Severe arterial thrombosis in a congenitally factor VII deficient patient

Summary. We report a patient with congenital factor VII deficiency who developed severe arterial thrombosis. A 63-year-old-woman presented low factor VII clotting activity, amidolytic activity and antigen level < 4%. Activated factor VII plasmatic level was < 0.03 ng/ml compared to 4 ng/ml for the control value. She developed severe aorto-iliac thrombosis. 7d before the thrombotic event, factor VII replacement therapy had been infused. Successful low molecular weight heparin therapy led to total disappearance of the aortoiliac thrombus without bleeding complications. This suggests that factor VII infusion might have a thrombogenic effect in vivo and might be responsible for thrombosis.     

Hypofibrinolysis is a risk factor for arterial thrombosis at young age

The relationship between defective fibrinolysis and arterial thrombosis is uncertain. The evaluation of the plasma fibrinolytic potential might provide stronger evidence linking fibrinolysis to arterial thrombosis than the evaluation of the individual fibrinolytic factors. We determined the plasma fibrinolytic potential of 335 young survivors of a first arterial thrombosis, including coronary artery disease ( n  = 198), ischaemic stroke ( n  = 103) and peripheral artery disease ( n  = 34), enrolled in a population-based case–control study and of 330 healthy individuals. Patients had significantly higher clot lysis times (CLTs) than the controls. Odds ratios (ORs) were calculated as a measure of relative risk. The OR for arterial thrombosis was determined in these subjects who had a CLT above the 60th, 70th, 80th, 90th and 95th percentiles of the values found in the control subjects. We found a progressive increase in risk of arterial thrombosis in subjects with hypofibrinolysis (OR: 1·7, 2·0, 2·3, 2·3 and 2·9, respectively). Relative risk estimates obtained in the whole group were comparable those obtained in the event-subgroups. In conclusion, a low plasma fibrinolytic potential, found in 10% of the population, increases the relative risk of arterial thrombosis twofold. This points to an important contribution of hypofibrinolysis to the burden of arterial thrombosis.     

The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis

Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor (TF)-mediated coagulation. In atherosclerotic plaques TFPI co-localizes with TF, where it is believed to play an important role in attenuating TF activity. Findings in animal models such as TFPI knockout models and gene transfer models are consistent on the role of TFPI in arterial thrombosis as they reveal an active role for TFPI in attenuating arterial thrombus formation. In addition, ample experimental evidence exists indicating that TFPI has inhibitory effects on both smooth muscle cell migration and proliferation, both which are recognized as important pathological features in atherosclerosis development. Nonetheless, the clinical relevance of these antithrombotic and atheroprotective effects remains unclear. Paradoxically, the majority of clinical studies find increased instead of decreased TFPI antigen and activity levels in atherothrombotic disease, particularly in atherosclerosis and coronary artery disease (CAD). Increased TFPI levels in cardiovascular disease might result from complex interactions with established cardiovascular risk factors, such as hypercholesterolemia, diabetes and smoking. Moreover, it is postulated that increased TFPI levels reflect either the amount of endothelial perturbation and platelet activation, or a compensatory mechanism for the increased procoagulant state observed in cardiovascular disease. In all, the prognostic value of plasma TFPI in cardiovascular disease remains to be established. The current review focuses on TFPI in clinical studies of asymptomatic and symptomatic atherosclerosis, coronary artery disease and ischemic stroke, and discusses potential atheroprotective actions of TFPI.     

Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor

We describe a 44-year-old man with non-Hodgkin's lymphoma receiving granulocyte colony-stimulating factor (G-CSF) who developed an acute arterial thrombosis. The removed thrombus contained large amounts of platelet aggregation. A rapid increase of platelets and increased adenosine diphosphate (ADP)- and collagen-induced platelet aggregation were observed at the time of the thrombotic event. A challenge test of G-CSF showed an increase in the platelet count and an augmentation of ADP- and collagen-induced platelet aggregation. In the use of G-CSF, patients who produce a rapid increase in platelet levels could be at greater risk for thrombotic events and need to be followed-up carefully.     

Tissue factor pathway inhibitor anticoagulant activity: risk for venous thrombosis and effect of hormonal state

Full-length tissue factor pathway inhibitor (TFPI) is assumed to be biologically more important than truncated TFPI because of its stronger anticoagulant effect in the diluted prothrombin time (dPT) assay. We have developed a dPT-based assay for TFPI anticoagulant activity. Here, we report the effect of hormonal state on TFPI anticoagulant activity and whether TFPI anticoagulant activity assesses the risk for deep-vein thrombosis (DVT) better than conventional TFPI assays. We undertook a case-control study of 474 patients with DVT and 474 controls and compared the odds ratio (OR) for DVT for those with low TFPI anticoagulant activity with the ORs obtained for TFPI free and total antigen, and TFPI chromogenic substrate activity. Hormonal state affected clot time in dPT, but this effect was ameliorated by anti-TFPI antibodies. Low TFPI anticoagulant activity gave an OR of 1.5 (0.97-2.1) for DVT, similar to the ORs obtained with conventional TFPI assays, ranging from 1.2 to 1.4. Individuals low in both the activity assays obtained an OR of 5.9 (1.7-20). We concluded that the effect of hormonal state on dPT was mediated through TFPI, and a dPT-based assay of TFPI anticoagulant activity did not assess the risk for DVT better than conventional TFPI assays.     

Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor

We describe a 44-year-old man with non-Hodgkin's lymphoma receiving granulocyte colony-stimulating factor (G-CSF) who developed an acute arterial thrombosis. The removed thrombus contained large amounts of platelet aggregation. A rapid increase of platelets and increased adenosine diphosphate (ADP)- and collagen-induced platelet aggregation were observed at the time of the thrombotic event. A challenge test of G-CSF showed an increase in the platelet count and an augmentation of ADP- and collagen-induced platelet aggregation. In the use of G-CSF, patients who produce a rapid increase in platelet levels could be at greater risk for thrombotic events and need to be followed-up carefully.     

Predictors of arterial thrombosis after diagnostic cardiac catheterization in infants and children randomized to two heparin dosages

Arterial thrombosis is the most frequent major complication of percutaneous arterial catheterization in children. We prospectively studied the effect of randomized dosage of heparin, 50 IU/kg—group I and 100 IU/kg—group II, on the incidence of arterial thrombosis in 366 children and analysed the various factors which may influence the occurrence of this complication. The age of patients ranged from 17 d to 11 yr (mean age 39.5 ± 40.9 mo) and mean weight was 11.2 ± 7.8 kg (range 3 to 39 kg). The incidence of arterial thrombosis was 9.8% in group I and 9.3% in group II (P = NS). There was no statistical difference in precatheterization and procedure variables in the two groups and also in the group with absent pulse (n = 35) to the group with pulse present post cath (n = 331). There were 24.9% infants in our study and 14.3% of these had arterial thrombosis. The loss of pulse was more often seen with more number of attempts at arterial puncture (P < 0.001), absence of back bleed at the end of the procedure (P < 0.001), and increased duration of catheterization (P < 0.01). Use of larger sheath size in a given weight and body surface area of children increased incidence of arterial thrombosis. The administration of heparin 50 IU/kg was equally efficacious to heparin 100 IU/kg. Of the patients with arterial thrombosis, 23 responded with intravenous heparin and 12 needed streptokinase. There was no bleeding or haematoma. Thus our study shows that less attempt for arterial puncture, use of smaller sheath size, maintaining shortest procedure time and ensuring back bleed minimises incidence of arterial thrombosis post catheterization. Cathet. Cardiovasc. Diagn. 41:400–403, 1997. © 1997 Wiley-Liss, Inc.     

Interactions of platelets, blood-borne tissue factor, and fibrin during arteriolar thrombus formation in vivo

Thrombus formation following vascular injury is an essential component of both hemostasis and pathologic vessel occlusion. This process occurs in a closed, pressurized environment in which blood flows rapidly over the injury site. Thrombus formation must occur quickly to reduce blood loss, but is carefully modulated to limit vessel occlusion. Circulating cells, plasma proteins, vessel wall components, and physical forces such as shear all influence thrombus formation. Historically, thrombus formation has been studied by isolating the separate components of blood involved in clot formation. With improved optical techniques, investigators have increasingly studied thrombus formation under conditions of flow in vitro and in live animals in vivo. Using multichannel fluorescence intravital videomicroscopy, the authors have studied the changes in the kinetics and deposition of platelets, fibrin, and tissue factor at the injury site during thrombosis in transgenic mice, bone marrow transplanted mice, and mice treated with pharmacological agents that modulate thrombosis. The differences in the kinetics of accumulation of the various components of thrombus in these mice have provided new insights about thrombus formation in arterioles. This review discusses the role of platelet intracellular signaling, P-selectin expression on platelets, and tissue factor-bearing microparticles in thrombus formation.     

The venous thrombosis risk factor 20210 A allele of the prothrombin gene is not a major risk factor for arterial thrombotic disease

A nucleotide change (G to A transition) at position 20210 has recently been demonstrated to be a risk factor for venous thrombosis. The relevance of this polymorphism to thrombotic disease was investigated by genotypic identification in three prospective case–control studies: 101 case patients with acute coronary heart disease (CHD), 104 patients with acute cerebrovascular disease (CVD), 82 patients with a confirmed diagnosis of deep venous thrombosis (DVT), and one control age- and sex-matched for each patient. The prevalence of the genetic variation was significantly associated with the occurrence of DVT, but did not differ in patients with CHD or CVD from that in controls, suggesting that this allele should not be considered a major risk factor for arterial thrombotic disease.     

POEMS syndrome, arterial thrombosis and thrombocythaemia

The case of a 22-year-old man with polyneuropathy, endocrinopathy, skin change and monoclonal gammopathy of IgG-lambda type is described. There was no solitary plasmocytoma, osteosclerotic myeloma or Castleman's disease. However, significant thrombocytosis occurred and the patient developed arterial thrombosis, these were attributed to essential thrombocythaemia in the absence of other aetiological factors.     

Resistance to activated protein C in thalassaemic patients: an underlying cause of thrombosis

Abstract: We evaluated 81 thalassaemia major and 4 thalassaemia intermedia patients (48 M, 37 F), median age 17 years; 62/85 patients were HCV-positive, 3/85 HIV-positive, 19/85 were splenectomized. Forty normal healthy children were recruited as the control group. The number of thrombotic events was studied retrospectively. Platelet poor plasma was filtered and quick-frozen at -70°C until time of assay. APC resistance was measured in an activated thromboplastin time and results were expressed as normalized ratio. All tests were done with diluted 1 in 5 (v/v) factor V deficient plasma and with undiluted plasma. Molecular genetic investigation of factor V gene was performed with polymerase chain reaction, followed by digestion of amplified products with restriction enzyme Mnl I. Data obtained with molecular investigation revealed the presence of 4 heterozygous subjects for factor V Leiden (4.7%). Functional tests were able to detect all heterozygotes for factor V Leiden both with undiluted and with diluted plasma, and there were no false negative subjects. However, undiluted plasma revealed a greater number of false positive subjects (n = 15) than did diluted plasma. Therefore, tests done with undiluted and diluted plasma revealed a 100% sensitivity, while specificity was 81 % for undiluted plasma and 97% for diluted plasma. Only one thrombotic event was observed in one of the 85 studied patients, as a case of stroke in a thalassaemia intermedia patient with APC resistance. In the same patient an additional thrombogenic risk factor was represented by a pronounced haematocrit increase at the beginning of her tranfusion regimen.     

Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor

Originally isolated from a haematophagous hookworm, recombinant nematode anticoagulant protein c2 (rNAPc2) is an 85-amino acid protein with potent anticoagulant properties. Unlike conventional anticoagulants that attenuate blood coagulation via inhibition of thrombin or activated factor X (FXa) at the downstream portion of the cascade, rNAPc2 is a potent inhibitor of the activated factor VII/tissue factor complex (FVIIa/TF), the key physiological initiator of blood coagulation. Its mechanism of action requires prerequisite binding to circulating FXa or zymogen factor X (FX) to form a binary complex prior to its interaction and inhibition of membrane-bound FVIIa/TF. The binding of rNAPc2 to FX results in an elimination half-life of longer than 50 h following either subcutaneous or intravenous administration. Recombinant NAPc2, like other inhibitors of FVIIa/TF including tissue factor pathway inhibitor (TFPI) and active site-blocked FVIIa (ASIS, FFR-rFVIIa or FVIIai), may have a promising role in the prevention and treatment of venous and arterial thrombosis, as well as potential efficacy in the management of disseminated intravascular coagulopathies because of their potent and selective inhibition of FVIIa/TF.     

Left ventricular thrombosis and arterial embolism in acute anterior myocardial infarction

Abstract. To study left ventricular thrombus (LVT) formation and arterial embolism (AE), 106 consecutive patients with a first acute anterior myocardial infarction (AAMI) underwent two-dimensional echocardiography before discharge. Repeated assessments for detection of AE were performed. Patients were non-randomly allocated to either no heparin, low-dose heparin or high-dose heparin. LVT was found in 25 (26.9%) of 93 patients with technically satisfactory echocardiograms. Left ventricular (LV) wall motion impairment (P = 0.0017) and treatment with either heparin or low-dose heparin (P = 0.0019) were independent predictors of LVT formation. AE, all strokes, occurred in 10 patients (9.4%) and was strongly associated with high age (P = 0.0013). In conclusion. LVT and AE are frequent complications to AAMI. LV wall motion impairment predisposes for LVT and low-dose heparin seems not to prevent these complications.     

Transcatheter arterial embolization for hepatocellular carcinoma with portal vein thrombosis

Abstract In order to evaluate the possible benefits of transcatheter arterial embolization (TAE) in hepatocellular carcinoma (HCC) patients with peripheral portal vein thrombosis, 96 consecutive HCC cases with peripheral portal vein thrombosis were analysed. Of them, 35 cases received TAE and 61 cases did not. Most (77.8%) of the TAE-treated cases showed decreased α-fetoprotein (AFP) levels after treatment, but 57.1% of them suffered another rise in AFP levels and subsequently died. One patient (2.8%) developed progressive jaundice after TAE and died within 1 month, while four of the non-TAE cases died within 1 month after diagnosis. In general, TAE is safe for HCC patients with peripheral portal vein thrombosis. In addition, using Cox's regression model for multivariate survival analysis, serum total bilirubin (≤, > 2 mg/dL; P = 0.0254), AFP (≤ 3155 ng/mL, > 3155 ng/mL; P = 0.0002) and treatments (TAE, non-TAE; P = 0.0059) were found to affect their prognosis. There was significant difference in survival between TAE and non-TAE groups, the 6 month, 1 year and 2 year survival rates were 91.4 versus 62.3%, 51.4 versus 26.2% and 17.1 versus 4.9% ( P = 0.0017). The median survival times of TAE and non-TAE groups were 10.3 versus 3.7 months, respectively. Though TAE only provided palliative treatment, it did prolong survival in HCC patients with peripheral portal vein thrombosis.     

Recurrent leg ulcers and arterial thrombosis in a 33-year-old homozygous variant of antithrombin

We report here a homozygous variant case of antithrombin (AT) associated with arterial thrombosis and recurrent leg ulcers. The deep vein thrombosis was recognized by the venogram of his pelvic veins. His leg ulcers were scattered around his left ankle and accompanied by lipodermatosclerosis, which was evident in venous insufficiency. The propositus had developed cerebral infarction 12 years prior to his leg ulcers. Coagulation study showed low heparin cofactor activity of his AT with a normal level of immunoreactive AT. Nucleotide sequence analysis of the exon 2 of his AT gene showed Arg47-Cys mutation, leading to the lack of affinity of AT for heparin. The propositus is a homozygote for this abnormality.     

Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis

AIM: To evaluate the prognostic factors and efficacy of hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis. METHODS: Fifty hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) were treated using hepatic arterial infusion chemotherapy (HAIC) via a subcutaneously implanted port. The epirubicin-cisplatin-5-fluorouracil (ECF) chemotherapeutic regimen consisted of 35 mg/m 2 epirubicin on day 1, 60 mg/m 2 cisplatin for 2 h on day 2, and 500 mg/m 2 5-fluorouracil for 5 h on days 1-3. The treatments were repeated every 3 or 4 wk. RESULTS: Three (6%) of the 50 patients achieved a complete response (CR), 13 (26%) showed partial responses (PR), and 22 (44%) had stable disease (SD).The median survival and time to progression were 7 and 2 mo, respectively. After 2 cycles of HAIC, CR was achieved in 1 patient (2%), PR in 10 patients (20%) and SD in 26 patients (52%). Significant pre-treatment prognostic factors were a tumor volume of < 400 cm 3 (P = 0.01) and normal levels of protein induced by vitamin K absence or antagonist (PIVKA)-Ⅱ (P = 0.022). After 2 cycles of treatment, disease control (CR + PR + SD) (P = 0.001), PVTT response (P = 0.003) and α-fetoprotein reduction of over 50% (P = 0.02) were independent factors for survival. Objective response (CR + PR), disease control, PVTT response, and combination therapy during the HAIC were also significant prognostic factors. Adverse events were tolerable and successfully managed. CONCLUSION: HAIC may be an effective treatment modality for advanced HCC with PVTT in patients with tumors < 400 cm 3 and good prognostic factors.     

中青年缺血性脑卒中危险因素的对照研究

目的：探讨中青年缺血性卒中的危险因素。方法：在100例缺血性卒中患与对照组间进行12项危险因素对照研究，并将中青年和老年前期分别与对照组进行比较。结果：高血压病、高脂血症、心电图异常、脑卒中家族史、眼底动脉硬化、糖尿病、风心病是中青年缺血性卒中的危险因素。结论：降低血压、血脂水平对预防缺血性卒中有极其重要的意义。