肝硬化静脉曲张出血患者门静脉血栓的临床特征

目的 探讨肝硬化伴食管胃静脉曲张出血（GVB）患者门静脉血栓（PVT）的发生情况及临床特征。方法 回顾性分析2015至2017年复旦大学附属中山医院收治的肝硬化伴GVB患者的临床资料，根据门静脉CT检查结果，将纳入的患者分为PVT组和无PVT组。比较两组实验室检查指标、肝静脉压力梯度（HVPG）和胃镜特征等。采用多因素logistic回归分析评估PVT的独立相关因素。结果 共纳入356例患者，其中117例（32.9%）有PVT。与无PVT组相比，PVT组脾切除率、白细胞计数、血小板计数和D-二聚体水平更高，血红蛋白水平更低（P<0.05）;PVT组重度食管静脉曲张和伴有红色征的食管静脉曲张发生率更高（P<0.05）。两组HVPG差异无统计学意义。多因素logistic分析显示，白细胞计数增加、D-二聚体水平升高和重度食管静脉曲张与PVT发生独立相关（P<0.05）。结论 肝硬化伴GVB患者PVT发生率较高；该类PVT患者机体炎症和促凝水平更高，伴有更严重的门静脉高压。     

Evaluation of bleeding and thrombotic events during long‐term use of romiplostim in patients with chronic immune thrombocytopenia (ITP)

Summary. Background: Romiplostim is a peptibody protein that raises platelet counts during long‐term treatment of patients with chronic immune thrombocytopenia (ITP). Clinical outcomes related to increased platelet counts include a reduced risk of bleeding and a potential risk of thrombosis. Objective: To evaluate bleeding and thrombotic events occurring in chronic ITP patients during two phase 3, randomized, placebo‐controlled, 24‐week studies of romiplostim and during subsequent treatment in an open‐label extension study. Patients/Methods: In the phase 3 trials, 125 patients were randomized to romiplostim or placebo; romiplostim dose was adjusted to maintain platelet counts of 50–200 × 10⁹ L^?1. Patients who completed the phase 3 trials could enroll in the extension study in which all patients received romiplostim. Results: In the phase 3 trials, a significantly greater percentage of patients treated with placebo (34%) had bleeding adverse events of moderate or greater severity than did patients treated with romiplostim (15%, P = 0.018). In the extension study, the incidence of bleeding adverse events of moderate or greater severity decreased from 23% of patients in the first 24 weeks to 12% after 24–48 weeks, remaining ≤ 6% thereafter. The exposure‐adjusted incidence of thrombotic events was 0.1 per 100 patient‐weeks in the phase 3 studies, and 0.08 per 100 patient‐weeks in the extension study where patients received romiplostim for up to 144 additional weeks. Conclusions: The incidence and severity of bleeding was decreased in chronic ITP patients treated with romiplostim compared with placebo, and the incidence of thrombotic events was not different between the two groups.     

Lower coated‐platelet levels are associated with early hemorrhagic transformation in patients with non‐lacunar brain infarction

Summary. Background: Coated‐platelets, representing a subset of platelets with procoagulant potential, are elevated in patients with non‐lacunar ischemic stroke and decreased in patients with spontaneous intracerebral hemorrhage. However, within the non‐lacunar patient population there are individuals with lower levels of coated‐platelets, which raises the possibility that these individuals would be susceptible to early hemorrhagic transformation (HT) of ischemic stroke. Objective: Because extremes in coated‐platelet potential may be associated with either thrombotic or hemorrhagic events, we undertook a pilot study to investigate whether there is an association between coated‐platelet production and the presence of early HT in patients with non‐lacunar ischemic stroke. Patients and methods: Coated‐platelet levels were determined in 115 consecutive eligible patients with a diagnosis of non‐lacunar ischemic stroke. Early HT was determined on CT scan examination and confirmed by MRI studies. The distribution of coated‐platelet levels was summarized using the median and interquartile range (25th–75th percentiles) and compared statistically between patients with and without early HT using the non‐parametric Wilcoxon rank sum test. Results: The median coated‐platelet level in all non‐lacunar stroke patients was 38.0% (interquartile range 30.5–48.3%). Early HT was detected in 11 patients (9.6%), and these patients had significantly lower coated‐platelet levels compared with those without early HT [median 25.1% (interquartile range 20.4–35.5%) vs. 39.2% (31.6–49.5%), P = 0.003]. Conclusions: Lower levels of coated‐platelets are associated with the presence of early HT in patients with non‐lacunar ischemic stroke.     

Relationship between post‐treatment platelet reactivity and ischemic and bleeding events at 1‐year follow‐up in patients receiving prasugrel

Summary. Background: Post‐treatment platelet reactivity (PR) is associated with ischemic and bleeding events in patients receiving P2Y12 receptor antagonists. Objectives: We aimed to study the relationship between post‐treatment PR after a 60‐mg loading dose (LD) of prasugrel and 1‐year thrombotic and bleeding events. Method: Patients were prospectively included in this multicenter study if they had a successful percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and received prasugrel. The platelet reactivity index (PRI) was measured using the Vasodilator‐Stimulated Phosphoprotein index (VASP) after a prasugrel LD. Endpoints included the rate of thrombotic events and bleeding events at 1 year. Results: Among the 301 patients enrolled, 9 (3%) were lost to follow‐up at 1 year. The rates of thrombotic and bleeding events at 1 year were of 7.5% and 6.8%, respectively. Receiver‐operating curve (ROC) analysis demonstrated an optimal cut‐off value of 53.5% of PRI to predict thrombotic events at 1 year. Using this cut‐off value we observed that patients exhibiting high on‐treatment platelet reactivity (HTPR) had a higher rate of thrombotic events (22.4% vs. 2.9%; P < 0.001). In parallel the optimal cut‐off value of PRI to predict bleeding was 16%. Patients with a PRI ≤ 16% had a higher rate of bleeding events compared with those with a PRI > 16% (15.6% vs. 3.3%; P < 0.001). In multivariate analysis, the PRI predicted both thrombotic and bleeding events (OR: 1.44, 95% confidence interval [CI]: 1.2–1.72; P < 0.001 and OR: 0.75, 95% CI: 0.59–0.96; P = 0.024 [respectively, per 10% increase]). Conclusion: Platelet reactivity measurement after a prasugrel LD predicts both ischemic and bleeding events at 1 year follow‐up for ACS patients undergoing PCI.     

A randomized,double‐blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill,non‐surgical patients: CERTIFY Study

Summary. Background: In medically ill patients, no contemporary double‐blind head‐to‐head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. Objectives: To compare the efficacy and safety of certoparin with those of UFH. Patients/Methods: In this double‐blind, randomized, controlled trial, acutely ill, non‐surgical patients aged ≥ 70 years were randomized to certoparin (3000 U of anti‐factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non‐fatal pulmonary embolism and venous thromboembolism‐related death, and was assessed by a blinded central adjudication committee. Non‐inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. Results: Three thousand two hundred and thirty‐nine patients aged 78.8 ± 6.3 years were treated for 9.1 ± 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of ? 0.59% [95% confidence interval (CI) ?2.09 to 0.92; P < 0.0001 for non‐inferiority], and an OR of 0.87 (95% CI 0.60–1.26; P = 0.0001 for non‐inferiority). Major bleeding occurred in 0.43% of certoparin‐treated patients and 0.62% of UFH‐treated patients (OR 0.69; 95% CI 0.26–1.83). Any bleeding occurred at 3.20% in certoparin‐treated patients vs. 4.58% in UFH‐treated patients (OR 0.69; 95% CI 0.48–0.99; P < 0.05), and 5.73% of certoparin‐treated patients and 6.63% of UFH‐treated patients experienced serious adverse events. All‐cause mortality was 1.27% in certoparin‐treated patients and 1.36% in UFH‐treated patients. Conclusions: In acutely ill, non‐surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti‐FXa once daily) was non‐inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.     

Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator‐stimulated phosphoprotein phosphorylation assay

Summary. Background and Aim: The prognostic value of the vasodilator‐stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) for thrombotic adverse events has been shown in independent studies. As no direct comparison between the two methods has been made so far, we investigated which laboratory approach has a better predictive value for stent thrombosis. Methods: The VASP phosphorylation assay and MEA were performed in 416 patients with coronary artery disease undergoing percutaneous coronary intervention. The rate of stent thrombosis was recorded during a 6‐month follow‐up. Results: Definite stent thrombosis occurred in three patients (0.7%) and probable stent thrombosis in four (1%). Receiver operating characteristic (ROC) analysis demonstrated that MEA distinguishes between patients with or without subsequent stent thrombosis better than the VASP phosphorylation assay: the area under the ROC curve was higher for MEA (0.92; P = 0.012) than for the VASP phosphorylation assay (0.60; P = 0.55). At equal levels of sensitivity (100%), the specificity was greater for MEA than for the VASP phosphorylation assay (86% vs. 37%). Stent thrombosis occurred in 9% of patients with platelet hyperreactivity in MEA, who were simultaneously clopidogrel non‐responders in the VASP phosphorylation assay. Interestingly, clopidogrel non‐responders in the VASP phosphorylation assay without platelet hyperreactivity in MEA did not suffer from stent thrombosis. Conclusions: Platelet hyperreactivity in MEA might be a better risk predictor for stent thrombosis than the assessment of the specific clopidogrel effect with the VASP phosphorylation assay.     

不同分型的肝硬化门静脉血栓的临床特点

目的探讨不同分型的肝硬化门静脉血栓(PVT)的临床特点及差异。方法回顾性分析2016年8月至2019年8月昆明医科大学第二附属医院消化内科收住的肝硬化合并PVT患者107例,依据解剖因素将其分为3组:单纯门静脉主干血栓形成组(主干组,n=17)、单纯分支血栓形成组(分支组,n=35)和门静脉主干并分支血栓形成组(主干+分支组,n=55)。分别从一般临床资料、实验室指标、影像学指标、肝储备及相关评分等方面对不同PVT部位进行比较分析。检验水准取α=0.05,采用分割χ²检验时,校正为α′=0.0125。结果主干+分支组患者更易合并消化道出血,主干组次之,分支组最低,三组间比较差异有统计学意义(χ²=27.832,P<0.01),两两比较示,分支组与主干+分支组、主干组与主干+分支组差异有统计学意义(P<0.0125);主干+分支组D-二聚体水平最高,主干组次之,分支组最低,三组间比较(H=37.439,P<0.01)及两两比较差异均有统计学意义(P<0.05,P<0.01);主干+分支组血浆D-二聚体和纤维蛋白原比值(D/F)最高,主干组次之,分支组最低,三组间比较(H=33.973,P<0.01)及两两比较差异均有统计学意义(P<0.05,P<0.01)。结论血栓累及主干+分支的肝硬化PVT患者,发生消化道出血的风险最高,主干次之,分支最低。D-二聚体、D/F水平的高低可能对不同部位的肝硬化PVT诊断有一定的参考价值。     

G‐protein β3 subunit polymorphism and bleeding in the orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16 trial

Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G‐protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41‐amino‐acid deletion) of the human G‐protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub‐study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re‐hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non‐T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). Conclusion: The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.     

Single intravenous administration of TB‐402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose‐escalating,randomized, controlled trial

Summary. Background: TB‐402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half‐life. We evaluated the efficacy and safety of a single administration of TB‐402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose‐escalating, randomized, enoxaparin‐controlled, open‐label study. Patients were post‐operatively assigned to a single dose of TB‐402 (0.3, 0.6 or 1.2 mg kg^?1) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB‐402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non‐major bleeding. Results: Total VTE was lower in all TB‐402 groups compared with enoxaparin: 16.7%(95% CI 9.8–26.9), 23.9%(95% CI 15.3–35.3), 24.1%(95% CI 16.0–34.5) and 39.0%(95% CI 28.8–50.1) for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively (P = 0.003 for TB‐402 0.3 mg kg^?1 vs. enoxaparin). The incidence of total VTE in the pooled TB‐402 groups was 21.6% (95%CI 16.6–27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2–29.6). Major or clinically relevant non‐major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively. Conclusions: TB‐402, as a single post‐operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non‐major bleeding was similar to enoxaparin 40 mg for TB‐402 0.3 and 0.6 mg kg^?1.     

Risk factors for post‐thrombotic syndrome in patients with a first deep venous thrombosis

Summary. Background: Post‐thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). Objectives: To determine the risk of PTS after DVT and to assess risk factors for PTS. Methods: Patients were recruited from the Multiple Environmental and Genetic Assessment (MEGA) study of risk factors for venous thrombosis. Consecutive patients who suffered a first DVT of the leg were included in a follow‐up study. All patients completed a questionnaire and DNA was obtained. PTS was ascertained in a structured interview using a clinical classification score. Results: The 1‐year cumulative incidence of PTS was 25% and 7% for severe PTS. Elastic compression stockings were prescribed in 1412 (85%) patients. The majority used their stockings every day. Women were at an increased risk compared with men [risk ratio (RR) 1.5, 95% confidence interval (CI) 1.3–1.8]. Similarly, obese patients had a 1.5‐fold increased risk of PTS compared with normal weight patients (RR 1.5, 95% CI 1.2–1.9), with a 1‐year cumulative incidence of 34% compared with 22%. Patients who already had varicose veins had an increased risk (RR 1.5, 95% CI 1.2–1.8) of PTS. DVT in the femoral and iliac vein was associated with a 1.3‐fold increased risk of PTS compared with popliteal vein thrombosis (RR 1.3, 95% CI 1.1–1.6). Patients over 60 years were less likely to develop PTS than patients below the age of 30 (RR 0.6, 95% CI 0.4–0.9). Malignancy, surgery, minor injury, plaster cast, pregnancy or hormone use did not influence the risk of PTS neither did factor (F)V Leiden nor the prothrombin 20210A mutation. Conclusions: PTS is a frequent complication of DVT, despite the widespread use of elastic compression stockings. Women, obese patients, patients with proximal DVT and those with varicose veins have an increased risk of PTS, whereas the elderly appeared to have a decreased risk.     

Fondaparinux treatment of acute heparin‐induced thrombocytopenia confirmed by the serotonin‐release assay: a 30‐month, 16‐patient case series

See also Greinacher A. Immunogenic but effective: the HIT‐fondaparinux brain puzzler. This issue, pp 2386–8; Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin‐induced thrombocytopenia: a case series. This issue, pp 2501–3. Summary. Background: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin‐induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet‐activating anti‐platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparin‐dependent, platelet‐activating antibodies. Objectives: To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin‐release assay (SRA), a sensitive and specific test for platelet‐activating HIT antibodies. Methods/Patients: We reviewed consecutive eligible patients with SRA‐positive HIT (mean peak serotonin release, 91% [normal, < 20%]; mean IgG‐specific PF4/heparin enzyme immunoassay result, 2.53 optical density units [normal, < 0.45 units]) in one medical center over a 30‐month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 × 10⁹ L^?1). Where available, plasma samples were used to measure thrombin–antithrombin (TAT) complex levels. Results: Sixteen patients with SRA‐positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty‐six per cent of patients had HIT‐associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progressive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. Conclusion: Fondaparinux shows promise for the treatment of patients with SRA‐positive acute HIT.     

Prevalence and predictors for post‐thrombotic syndrome 3 to 16 years after pregnancy‐related venous thrombosis: a population‐based,cross‐sectional,case‐control study

Background:  The long‐term outcome of pregnancy‐related venous thrombosis (VT) is not known. Objectives:  To assess predictors and long‐term frequency of post‐thrombotic syndrome (PTS) after pregnancy‐related VT. Patients/Methods:  In 2006, 313 women with pregnancy‐related VT during 1990–2003 and 353 controls answered a comprehensive questionnaire that included self‐reported Villalta score as a measure of PTS. Cases were identified from 18 Norwegian hospitals using the Norwegian Patient Registry and the Medical Birth Registry of Norway. The latter was used to select as possible controls women who gave birth at the same time as a case. Thirty‐nine patients and four controls were excluded because of VT outside the lower limbs/lungs or missing Villalta scores. Two hundred and four patients had DVT in the lower limb and 70 had pulmonary embolism (PE). The control group comprised 349 women naive for VT at the time of the index pregnancy. Results:  Forty‐two per cent of cases with DVT in the lower limb, compared with 24% of cases with PE and 10% of controls, reported a Villalta score of ≥ 5. Severe PTS (Villalta score of ≥ 15) was reported among 7%, 4% and 1%. Proximal postnatal, but not antenatal, thrombosis was a strong predictor of PTS with an adjusted odds ratio of 6.3 (95% confidence interval, 2.0–19.8; P = 0.002). Daily smoking before the index pregnancy and age above 33 years at event were independent predictors for post‐thrombotic syndrome. Conclusions:  PTS is a common long‐term complication after pregnancy‐related DVT. Proximal postnatal thrombosis, smoking and higher age were independent predictors of the development of PTS.     

Predictors of the post‐thrombotic syndrome with non‐invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis

Summary. Background: Post‐thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) affecting a large number of patients. Because of its potential debilitating effects, identification of patients at high risk for the development of this syndrome is relevant, and only a few predictors are known. Objectives: To assess the incidence and potential predictors of PTS. Methods: We prospectively followed 111 consecutive patients for 2 years after a first episode of objectively documented DVT of the leg. With non‐invasive venous examinations, residual thrombosis, valvular reflux, calf muscle pump function and venous outflow resistance were assessed at 6 weeks, 3 months, 6 months, 1 year, and 2 years. The Clinical, Etiologic, Anatomic, and Pathophysiologi classification was used to record the occurrence and severity of PTS. Regression analysis with area under the receiver operating characteristic (ROC) curve was performed to identify potential predictors. Results: The cumulative incidence of PTS was 46% after 3 months, and the incidence and severity did not increase further. Men appeared to be at increased risk as compared with women (risk ratio [RR] 1.4, 95% confidence interval [CI] 0.9–2.2), as were patients over 50 years as compared with younger patients (RR 1.4%, 95% CI 0.9–2.1). Patients with thrombosis localized in the proximal veins at diagnosis had an increased risk of PTS as compared with patients with distal thrombosis (RR 2.3%, 95% CI 1.0–5.6). PTS developed in 32 of 52 patients (62%) with residual thrombosis in the proximal veins 6 weeks after diagnosis, as compared with 17 of 45 patients (38%) without residual proximal thrombosis, leading to a 1.6‐fold increased risk (95% CI 1.0–2.5). The presence of valvular reflux in the superficial veins was also a predictor at 6 weeks, with a 1.6‐fold increased risk as compared with patients without superficial reflux (95% CI 1.1–2.3). A multivariate analysis of these predictors yielded an area under the ROC curve of 0.72 (95% CI 0.62–0.82). Conclusions: PTS develops in half of all patients within 3 months, with no further increase being seen up to 2 years of follow‐up. Male sex, age over 50 years, proximal localization of the thrombus at entry, residual proximal thrombosis and superficial valvular reflux at 6 weeks seem to be the most important predictors of PTS in patients with a first episode of DVT. Duplex scanning 6 weeks after diagnosis appears to be clinically useful for the identification of patients at risk of PTS.     

High rate of unprovoked recurrent venous thrombosis is associated with high thrombin‐generating potential in a prospective cohort study

Summary. Objective: To determine the predictive value of measurement of parameters of thrombin generation for unprovoked recurrent venous thrombosis. Methods: Measurements were made of thrombin generation in a prospective cohort study of 188 patients with a first episode of venous thrombosis that was unprovoked, or provoked by a non‐surgical trigger. Results: The endogenous thrombin potential (ETP) was the only parameter associated with unprovoked recurrent thrombosis in a multivariate model [hazard ratio (HR) 1.3 per 100 nmol L min^?1 increase, 95% confidence interval (CI) 1.0–1.6]. Patients with a high ETP had a significantly higher rate of unprovoked recurrence than those with a low ETP (HR 2.9, 95% CI  1.3–6.6, cumulative recurrence at 4 years 27% vs. 11%). Patients with an unprovoked first event had a significantly higher rate of unprovoked recurrence than those with a provoking factor (HR 2.7, 95% CI  1.2–6.1), and in these patients there was a significantly higher rate of unprovoked recurrence in association with a high ETP (HR 4.0, 95% CI  1.3–11.8). After adjustment for D‐dimer, thrombophilia, sex, and whether or not the first event was unprovoked, a high ETP remained a significant predictor of recurrence (HR 2.6, 95% CI  1.2–6.0). Conclusions: This study demonstrates a high rate of unprovoked recurrent venous thrombosis in patients presenting with a first episode of venous thrombosis and a high ETP.     

Neutrophil extracellular traps are associated with enhanced procoagulant activity in liver cirrhosis patients with portal vein thrombosis

ObjectivePatients with liver cirrhosis (LC) commonly exhibit hypercoagulability and tend to develop thrombosis. Neutrophil extracellular traps (NETs) are associated with a variety of thrombotic conditions, but their possible value in portal vein thrombosis (PVT) is not known. We assessed whether NETs promote thrombosis and contribute to the procoagulant state in patients with LC.MethodsThe circulating levels of NETs markers (myeloperoxidase, neutrophil elastase, citrullinated histone H3) were measured in 72 patients (median age, 55 years; 48 [66.7%] men) with LC from September 2020 to February 2021. Then they were divided into two groups: patients with or without PVT. NETs procoagulant activity was assessed based on thrombin–antithrombin complex (TAT complex) and Factor X. The levels of plasma markers were determined by ELISA.ResultsThere were 28 patients with PVT and 44 patients without PVT. The levels of NETs markers and hypercoagulability markers in the plasma of cirrhosis patients with PVT were significantly higher than those of cirrhosis patients without PVT (p < 0.05). Additionally, the levels of the NETs markers correlated with TAT complex and Factor X (Spearman correlation rho >0.73, p < 0.0001).ConclusionsNeutrophil extracellular traps seem to enhance procoagulant activity in LC patients with PVT; thus, they may be a practical predictor of PVT as well as a rapid and easy‐to‐use diagnostic and treatment guide for PVT in patients with cirrhosis.     

Thrombosis of the portal venous system

Portal vein thrombosis (PVT) is a rare cause of portal hypertension. Its diagnosis has been facilitated by improvements in imaging techniques, in particular Doppler sonography. The prevalence is about 1% in the general population, but much higher rates are observed in patients with hepatic cirrhosis (7%, range 0.6–17%), particularly those who also have hepatocellular carcinoma (HCC) (35%). The most common causes of PVT are myeloproliferative disorders, deficiencies of anticoagulant proteins, prothrombotic gene mutations, cirrhosis with portal hypertension, and HCC. Its development often requires the presence of two or more risk factors (local and/or systemic), e.g., a genetically determined thrombophilic state plus an infectious episode or abdominal surgery. It is clinically useful to distinguish between cirrhotic and noncirrhotic forms. Portal vein thrombosis is also traditionally classified as acute or chronic, but this distinction is often difficult. Color Doppler ultrasound is the first-line imaging study for diagnosis of PVT; magnetic resonance angiography and CT angiography are valid alternatives. The main complications are ischemic intestinal necrosis (in acute PVT) and esophageal varices (in chronic cases); the natural history of the latter differs depending on whether or not the thrombosis is associated with cirrhosis. The treatment of choice for PVT has never been adequately investigated. It is currently based on the use of anticoagulants associated, in some cases, with thrombolytics, but experience with the latter agents is too limited to draw any definite conclusions. In chronic thrombosis (even forms associated with cirrhosis), anticoagulant therapy is recommended and possibly, beta-blockers as well. Naturally, treatment of the underlying pathology is essential.     

D‐dimer testing in pregnant patients: towards determining the next ‘level’ in the diagnosis of deep vein thrombosis

Summary. Background: The role of D‐dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. We hypothesized that the specificity of sensitive D‐dimer assays could be improved without compromising sensitivity by using higher D‐dimer cut‐off values. Objective: To determine the test characteristics of two rapid enzyme‐linked immunosorbent assays and three latex agglutination assays in pregnancy. Method: We recruited consecutive pregnant women who presented to participating centers with suspected DVT for the study. Symptomatic women were investigated with compression ultrasonography, and received 3 months of clinical follow‐up to assess for the presence of venous thrombosis. Plasma samples for D‐dimer were collected and frozen at the time of presentation. The median and mean D‐dimer values for respective trimesters of pregnancy in patients with and without DVT were calculated. Receiver operating curves (ROCs) were plotted for respective assays to establish the best cut‐points. The test characteristics corresponding to standard cut‐points and these ‘pregnancy’ cut‐points are presented. Results: The prevalence of DVT in our cohort was 6.6% (95% confidence interval 4.0–10.6%). The mean and median D‐dimer values were significantly increased throughout pregnancy. Overall, women with confirmed DVT had higher D‐dimer levels than women without DVT (P < 0.0001). Improved specificities (62–79%) were observed with the use of higher cut‐points obtained from ROCs for all five assays, and high sensitivities were manintained (80–100%) for DVT diagnosis. Conclusion: Using higher cut‐points than those used in non‐pregnant patients, the specificity of D‐dimer assays for the diagnosis of DVT in pregnancy can be improved without compromising sensitivity. Validation in prospective management studies is needed.     

Sex hormone‐binding globulin levels are not causally related to venous thrombosis risk in women not using hormonal contraceptives

Summary. Background: Oral contraceptive use increases the risk of venous thrombosis as well as sex hormone‐binding globulin (SHBG) levels. Furthermore, increased SHBG levels are positively associated with activated protein C (APC) resistance and thrombotic risk in oral contraceptive users. Objectives: To determine whether increased SHBG levels are causally related to venous thrombosis in women not using hormonal contraceptives. Methods: Premenopausal women were selected from a case–control study on venous thrombosis, the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study (23 patients; 258 controls). Women using hormonal contraceptives were excluded. First, the risk of venous thrombosis with SHBG levels above the normal reference range (70 nm ) was determined. Second, because multiple regulatory factors affect SHBG levels and residual confounding may remain, we determined six single‐nucleotide polymorphisms (SNPs) in the SHBG gene and assessed the risk of venous thrombosis in a different case–control study, the Leiden Thrombophilia Study (LETS) (20 patients; 74 controls), and in the MEGA study. Finally, the association between SHBG levels and the normalized activated partial thromboplastin time‐based APC resistance (an intermediate endpoint for venous thrombosis) was determined. Results: Elevated SHBG levels (> 70.0 nm ) were associated with venous thrombosis (odds ratio 1.92; 95% confidence interval [CI] 0.74–5.00). However, this finding can be explained by residual confounding. Two SNPs in the SHBG gene affected SHBG levels, but not venous thrombosis risk. Furthermore, SHBG levels in controls were not associated with APC resistance (SHBG level, > 70.0 vs. ≤ 70.0 nm : mean difference in normalized APC sensitivity ratio, 0.03; 95% CI ?0.05 to 0.10). Exclusion of women with FV Leiden did not materially change these results. Conclusions: Increased SHBG levels are not causally related to the risk of venous thrombosis.     

Genome scan of clot lysis time and its association with thrombosis in a protein C‐deficient kindred

Summary. Background: Previously, we found increased clot‐lysis time (CLT), as measured with a plasma‐based assay, to increase the risk of venous thrombosis in two population‐based case–control studies. The genes influencing CLT are as yet unknown. Patients/Methods: We tested CLT as risk factor for venous thrombosis in Kindred Vermont II (n = 346), a pedigree suffering from a high thrombosis risk, partially attributable to a type I protein C deficiency. Furthermore, we tested for quantitative trait loci (QTLs) for CLT, using variance component linkage analysis. Results: Protein C‐deficient family members had shorter CLTs than non‐deficient members (median CLT 67 min vs. 75 min). One standard deviation increase in CLT increased the risk of venous thrombosis 2.4‐fold in non‐deficient family members. Protein C deficiency without elevated CLT increased the risk 6.9‐fold. Combining both risk factors yielded a 27.8‐fold increased risk. The heritability of CLT was 42–52%. We found suggestive evidence of linkage on chromosome 11 (62 cM), partly explained by the prothrombin 20210A mutation, and on chromosome 13 (52 cM). Thrombin‐activatable fibrinolysis inhibitor genotypes did not explain the variation in CLT. Conclusion: Hypofibrinolysis appears to increase thrombosis risk in this family, especially in combination with protein C deficiency. Protein C deficiency is associated with short CLT. CLT is partly genetically regulated. Suggestive QTLs were found on chromosomes 11 and 13.     

血栓弹力图对肝硬化患者门静脉血栓形成的预测价值

目的 探讨血栓弹力图（TEG）及常规凝血试验评价肝硬化患者门静脉血栓形成（PVT）的价值。方法 选择2015年12月至2017年2月复旦大学附属中山医院消化科收治的肝硬化失代偿期患者，根据是否合并PVT分组。比较PVT组与非PVT组TEG参数、常规凝血指标、相关临床资料等的差异。结果 共纳入199例患者，PVT组82例（41.2%）、无PVT组117例（58.8%）。两组患者TEG各项参数差异均无统计学意义。Logistic回归分析显示，女性（OR=3.061,95%CI 1.389～6.744,P=0.005）、脾切除史（OR=5.740,95%CI 1.876～17.568,P=0.002）、D-二聚体升高（OR=1.533,95%CI 1.182～1.989,P=0.001）是PVT的独立相关因素；Child B+C级（OR=12.844,95%CI 2.452～67.263,P=0.003）、R时间缩短（OR=0.526, 95%CI0.294～0.942,P=0.031）、血小板增多（OR=1.013, 95%CI 1.005～1.021,P=0.001）是门脉海绵样变的独立...