Dkk3 levels in patients with myeloproliferative neoplasms

Introduction

Dickkopf-3 (Dkk3) has been proposed as tumor suppressor gene and a marker for tumor blood vessels and has pro-angiogenic properties. Dkk3 is expressed in platelets and megakaryocytes from healthy controls and patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN). The aim of this study is, to find out whether patients with MPN have higher Dkk3 serum levels than normal controls.

Material & methods

We analyzed Dkk3 serum levels with ELISA in patients with newly diagnosed and untreated MPN, including 10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 primary meylofibrosis (PMF) and 10 healthy blood donors and correlated these findings with biological and clinical key data and the JAK2-V617F status. Dkk3 levels were corrected to platelet count, Dkk3c, as patients with MPN have higher platelet counts than controls.

Results

As expected, patients with MPN have higher platelet counts than normal controls. Dkk3 serum levels of patients with MPN (5.4 ± 6.1 ng/ml) showed no significant difference compared to normal controls (4.4 ± 3.8 ng/ml). Regarding Dkk3c, a significant difference to controls was found in PV (8.5 ± 8.7 ng/ml; p = 0.04), but not in ET and PMF (5.7 ± 3.8 ng/ml; p = 0.07 and 2.7 ± 3.6 ng/ml; p = 0.9; respectively. Dkk3c correlated with the JAK2-V617F mutational burden (p = 0.014, Rho = 0.445).

Conclusion

Dkk3 levels corrected to platelet count showed higher levels in PV than normal controls. Elevated Dkk3c level could possibly correlate to platelet activation in PV patients and increased Dkk3 release. Whether this remains a surrogate marker of platelet release or it contributes to the thrombophilic state through its pro-angiogenic properties remains to be shown.     

Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: A role for the JAK2 V617F mutation re-evaluation

Introduction

Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN.

Materials and Methods

A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed.

Results

In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation.The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p = 0.032). The thrombosis-free survival was lower in patients with (p = 0.04) or developing later MPN and the JAK2 V617F mutation (p = 0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups.

Conclusions

MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients.     

ADP-induced platelet aggregation and thrombin generation are increased in Essential Thrombocythemia and Polycythemia Vera

Introduction

Essential Thrombocythemia (ET) and Polycythemia Vera (PV) patients are characterized by an increased rate of thrombotic complications and by several abnormalities of platelets, more pronounced in JAK2V617F positive patients. The aim of this study was to characterize the platelet aggregation as well as the platelet procoagulant potential induced by several different agonists in ET and PV patients.

Materials and Methods

Venous blood samples were obtained from 65 ET and 51 PV patients. Whole blood impedance aggregometry was utilized to characterize platelet aggregation induced by collagen, ADP, thrombin receptor activating peptide and arachidonic acid, while the Calibrated Automated Thrombogram (CAT) assay was used to determine the thrombin generation (TG) potential induced by ADP in platelet-rich plasma. CAT assay was also performed in the presence of annexin V to evaluate the contribution of platelet phospholipids to TG.

Results and Conclusions

ADP-induced platelet aggregation and TG were significantly increased in ET and PV patients compared to controls. The highest values were observed in JAK2V617F positive patients and in patients on aspirin. In these subjects, annexin V was less effective in inhibiting both basal and ADP-induced TG.This study demonstrates for first time that platelets from ET and PV patients are more responsive to the ADP stimulus, in terms of both increased platelet aggregation, and enhanced TG, particularly in the JAK2V617F positive patients. Our data support the hypothesis that the use of ADP receptor inhibitors, in addition to aspirin, might be considered in the prevention of thrombosis in these conditions, by allowing a more complete inhibition of platelet functions.     

Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria phenotype in patients with splanchnic vein thrombosis

Introduction

Splanchnic vein thrombosis (SVT) is a serious complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). Mutant PNH clones can be associated with an increased risk of SVT even in the absence of overt disease, but their prevalence in non-selected SVT patients remains unknown.

Materials and Methods

Patients with objective diagnosis of SVT and without known PNH were tested for the presence of PNH clone using high-sensitivity flow cytometric analysis.

Results

A total of 202 SVT patients were eligible, 58.4% were males, mean age was 54.6 years (range 17–94), site of thrombosis was portal in 103 patients, mesenteric in 67, splenic in 37, and supra-hepatic in 10. SVT was associated with JAK2 V6167F in 28 of 126 (22.2%) screened patients, liver cirrhosis in 15.3% patients, recent surgery in 10.9%, and myeloproliferative neoplasm in 10.6%, whereas in 34.6% of patients neither permanent nor transient risk factors were detected. None of the patients had a clearly demonstrable PNH clone, but in two patients (0.99%, 95% CI 0.17-3.91) we observed very small PNH clones (size 0.014% and 0.16%) confirmed in two independent samples. One patient had portal vein thrombosis and no associated risk factors, the second had superior mesenteric vein thrombosis and inflammatory bowel disease.

Conclusions

Very small PNH clones can be detected in patients with SVT and no clinical manifestations of disease. Future studies are needed to explore the potential role of this finding in the pathogenesis of SVT.     

Characteristics of neurological manifestations of Behçet's disease: A retrospective monocentric study in Tunisia

Objective

The aim of the present study was to analyze demographic, clinical and genetic features of Behçet's disease patients with neurological involvement through a monocentric study of a homogenous group of hospitalized patients observed in the same department and to compare them with those of other ethnic and geographic groups.

Methods

Four hundred and thirty Behçet's disease (BD) patients were retrospectively studied. Diagnosis of BD was made according to the international study group for Behçet's disease criteria. Patients with neurological findings suggestive of involvement of the nervous system by BD were further studied according to clinical examination, laboratory tests and neuroradiological investigations.

Results

Neurological involvement was observed in 121 patients (28.1%). The mean age at neuro-Behçet's disease (NBD) onset was 29.7 years. Average disease duration of BD before neurological manifestations onset was 6.4 years. Male to female ratio was 1.8. Of the 121 NBD patients, parenchymal involvement occurred in 74 patients (61%). Among them 26 (21.4%) presented with brainstem involvement, 24 (19.8%) with hemispheric involvement and 2 (1.6%) with spinal cord involvement. Non-parenchymal NBD occurred in 47 patients (39%). Involvement of the main vascular structures (Vasculo-NBD) was the most common non-parenchymal NBD lesion found in 35 patients (28.9%) consisting of cerebral vein thrombosis (CVT) in 24 cases and cerebral arterial thrombosis in 11 cases. Forty-nine (40.5%) patients with NBD have been followed-up for a median of 3 years (range 1–19 years). Forty-one of them recovered well without significant residual disability, 5 patients made no improvement and are left with severe neurological impairments and 3 died. Male gender and CNS parenchymal lesions occurrence were significantly associated with a poorer prognosis.

Conclusion

Clinical and epidemiological features of NBD are various. In our Tunisian cohort of NBD patients the main characteristic features were male predominance, a relatively high prevalence of CVT, a low prevalence of intra-cranial hypertension and a significant lower frequency of HLA-B51 haplotype.     

Haplotypes of TAFI gene and the risk of cerebral venous thrombosis - a case-control study

Introduction

Cerebral venous thrombosis (CVT) is an uncommon disease with some differences compared to other-site thrombosis, including a higher frequency in young people, female sex and oral contraceptive users. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a regulator of fibrinolysis, whose levels are genetically controlled and its increase is associated to thrombosis. Our objective was to investigate in a case-control study the association between CVT and TAFI single nucleotide polymorphisms (SNPs) and its haplotypes in comparison to other-site venous thrombosis and controls.

Materials and Methods

Seventy two patients with CVT were compared to 143 individuals with no history of thromboembolic events (control group) and to 128 patients with deep vein thrombosis in the limbs and/or pulmonary embolism (venous thromboembolism-VTE group). SNPs were genotyped by restriction fragment length polymorphism or allele-specific PCR for F2 20210G > A, F5 1691G > A, TAFI (-1053C > T, -438G > A, 505G > A, 1040C > T and + 1542C > G).

Results

The GTC haplotype for TAFI 505G > A/1040C > T/+ 1542C > G SNPs was associated with an increased risk of CVT compared to controls [odds ratio (OR) 2.67, 95% confidence interval (CI): 1.13 - 6.34) and VTE group (OR 2.51, 95%CI: 1.07 - 8.06). The CVT risk became even more pronounced when evaluating unprovoked or hormone-related thrombosis cases: CVT compared to controls (OR 3.24, 95%CI: 1.19 - 8.82) and VTE group (OR 4.32, 95%CI: 1.27 - 14.63).

Conclusions

Our data indicate that the GTC haplotype for TAFI 505G > A/1040C > T/+ 1542C > G SNPs increased the risk of CVT in comparison to controls and VTE cases. Further studies are required to confirm our findings.     

Interobserver variability in the detection of cerebral venous thrombosis using CT venography with matched mask bone elimination

Objectives

Computed tomography venography (CTV) has proven to be a reliable imaging method in the evaluation of cerebral venous thrombosis with good correlation to magnetic resonance (MR) imaging and digital subtraction angiography (DSA). It is fast and widely accessible, especially in the emergency setting. For better visualization of vascular structures bone is often removed from the images. The purpose of this study was to evaluate the quality of a fully automatic bone removal method, matched mask bone elimination (MMBE), and to assess the interobserver variability of the CTV technique.

Patients and methods

Fifty patients with clinical suspicion of cerebral venous thrombosis underwent multislice CTV with MMBE post-processing. Axial source images and maximum intensity projections were retrospectively evaluated by two neuroradiologists for quality of bone removal and for the presence or absence of thrombosis in nine dural sinuses and five deep cerebral veins. A per sinus/vein and a per patient analysis (thrombosis in at least one sinus or vein) was performed and interobserver agreement was assessed.

Results

Both observers considered bone removal good in all patients (100%). Interobserver agreement per patient was excellent (κ = 0.83), with a full agreement in 47 of 50 patients (94%). The interobserver agreement per sinus or vein was good (κ = 0.76), with a full agreement in 679 of 700 sinuses or veins (97%).

Conclusion

CTV aided with MMBE is a robust technique for visualization of the intracranial venous circulation, removing bone effectively. CTV has high interobserver agreement for presence or absence of cerebral venous thrombosis.     

Molecular basis and thrombotic manifestations of antithrombin deficiency in 15 unrelated Chinese patients

Introduction

Antithrombin (AT) deficiency is associated with an increasing risk of thrombosis.

Materials and methods

15 unrelated patients with AT deficiency defined by thrombophilic assays were recruited and detailed clinical information about patients, focusing on the personal and family history of thromboembolism (TE), were recorded. Mutation analysis was performed by direct sequencing of an AT gene (SERPINC1) in the patients and their family members.

Results

A total of 15 heterozygous causative mutations, each being identified in one family, were identified. Five mutations (33.3%) were reported here for the first time, including three null mutations (Ser36X, Lys70X and Try307X) and two missense mutations (Phe123Cys and Leu340Phe) probably impairing the structural integrity and stability of protein based on the AT structural analysis. Of the 15 patients, 33.3% (5/15) had additional risk factors and only one patient presented with additional genetic alteration causing an early onset of thrombosis. Fourteen patients (93.9%) suffered from multisite recurrent thrombotic episodes after a first episode of thrombosis. 93.3% of the patients experienced deep vein thrombosis (DVT) and 40.0% presented with mesenteric venous thrombosis (MVT). In addition, both venous and arterial thrombosis was present in two unrelated patients. 51.0% subjects with AT deficiency in the 15 unrelated pedigrees experienced TE events.

Conclusions

Prophylactic anticoagulation may be suggested in AT-deficient patients to avoid the recurrent and multisite thrombosis. The association of primary MVT and AT deficiency is highlighted.     

Two years outcome of isolated distal deep vein thrombosis

Background

Isolated distal deep vein thrombosis (IDDVT) is frequently found in symptomatic outpatients, but its long term outcome is still uncertain.

Aims

To assess IDDVT long term outcome and the impact of IDDVT characteristics on outcome.

Methods

In a prospective, single center study we enrolled symptomatic outpatients in whom IDDVT was detected by whole-leg compression ultrasonography. Patients with provoked IDDVT were treated with low molecular weight heparins (LMWH) for 30 days while those with unprovoked IDDVT received with vitamin K antagonists (VKA) for three months. The primary end-point was the rate of the composite of pulmonary embolism (PE), proximal deep vein thrombosis (DVT), and IDDVT recurrence/extension during 24 month follow-up.

Results

90 patients (age 61 ± 18, male 48.9%) were enrolled. Risk factors for thrombosis were reduced mobility (34.4%), obesity (25.3%), surgery (15.6%), and previous DVT (15.6%) and cancer in 8 patients (8.9%). Eighty-eight patients were treated (56 with LMWH and 32 with VKA). During follow-up (median 24 ± 2 months), 17 events were recorded, which included 3 PE (two in cancer patients), 4 proximal DVTs (one in cancer patient) and 10 IDDVT. Male sex (HR 4.73 CI95%: 1.55-14.5; p = 0.006) and cancer (HR 5.47 CI95%: 1.76-17.6; p = 0.003) were associated with a higher risk of complications, whereas IDDVT anatomical characteristics, anticoagulant therapy type, and provoked IDDVT were not.

Conclusions

The risk of recurrent venous thromboembolism after IDDVT may be relevant in male patients or in patients with active cancer. Larger studies are needed to address this issue.     

Inferior vena cava thrombosis and its relationship with the JAK2V617F mutation and chronic myeloproliferative disease

Background

Splanchnic vein thrombosis (SVT) is a typical manifestation of polycythaemia vera (PV) or essential thrombocythaemia (ET). The recently discovered JAK2V617F somatic mutation is closely associated with chronic myeloproliferative disease (CMD). We investigated whether thrombosis involving the inferior vena cava (IVC) is also related to the JAK2V617F mutation or CMD.

Methods

Blood samples were obtained from 40 IVC thrombosis patients. Fifty-three patients with isolated lower extremity deep vein thrombosis (LE-DVT) and 20 SVT patients served as controls. The presence of the JAK2V617F mutation was assessed by real-time polymerase chain reaction (RT-PCR).

Results

The JAK2V617F allele was not detected in any of the IVC thrombosis patients but was detected in one patient (2%) with isolated LE-DVT. However, the mutation-carrying patient did not exhibit symptoms of CMD. Even after an observation period of 30 months, the patient's complete blood cell count did not exhibit any pathology. In contrast, the JAK2V617F allele was detected in four patients with SVT (20%) and CMD.

Conclusion

According to our data, there is no evidence that IVC thrombosis is associated with the JAK2V617F mutation or the presence of chronic myeloproliferative disease.     

Thrombosis of the inferior vena cava and malignant disease

Background

Inferior vena cava thrombosis (IVCT) is a rare event, and studies detailing its underlying aetiologies are scarce.

Methods

One hundred and forty-one IVCT patients (57% females, median age 47 years) were analysed with a focus on malignancy-related thrombosis and compared with 141 age- and sex-matched control patients with isolated lower-extremity deep vein thrombosis.

Results

Malignancies were more prevalent among IVCT patients compared with the control group (39% vs. 7.8%; P < 0.001). Malignancy-related IVCT more frequently involved the suprarenal and hepatic segments of the IVC and extended more often to the right atrium than IVCT did in non-cancer patients. Among IVCT patients with malignancies, renal cell carcinoma (38%) and other malignancies of the genitourinary tract (25%) were the most common tumours. Analysis of the underlying pathological mechanisms of malignancy-related thrombosis identified external compression of the IVC by tumour masses in 9 cases (16%), and progression of malignancy into the IVC (so-called “tumour thrombosis”) in 24 cases (44%). The remaining 22 cases (40%) were attributed to malignancy-related hypercoagulability and the presence of additional venous thromboembolism risk factors, such as previous surgery, immobilisation, or chemotherapy.

Conclusions

Malignancies substantially contribute to the risk of thrombosis involving the IVC. Tumour invasion, especially in cases of renal cell cancer and malignancy-related hypercoagulability are major triggering factors for thrombogenesis.     

Comparison of catheter-related large vein thrombosis in centrally inserted versus peripherally inserted central venous lines in the neurological intensive care unit

Objective

To compare cumulative complication rates of peripherally (PICC) and centrally (CICVC) inserted central venous catheters, including catheter-related large vein thrombosis (CRLVT), central line-associated bloodstream infection (CLABSI), and line insertion-related complications in neurological intensive care patients.

Methods

Retrospective cohort study and detailed chart review for 431 consecutive PICCs and 141 CICVCs placed in patients under neurological intensive care from March 2008 through February 2010. Cumulative incidence of CRLVT, CLABSI, and line insertion-related complications were compared between PICC and CICVC groups. Risk factors for CRLVT including mannitol therapy during dwell time, previous history of venous thromboembolism, surgery longer than 1 h during dwell time, and line placement in a paretic arm were also compared between groups.

Results

During the study period, 431 unique PICCs were placed with cumulative incidence of symptomatic thrombosis of 8.4%, CLABSI 2.8%, and line insertion-related complications 0.0%. During the same period, 141 unique CICVCs were placed with cumulative incidence of symptomatic thrombosis of 1.4%, CLABSI 1.4%, and line insertion-related complications 0.7%. There was a statistically significant difference in CRLVT with no difference in CLABSI or line insertion-related complications.

Conclusions

In neurological critical care patients, CICVCs appear to have a better risk profile compared to PICCs, with a decreased risk of CRLVT. As use of PICCs in critical care patients increases, a prospective randomized trial comparing PICCs and CICVCs in neurological critical care patients is necessary to assist in choosing the appropriate catheter and to minimize risks of morbidity and mortality associated with central venous access.     

Incidence of thrombosis in children with tunneled central venous access devices versus peripherally inserted central catheters (PICCs)

Introduction

The recent proliferation of deep vein thrombosis in children has been attributed to the increased use of central venous catheters, specifically tunneled lines and peripherally inserted central catheters. A formal comparison of the incidence rate for deep vein thrombosis between tunneled lines and peripherally inserted central catheters has not been undertaken.

Methods

Children < 18 years of age who were admitted to Children’s Hospital Los Angeles from July, 2005 to July, 2012 were eligible for inclusion. Data were extracted from the hospital discharge database which includes data on all procedures and up to 20 diagnoses per admission. Diagnoses and procedures were identified by International Classification of Disease, Ninth Revision coding. Patients were excluded if they received more than one central line. Data collected included type of central line, deep vein thrombosis event, and underlying medical illnesses classified according to chronic complex conditions.

Results

Over the seven year study period there was an overall rate of 73 deep vein thromboses per 10,000 hospital discharges. Of the 6915 eligible subjects, 181 had a deep vein thrombosis for an overall incidence rate of 2.6%. There were 152 thrombi (2.6%) in subjects with peripherally inserted central catheters and 29 thrombi (3.1%) in subjects with tunneled lines [OR = .83 (0.55, 1.29), p = 0.38].

Conclusion

Despite the relative ease and simplicity of use of peripherally inserted central catheters leading to a substantial rise in their use, this study demonstrates that such lines pose a substantial risk for venous thrombosis and no difference in incidence was detected between such lines and tunneled lines.     

Silent pulmonary embolism in patients with distal deep venous thrombosis: Systematic review

Purpose

The purpose of this investigation was to determine the prevalence of silent pulmonary embolism (PE) in patients with deep venous thrombosis (DVT) limited to the calf veins.

Methods

This is a systematic review. We attempted to identify all published investigations that reported the prevalence of silent PE in patients with infrapopliteal DVT. Studies were identified by searching PubMed through January 2014. The search was augmented by manually reviewing the references in all original articles and in reviews.

Results

The prevalence of silent PE in patients with DVT limited to the calf veins was described in 6 investigations. Pooled data showed a prevalence of 24 of 183 (13.1%) (95% CI 8.9-18.8%).

Conclusion

Silent PE in patients with DVT limited to the calf veins is not rare. Imaging at the time of diagnosis of calf vein DVT, typically with a perfusion scan alone, may be useful, but there is an economic cost and exposure to radiation.     

Evaluation of the prevalence of severe hyperhomocysteinemia in adult patients with thrombosis who underwent screening for thrombophilia

Introduction

Treatment with B-vitamins and betaine reduces the high risk of thrombosis in patients with homocystinuria, a metabolic syndrome that is characterized by severe hyperhomocysteinemia (HHcy). In contrast, there is no clear demonstration that B-vitamins reduce the risk of thrombosis in patients with mild HHcy: for this reason, many question the clinical utility of measuring total Hcy (tHcy) in patients with thrombosis. However, thrombosis may be the first clinical manifestation of homocystinuria in patients reaching adulthood without signs and symptoms of the syndrome.

Aim

1) to measure the prevalence of severe, previously undiagnosed, HHcy among patients with thrombosis 2) to profile these patients on the basis of their characteristics.

Methods

Six Italian Thrombosis Centers completed a first questionnaire, reporting tHcy levels in patients with thrombosis who underwent thrombophilia screening, and a second questionnaire, reporting the characteristics of patients with severe HHcy (tHcy > 100 μmol/L).

Results

Of 19,678 cross-sectionally collected patients with thrombosis who underwent thrombophilia screening in the last 12.5 years (median value, range 6-17), 38 had severe HHcy (0.2%). Their median age at diagnosis was 47 years (range 19-83) and the median level of tHcy was 130 μmol/L (range 101-262). Venous thromboembolism (71%) was more frequent than arterial thromboembolism (26%); recurrent thrombosis occurred in 42% of cases.

Conclusions

Measurement of tHcy in adult patients with thrombosis may reveal the presence of severe HHcy. Since treatment of patients with severe HHcy decreases the risk of thrombosis, measurement of tHcy in patients with thrombosis may prove clinically useful.     

MTHFR and the risk for cerebral venous thrombosis- a meta-analysis

Background

The association between methylenotetrahydrofolate reductase (MTHFR) 677TT and the increased risk of venous thrombosis is uncertain. Studies of this polymorphism in cerebral venous thrombosis (CVT) are inconclusive.

Objectives

With a systematic review, we aimed to collect all case-control studies comparing the frequency of this polymorphism in CVT patients (cases) and healthy controls.

Methods

We used the MEDLINE, Cochrane Library and the ISI web of knowledge electronic databases and reference lists of retrieved articles in order to identify published case-control studies that evaluated the presence of MTHFR 677C>T polymorphism in CVT. Two reviewers independently selected studies. We compared the frequency of 677TT between cases and controls using the Mantel-Haenszel method, a fixed and a random-effects model in the pooled data.

Results

Nine case-control studies were included. The pooled analysis included 382 patients with CVT and 1217 controls. The frequency of 677TT genotype among CVT patients was not significantly higher compared with controls (15.7% versus 14.6%; OR = 1.12, 95% confidence interval (95% CI) 0.80 to 1.58; p = 0.50). There was significant heterogeneity between studies.

Conclusions

This meta-analysis confirmed that there is currently insufficient data supporting that 677TT genotype is a risk factor for CVT. These results imply a continuing searching for the cause of CVT in patients with this polymorphism.     

骨髓增殖性肿瘤伴发卒中的临床分析

目的 提高对骨髓增殖性肿瘤伴发卒中诊断和治疗的认识。 方法 收集2008年11月～2011年12月北京天坛医院血液科收治的骨髓增殖性肿瘤伴卒中患者的临床资料、实验室及影像学检查结果［包括病史、年龄、临床表现、颈部血管彩色多普勒超声、颅脑计算机断层扫描（computed tomography,CT）或磁共振成像（magnetic resonance imaging,MRI）、全血细胞计数、JAK2V617F基因突变检查］,并对治疗随访评价。 结果 骨髓增殖性肿瘤伴卒中16例,其中脑梗死13例,脑出血1例,短暂性脑缺血发作2例;脑梗死患者中4例患者梗死复发。真性红细胞增多症7例,原发性血小板增多症4例,原发性骨髓纤维化5例。7例患者卒中于骨髓增殖性肿瘤诊断前发生,8例同时诊断,1例骨髓增殖性肿瘤诊断后发生。13例有不同程度血细胞升高,13例行JAK2基因突变检测,阳性率76.9%。14例行颈部血管彩色多普勒超声检查均显示颈动脉和锁骨下动脉不同程度增厚、斑块形成伴狭窄。16例患者均服用阿司匹林治疗,其中15例患者同时接受羟基脲和（或）α干扰素治疗。 结论 本组病例结果提示,卒中患者需仔细阅读全血细胞计数,重视骨髓增殖性肿瘤的诊断,JAK2基因突变检测有助于骨髓增殖性肿瘤的早期诊断。骨髓增殖性肿瘤患者常伴有颈部血管的结构异常。卒中患者需重视骨髓增殖性肿瘤的诊治。     

Increased Dkk3 protein expression in platelets and megakaryocytes of patients with myeloproliferative neoplasms

Dickkopf-3 (Dkk3) has been proposed as tumour suppressor gene and a marker for tumour blood vessels. We analysed the expression and function of Dkk3 in platelets and megakaryocytes from healthy controls and patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN). Dkk3 protein and gene expression in platelets was compared with endothelial and other blood cell populations by ELISA, real-time PCR, and immunofluorescence. Moreover, megakaryocytes were isolated from bone marrow aspirates by CD61 microbeads. Immunohistochemical studies of Dkk3 expression were performed in essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF) and control reactive bone marrow cases (each n=10). Compared to all other blood cell populations platelets showed the highest concentration of Dkk3 protein (150 ± 19 ng/mg total protein). A strong DKK3 gene and protein expression was also observed in isolated megakaryocytes. Dkk3 co-localised with VEGF in α-granules of platelets and was released similar to VEGF upon stimulation. Addition of recombinant Dkk3 had no influence on blood coagulation (aPTT, INR) and platelet aggregation. Significantly more Dkk3+ megakaryocytes/mm2 could be found in bone marrow biopsies from patients with MPN (ET 40 ± 10, PV 31 ± 4, PMF 22 ± 3) than in controls (15 ± 3). The mean proportion of Dkk3+ megakaryocytes was increased in MPN as well (ET 83% ± 15%; PV 84% ± 12%; PMF 77% ± 8%) compared to controls (53% ± 11%). Dkk3+ megakaryocytes correlated with microvessel density in PV and PMF. We conclude that Dkk3 might be involved in the pathogenesis of MPN.     

Superficial vein thrombosis,thrombin generation and activated protein C resistance as predictors of thromboembolic events in lupus and antiphospholipid patients. A prospective cohort study

Introduction

Predicting thrombosis in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (aPL) is still challenging. Our objective was to determine risk factors for thrombotic events including activated protein C (APC) resistance proven by a thrombin generation (TG) assay in patients with SLE and/or aPL.

Materials and methods

We performed a prospective cohort study in a French University Hospital and tertiary care center. Ninety-two consecutive patients with SLE and/or aPL without ongoing anticoagulant treatment were enrolled. The outcome was time to thrombotic event. We evaluated clinical and laboratory variables including APC sensitivity ratio (APCsr) determined by TG. An APCsr > 90th percentile of a control population indicated APC resistance.

Results

Patients were followed-up for a median duration of 35 months (inter-quartile range: 26 to 62; 320 patient-years). Thrombosis during follow-up occurred in 18 patients. In univariate analysis, together with history of hypertension, superficial vein thrombosis (SVT) and arterial thrombosis, patients with both aPL and APC resistance had an increased risk for incident thromboembolic events (HR, 3.67[95% confidence interval, 1.31 to 10.31]). In multivariate analysis, only history of hypertension (HR, 10.77 [95% confidence interval, 3.15 to 36.83]), SVT (HR, 7.45 [95% confidence interval, 2.25 to 24.66]) and arterial thrombosis (HR, 3.31 [95% confidence interval, 1.14 to 9.55]) remained independent risk factors.

Conclusions

History of thrombosis including seemingly benign SVT have a higher predictive value for incident thrombotic events in SLE or aPL patients than APC resistance proven by TG.     

Association between obstructive sleep apnea and deep vein thrombosis / pulmonary embolism: A population-based retrospective cohort study

Background

Obstructive sleep apnea (OSA) is a major contributor to cardiovascular disease, and may cause severe morbidity and mortality. Recent studies have indicated that OSA patients exhibited elevated platelet activity, fibrinogen levels, and platelet aggregation.

Objectives

We investigated the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients diagnosed with OSA compared with age- and sex-matched unaffected people.

Patients/Methods

This longitudinal, nationwide, population-based cohort study was conducted using data from Taiwan National Health Insurance Research Database (NHIRD) recorded between January 2000 and December 2011. The study consisted of 3511 patients with OSA and 35110 matched comparison individuals. A Cox proportional hazard regression was used to compute the risk of DVT and PE in patients with OSA compared with those without OSA.

Results

The DVT and PE risks were 3.50- and 3.97-fold higher (95% CI = 1.83–6.69 and 1.85–8.51) respectively, in the OSA cohort than in the reference cohort after we adjusted for age, sex, and comorbidities.

Conclusion

This nationwide population-based cohort study indicates that patients with OSA exhibit a higher risk of subsequent DVT and PE.