OBJECTIVE:To report a novel pathogenic frameshift mutation in the histidine-rich glycoprotein (HRG) gene causing hereditary thrombophilia, and to discuss its clinical implications for kidney transplantation decision-making. METHODS:A 42-year-old female with end-stage renal disease on maintenance hemodialysis presented with recurrent dialysis access thrombosis. Routine coagulation tests were normal, but decreased antithrombin and elevated D-dimer prompted genetic investigation. Whole-exome sequencing was performed to identify potential genetic etiologies. RESULTS:Whole-exome sequencing identified a previously unreported pathogenic frameshift mutation in the HRG gene: c.694delG (p.E232fs). This mutation explained the patient's prothrombotic phenotype. Given the significantly elevated risk of renal allograft thrombosis associated with this condition, a multidisciplinary risk assessment led to deferral of the planned kidney transplantation. CONCLUSIONS:This case highlights the critical role of early genetic testing in patients with unexplained recurrent thrombosis. Identifying a novel HRG mutation not only establishes a rare etiology of hereditary thrombophilia but also guides personalized management and high-stakes surgical decisions, such as deferral of organ transplantation to avoid graft loss.
BACKGROUND:Acquired hemophilia A (AHA) is a rare hemorrhagic disease with scarce published information from developing countries. OBJECTIVES:The main objective was to describe the clinical manifestation and treatment, as well as laboratory characteristics of patients with AHA. PATIENTS/METHODS:We conducted a multicenter retrospective cohort study that included consecutive adult patients with AHA between 1999 and 2020 from Argentine hospitals. A comparison was made between the group achieving complete remission and the nonremission group. Logistic regression analysis was conducted to assess factors associated with death. RESULTS:The study included 68 patients. Nineteen hospitals from 11 cities were involved. The median follow-up was 12.5 months [interquartile range (IQR) 4-36]. Sixty-six patients (97%) had spontaneous bleeding at diagnosis (66% major bleeding). The median inhibitor titer was 27 (IQR 13-98) Bethesda units/ml (BU/ml). Hemostatic therapy was employed in 52 cases (67% utilized bypassing agents). The most used therapy was corticosteroids plus cyclophosphamide (40%). Complete remission was achieved in 45 patients (66%), with a median of 6 weeks (IQR 3-12). No differences were found in achieving complete remission with FVIII or inhibitor titer, nor in therapies. Nineteen patients died (28%). Eleven of the deaths were related to AHA or their treatments. The main cause of death was bleeding (n = 8). Seven out of eight deaths due to bleeding occurred within 72 h. CONCLUSION:We present the most extensive AHA study in Latin America. Unlike studies from other regions, we found a high rate of bleeding-related deaths. It may be necessary to improve early suspicion and diagnosis and enhance therapeutic management in our area.
Heparin-induced thrombocytopenia (HIT) requires clinical evaluation and laboratory testing using immunological assays with confirmation by functional assays such as serotonin release assay (SRA). The HIT-IgG chemiluminescence immunoassay (CLIA) is a rapid immunological assay; we aimed to assess the effect of heparin on this assay. The effect of low-dose (0.1 U/ml) and high-dose (100 U/ml) heparin on the CLIA HIT-IgG assay was evaluated, these concentrations aligning to those used for SRA. A cohort of available pretested patient material (plasma or serum) comprised samples negative for HIT-IgG (i.e., <1.0 U/ml) (n = 22), or positive for HIT-IgG (i.e., ≥1.0 U/ml) ( n = 25), with the latter split into 'low positive' (1.0-<10 U/ml; n = 16) and 'high positive' (≥10 U/ml; n = 9). Low-dose heparin, used for initiating serotonin release in SRA, had no appreciable effect on the CLIA HIT-IgG assay for any HIT-IgG group. High-dose heparin, used for inhibiting serotonin release in SRA, had a variable effect on HIT-IgG testing, generally reducing detected HIT-IgG levels in high positive samples, and mostly reducing detected HIT-IgG levels in low positive samples. However, some samples from negative and low positive groups showed counterintuitive increases in HIT-IgG signal. Heparin levels may influence HIT-IgG test values in various ways. Although high positive samples showed an expected decrease in signal with high-dose heparin, some low positive and negative samples showed unexpected increases in signal. Whether these findings improve identification of pathological HIT, or of variable HIT subtypes, requires further investigation.
Intracardiac thrombus is a rare but difficult-to-treat complication in premature infants, with limited therapeutic options. If an urgent neonatal surgical procedure is needed, rescue systemic thrombolysis may be considered as an option to hasten thrombus resolution. In the present case, we illustrate the successful lysis of a right ventricle intracardiac thrombus in a premature child prior to a neonatal emergent surgery for a severe congenital diaphragmatic hernia. The 1-day-old premature child with right-sided diaphragmatic hernia contracted preoperatively a right ventricle thrombus in the context of an early-onset septic shock. Systemic low-dose thrombolysis with urokinase (2000 then 3000 U/kg/h) was infused for 6 days with resolution of the thrombus and no immediate or delayed intracranial or postcongenital diaphragmatic hernia hemorrhagic complication, performed 72 h after thrombolysis cessation. Low-dose thrombolysis should be discussed if rapid thrombus resolution is required in case of intracardiac thrombus without thrombectomy option.
OBJECTIVE:The study explored the ex vivo effects of N. mossambica venom on blood morphology and coagulation. METHODS:Human blood was exposed ex vivo to 0.15 ng/μl N. mossambica venom. The 20-WBCT and standard laboratory coagulation assays; prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen levels were measured to analyze coagulation. Thromboelastography (TEG) was used to evaluate the viscoelastic properties of whole blood. Additionally, scanning electron microscopy (SEM) was performed to analyze red blood cell (RBC) morphology and clot structure. RESULTS:The 20-WBCT revealed a significantly longer clot formation time of venom-exposed samples; however, recorded results were within the accepted reference interval. Venom-exposed samples also showed decreased clot strength and stability. Morphological studies of venom-exposed samples revealed abnormal RBCs with extensive spicules on cell membranes. Furthermore, moderate fibrin fusion was visible in the fibrin network of exposed samples. Lastly, TEG was able to indicate changes in coagulation parameters where the others did not. CONCLUSION:N. mossambica venom interferes with hemostasis and contributes to RBC membrane instability. The study provides comparisons between laboratory-based and point-of-care coagulation analysis when exposed to N. mossambica venom. Additionally, it demonstrates the valuable insight TEG provides as a point-of-care test in snakebite management.
To investigate the effects of chronic hypoxia on platelet characteristics and overall coagulation function, and to elucidate the mechanisms underlying high-altitude-induced blood system disorders. Rats were exposed to chronic hypoxic conditions. Platelet counts were measured using routine blood analysis. Plasma levels of platelet activation markers (P-selectin and sCD40L) were quantified by ELISA. A label-free quantitative proteomic approach was employed to identify alterations in the platelet coagulation cascade proteome, with key findings validated by western blotting. Coagulation function was assessed via prothrombin time (PT) and thromboelastography (TEG). Chronic hypoxia resulted in a significant decrease in platelet count compared with controls. This was accompanied by a significant increase in plasma markers of platelet activation, P-selectin, and sCD40L (P < 0.05). Proteomic analysis revealed substantial alterations in the expression of coagulation-related proteins in platelets. These changes were confirmed by western blot, which showed significant upregulation of key coagulation factors, including F2, F9, F10, and F12. Consistent with these molecular changes, functional assays demonstrated a significant prolongation of PT and a marked reduction in overall coagulation function as measured by TEG, evidenced by a prolonged R-time and decreased α-angle and maximum amplitude values. Chronic hypoxia induces a state of platelet activation and thrombocytopenia but, paradoxically, leads to an overall net reduction in coagulation function. This dysfunction is linked to significant alterations in the expression of multiple coagulation factors within platelets, suggesting a complex regulatory mechanism beyond simple platelet counts that may contribute to the bleeding diathesis observed in high-altitude environments.
The use of inferior vena cava (IVC) filter is associated with long-term complications, including recurrent venous thromboembolism (VTE), particularly when filters remain indwelling. Current guidelines recommend the use of retrievable filters with removal whenever feasible. However, there is limited guidance regarding long-term anticoagulation management in patients with indwelling filters. We report the case of a 68-year-old man with an indwelling IVC filter, who developed a pulmonary embolism (PE) 3 months after completing 6 years anticoagulation for femoropopliteal deep vein thrombosis (DVT). During treatment for DVT, he had a prophylactic placement of retrievable IVC filter for a femur fracture with a high perioperative risk for VTE. Filter removal was unsuccessful. Three months after switching to extended thromboprophylaxis with sulodexide, and following a prolonged journey, he developed recurrent DVT and PE. Anticoagulation was restarted. This case highlights the potential prothrombotic role of indwelling IVC filters and the uncertainty regarding optimal anticoagulation strategies.
Hemophilia is an inherited bleeding disorder associated with substantial physical, emotional, and social challenges. This study evaluated the association of disease severity, bleeding frequency, and laboratory parameters with quality of life (QoL) among patients with hemophilia. A cross-sectional study was conducted among patients with hemophilia attending Cluster 2 Hospitals, Jeddah, Saudi Arabia. Clinical, haematological, and biochemical data were collected, and QoL was assessed using the 36-Item Short Form Health Survey (SF-36). Pearson's correlation, one-way analysis of variance, and multivariable logistic regression were performed. Patients with severe hemophilia demonstrated significantly lower physical functioning (35.58 vs. 55.92; P = 0.039) and emotional well being scores (48.59 vs. 61.32; P = 0.031) than those with mild disease. Recurrent joint bleeding (≥2 episodes within 6 months) independently predicted impaired QoL (AOR = 5.2; P < 0.001), while severe disease was also a significant predictor (AOR = 4.1; P = 0.001). Age was negatively correlated with QoL ( r = -0.48; P < 0.001). Serum ferritin showed a weak negative association ( r = -0.27; P = 0.003), whereas INR correlated positively with QoL ( r = 0.44; P < 0.001). Disease severity, recurrent bleeding, and advancing age are major determinants of reduced QoL in hemophilia. These findings support individualized prophylactic and multidisciplinary management strategies to improve patient outcomes.
Haemophilia A and haemophilia B are rare bleeding disorders characterized by prolonged bleeding episodes, bruising, and spontaneous bleeds. As the treatment landscape evolves, real-world data are essential to assess disease management practices. This study aimed to describe clinical outcomes for haemophilia A and haemophilia B patients in a real-world setting. Data were drawn from the Adelphi Haemophilia Disease Specific Programme (DSP), a cross-sectional survey of physicians and their patients conducted in France, Germany, Italy, Spain, the United Kingdom, and the United States between February 2020 and May 2021. Physicians provided data on patient demographics, clinical characteristics, bleed history, and treatment patterns. Analyses were descriptive. Overall, 75 physicians reported data for 739 patients with haemophilia A and 131 patients with haemophilia B, with a mean [standard deviation (SD)] age of 27 (14.9) and 25.5 (15.8) years. At data collection, the most common treatment received by haemophilia A patients was emicizumab (40%), while for haemophilia B, this was extended half-life factor (55%). Since switching to their current prophylactic treatment, 48% of haemophilia A patients and 54% of haemophilia B patients had experienced one or more episodes of breakthrough bleeding. Of these patients, the most common bleed type experienced in the 12 months prior to data collection was joint bleeds (53% of haemophilia A patients and 57% of haemophilia B patients). These findings highlight that despite prophylactic treatment, breakthrough bleeding, particularly within the joints, remains common, emphasizing the need for more effective therapeutic strategies.
BACKGROUND:Portal vein thrombosis (PVT) occurs in ~14% of patients with cirrhosis. Although apixaban and rivaroxaban are increasingly used in this population, comparative data are lacking. METHODS:We conducted a retrospective cohort study of adults with cirrhosis and PVT initiating apixaban or rivaroxaban. Propensity score matching (3 : 1) was used to balance baseline characteristics. The effectiveness outcome was a composite of hepatic decompensation or recurrent PVT and the safety outcome was a composite of gastrointestinal or intracranial bleeding. Cox proportional hazard models estimated hazard ratios (HRs). RESULTS:After matching, 312 patients were included (206 apixaban, 106 rivaroxaban). Use of apixaban (vs. rivaroxaban) was associated with similar effectiveness [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.50-2.06] and lower risk of bleeding (HR 0.62, 95% CI 0.19-2.12), although CI crossed the null value of 1. CONCLUSIONS:In this real-world cohort, apixaban and rivaroxaban demonstrated comparable effectiveness, with possible lower bleeding risk with apixaban.
Atypical thrombosis occurs in unconventional anatomical sites such as splanchnic, renal, gonadal, and cerebral venous vessels [1] . Genetic factors, as inherited thrombophilia could increase the risk of atypical thrombosis. Likewise, acquired disease, as cancer, autoimmune diseases (e.g. systemic lupus erythematosus and APS) or infections [e.g. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections], can trigger such an inflammatory response which lead to thrombocytosis and endothelial injury, thus promoting a hypercoagulability state [2,3] . Among cancers, myeloproliferative disorders are associated to an elevated risk of atypical thrombosis due to the increase in platelets or red blood cell count and the alteration of the balance between pro-coagulant e anticoagulant endothelial factors [4-6] . Other conditions that may predispose to atypical thrombotic events are platelet disfunction or structural abnormalities, chronic vascular diseases, pregnancy and medications. This case highlights the interplay of factors contributing to the development of thrombosis in an unconventional site and underscores the importance of a comprehensive diagnostic approach.
A 35-year-old woman presented with a deep vein thrombosis (DVT) and was diagnosed with protein S deficiency. She was treated with parenteral anticoagulation before switching to a direct oral anticoagulant. She presented to our practice 5 years later, where testing was repeated, demonstrating a type III deficiency pattern and a variant of uncertain significance in PROS1: c.1424G>A; p.Cys475Tyr. This cysteine residue participates in a disulfide bond in the sex hormone-binding globulin-like domain, which interacts with C4b-binding protein and is involved in several antithrombotic roles of protein S. This case report and the biochemical context support its pathogenicity.
Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) share overlapping symptoms, and emerging evidence implicates persistent fibrinoid microclots in their pathophysiology, contributing to impaired microcirculation. This review explores the role of microclots and evaluates thromboelastography (TEG) as a potential diagnostic tool. A comprehensive literature review was conducted using major biomedical databases. Studies indicate microclots are prevalent in both conditions. Long COVID patients demonstrate a TEG profile of increased clot strength (maximum amplitude) and reduced fibrinolysis (LY30), suggesting a persistent hypercoagulable state. Despite its advantages in real-time assessment, TEG interpretation faces challenges from preanalytical variability and a lack of standardized protocols. Promising therapeutic trials, including anticoagulants (e.g., apixaban) and fibrinolytics (e.g., lumbrokinase), require further validation. Technological advancements like AI-driven TEG analysis and portable devices could improve diagnostic precision. In conclusion, persistent microclots are a key pathophysiological feature. TEG provides a promising, novel approach for detecting coagulation abnormalities and could guide treatment, but requires standardization in future clinical trials. Future research should integrate multiomics biomarkers for precision therapeutics to improve patient outcomes.
Background Uterine fibroids are a prevalent gynecologic condition traditionally associated with heavy menstrual bleeding and pelvic pressure. However, emerging evidence suggests that large uterine fibroids may also contribute to venous thromboembolism (VTE) by causing mechanical compression of pelvic veins and the inferior vena cava, leading to venous stasis and subsequent thrombosis. This narrative review aims to consolidate current knowledge, discuss diagnostic strategies and management approaches for fibroid-associated VTE, and raise clinical awareness about this often-overlooked complication. Methods A comprehensive literature search was conducted across PubMed, PubMed Central, Embase, Scopus, and Google Scholar from January 2000 to April 2024. Studies examining the relationship between uterine fibroids and VTE, including case reports, observational studies, reviews, and management guidelines, were included. A descriptive synthesis of findings was performed. Results Twenty-four studies were included, demonstrating a consistent association between large uterine fibroids and increased VTE risk. Key mechanisms included venous compression, hormonal influences, and a fibroid-associated hypercoagulable state. Clinical presentations ranged from isolated deep vein thrombosis (DVT) to life-threatening pulmonary embolism (PE). Early diagnosis often relied on pelvic imaging such as ultrasound and MRI. Management strategies involved prompt anticoagulation, individualized surgical planning (primarily hysterectomy), and multidisciplinary coordination. In select cases, prophylactic anticoagulation was suggested for high-risk patients pending surgery. Conclusion Uterine fibroids should be recognized as a potential etiology for unexplained VTE, particularly in women without classic risk factors. Early imaging, anticoagulation, and surgical intervention, when appropriate, can optimize outcomes. Further research is needed to establish standardized screening and management guidelines for this underrecognized cause of thromboembolic disease.
Glanzmann thrombasthenia is an inherited platelet disorder resulting from defects in the integrin αIIbβ3 complex due to mutations in the ITGA2B or ITGB3 genes. This study aimed to elucidate the molecular and clinical characteristics of Glanzmann thrombasthenia in a Tunisian cohort. Twelve patients from 11 unrelated families were evaluated using clinical examination, platelet function assays, and comprehensive genetic analysis. Genomic DNA was extracted from peripheral blood, and the entire coding regions along with intron-exon boundaries of ITGA2B were amplified and sequenced via Sanger sequencing. Molecular analysis identified seven likely pathogenic variants in 9 out of 12 patients, including five missense mutations, of which two were novel (p.Tyr221Asp and p.Gly929Trp), one frameshift mutation, and one large deletion spanning exons 19-29. Additionally, three benign variants were detected in five patients, while one patient exhibited no ITGA2B mutation, suggesting a potential defect in ITGB3 . Three previously reported missense variants (p.Gln165His, p.Arg584Gln, and p.Ser957Leu) and an intronic splicing variant (c.2095-22_2095-19del) were also identified. Clinically, patients presented with heterogeneous bleeding phenotypes, predominantly epistaxis and gingival bleeding. Genotype-phenotype correlations underscore that mutation type and location critically influence disease severity. These findings expand the mutational spectrum of ITGA2B and emphasize the need for further functional studies to inform targeted therapies.
Alpha-2 antiplasmin (α2AP) deficiency is a rare fibrinolytic disorder characterized by unregulated plasmin activity and premature clot breakdown. Mechanistically, α2AP restrains fibrinolysis by (i) forming a covalent serpin complex with plasmin, (ii) blocking plasminogen binding to fibrin, and (iii) undergoing factor XIIIa-mediated cross-linking into fibrin to harden clots against local lysis. We describe a woman with decades of delayed postoperative bleeding, transfusion dependence, and a presumed diagnosis of von Willebrand disease, ultimately found to have congenital α2AP deficiency. Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis. Standard hemostatic panels may fail to detect α2AP deficiency, and testing with functional activity assays or genetic analysis is required. This case highlights diagnostic pitfalls and underscores the importance of considering fibrinolytic disorders in patients with unexplained or delayed bleeding.
Background Whole blood viscoelastic tests (VETs) are key for detecting fibrinolysis during orthotopic liver transplantation (OLT). The Quantra System introduces a novel parameter, clot stability to lysis (CSL), for quantifying fibrinolysis. The objective was to assess CSL performance relative to established VET measures. Methods Data were drawn from a multicenter, prospective study of adults undergoing OLT, with Quantra and ROTEM delta testing performed in parallel. This sub-analysis focused on fibrinolysis-positive samples, emphasizing discordant findings between platforms. Results Among 125 enrolled patients, 13 intraoperative samples involving the use of heparin showed discordant results. Calibrated automated thrombinography revealed that Quantra reagents produce slower, reduced thrombin generation compared to ROTEM, diminishing thrombin activatable fibrinolysis inhibitor (TAFI) activity. This enhances sensitivity of Quantra to detect fibrinolysis in these samples. Conclusions Quantra's CSL parameter demonstrated improved detection of fibrinolysis in heparinized samples and may support individualized fibrinolysis management during OLT. Broader clinical validation is warranted.
The most common type of stroke is ischemic stroke. Key regulators of thrombosis including KLF2, eNOS, TM and PAI-1 are considered as potential causes in ischemic stroke pathogenesis. This study examined gene expression and DNA methylation status of KLF2 and THBD genes in ischemic stroke patients. We selected 48 ischemic stroke patients and 48 healthy controls. Gene expression and methylation status of KLF2 and THBD genes were evaluated by real-time RT-PCR and MS-PCR, respectively. Clinical characteristics were also evaluated based on the methylation status of the patients. Statistical analysis was done using SPSS-26 software. mRNA expression of KLF2 ( P = 0.0157) and THBD ( P = 0.0070) was significantly reduced in ischemic stroke compared to the control. The hypermethylation of KLF2 and THBD genes significantly increased in ischemic stroke group ( P = 0.026 and P = 0.021, respectively). Moreover, significantly increased methylation of KLF2 and THBD genes were seen in early onset ischemic stroke group than control group ( P < 0.05). Hypermethylation in KLF2 and THBD was significantly associated with the occurrence of global aphasia. Also, hypermethylation in KLF2 was associated with dysarthria. The binary logistic regression analysis showed that KLF2 methylation, THBD methylation, obesity and asthma significantly and independently associated with the occurrence of ischemic stroke. However, diabetes and smoking revealed borderline association. Our study identified hypermethylation in KLF2 and THBD genes as a novel risk marker for ischemic stroke development. So, appropriate management of hypermethylation in KLF2 and THBD genes may be considered as therapeutic strategies for ischemic stroke patients.
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. We report a 36-year-old male cTTP patient with three compound heterozygous mutations. The patient was admitted for acute thrombocytopenia, with a 5-year history of chronic thrombocytopenia and 3 months of renal dysfunction. Initially diagnosed with immune thrombocytopenia, he was treated with glucocorticoids and the thrombopoietin receptor agonist, which provided temporary relief but failed to prevent recurrent thrombocytopenia. Ultimately, cTTP was confirmed by severely reduced ADAMTS13 activity (3.81%), the absence of ADAMTS13 inhibitors, and the identification of compound heterozygous mutations, including one novel pathogenic variant. Genetic analysis of the entire family helped in the characterization of the inheritance of this mutation. The patient was treated with fresh frozen plasma and later with prophylactic infusions. No clinical relapses occurred during follow-up.
OBJECTIVE:Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal blood disorder due to deficiency of the enzyme ADAMTS13. Recombinant ADAMTS13 (rADAMTS13) is a new treatment aimed at restoring enzyme activity. This study aimed to evaluate the efficacy and safety of rADAMTS13 compared to standard therapy or placebo in patients with congenital or acquired TTP using a systematic review and meta-analysis. METHODS:This PRISMA-compliant review searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and others up to March 30, 2025. We included randomized controlled trials (RCTs) comparing rADAMTS13 to standard therapy or placebo in patients with TTP. RESULTS:Two RCTs (one phase 3, one phase 2) involving 129 patients (67 rADAMTS13, 62 placebo) met inclusion criteria. No significant differences were observed for the primary clinical outcomes of acute TTP events (risk ratio (RR) = 0.58 [95% CI, 0.20-1.70]) or serious treatment-emergent adverse events (RR = 0.64 [95% CI, 0.31-1.34]). However, rADAMTS13 significantly increased ADAMTS13 activity levels (MD, 0.92 IU/ml [95% CI, 0.59-1.26]; P < 0.0001). Urticaria was significantly lower in the rADAMTS13 group (RR = 0.25 [95% CI, 0.06-0.96]; P = 0.04). No significant differences were noted for other adverse events (all P > 0.05). CONCLUSION:rADAMTS13 significantly enhances ADAMTS13 activity but did not demonstrate a significant improvement in key clinical outcomes. These findings, based on two RCTs, are of moderate to low certainty per GRADE assessment. Larger trials are needed to confirm the clinical benefits of rADAMTS13.
