Journal of Thrombosis and Haemostasis, 13: 332
DOI: 10.1111/jth.12863
WHAT THE NEIGHBORS SAY
Without help An important safety concern in factor IX gene therapy is the possibility that the promoter of the therapeutic FIX gene can become integrated close to an oncogene, which could lead to oncogenic transformation of hepatocytes. Barzel et al. tested an approach in mice in which a promoterless FIX gene was targeted to the albumin locus (Nature). Indeed, it appears that therapeutic FIX levels could be achieved without the help of a gene promoter. Maintaining billions Approximately 100 billion platelets are produced each day by the human body. This production is under the control of thrombopoietin, but how the body senses the exact need for platelets is largely unknown. An article by Grozovsky et al. reveals a feedback mechanism involving the Ashwell–Morell receptor by which aging human platelets stimulate thrombopoietin synthesis by hepatocytes to support homeostasis of platelet numbers (Nature Medicine). Thrombus growth Initial adhesion of platelets to sites of vascular injury is dependent on an interaction between platelet glycoprotein Iba and von Willebrand factor. There is evidence that thrombospondin 1 might also play a role. Prakash et al. studied this in a series of single and multiple knockout mice (Blood). From these studies, the conclusion is that thrombospondin 1 does indeed contribute to thrombus growth, but requires von Willebrand factor in order to achieve this. The Yin and Yang of warfarin Warfarin inhibits c-carboxylation not only of coagulation proteins but also of matrix GLA. In rodents, this effect of warfarin produces extensive calcification of the vessel wall. This has led to speculation that patients on warfarin might be more likely to develop vascular abnormalities. A study by Tantisattamo et al. looked into this by examining vascular calcifications in mammograms (ATVB). The results show that calcification of arteries in breast tissue is indeed more extensive in women taking warfarin. D-dimer testing for risk profiling Individualized prolongation of anticoagulation would reduce the number of recurrent venous thrombotic events without inducing a high number of hemorrhages. Kearon et al. evaluated a cohort of 410 patients with an
unprovoked venous thrombotic event by D-dimer testing after the initial treatment (Annals of Internal Medicine). In the 78% of patients with low D-dimer levels, anticoagulation was stopped. Over a 2-year follow-up period, the rate of recurrence was 6.7% per year. The incidence was higher in men than in women (9.7% vs. 5.4%), and the authors concluded that, in men, the recurrence rate after a negative D-dimer test result is not low enough to consider discontinuation of anticoagulation, whereas it may be so in women. Let’s target FXI In the ongoing quest for an anticoagulant that does not increase the risk of bleeding, B€ uller et al. tested an antisense oligonucleotide in a randomized trial for the prevention of venous thrombosis (New England Journal of Medicine). Three hundred patients who underwent knee replacement received either enoxaparin or anti-FXI, in two doses. The antisense oligonucleotide clearly reduced FXI levels. Venous thrombosis, as assessed by venography, occurred at similar rates in the enoxaparin and the low-dose anti-FXI groups, and at a substantially lower rate in the high-dose anti-FXI group (30% vs. 4%), whereas bleeding was less frequent in the anti-FXI group than in the enoxaparin group. Fat clots There is no end to the adverse effects of obesity. Campello et al. examined 80 individuals with mild to severe obesity, and found evidence of hypercoagulability as shown by various assays (Thrombosis and Haemostasis). As compared with individuals of normal weight, obese people had increased thrombin generation and increased numbers of microvesicles. As it is well established that obesity is related to an increased risk of venous thrombosis, these findings may assist in elucidating the mechanism behind this association. Don’t blame the surgeon Patients with cancer face a high risk of thrombosis, which is related not only to the biological properties of the malignancy itself, but also to the treatment of it. Becattini et al. (Haematologica) followed 305 patients with colorectal cancer who underwent surgery, and assessed risk factors for thrombosis. Thromboses occurred in 18%, but only 2% of these were symptomatic or proximal. Apart from the cancer stage, advanced age and obesity were related to the risk of postsurgical thrombosis, but surgery-related factors were not.
© 2015 International Society on Thrombosis and Haemostasis
Copyright of Journal of Thrombosis & Haemostasis is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
DOI: 10.1111/jth.12863
WHAT THE NEIGHBORS SAY
Without help An important safety concern in factor IX gene therapy is the possibility that the promoter of the therapeutic FIX gene can become integrated close to an oncogene, which could lead to oncogenic transformation of hepatocytes. Barzel et al. tested an approach in mice in which a promoterless FIX gene was targeted to the albumin locus (Nature). Indeed, it appears that therapeutic FIX levels could be achieved without the help of a gene promoter. Maintaining billions Approximately 100 billion platelets are produced each day by the human body. This production is under the control of thrombopoietin, but how the body senses the exact need for platelets is largely unknown. An article by Grozovsky et al. reveals a feedback mechanism involving the Ashwell–Morell receptor by which aging human platelets stimulate thrombopoietin synthesis by hepatocytes to support homeostasis of platelet numbers (Nature Medicine). Thrombus growth Initial adhesion of platelets to sites of vascular injury is dependent on an interaction between platelet glycoprotein Iba and von Willebrand factor. There is evidence that thrombospondin 1 might also play a role. Prakash et al. studied this in a series of single and multiple knockout mice (Blood). From these studies, the conclusion is that thrombospondin 1 does indeed contribute to thrombus growth, but requires von Willebrand factor in order to achieve this. The Yin and Yang of warfarin Warfarin inhibits c-carboxylation not only of coagulation proteins but also of matrix GLA. In rodents, this effect of warfarin produces extensive calcification of the vessel wall. This has led to speculation that patients on warfarin might be more likely to develop vascular abnormalities. A study by Tantisattamo et al. looked into this by examining vascular calcifications in mammograms (ATVB). The results show that calcification of arteries in breast tissue is indeed more extensive in women taking warfarin. D-dimer testing for risk profiling Individualized prolongation of anticoagulation would reduce the number of recurrent venous thrombotic events without inducing a high number of hemorrhages. Kearon et al. evaluated a cohort of 410 patients with an
unprovoked venous thrombotic event by D-dimer testing after the initial treatment (Annals of Internal Medicine). In the 78% of patients with low D-dimer levels, anticoagulation was stopped. Over a 2-year follow-up period, the rate of recurrence was 6.7% per year. The incidence was higher in men than in women (9.7% vs. 5.4%), and the authors concluded that, in men, the recurrence rate after a negative D-dimer test result is not low enough to consider discontinuation of anticoagulation, whereas it may be so in women. Let’s target FXI In the ongoing quest for an anticoagulant that does not increase the risk of bleeding, B€ uller et al. tested an antisense oligonucleotide in a randomized trial for the prevention of venous thrombosis (New England Journal of Medicine). Three hundred patients who underwent knee replacement received either enoxaparin or anti-FXI, in two doses. The antisense oligonucleotide clearly reduced FXI levels. Venous thrombosis, as assessed by venography, occurred at similar rates in the enoxaparin and the low-dose anti-FXI groups, and at a substantially lower rate in the high-dose anti-FXI group (30% vs. 4%), whereas bleeding was less frequent in the anti-FXI group than in the enoxaparin group. Fat clots There is no end to the adverse effects of obesity. Campello et al. examined 80 individuals with mild to severe obesity, and found evidence of hypercoagulability as shown by various assays (Thrombosis and Haemostasis). As compared with individuals of normal weight, obese people had increased thrombin generation and increased numbers of microvesicles. As it is well established that obesity is related to an increased risk of venous thrombosis, these findings may assist in elucidating the mechanism behind this association. Don’t blame the surgeon Patients with cancer face a high risk of thrombosis, which is related not only to the biological properties of the malignancy itself, but also to the treatment of it. Becattini et al. (Haematologica) followed 305 patients with colorectal cancer who underwent surgery, and assessed risk factors for thrombosis. Thromboses occurred in 18%, but only 2% of these were symptomatic or proximal. Apart from the cancer stage, advanced age and obesity were related to the risk of postsurgical thrombosis, but surgery-related factors were not.
© 2015 International Society on Thrombosis and Haemostasis
Copyright of Journal of Thrombosis & Haemostasis is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
