[Environmental diagnostics for venous thromboembolism - thrombophilia and tumor screening]. / Umfelddiagnostik bei venöser Thromboembolie ­ Thrombophilie- und Tumor-Screening.

Inadequate treatment of venous thromboembolism can have fatal consequences that are often irreversible. If the indication is given, long-term therapeutic anticoagulation may be necessary to reduce the risk of recurrence for those affected. On the other hand, there is an increased risk of bleeding due to continued anticoagulation, so an individual risk/benefit assessment is necessary. A careful assessment of possible contributing factors is therefore essential. If uncertainty persists, comprehensive environmental diagnostics with regard to thrombophilia or cancer can be helpful.

[Comparison of thrombodynamic methods and routine hemostasis tests in the evaluation of hypercoagulable syndrome in chronic glomerulonephritis].

BACKGROUND: Nephrotic syndrome (NS) is associated with a high risk of thrombotic complications. In this group of patients, routine local tests for assessing hemostasis do not accurately reflect hypercoagulable state. Global functional tests for assessing hemostasis, including thrombodynamics (TD), are considered promising for assessing disorders in the blood coagulation system of these patients. AIM: To compare the rate of hypercoagulability according to routine hemostatic tests and TD and to evaluate the factors associated with increased risk of thrombotic complications in patients with chronic glomerulonephritis (CGN). MATERIALS AND METHODS: The study included 94 patients with active CGN who were not receiving anticoagulant therapy; 63 (80.3%) patients had NS, and 31 (19.7%) had active CGN without NS. Hemostasis parameters were assessed using local coagulation tests and TD test. Using logistic regression analysis, factors associated with the risk of thrombosis were assessed. RESULTS: Of the 94 patients with active CGN in 63 without preventive anticoagulant therapy, hypercoagulability according to routine tests was detected in 6 (9.5%) patients with NS and in 3 (9.7%) patients without NS (p<0.05). Hypercoagulability according to the TD test was detected in 24 (53.9%) patients with NS and in 5 (32.2%) without NS (p<0.05). The formation of spontaneous clots was observed in 29 (30.9%) of patients with CGN, most of them 24 (83%) with NS. 10.6% of patients in our cohort experienced thromboembolic events. The risk of thromboembolic events according to the univariate regression analysis was associated with older age, higher lipid levels, use of glucocorticosteroids and detection of spontaneous clots by the TD test. No association of thromboembolic events with abnormalities in routine hemostasis tests was obtained. CONCLUSION: In patients with CGN with nephrotic syndrome, hypercoagulability is detected in 9.5% of cases with routine coagulation tests and in 53.9% of cases with TD test. Detection of spontaneous clots by TD test is associated with a risk of thromboembolic events.

Pediatric antiphospholipid syndrome: is it the same as an adult?

IMPORTANCE: Antiphospholipid syndrome in neonates and children is a rare, but in some cases life-threatening condition with arterial and/or venous thrombosis and/or non-thrombotic neurological, skin, ophthalmological and other manifestations. OBSERVATIONS: This review highlights the available information about the features of pediatric APS, including the rare catastrophic form, the differences between pediatric and adult APS, and the role of genetic thrombophilia in APS manifestation. CONCLUSIONS AND RELEVANCE: The clinical manifestations and treatment options for APS in children may differ from those in adults, and prescribing therapy can be challenging due to the unique clinical and morphological characteristics of the pediatric patient. Pediatric APS may be a predictor of the development of certain autoimmune diseases and classic manifestations of APS in adulthood, therefore, a revision of the existing criteria for the diagnosis and treatment of APS in children is necessary.

A systematic review and meta-analysis of the association between the D-dimer and rheumatic diseases.

INTRODUCTION: There is good evidence that specific autoimmune rheumatic diseases (RDs), for example, rheumatoid arthritis and systemic lupus erythematosus (SLE), are associated with a state of hypercoagulability and an increased risk of venous thromboembolism (VTE). However, limited information regarding this association is available for other autoimmune or autoinflammatory RDs. We sought to address this issue by conducting a systematic review and meta-analysis of the association between the d-dimer, an established marker of hypercoagulability and VTE, and RDs and the possible clinical and demographic factors mediating this association. METHODS: We searched the electronic databases PubMed, Web of Science, and Scopus from inception to January 31, 2024. The risk of bias and the certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. RESULTS: In 31 studies selected for analysis (2724 RD patients and 3437 healthy controls), RD patients had overall significantly higher d-dimer concentrations when compared to controls (standard mean difference = 0.93, 95% CI 0.76-1.10, p < .001; I2 = 86.1%, p < .001; moderate certainty of evidence). The results were stable in a sensitivity analysis. Significant associations were observed between the effect size of the between-group differences in d-dimer concentration and age, specific RD and RD category, RD duration, fibrinogen, plasminogen activator inhibitor, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: Overall, patients with RDs have significantly higher d-dimer concentrations when compared with healthy controls, indicating a state of hypercoagulability. The alterations in d-dimer concentrations are mediated by age, specific RD and RD category, RD duration, and markers of anticoagulation and inflammation. Further research is warranted to investigate d-dimer concentrations across the spectrum of RDs and their utility in predicting and managing VTE in these patients (PROSPERO registration number: CRD42024517712).

A Compact Differential Dynamic Microscopy-based Device (cDDM): An Approach Tool for Early Detection of Hypercoagulable State in Transfusion-Dependent-ß-Thalassemia Patients.

ß-Thalassemia especially transfusion-dependent thalassemia (TDT) associates with a hypercoagulable state, which is the main cause of thromboembolic events (TEE). Plasma viscosity and rheological parameters could be essential markers for determining hypercoagulable state in ß-thalassemia patients. The traditional methods for measuring viscosity are often limited by large sample volumes and are impractical for routine clinical monitoring. The compact differential dynamic microscopy-based device (cDDM), an optical microscopy for quantitative rheological assessment, was developed and applied for prognosis of the hypercoagulable state in ß-TDT with and without splenectomy. The device was performed plasma viscosity measurement using low plasma volume (8 µL) and revealed a value as modulus of complex viscosity |η(ω)| in 7 min. We also parallelly demonstrated the correlation of the viscosity and related-coagulable parameters: complete blood count, prothrombin time (PT), activated partial thromboplastin time (APTT), protein C (PC), protein S (PS), CD62P and CD63 expression, and platelet aggregation test. The thalassemia plasma exhibited a higher value of |η(ω)| than healthy plasma, which can represent a different viscoelastic property among the groups. Even all related-coagulable parameters indicated hypercoagulable state in both nonsplenectomies and splenectomies ß-TDT patients when compared to control, only high platelet numbers significantly correlated to high plasma viscosity in the splenectomy group. However, the other coagulable parameters have shown a trend of positive relationship with high plasma viscosity in all ß-1thalassemia TDT patients. The relative results suggested that our device would be an approach tool for early detection of hypercoagulable state in transfusion-dependent-ß-thalassemia patients, which can help to prevent TEE and the critical consequent-complications.

Enhancing Thrombophilia Risk Prediction Through AI-Based Methodologies.

Thrombophilia, a predisposition to thrombosis, poses significant diagnostic challenges due to its multi-factorial nature, encompassing genetic and acquired factors. Current diagnostic paradigms, primarily relying on a combination of clinical assessment and targeted laboratory tests, often fail to capture the complex interplay of factors contributing to thrombophilia risk. This paper proposes an innovative artificial intelligence (AI)-based methodology aimed to enhance the prediction of thrombophilia risk. The designed multidimensional risk assessment model integrates and elaborates through AI a comprehensive collection of patient data types, including genetic markers, clinical parameters, patient history, and lifestyle factors, in order to obtain advanced and personalized explainable diagnoses.

Venous thromboembolism characteristics and outcomes among RIETE patients tested and untested for inherited thrombophilia.

ABSTRACT: Inherited thrombophilia (IT) workup is commonly pursued in patients with venous thromboembolism (VTE). Recent American Society of Hematology guidelines recommend a selective approach to IT testing, nevertheless, evidence on whether thrombophilia testing can actually improve patient-important outcomes through tailored management is limited. Data from the large, prospective Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry were analyzed to compare VTE risk factors, management, and outcomes between patients who were tested for IT and untested patients, during anticoagulant treatment and after its discontinuation. Among 103 818 patients enrolled in RIETE, 21 089 (20.3%) were tested for IT, 8422 (8.1%) tested positive, and 82 729 (79.7%) were not tested. IT testing was more frequent in patients with VTE provoked by minor risk factors and less common in those with major risk factors such as surgery or active cancer. Choices of anticoagulant treatment did not differ based on IT testing results. Untested patients exhibited inferior outcomes across all VTE categories, with higher rates of VTE recurrence, major bleeding, mortality, and notably, cancer-related mortality. After treatment discontinuation, IT-negative patients with surgically provoked VTE showed lower recurrence rates. For immobilization-related VTE as well as in estrogen-related VTE, no significant differences in recurrence rates were observed between IT-negative and IT-positive patients. However, IT-negative patients with pregnancy or postpartum-related VTE had significantly lower recurrence rates. Patients with unprovoked VTE, particularly those testing positive for IT, had high recurrence rates after treatment. These findings underscore the complex role of IT testing in managing VTE, supporting personalized treatment strategies that consider VTE risk factors and comorbidities. The trial was registered at www.clinicaltrials.gov as #NCT02832245.

Decision theoretical foundations of clinical practice guidelines: an extension of the ASH thrombophilia guidelines.

ABSTRACT: Decision analysis can play an essential role in informing practice guidelines. The American Society of Hematology (ASH) thrombophilia guidelines have made a significant step forward in demonstrating how decision modeling integrated within Grading of Recommendations Assessment, Developing, and Evaluation (GRADE) methodology can advance the field of guideline development. Although the ASH model was transparent and understandable, it does, however, suffer from certain limitations that may have generated potentially wrong recommendations. That is, the panel considered 2 models separately: after 3 to 6 months of index venous thromboembolism (VTE), the panel compared thrombophilia testing (A) vs discontinuing anticoagulants (B) and testing (A) vs recommending indefinite anticoagulation to all patients (C), instead of considering all relevant options simultaneously (A vs B vs C). Our study aimed to avoid what we refer to as the omitted choice bias by integrating 2 ASH models into a single unifying threshold decision model. We analyzed 6 ASH panel's recommendations related to the testing for thrombophilia in settings of "provoked" vs "unprovoked" VTE and low vs high bleeding risk (total 12 recommendations). Our model disagreed with the ASH guideline panels' recommendations in 4 of the 12 recommendations we considered. Considering all 3 options simultaneously, our model provided results that would have produced sounder recommendations for patient care. By revisiting the ASH guidelines methodology, we have not only improved the recommendations for thrombophilia but also provided a method that can be easily applied to other clinical problems and promises to improve the current guidelines' methodology.

Comprehensive evaluation of genetic and acquired thrombophilia markers for an individualized prediction of clinical thrombosis in patients with lymphoma and multiple myeloma.

Patients diagnosed with lymphoma or multiple myeloma are at elevated risk of venous thromboembolism (VTE). Optimum risk stratification and effective thromboprophylaxis can only be achieved through the development of a multiple-specific risk score that successfully captures all aspects of the heterogeneous prothrombotic environment existing in these patients. Our aim was to identify risk factors for thrombosis and suggest an improved tool combining clinical data, thrombo-inflammatory biomarkers and genetic (Thrombo inCode® test) variables for predicting thrombotic risk in patients with lymphoma and multiple myeloma. A prospective longitudinal study was conducted on newly-diagnosed lymphoma and multiple myeloma patients who presented at our institution between February 2020 and January 2021. The study included 47 patients with lymphoma and 16 patients with multiple myeloma. We performed a follow-up of 1 year or until September 2021. The incidence of venous thrombosis and associated risk factors were analysed, including the genetic Thrombo inCode® test. Khorana and ThroLy scores for lymphoma patients and IMPEDE VTE score for myeloma patients were calculated. At a median follow-up of 9.1 months, VTE incidence was 9.5% (6/63), with 4 and 2 patients with lymphoma and myeloma who developed the events, respectively. Univariate analysis showed that the incidence of thrombosis was significantly higher in patients with ECOG ≥ 2 and prior immobility. Median factor VIII levels were significantly higher in patients with thrombosis (with increased values in all of them). Moreover, there was a trend in genetic variant rs5985 (factor XIII) as a protective factor, and a trend to higher thrombotic risk in patients with factor V Leiden, rs2232698 variant (serpinA10), low total protein S activity, elevated D-dimer, aggressive lymphoma and treatment with dexamethasone. The results of our study demonstrate promise for the potential use of widely accessible markers to increase precision in risk prediction for VTE in patients with lymphoma and multiple myeloma, particularly ECOG ≥ 2, immobility and higher factor VIII levels, as well as lymphoma aggressiveness, treatment with dexamethasone and the haemostatic biomarkers D-dimer and total protein S activity. Additionally, genetic variants factor V Leiden, serpinA10 rs2232698 and factor XIII-A Val34Leu warrant further investigation for use in the research setting.

Hypercoagulability based on thromboelastography is common in dogs undergoing adrenalectomy.

OBJECTIVE: Thromboelastography (TEG) is a whole blood assay that yields global assessment of hemostasis, as it evaluates clot time, strength, and kinematics of clot formation and lysis. The main objective was to describe preoperative TEG findings in dogs that had an adrenalectomy performed and, secondarily, to describe TEG findings in the dogs with or without hyperadrenocorticism (HAC). ANIMALS: 30 dogs that had preoperative TEG and adrenalectomy performed. METHODS: Medical records between 2018 and 2022 were reviewed. Signalment, diagnostic data, and perioperative treatment were abstracted. RESULTS: 53% (16/30) of the dogs were hypercoagulable, and none were hypocoagulable. Based on histopathology, 6 of 9 dogs with adenocarcinoma were hypercoagulable, 4 of 8 with pheochromocytoma were hypercoagulable, and 6 of 10 with adenoma were hypercoagulable. None of the 3 dogs with other histopathologic diagnoses or combinations of diagnoses (adrenocortical hyperplasia, poorly differentiated sarcoma, and both adrenocortical adenocarcinoma and pheochromocytoma) were hypercoagulable. Of the 14 dogs tested preoperatively for HAC, 4 of 8 HAC dogs were hypercoagulable and 2 of 6 non-HAC dogs were hypercoagulable. CLINICAL RELEVANCE: The present report describes for the first time TEG findings for dogs undergoing adrenalectomy and suggests that the majority of dogs with adrenal neoplasia are hypercoagulable based on TEG results.

The Role of Hereditary Thrombophilia Testing in Management of First-Time Pulmonary Embolism.

AIM: Hereditary thrombophilia (HT) testing is frequently conducted during the evaluation of patients with pulmonary embolism (PE). However, the utility of routine HT testing in this setting is unclear. We sought to assess the association of HT with risk of recurrent venous thromboembolism (VTE) following first-time PE. METHODS: We conducted a multi-hospital retrospective study. Two hundred and ninety (290) patients with a first-time PE, who had been tested for HT, completed at least 3 months of therapeutic anticoagulation (AC), subsequently discontinued AC, and were followed for at least 36 months thereafter, were included. RESULTS: HT was present in 48 of the 290 included patients (17%). Median follow-up after discontinuing AC was 61 months (interquartile range, 43-79 months). The overall recurrence rate of VTE during follow-up was 58 per 290 (20%). A total of 47 of 242 patients (19%) in the HT-absent group had a recurrent VTE, compared with 11 of 48 (22%) in the HT-present group. There was no significant difference in VTE-free survival between groups on Kaplan-Meier analysis; the hazard ratio (HR) for VTE recurrence for those with HT compared to those without (HR HT-present: HT-absent) was 1.240 (95% confidence interval [CI] 0.614-2.502; p=0.548). On multivariable analysis, HT was not associated with risk of recurrent VTE (HR 1.262; 95% CI 0.640-2.488), and the only variable associated with VTE recurrence was unprovoked PE (HR 2.954; 95% CI 1.64-5.314). CONCLUSIONS: These findings demonstrate that the presence of HT is not associated with the risk of recurrent VTE following first PE, and support limiting the use of HT testing among patients with first PE.

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus.

Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.

Triad of cluster-like headaches, hypertension and hypercoagulability a pointer to pheochromocytoma.

We report the case of a middle-aged hypertensive woman presenting to the neurology department with short-lasting episodic headaches for 4 years. She was initially diagnosed and treated with cluster headaches for one year. Following this, she presented with right lower limb arterial claudication. Arterial Doppler of lower limbs showed thrombosis of the bilateral common femoral arteries. Further computed tomography (CT) angiogram of the lower limbs confirmed extensive arterial thrombosis in bilateral lower limbs. The CT angiogram incidentally detected a left adrenal lesion. She had elevated urinary vanillylmandelic Acid and 24-hour metanephrines suggesting the presence of a pheochromocytoma. She was initially medically managed and later underwent left open adrenalectomy. Histopathology examination of the sections proved pheochromocytoma. Postsurgery, the patient's symptoms improved remarkably. This case highlights the importance of diagnosing pheochromocytoma when you encounter a patient with refractory short-lasting headaches, hypertension and hypercoagulability.

Investigating the Impact on Long-Term Outcomes and the Necessity of Hereditary Thrombophilia Screening in Presumed or Perinatal Arterial Ischemic Stroke.

This study aimed to investigate the influence of prothrombotic risk factors on long-term outcomes of patients with perinatal arterial ischemic stroke. The study was conducted through an analysis of monitoring results that were regularly maintained for approximately 20 years at a tertiary stroke-monitoring center. The study assessed prothrombotic risk factors, radiological area of involvement, clinical presentation, treatments, clinical outcomes, and long-term outcomes of the 48 patients included in the study, with a mean monitoring time of 77.6 ± 45.7 months (range: 6-204). Our results showed that the presence of prothrombotic risk factors did not affect long-term outcomes. However, patients with middle cerebral artery infarction had the highest risk of developing cerebral palsy, whereas those with presumed stroke had the highest risk of developing epilepsy. This study suggests that prothrombotic risk factors should not be evaluated during the acute stage unless there is a strong suspicion of the patient's history, and prevention or early diagnosis of presumed stroke patients will positively impact their long-term prognosis.