A comment on congenital prothrombin abnormalities associated with thrombosis but not with bleeding

Journal of Thrombosis and Thrombolysis -     

Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review

A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty-two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.     

Long-haul flights and deep vein thrombosis: a significant risk only when additional factors are also present

To address the association between travel and deep vein thrombosis (DVT) we examined the risk factors for DVT in 568 consecutive patients with suspected DVT attending King's College Hospital in London. No significant link between DVT and long-haul travel was demonstrable in this cohort, with an odds ratio of 1.3 (CI 0.6-2.8). Risk of DVT was only increased in long-haul travellers if one or more additional risk factors were present, with an odds ratio of 3.0 (CI 1.1-8.2). Such individuals may benefit from prophylactic measures to minimize risk.     

Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence

Measurement of the thrombin generating potential could provide a method for quantifying the composite effect of multiple risk factors. This study assessed the risk of a first as well as a recurrent venous thrombotic event associated with an increased endogenous thrombin potential (ETP). Analyses were performed in 360 patients and 404 control subjects of the Leiden Thrombophilia Study. The ETP was measured directly using a fluorogenic assay (Thrombinoscope). Individuals with an increased ETP, i.e. above 90th percentile measured in control subjects (>2109.0 nM x min) had a 1.5-fold [95% confidence interval (CI): 0.9-2.3] increased risk of a first deep venous thrombosis. The risk was more pronounced after the analysis was restricted to idiopathic thromboses, i.e. 1.7-fold (95% CI: 1.0-2.8). Overall, the hazard ratio of a recurrent thrombotic event associated with a high ETP, adjusted for age, sex and oral anticoagulant use was 1.1 (95% CI: 0.5-2.2). Thus, a high ETP was not associated with an increased relative risk of recurrent venous thrombosis. At present, the clinical relevance of the thrombin generation assay in predicting recurrent venous thrombosis remains uncertain.     

Case report: portal vein thrombosis associated with hereditary protein C deficiency: a report of two cases

Protein C deficiency is one of the causes of curable or preventable portal vein thrombosis. We report two patients of portal vein thrombosis associated with hereditary protein C deficiency. The first patient presented with continuous right upper quadrant pain and high fever. The abdominal sonography revealed normal liver parenchyma but portal vein and superior mesenteric vein thrombosis. Based on a 55% (normal 70-140%) plasma protein C level, he was diagnosed as having protein C deficiency. A trace of his family history showed that his elder brother also had protein C deficiency with a 50% plasma C level. Both patients received anticoagulant therapy. The younger brother showed good response. Unfortunately, the elder one suffered from recurrent episodes of variceal bleeding and received a life-saving splenectomy and devascularization. We herein remind clinicians that early screening and therapy are helpful in preventing late complications of protein C deficiency with portal vein thrombosis.     

Personal practice: how we manage the risk of bleeding and thrombosis in children and young adults with acute lymphoblastic leukaemia

Bleeding and thrombosis are not infrequent problems in children receiving treatment for acute lymphoblastic leukaemia (ALL). The exact frequency varies with age, co-morbidity and treatment schedule, but the risk is highest in the first few weeks of treatment when disease and treatment-related haemostatic abnormalities prevail. Recommendations for prevention and management are lacking due to a weak evidence base, resulting in considerable variation in practice. This article describes our personal practice in this area with reference to the available literature on the subject.     

Thrombosis in myelofibrosis: prior thrombosis is the only predictive factor and most venous events are provoked

In a retrospective analysis of 205 patients (median age 62 years) with primary myelofibrosis and known JAK2V617F mutational status, 13.2% experienced a vaso-occlusive event at or prior to their diagnosis. After a median follow up of 31 months, post-diagnosis thrombosis occurred in 22 patients (10.7%), including 9 (4.4%) and 16 (7.8%) patients with a total of 9 arterial and 24 venous events, respectively. The majority (71%) of the venous events were temporally associated with other exogenous risk factors for thrombosis such as surgery, line placement or hormonal therapy. On multivariable analysis that included age, JAK2V617F mutation status and leukocyte count as covariates, history of thrombosis was the only predictive variable in general (P=0.04) or when arterial (P=0.007) and venous (P=0.02) thromboses were analyzed separately. The current study demonstrates a higher prevalence of venous, as opposed to arterial, events in PMF, post-diagnosis, and clarifies their nature as being mostly provoked.     

Erythropoiesis-stimulating agents are not associated with increased risk of thrombosis in patients with myelodysplastic syndromes

Background

There are limited reports of thrombosis among myelodysplastic syndrome patients exposed to erythropoiesis stimulating agents. It is not clear whether erythropoiesis stimulating agents are associated with an increased risk of thrombosis in myelodysplastic syndromes, as they are among patients with solid tumors.

Design and Methods

The association between use of erythropoiesis stimulating agent and transient thrombosis risk in patients with myelodysplastic syndromes was assessed in a case-crossover study nested within a cohort of incident myelodysplastic syndrome patients. Using the US Surveillance, Epidemiology, and End Results Medicare-linked database, cases with an incident diagnosis of deep vein thrombosis were identified. Using conditional logistical regression, the odds of exposure to erythropoiesis stimulating agents in the 12 weeks prior to the incident deep vein thrombosis (hazard period) was compared to the exposure odds in a prior 12-week comparison period.

Results

Within the cohort of eligibles with myelodysplastic syndromes (n=5,673) there were 212 incident cases of deep vein thrombosis events. Mean age was 76.2 (standard deviation=±8.6) years. Use of erythropoiesis stimulating agents was not associated with deep vein thrombosis in the crude nor the adjusted models (OR=1.21, 95% CI: 0.60, 2.43). Central venous catheter placement (OR=6.47, 95% CI: 2.37, 17.62) and red blood cell transfusion (OR=4.60, 95% CI: 2.29, 9.23) were associated with deep vein thrombosis.

Conclusions

Despite the link between use of erythropoiesis stimulating agents and thrombosis among patients with solid tumors, this study provides evidence that their safety profile may be different among patients with myelodysplastic syndromes.     

Lupus anticoagulant associated with transient severe factor X deficiency: a report of two patients presenting with major bleeding complications

Acquired factor X (FX) deficiency is rare, but has been reported in diverse disease states, including systemic amyloidosis and respiratory infections. FX deficiency associated with lupus anticoagulant (LA) and a bleeding diathesis has not been previously reported. We report two patients both of whom presented with a severe bleeding diathesis after a preceding respiratory infection due to isolated FX deficiency associated with a LA. The FX deficiency and LA were transient. We conclude that patients with LA may rarely present with severe acquired FX deficiency. This may be another mechanism whereby patients with antiphospholipid antibodies present with bleeding complications.     

The prothrombin 20210A allele and the factor V Leiden are associated with venous thrombosis but not with early coronary artery disease.

This study was performed in order to establish the role of the prothrombin 20210 G/A and factor V Leiden (R506Q) polymorphisms in the susceptibility to develop venous thromboembolism and early coronary artery disease (CAD). These polymorphisms were determined in 82 consecutive patients with venous thromboembolism, 175 male patients with early CAD, and 200 healthy controls from the same Caucasian population (Asturias, Northern Spain). DNA was amplified using polymerase chain reactions and digested with the appropriate restriction enzymes in order to define the prothrombin and factor V genotypes. The prevalence of the heterozygous for the prothrombin A allele was 3.5% in the general population and 15.8% in patients with venous thrombosis (P = 0.0007); the frequency was 4% in patients with early CAD. No sex-related differences in the prevalence of the A allele were observed, and the average age at the first venous thromboembolic event was similar between GG and AG patients. The frequency of carriers of the factor V Leiden polymorphism was 9.75% among patients with venous thromboembolism, compared with 3.5% among controls, and 3.4% in the patients with CAD. Our data showed an association between venous thromboembolism and the AG genotype at the prothrombin 20210 G/A polymorphism. This polymorphism was not related to an increased risk for early CAD in our population of male patients.     

From the Cover: Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline

Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this phenotype but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.     

Pancreatic resections are not only safest but also most cost-effective when performed in a high-volume centre: A Finnish register study

BackgroundIt is not known whether the treatment costs of pancreatic surgery can be reduced by centralisation. The aim of this study was to analyse the impact of hospital volume on the short-term prognosis and costs in a nationwide study.MethodsThe National registry was searched for patients undergoing pancreatoduodenectomy (PD) in Finland between 2012 and 2014. Patient data was recorded up to ninety days postoperatively and Charlson comorbidity index (CCI) calculated. Complications were classified according to Clavien-Dindo. A CCI was calculated for each patient. The hospitals were categorized by yearly resection rate: high (≥20, HVC), medium (6–19, MVC) and low (≤5, LVC). Costs were calculated according to the 2012 billing list.ResultsThe study population comprised 466 patients. Demographics were similar in the HVC, MVC and LVC groups. Mortality was lower in the HVCs than in MVCs and LVCs at 30 days (0.8% vs. 8.8–12.9%; p < 0.01) and at 90 days (1.9% vs. 10.5–16.1%; p < 0.01). Hospital volume and CCI were significant factors for mortality in multivariate analysis. Median costs among all patients were lower in the HVC group than in the MVC/LVC groups (p = 0.019), among Clavien-Dindo class III (0.020), among patients over 75 years (p < 0.001) and among patients who survived over five days (p = 0.015).ConclusionsThirty- and 90-day mortality is 10 times lower when the patient is operated on in an HVC. The study shows that the median overall costs of surgical treatment are 82–88% of the median costs in lower volume centres.