygous PAI-1 gene mutation (Table 1). Both findings represent predisposing factors for thrombotic risk. Furthermore, a homozygous methylene tetrahydrofolate reductase (C677T) T/T genotype was observed but was associated with a normal methylene tetrahydrofolate reductase (A1298C) polymorphism and low homocysteine levels of 2.20 µMol/L (4.44–13.56 µMol/L). The factor II gene result was wild-type. At this point, we investigated the cause of the factor deficiency. A hepatic synthesis defect was ruled out since liver function tests and abdominal ultrasound did not indicate cirrhosis. Given these findings, the factor deficiencies were attributed to malabsorption induced by the surgical procedure. This was also supported by laboratory findings, specifically low hemoglobin 9.8 g/dL (12–16 g/dL) and albumin levels 2.6 g/dL (3.5–5.0 g/dL), a condition that was absent in the presurgery state. Thrombophilia is an inherited or acquired blood disorder characterized by a tendency to form blood clots in the arteries and veins, often as a result of multifactorial causes (1). The most common causes of inherited thrombophilia are linked to the FVL mutation; factor II mutation; congenital dysfibrinogenemia; and PC, PS, and AT deficiencies. These genetic defects lead to an imbalance in the coagulation system, increasing the risk of clot formation (2). On the other hand, important acquired thrombophilias include antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative neoplasms, and the presence of the JAK2 mutation without a myeloproliferative neoplasm phenotype. In addition, acquired thrombophilias can be triggered by medical conditions like cancer, obesity, diabetes, heart failure, inflammation, certain medications, prolonged periods of immobility, or surgical procedures. Hormonal factors like pregnancy or the use of hormonal contraceptives and hormone replacement therapy may also have a relevant role in this pathological process (3). Thrombophilia testing should be considered in the following situations: DVT/pulmonary embolism in individuals under 45 years old, thrombosis in unusual sites (e.g., cerebral, mesenteric, portal, hepatic veins), recurrent DVT/pulmonary embolism, DVT with no obvious risk factors, pregnancy complications like recurrent fetal loss or stillbirth, and a family history of thrombosis (4). This interesting clinical case highlights a clinical paradox: an initial difficulty in identifying the real origin of thrombotic events, despite the deficiency of both coagulant and anticoagulant factors. This raised the question of a common cause for both coagulation factor deficiency and reduced PC/PS. Vitamin K deficiency was considered because vitamin K is required for posttranslational γ-carboxylation of vitamin K–dependent proteins. γ-Carboxylation converts glutamate to γ-carboxyglutamate, forming Ca²⁺-binding Gla domains essential for phospholipid-membrane localization and activity of factors II, VII, IX, and X and PS and PC; thus, it is a key biochemical checkpoint. Consistent with this mechanism, the hypothesis was further supported by the selective deficiency of vitamin K–dependent coagulation factors (Table 1) and by the presence of a fat malabsorption context. Indeed, vitamin K insufficiency is a known postoperative complication of this type of surgery (5–7). As expected, quantification of vitamin K in serum, by LC-MS, was found to be undetectable (Table 1), confirming the laboratory suspicion. Meanwhile, the reduction of non–vitamin K–dependent factors is consistent with a broader acquired malabsorptive state and chronic intestinal inflammation, which together may impair hepatic protein synthesis and contribute to the overall coagulation deficiencies observed. The presence of multiple low activity levels of both vitamin K–dependent and non–vitamin K coagulation factors, which typically is associated with a hemorrhagic tendency, and of natural anticoagulants linked to clot formation may be interpreted as indicating that the condition was at equilibrium. However, vitamin K deficiency is a critical risk factor, well-described in malabsorptive settings, and contributes to a prothrombotic shift by impairing the activity of natural anticoagulants PC and PS. Accordingly, thrombosis is a recognized complication of bariatric surgery (8, 9), particularly in cases involving multiple thrombophilic mutations post–bariatric surgery (10). In support, reports outside the bariatric field (11–13) link acquired vitamin K deficiency (e.g., in celiac disease) with inherited thrombophilia (e.g., FVL) in thrombosis cases, providing biological plausibility for combined mechanisms. This case illustrates an acquired deficiency of the physiological anticoagulants PC, PS, and AT in association with mutations in FVL and PAI-1. In this clinical context, the quantity and functional activity of PC are significantly impaired (Table 1). Given the patient’s thrombotic history and overall risk profile, anticoagulant therapy was initiated for prophylactic purposes. No further venous thromboembolism events have been observed during follow-up. To the best of our knowledge, no previously published cases has described a bariatric surgical patient with biochemically confirmed vitamin K deficiency, recurrent thrombosis, and a distinctive coexisting inherited thrombophilia profile. This unique combination underscores an important yet underrecognized interplay between nutrient-related acquired anticoagulant impairment and this particular genetic predisposition to thrombosis. Based on these findings, a targeted diagnostic evaluation focusing on specific genetic risk factors, particularly FVL, which is associated with a 3- to 8-fold increased risk of venous thromboembolism (14), may be considered in bariatric surgery candidates. If an FVL mutation is identified, a more comprehensive thrombophilia panel may be pursued. Such an approach could enable the recognition and optimization of malabsorption-related nutritional deficiencies, ultimately contributing to the prevention of patient-specific thrombotic complications. Bariatric surgery can cause malabsorption leading to vitamin K deficiency and acquired reductions of PC, PS, AT, and vitamin K–dependent clotting factors. Preoperative thrombophilia screening may identify genetic predispositions (e.g., FVL, PAI-1) that increase thrombotic risk. A paradoxical prothrombotic state may arise when inherited mutations coexist with acquired deficiencies usually associated with bleeding. Individual thrombotic risk assessment and personalized prophylaxis are essential in bariatric surgery candidates. Interdisciplinary collaboration between clinicians and laboratories is crucial for timely diagnosis and patient management. Nonstandard Abbreviations: DVT, deep vein thrombosis; PC, protein C; PS, protein S; AT, antithrombin; FVL, factor V Leiden G1691A. Author Contributions: The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest. Acknowledgments: The authors would like to thank the clinical professors and staff of the Internal Medicine Obesity Medical Center at Tor Vergata University Hospital, whose expertise and collaboration greatly contributed to the management of the patient and the development of this case report. A special thanks goes to Prof. Paolo Sbraccia (head of department) and to Prof. Monica D'Adamo.