Prevalence, Genetic Background, and Clinical Phenotype of Congenital Thrombophilia in Chronic Thromboembolic Pulmonary Hypertension.

Background: The role of congenital thrombophilia in chronic thromboembolic pulmonary hypertension (CTEPH) remains unresolved. Objectives: The purpose of this study was to investigate the prevalence, genetic background, and clinical phenotype of congenital thrombophilia in CTEPH. Methods: In total, 367 patients with CTEPH from May 2013 to December 2020 were consecutively enrolled in this cross-sectional study in FuWai Hospital and Peking Union Medical College Hospital in China. The primary outcome was the occurrence of congenital thrombophilia diagnosed through tests for congenital anticoagulants activity (including protein C, protein S, and antithrombin III), factor V Leiden and prothrombin G20210A sequence variants. Next-generation sequencing was conducted for patients with congenital thrombophilia. Clinical phenotype was compared between patients with and without thrombophilia. Results: A total of 36 (9.8%; 95% CI: 6.8%-12.9%) patients were diagnosed as congenital thrombophilia, including 13 protein C deficiency (3.5%; 95% CI: 1.6%-5.4%), 19 protein S deficiency (5.2%; 95% CI: 2.9%-7.5%), and 4 antithrombin III deficiency (1.1%; 95% CI: 0%-2.2%). No factor V Leiden or prothrombin G20210A sequence variants were identified. Genotype for patients with thrombophilia revealed that 10 (76.9%) protein C deficiency patients were PROC sequence variant carriers, 4 (21.1%) protein S deficiency were PROS1 sequence variant carriers, and 2 (50.0%) antithrombin III deficiency were SERPINC1 sequence variant carriers. In the logistic regression model, male sex (OR: 3.24; 95% CI: 1.43-7.31) and proximal lesion in pulmonary arteries (OR: 4.10; 95% CI: 1.91-8.85) had significant differences between the congenital thrombophilia and nonthrombophilia group in CTEPH patients. Conclusions: Congenital thrombophilia was not rare. Male sex and proximal lesion in pulmonary arteries might be the specific clinical phenotype for CTEPH patients with congenital thrombophilia.

miR-3064-5p and miR-4745-5p affect heparin sensitivity in patients undergoing cardiac surgery by regulating AT-III and factor X mRNA levels.

Subject: Perioperative regulation of coagulation function through heparin in patients undergoing cardiac surgery with cardiopulmonary bypass is an important part of performing cardiac surgery, and postoperative bleeding due to abnormal coagulation function caused by differences in heparin sensitivity in different individuals is an independent risk factor for postoperative complications and death. Method: Using an online database, 10 miRNAs interacting with AT-III and FX genes were predicted. Patients were divided into three groups according to the difference in activated clotting time (ACT) after the first dose of heparin (2.5 mg kg-1): group A: hyposensitive group (ACT < 480 s); group B: sensitive group (480 s ≤ ACT ≤ 760 s); and group C: hypersensitive group (ACT > 760 s). Perioperative and 24 h postoperative blood loss and other clinical data of patients in the three groups were recorded. Blood samples were collected before surgery, and RT-PCR was used to detect the levels of AT-III and FX gene mRNA and the levels of predicted 10 miRNAs. Result: Heparin sensitivity was positively correlated with AT-III mRNA levels and negatively correlated with FX gene mRNA levels in the three groups, and the blood loss in group B was significantly lower than that in groups A and C, which was statistically significant (p < 0.05). miR-3064-5p and miR-4745-5p expression levels were significantly different among group A, group B, and group C (p < 0.05) and were closely correlated with AT-III and FX gene mRNA expression levels, respectively. Conclusion: Differences in heparin sensitivity in patients undergoing cardiac surgery were associated with the mRNA expression of AT-III and FX genes, and the expression levels of miR-3064-5p and miR-4745-5p were found to be closely related to the AT-III and FX gene mRNA, respectively, indicating that miR-3064-5p and miR-4745-5p affect the differences in heparin sensitivity among different individuals by regulating the mRNA expression levels of AT-III and FX genes. Clinical Trial Registration: http://www.chictr.org.cn/abouten.aspx, identifier registration number: ChiCTR-2100047348.

Inherited and acquired causes renal vein thrombosis in an 11-year-old boy who was relieved after piperacillin-tazobactam and rivaroxaban treatment: a case report.

Background: Physiological hypercoagulability is a well-known condition in older populations, whereas thrombosis, especially in renal veins, is a rare occurrence in teenagers. This paper presents a pediatric case of renal venous infarction and thrombosis. Case Description: We report the case of an 11-year-old Chinese boy who presented with low back discomfort and was afraid to walk. Computed tomography (CT) revealed thrombosis in his renal veins and inferior vena cava. He was being treated for severe refractory mycoplasma pneumoniae pneumonia (MPP). He was treated with rivaroxaban and urokinase for thrombosis, and azithromycin for MPP. On day 2 after admission, his symptoms improved. Therefore, the dosage of rivaroxaban was decreased from 10 to 5 mg twice per day. On day 3 after admission, enhanced CT revealed new thromboses in the bilateral pulmonary trunks and arteries, inferior cava, right renal veins, bilateral common iliac veins, and internal iliac vein. The ultrasonography showed a strip hypoecho at the pulmonary artery bifurcation. All the above imaging suggested that antithrombotic therapy was insufficient. His plasma antithrombin (AT) III activity remained consistently low during hospitalization. The family history was re-examined and revealed that both his father and grandfather had experienced spontaneous pulmonary thrombosis around the age of 30. He was diagnosed with acquired and inherited thrombosis and inherited AT III deficiency. Following a medication regimen of piperacillin-tazobactam for 1 week and rivaroxaban (10 mg, twice daily), he was discharged and no thrombosis and other side effects or complications occurred in the following 3 months. Conclusions: This is a rare case of a teenager with inherited and acquired hypercoagulability. For refractory MPP pediatric patients with thrombosis, clinicians should consider whether hereditary factors, such as inherited AT III deficiency, are involved in thrombosis.

Low level of postoperative plasma antithrombin III is associated with portal vein thrombosis after liver surgery.

PURPOSE: Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy. METHODS: Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics. RESULTS: Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489). CONCLUSIONS: Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.

Association of Thrombophilic Factors in Pathogenesis of Osteonecrosis of Femoral Head in Indian Population.

PURPOSE: Role of heritable blood clotting disorders, both thrombophilias and hypofibrinolysis in causing avascular necrosis (AVN) of femoral head have been studied in regions like Europe and U.S.A. This study was done to investigate the role of heritable thrombophilias in ethnic Indian population. MATERIALS AND METHODS: A case control study of 150 patients (100 cases and 50 age and sex matched controls) of Indian Ethnicity with clinico-radiographically documented idiopathic AVN of femoral head was done after ethics committee approval. DNA was extracted from the blood and PCR analysis was used to study heritable thrombophilic gene mutation (G1691A Factor V Leiden). Enzyme-linked immunosorbent assay (ELISA)-based assays, were utilized to measure antigen levels of protein C, antithrombin III levels and protein S. RESULTS: Nine cases out of 100 showed deficiency of Protein C (9%) while no control showed deficiency of Protein C (p value: 0.028-significant, Odds ratio: 9.791) Ten cases showed deficiency of Protein S (10%) in study population as compared to one case (2%) in control population (p value: 0.038-significant, Odds ratio: 5.44). ATIII deficiency was more prevalent in control group i.e. 22% compared to 11% in study group. Factor V mutation was present in 3% cases as compared to one (2%) in control group. (p value is 0.393-not significant). CONCLUSION: Difference in thrombophilic mutations in various populations indicates possible effect of ethnicity on genetic profile in the development of AVN. This risk stratification will enable in near future early diagnosis and possible role of antithrombotics in disease prevention.

Long Term Survival of Patients Undergoing TIPS in Budd-Chiari Syndrome.

BACKGROUND: There has been significant improvement in understanding the etiology and management of Budd-Chiari Syndrome (BCS). Patients with chronic or acute-on-chronic BCS need radiological interventions in the form of angioplasty, hepatic vein/inferior vena cava stenting or Transjugular Intrahepatic Portosystemic Shunt (TIPS). Data regarding the long term follow up of patients undergoing TIPS is limited. We thus prospectively followed-up BCS patients who underwent TIPS at our center. METHODS: This study included 42 patients with BCS who underwent TIPS with a covered stent between 2004 and 2014. We analyzed the etiology, symptoms, severity, laboratory parameters and imaging pre and post TIPS. All patients underwent surveillance for hepatocellular carcinoma. RESULTS: Patients demographics included 26 males and 16 females with a mean age of 40.5 years (19-68 years). The mean Model for End-Stage Liver Disease score of the entire cohort was 15.38 (range: 9-25). Thirty-four patients were grouped into Rotterdam Class 2 and remaining into Class 3. There was significant improvement in ascites, gastrointestinal bleed, renal function and transaminase levels post TIPS. There were 11 deaths over the follow-up period - 4 within one month, 2 within six months and the rest after 3 years following TIPS. Median duration from clinical presentation to TIPS was 2.1 weeks and median survival till follow-up was 45.5 months (0-130 months). 33/42 patients underwent TIPS prior to 2013, and their median survival till follow-up was 55 months. Six out of eleven deaths that occurred within six months post-TIPS were before 2006; when the technique of TIPS creation was evolving. The cumulative 1 year, 5 years and 10 years OLT-free survival was 86%, 81% and 76%, respectively. Two patients underwent a liver transplant at 4 and 7 years after TIPS. CONCLUSION: Our results validate the role of TIPS in the management of patients with BCS. With the accessibility of TIPS, the requirement for liver transplantation has become rare.

Role of altered coagulation-fibrinolytic system in the pathophysiology of diabetic retinopathy.

The implications of altered coagulation-fibrinolytic system in the pathophysiology of several vascular disorders, such as stroke and myocardial infarction, have been well researched upon and established. However, its role in the progression of diabetic retinopathy has not been explored much. Since a decade, it is known that hyperglycemia is associated with a hypercoagulated state and the various impairments it causes are well acknowledged as independent risk factors for the development of cardiovascular diseases. But recent studies suggest that the hypercoagulative state and diminished fibrinolytic responses might also alter retinal homeostasis and induce several deleterious molecular changes in retinal cells which aggravate the already existing hyperglycemia-induced pathological conditions and thereby lead to the progression of diabetic retinopathy. The major mediators of coagulation-fibrinolytic system whose concentration or activity get altered during hyperglycemia include fibrinogen, antithrombin-III (AT-III), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF). Inhibiting the pathways by which these altered mediators get involved in the pathophysiology of diabetic retinopathy can serve as potential targets for the development of an adjuvant novel alternative therapy for diabetic retinopathy.

Initial diagnosis of the congenital disorder of glycosylation PMM2-CDG (CDG1a) in a 4-year-old girl after neurosurgical intervention for cerebral hemorrhage.

The congenital disorder of glycosylation characterized by a deficiency of phosphomannomutase 2 (PMM2-CDG) is the most common variant of congenital disorders of glycosylation. Besides typical clinical features, such as dysmorphism and abnormal body fat distribution, coagulation abnormities often lead to thromboembolic and hemorrhagic events in these patients. However, only 2 cases of intracerebral bleeding in patients with PMM2-CDG have been described so far. A 4-year-old girl who initially presented with symptoms resulting from raised intracranial pressure underwent acute neurosurgical intervention for intracranial hemorrhage. The differential diagnoses after MRI included arteriovenous malformation and intraparenchymal brain tumor. However, clinical investigations promoted the diagnosis of PMM2-CDG, which was supported further by neuropathological findings and finally confirmed by isoelectric focusing and mutational analysis. No major complications or neurological deficits were evident after surgery, and the patient was able to attend an integrated kindergarten. Unexplained intracranial hemorrhage should raise suspicion of a metabolic disorder and should be discussed with specialists to rule out an orphan disease such as PMM2-CDG.

Protective effects of antithrombin on free groin flaps after secondary venous stasis in the rat model.

BACKGROUND: The anticoagulant activity of heparin is well established and led to its widespread clinical use for the prophylaxis and treatment of venous thrombosis in microsurgery. Heparin accelerates antithrombin (AT)-mediated inhibition of clotting and fibrinolytic proteinases. AIM: The aim of the study is to determine whether the focussed delivery of AT by rinsing of free adipocutaneous groin flaps shows protective effects on flap survival, following a fatal secondary venous stasis in the rat model. Further, intravital video microscopy (IVM) is used to detect substance-specific alterations in microvascular perfusion with special focus on regional differences between central and peripheral flap regions. METHODS: Free microvascular groin flaps (n = 22) were transplanted to the neck in adult Sprague-Dawley rats. The flap pedicle was re-explored and the distal stump of the flap artery was catheterised 20 h later. Animals in group I (n = 11) were treated with 1 ml of Ringer's solution administered over 10 min via intraarterial infusion. Those in group II (n = 11) received 1 ml of AT (50 IU/kg). Afterwards, the flap vein was clamped for 35 min. The skin of the flaps and the native contralateral groin was examined by IVM using the plasma-marker fluorescein isothiocyanate (FITC)-dextran and carboxyfluorescein diacetate succinimidyl ester (CFDA-SE)-labelled thrombocytes. After 14 days, the viability of the flaps was evaluated. RESULTS: The treatment with AT significantly increased the functional capillary density (FCD) of the flaps. After 14 days, flap necrosis occurred in nine animals of group I and three animals of group II, respectively. No partial flap loss was detected. CONCLUSIONS: The focussed delivery of AT resulted in significantly improved flap salvage. The results may reinforce the clinical custom of AT substitution in the setting of major surgical procedures such as elaborate microsurgical reconstructions, at least in cases with diminished AT levels.

Deficiency Of Antithrombin III (AT III) - Case Report and Review of the Literature.

Antithrombin III (AT III) is a plasmatic α-glicoprotein formed by a single peptidic chain. AT III inhibits thrombin (first target) and free Xa, IXa ,VIIa plasmatic factors. In plasma AT III is found under two forms: α-antithrombin and ß-antithrombin. Deficiency of AT III represents a risk factor for thromboembolic disease. There are known both quantitative and qualitative AT III deficiencies. Incidence of AT III inherited deficiency is relative rare (1:10.000). Acquired deficiency of AT III is more frequent. The transmission of AT III deficiency is autosomal dominant with variable shield factor. Homozygous is incompatible with life (death immediately after birth). Thrombosis appears around the age of twenty years, and in 4-5 decades of life 2/3 of patients are symptomatics. Traumatisms, surgical interventions, estrogenic treatment, precipitated thrombotic complications. Obesity and dyslipidemic syndrome are risk factors. Thrombosis affects the venous system at these patients. Arterial thrombosis are less reported. The most frequent localisations are: the veins of the legs, mesenteric veins, cave veins, superficial periombilical veins. Treatment of AT III deficiency is: administration of AT III concentrates (with a plasmatic level by 80% from normal value) and heparinotherapy. The treatment with AT III concentrates is for patients which faced major surgical interventions, pregnant women with AT III deficiency. The women with AT III deficiency should avoid the utilisation of oral contraceptives.

Controllable production of low molecular weight heparins by combinations of heparinase I/II/III.

Enzymatic depolymerization of heparin by heparinases is promising for production of low molecular weight heparins (LMWHs) as anticoagulants, due to its mild reaction conditions and high selectivity. Here, different heparinase combinations were used to depolymerize heparin. Heparinase I and heparinase II can depolymerize heparin more efficiently than heparinase III, respectively, but heparinase III was the best able to protect the anticoagulant activities of LMWHs. Heparinase III and heparinase I/II combinations were able to efficiently depolymerize heparin to LMWHs with higher anticoagulant activity than the LMWHs produced by the respective heparinase I and heparinase II. HepIII and HepI is the best combination for maintaining high anti-IIa activity (75.7 ± 4.21 IU/mg) at the same Mw value. Furthermore, considering both the changes in molecular weight and anticoagulant activity, the action patterns of heparinase I and heparinase II were found not to follow the exolytic and processive depolymerizing mechanism from the reducing end of heparin.

ALG1-CDG: a new case with early fatal outcome.

Congenital disorders of glycosylation (CDG) are a growing group of inherited metabolic disorders where enzymatic defects in the formation or processing of glycolipids and/or glycoproteins lead to variety of different diseases. The deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, encoded by the human ortholog of ALG1 from yeast, is known as ALG1-CDG (CDG-Ik). The phenotypical, molecular and biochemical analysis of a severely affected ALG1-CDG patient is the focus of this paper. The patient's main symptoms were feeding problems and diarrhea, profound hypoproteinemia with massive ascites, muscular hypertonia, seizures refractory to treatment, recurrent episodes of apnoea, cardiac and hepatic involvement and coagulation anomalies. Compound heterozygosity for the mutations c.1145T>C (M382T) and c.1312C>T (R438W) was detected in the patient's ALG1-coding sequence. In contrast to a previously reported speculation on R438W we confirmed both mutations as disease-causing in ALG1-CDG.

A case of acute arterial thrombosis caused by nephrotic syndrome.

Venous thromboembolic complications are frequently caused by nephrotic syndrome, while arterial thrombosis has rarely been reported. We report the successful treatment of a 53-year-old man who suffered from sudden severe pain of the left lower limb and facial edema. Abdominal computed tomography showed that the left common iliac artery was occluded from its origin. Although he had left peroneal nerve paralysis, thrombectomy and fasciotomy were performed for limb salvage. Renal biopsy revealed minimal change nephrotic syndrome after the operation. No recurrence has been observed. Nephrotic syndrome might be considered as a cause of acute arterial thrombosis.

Antithrombin III Prevents Early Bacterial Translocation in Burn Injury.

We experimentally studied the effects of antithrombin III (AT III) on bacterial translocation (BT) and intestinal morphology in the early period of burn injury. For this aim, 30 male albino rats were used. A sham burn group (group 1, no. 10) was exposed to 21 °C water. A burn group (group 2, no. 10) and a burn + AT III group (group 3, no. 10) were exposed to 95 °C water for 10 sec, producing full-thickness burn in 30% of the total body surface area. In group 3 the rats received 250 U/kg AT III via the right jugular vein, 15 min before burn injury. One ml 0.9% NaCl was given as a placebo in group 1 and in two rats by the same route. All group 3 rats were sacrificed on day 2 post-burn using an overdose anaesthetic. Cultures of the mesenteric lymph nodes, liver, spleen, blood, and caecal contents were performed. Histopathological examinations, including polymorph nuclear leukocyte (PNL) infiltration and villus morphologies, were qualitatively evaluated on the resected distal ileal segment. The incidence of BT was 1/10 (10%) in group 1, 7/10 (70%) in group 2, and 1/10 (10%) in group 3. A significant increase in BT incidence was observed in group 2 compared with groups 1 and 3 (p = 0.02), while a significant decrease in BT incidence was found in group 3 rats with AT III treatment. Although the PNL infiltration rate was reduced by AT III treatment, a significant decrease was not found compared with group 2 (50% and 90%, respectively). On the other hand, the villus degeneration rate was significantly reduced by AT III treatment compared with group 2 (30% and 90%, respectively). These results suggest that the incidence of BT was enhanced by the burn injury. AT III decreased the incidence of BT in the early period of burn injury. We conclude that AT III can be effectively used to protect from intestinal mucosal injury and to prevent bacterial translocation, especially in early post-burn period.

Changes of AT-Ⅲ and PAI-1 in the Blood of Patients With Sudden Sensorineural Hearing Loss / 听力学及言语疾病杂志

Objective To study the changes of AT-III and PAI-1 in the blood of patients with sudden sensorineural hearing loss(SSHL) and investigate the relationship between their levels and the disease.Methods The levels of AT-III and PAI-1 in the blood of 44 patients with SSHL and 30 healthy volunteers were detected using chromogentic substrate method.Results The changes of AT-III and PAI-1 in the blood of patients with SSHL were correlated with the process of the disease.There was significant difference between the levels of AT-III and PAI-1 in the blood of patients within 3 days and that of patients beyond 1 week(P

THE STUDY OF ANTITHROMBOTIC EFFECT AND MECHANISM OF PROPYLENE GLYCOL MANNATE SUFATE / 中国海洋药物

The influences of propylene glycol mannate sulfate (PGMS) on experimental thrombosis and thrombolysis in vivo were studies after iv 8. 125, 6. 25, 12. 5 , 25mg/Kg in rabbits, and the effect of antithrombosis of PGMS was compared with that of heparin. The results showed that PGMS possessed remarkable effect of antithrombosis. In order to explore the mechanism of antithrombosis of PGMS, we studied the influences on the fibrinolytic and coagulant function of rabbits. The results showed that PGMS can pronouncedly prolong the prothrombin time (PT), thrombin time (TT), kaolin partial thromboplastin time (KPTT), and enhance the activity of antithrombin-III (AT -III). PGMS can cause a remarkable increase in fibrin degradation product (FDP) , shorten euglobulin lysis time (ELT) , and a decrease in the contents of fibrinogen and plasminogen activity. These results suggested that PGMS probably exert the antithrombotic effect by inhibiting coagulation and activating fibrinolysis.