Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10⁻⁰⁵) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10⁻⁰⁵) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.     

Risk of thromboembolism in relation to an in-vitro fertilization programme: three case reports

Severe thrombotic events following ovarian stimulation for in-vitrofertilization (IVF) procedures in three women are reported.None of these patients presented any concomitant clinical signof ovarian hyperstimulation syndrome. Coagulation inhibitorswere in the normal range but cardiovascular risk factors werepresent. It is postulated that early thrombosis could be favouredby high endogenous plasma oestrogen concentrations subsequentto ovarian stimulation when associated with another risk factor.Our data are discussed in relation to previous publications.It is suggested that risk factors must be considered individuallybefore each IVF attempt. In patients at high risk, clinicalmanagement of the post-transfer period is recommended.     

Intraosseous thrombosis in ischemic necrosis of bone and osteoarthritis

It has been proposed that nontraumatic ischemic necrosis of bone (INB) is a result of lipid associated intraosseous thrombosis. A histological study of 15 patients with INB confirmed the presence of intravascular lipid and thrombosis in the vessels of the femoral head. A similar analysis of 11 patients with primary osteoarthritis (OA) showed similar changes at lower levels. These changes were not observed in seven control femoral heads. The possibility that both INB and OA result from intraosseous thrombosis is discussed.     

Incidence of deep venous thrombosis after gynaecological laparoscopy

目的　研究妇科腹腔镜术后深静脉血栓的发生率。方法　在澳大利亚悉尼Liverpool医院 1997年 5月～ 1997年 9月 72例妇科腹腔镜手术采用Doppler超声检查静脉血流的通畅性和血管腔内的回声团用以诊断深静脉血栓。 61例患者充气时间 <60分钟为小手术组 ,11例 >60分钟为大手术组。每例患者在术后 2 4小时内及术后 7天行两次超声Doppler检查 ,所有 72人均行术后 2 4小时内的超声Doppler检查 ,小手术组 61例中 4 0例、大手术组 11例中 9例行二次超声检查。 2 3例未行二次超声检查者均行电话随访。结果　在我们的研究中两组患者均未发现DVT。本文同时报道北京复兴医院一例腹腔镜下右卵巢巧克力囊肿剥除术、左卵巢及部分输卵管切除术患者术后并发DVT ,其诊断及治疗经过。结论　这项研究证实妇科腹腔镜手术DVT虽发生率极低 ,一旦发生需及时诊治 ,以免发生肺栓塞等致命并发症。     

顺行和逆行取栓对静脉瓣膜及血管壁的影响

目的：比较顺行取栓与逆行取栓在猪腋静脉急性血栓形成对于其瓣膜功能和静脉壁形态的影响。方法：分别结扎猪的腋静脉的近远端,于结扎段内注入凝血酶原,放置６ｈ使形成血栓。随机分配为顺行取栓和逆行取栓组,对血栓段进行取栓。取栓后２４ｈ行取栓静脉插管逆行造影以评估瓣膜功能;切取此段静脉作ＣＤ８＾＋细胞免疫组化和苏木精－伊红（ＨＥ）染色以对比血管内膜及平滑肌的损伤程度。结果：逆行与顺行取栓在所有的例数中都成功地     

MN9202保护血栓大鼠尾动脉血管作用

观察新二氢吡啶类钙拮抗剂２,６－二甲基－４－（３－硝基苯基）－１,４－二氢－３,５－吡啶二羧酸－３－甲酯－５－正戊酯（ＭＮ９２０２）对血栓形成大鼠尾动脉血管平滑肌及内皮功能的影响。方法大鼠脚趾ｓｃ注射角叉来胶制备血栓模型,并于注射角叉菜胶前２４ｈ,１ｈ及注射后２４ｈｉｐＭＮ９２０２１μＭＯＬ．ＫＧ＾－１,取尾动脉血栓波及不同区域的三段血管,以去甲肾上腺素（ＮＥ）,乙酰胆碱（ＡＣｈ）,亚硝酸钠（Ｎａ     

多烯脂肪酸对脑血栓伴高脂血症病人降脂作用的疗效观察

目的：研究多烯脂肪酸胶囊对脑血栓伴高脂血症病人的降脂作用。选血脂康作对照。方法：６０例脑血栓伴高脂血症病人随机分为二组：治疗组（ｎ＝３１）及对照组（ｎ＝２９）。服药前及服药后４周,８周查血脂。结果：⑴服药４周后ＴＣ和ＬＤＬ－Ｃ分别降低２１．０２％和２８．９３％（多烯脂肪酸组）。⑵多烯脂肪酸组降低了３４．０６％的血清ＴＧ水平,效果显,结论：多烯脂肪酸胶囊降ＴＧ和ＬＤＬ－Ｃ水平与血脂康作用相近,其降     

Endotheliopathy of liver sinusoidal endothelial cells in liver disease

Liver is the largest solid organ in the abdominal cavity, with sinusoid occupying about half of its volume. Under liver disease, hemodynamics in the liver tissue dynamically change, resulting in injury to liver sinusoidal endothelial cells (LSECs). We discuss the injury of LSECs in liver diseases in this article. Generally, in noninflamed tissues, vascular endothelial cells maintain quiescence of circulating leukocytes, and unnecessary blood clotting is inhibited by multiple antithrombotic factors produced by the endothelial cells. In the setting of inflammation, injured endothelial cells lose these functions, defined as inflammatory endotheliopathy. In chronic hepatitis C, inflammatory endotheliopathy in LSECs contributes to platelet accumulation in the liver tissue, and the improvement of thrombocytopenia by splenectomy is attenuated in cases with severe hepatic inflammation. In COVID-19, LSEC endotheliopathy induced by interleukin (IL)-6 trans-signaling promotes neutrophil accumulation and platelet microthrombosis in the liver sinusoids, resulting in liver injury. IL-6 trans-signaling promotes the expression of intercellular adhesion molecule-1, chemokine (C-X-C motif) ligand (CXCL1), and CXCL2, which are the neutrophil chemotactic mediators, and P-selectin, E-selectin, and von Willebrand factor, which are involved in platelet adhesion to endothelial cells, in LSECs. Restoring LSECs function is important for ameliorating liver injury. Prevention of endotheliopathy is a potential therapeutic strategy in liver disease.     

Anti-thrombotic effects and bleeding risk of AJvW-2, a monoclonal antibody against human von Willebrand factor

1. A murine anti-human vWF monoclonal antibody, AJvW-2, was developed that inhibited the interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (vWF) during the ristocetin- (IC₅₀=0.7±0.1 μg ml⁻¹) and botrocetin- (IC₅₀=1.8±0.3 μg ml⁻¹) induced aggregation of human platelets.
2. AJvW-2 inhibited the high shear stress (10.8 N m⁻²) induced aggregation of human platelets dose-dependently with an IC₅₀=2.4±0.3 μg ml⁻¹, but had no effect on low shear stress induced platelet aggregation (1.2 N m⁻²) up to 100 μg ml⁻¹.
3. AJvW-2 also inhibited the high shear stress (5.0 N m⁻²) induced adhesion of human platelets to collagen I with the same efficacy (IC₅₀=2.4±0.3 μg ml⁻¹), but had no effect at low shear conditions (1.5 N m⁻²).
4. AJvW-2 inhibited the botrocetin-induced aggregation of platelets from guinea-pig, rat, rabbit, dog and pig at the same concentration range as human platelets; it likewise also inhibited the high shear stress induced aggregation and adhesion to collagen I of guinea-pig platelets.
5. AJvW-2 prevented arterial thrombus formation in guinea-pigs at a dose of 100 μg kg⁻¹ without prolonging the template bleeding time, whereas the GPIIb/IIIa antagonist lamifiban mediated inhibition of thrombosis at 1000 μg kg⁻¹ was accompanied by a significant prolongation of the bleeding time.
6. These results suggest that AJvW-2 is a potent inhibitor of the GPIb-vWF interaction and a potential novel antithrombotic agent with lower bleeding risk than GPIIb/IIIa antagonists.