Summary. During the haemostatic response, the formation of a primary platelet plug limits bleedi... more Summary. During the haemostatic response, the formation of a primary platelet plug limits bleeding and provides a surface for clotting factors to assemble and become activated. The initial platelet plug is stabilized by fibrin monomers, covalently cross‐linked by FXIII, forming a platelets‐fibrin thrombus. Defects in platelets as well as inherited deficiencies of coagulation factors including fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI and FXIII deficiencies, generally lead to lifelong bleeding disorders, whose severity of bleeding symptoms is heterogeneous in platelets abnormalities but generally inversely proportional to the degree of the factor deficiency in rare bleeding disorders (RBDs). The prevalence of platelet defects among the general population has not been established, whereas for RBDs it ranges from approximately 1 in 2 million to 1 in 500 000, being higher in countries where consanguineous marriages are diffused. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not well established. In this review the main features, diagnosis, available treatment options and treatment complications of the platelet disorders, caused by abnormalities in platelet receptors for adhesive proteins, platelet receptors for soluble agonists, platelet granules, signal transduction pathways, or procoagulant phospholipids will be discussed by Dr Cattaneo, whereas fibrinogen deficiency and FXIII deficiency will be described by Dr Inbal and Dr de Moerloose, respectively. Finally, the update of the Rare Bleeding Disorders Database will be presented by Dr Spreafico.
Background: Refractoriness to platelet transfusion is prevalent among 15-25% of hemato-oncology p... more Background: Refractoriness to platelet transfusion is prevalent among 15-25% of hemato-oncology patients. Refractoriness has been linked to inferior clinical outcomes, including bleeding and mortality, as well as higher health care costs. Suggested etiologies to refractoriness include both non-immune and immune causes. Methods to manage refractoriness include leuko-reduction, HLA- and HPA- matched platelets, use of ABO compatible transfusions and platelet cross-matching. Leuko-reduction has been proven to decrease the rates of allo-immunization and is widely used in hemato-oncology units. Other methods have demonstrated modest effectiveness in some studies, but some of these (HLA- and HPA- matched platelets) are not widely available. There are only a few reports in the literature of continuous platelet transfusion (CPT) as an alternative method for increasing post-transfusion platelet increments. Those reports prompted the current analysis of CPT in platelet refractory patients. Aim: To evaluate the effectiveness of CPT in producing satisfactory platelet increments in refractory patients compared to the standard care of routinely prepared single donor platelet transfusions. Patients and Methods: Patients included in this study were treated for hematological malignancies in our Institution between January 2007 and December 2013. A retrospective analysis of the increment of platelets achieved in refractory patients was performed. Refractoriness was defined as a corrected calculated increment (CCI) less than 10,000 platelets per micro-liter following two successive platelet transfusions. The CCI was calculated as PPI (post-transfusion platelet count minus pre-transfusion platelet count) x BSA (body surface area measured in square meters m2) x 1011/number of platelets transfused. All refractory patients included in this analysis received single donor platelet transfusions. The practice of CPT was adopted by us in March 2008. All refractory patients who received CPT between March 2008 and December 2013 were included. These patients received a continuous 24 hour transfusion of single donor platelet units, each dose given over 4 to 6 hours, comprising of 1.5 x 1011 platelets and equaling to half a single donor platelet unit. Their outcome was compared with that of our refractory patients treated with single donor transfusions in the routine manner, between January 2007 and March 2008 (i.e. before the introduction of CPT). The CCI was used to monitor the effectiveness of each platelet unit at 12 and 24 hours post-transfusion intervals. To account for prior antigen-exposure of the patients, we chose to include for each patient the 11th consecutive platelet transfusion. Factors known to contribute to the development of refractoriness, such as infection, disseminated intravascular coagulation (DIC) and splenomegaly were evaluated for impact on the CCI. The statistical analysis was generated using SAS Software, Version 9.4. Continuous variables were presented as mean ± STD, Categorical variables were presented by (N, %). t-tests and non-parametric Wilcoxon tests were used to compare the value of continuous variables between study groups. Results: Twenty eight patients with hematologic malignancies received at least eleven single-donor platelet transfusions during 2007-2013. Twenty one of the 28 patients received CPT due to refractoriness and seven patients were treated before the introduction of this approach. CPT resulted in a significantly higher post-transfusion mean increment at 24 hours (1.16 vs. 0.37, p<0.05). Increments were higher, albeit not significantly, at 12 hours post-transfusion in the CPT group (2.45 vs. 0.36, p=0.058). Patient's gender, age (younger than 35 years old versus older), renal failure, high grade fever, infection and DIC, splenomegaly or donor-recipient ABO compatibility were not found to significantly influence the increment. Conclusions: CPT results in significantly higher increments at 24 hours post-transfusion, and therefore suggest an effective approach to the treatment of platelet refractoriness in patients treated for hematological malignancies. Disclosures No relevant conflicts of interest to declare.
Endothelial cells (EC) were cultured from the umbilical cord of a male neonate whose mother was p... more Endothelial cells (EC) were cultured from the umbilical cord of a male neonate whose mother was previously diagnosed with type IIA von Willebrand's disease (vWd). The diagnosis of type IIA vWd in the proband was confirmed by low ristocetin activity and the absence of the highest molecular weight (MW) forms of von Willebrand factor (vWf) in his platelet poor plasma. The vWf of EC cultured from the neonate's umbilical cord differed from that of control EC and the cell line EA.hy926 in two respects. Firstly, the full range of molecular weight forms was present in the patient EC lysate and, secondly, vWf:Ag expression was approximately seven‐fold greater than that of control cells, Platelet lysates prepared from other affected members of the type IIA vWd family in the presence or absence of proteolytic inhibitors demonstrated a near normal vWf multimeric distribution. Resistance of these high MW forms to heat degradation was conferred by the presence of proteolytic inhibitors. Moreover, the full plasma vWf multimeric distribution could not be restored by the inclusion of EDTA, N‐ethylmaleimide and leupeptin in the anticoagulant during the rapid preparation of platelet poor plasma. These findings lend support to the heterogeneous nature of type IIA vWd and has possible implications in the understanding of the intracellular processes involved in the biosynthesis and storage of the vWf macromolecular complex as well as the pathogenesis of type IIA vWd.
Seminars in Thrombosis and Hemostasis, Aug 24, 2016
Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with p... more Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with potentially life-threatening consequences. FXIII is composed of two subunits (A and B), and a deficiency or dysfunction of either can result in FXIII deficiency. Traditionally, FXIII deficiency has been managed by infusing plasma-derived products containing FXIII (fresh frozen plasma, cryoprecipitate, and plasma-derived FXIII concentrates), all of which contain both subunits. Despite the increased safety of plasma-derived products, concern remains regarding potential viral safety issues. This review describes the development, from concept to clinical use, of a recombinant FXIII molecule (containing subunit A only; rFXIII-A2) for congenital FXIII-A subunit deficiency. Unmet needs and ongoing challenges in congenital FXIII deficiency are also discussed. Despite the challenges in developing a product for a very rare bleeding disorder, the information gathered on efficacy, safety, and pharmacokinetics of FXIII replacement therapy represents the largest dataset on congenital FXIII-A subunit deficiency in the world. It also provides evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg of rFXIII-A2 in patients with FXIII-A subunit deficiency. The issues encountered and overcome, along with lessons learned, may be applied to and encourage the development of new recombinant products for other rare bleeding disorders.
In order to analyze the interaction of platelets with von Willebrand factor (vWF) and collagen, w... more In order to analyze the interaction of platelets with von Willebrand factor (vWF) and collagen, we studied the binding of glycocalicin (GC) and formalin-fixed platelets to vWF adsorbed onto uncoated or collagen-coated polystyrene surfaces. These studies show that three-fold more vWF binds to collagen-coated polystyrene than to polystyrene coated with fibrin monomer or fibrinogen. At saturation, 37 +/- 2.9 ng vWF bound to the collagen-coated wells, compared to 12.8 +/- 5.4 ng, and 10.9 +/- 2.7 ng of vWF bound to wells coated with fibrin monomer and fibrinogen, respectively. GC also bound significantly more to collagen-coated wells than to wells coated with fibrinogen, and this binding was increased approximately two-fold (from 7 +/- 0.65 ng to 14 +/- 1.1 ng) in the presence of vWF adsorbed to the collagen-coated surface. Only 2 ng of GC was bound to 3000 ng of vWF when the latter was adsorbed directly onto a polystyrene surface. In contrast, GC binding to vWF adsorbed onto a collagen-coated surface was enhanced 600-fold with 7.0 ng of GC bound to 18 ng of immobilized vWF. Formalin-fixed platelets showed little binding to vWF adsorbed onto the microtiter wells. At saturation, 7 x 10(4) platelets bound to 3000 ng of vWF; a 6-fold increase in platelet binding was observed using collagen-coated wells and this binding was increased even further in the presence of vWF, resulting in 250-fold increase in platelet binding to vWF when the latter was adsorbed onto a collagen surface. These studies suggest that (1) GC is involved in platelet binding to collagen and this binding is increased by vWF; (2) GC binding to vWF is enhanced by the collagen-coated surface; (3) the adsorption of vWF onto a collagen surface may induce conformational changes in vWF that promote its interaction with GC or glycoprotein Ib.
We describe a patient with hemophagocytic syndrome resembling malignant histiocytosis which was c... more We describe a patient with hemophagocytic syndrome resembling malignant histiocytosis which was complicating myelodysplastic disease of 3 years duration. Detailed morphological and ultrastructural studies indicate that the histiocytic component did not demonstrate features of malignancy. A review of other known malignancies ending up in the hemophagocytic syndrome is given, and the significance of this syndrome is discussed.
Factor XIII subunit A (FXIII A) is synthesized by megakaryocytes, and monocytes/macrophages. In a... more Factor XIII subunit A (FXIII A) is synthesized by megakaryocytes, and monocytes/macrophages. In addition, the liver has been reported as an extrahaematopoietic source of FXIII A. At present, the extent of contribution of either haematopoietic or extrahaematopoietic sources to the plasma FXIII A level is unknown. We studied the effect of bone marrow aplasia due to high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ASCT) on plasma FXIII A activity and concentration in 20 patients with haematological or solid tumour malignancies. A multiple linear regression model was used to assess the effect of gender, age, malignancy and treatment types, platelet and monocyte counts, abnormal liver function tests, prothrombin time, and number of platelet transfusions on FXIII activity measured in plasma before and following ASCT. Significant correlation between platelet counts and FXIII A activity in plasma was observed (r = 0.51, P = 0.0001), which remained after the adjustment for the aforementioned parameters (multiple R = 0.52, P = 0.0001). In contrast, no significant correlation between FXIII A levels and monocyte counts was observed (r = 0.19), and this lack of correlation persisted after the adjustment. These results suggest that in the ASCT model, following myeloablation, platelets but not monocytes are the haematopoietic cells that contribute significantly to plasma FXIII A levels. In addition, extra-haematopoietic sources of FXIII synthesis may also contribute to FXIII levels in plasma.
Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. ... more Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. With the advent of highly efficacious therapy, the focus has shifted toward managing TKI adverse effects, such as vascular adverse events (VAEs). We used an in vitro angiogenesis model to investigate the TKI-associated VAEs. Our data show that imatinib, nilotinib, and ponatinib reduce human umbilical vein endothelial cells (HUVECs) viability. Pharmacological concentrations of ponatinib induced apoptosis, reduced migration, inhibited tube formation of HUVECs, and had a negative effect on endothelial progenitor cell (EPC) function. Furthermore, in HUVECs transfected with VEGF receptor 2 (VEGFR2), the effect of ponatinib on tube formation and on all parameters representing normal endothelial cell function was less prominent than in control cells. This is the first report regarding the pathogenesis of ponatinib-associated VAEs. The antiangiogenic effect of ponatinib, possibly mediated by VEGFR2 inhibition, as shown in our study, is another piece in the intricate puzzle of TKI-associated VAEs.
Summary. During the haemostatic response, the formation of a primary platelet plug limits bleedi... more Summary. During the haemostatic response, the formation of a primary platelet plug limits bleeding and provides a surface for clotting factors to assemble and become activated. The initial platelet plug is stabilized by fibrin monomers, covalently cross‐linked by FXIII, forming a platelets‐fibrin thrombus. Defects in platelets as well as inherited deficiencies of coagulation factors including fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI and FXIII deficiencies, generally lead to lifelong bleeding disorders, whose severity of bleeding symptoms is heterogeneous in platelets abnormalities but generally inversely proportional to the degree of the factor deficiency in rare bleeding disorders (RBDs). The prevalence of platelet defects among the general population has not been established, whereas for RBDs it ranges from approximately 1 in 2 million to 1 in 500 000, being higher in countries where consanguineous marriages are diffused. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not well established. In this review the main features, diagnosis, available treatment options and treatment complications of the platelet disorders, caused by abnormalities in platelet receptors for adhesive proteins, platelet receptors for soluble agonists, platelet granules, signal transduction pathways, or procoagulant phospholipids will be discussed by Dr Cattaneo, whereas fibrinogen deficiency and FXIII deficiency will be described by Dr Inbal and Dr de Moerloose, respectively. Finally, the update of the Rare Bleeding Disorders Database will be presented by Dr Spreafico.
Background: Refractoriness to platelet transfusion is prevalent among 15-25% of hemato-oncology p... more Background: Refractoriness to platelet transfusion is prevalent among 15-25% of hemato-oncology patients. Refractoriness has been linked to inferior clinical outcomes, including bleeding and mortality, as well as higher health care costs. Suggested etiologies to refractoriness include both non-immune and immune causes. Methods to manage refractoriness include leuko-reduction, HLA- and HPA- matched platelets, use of ABO compatible transfusions and platelet cross-matching. Leuko-reduction has been proven to decrease the rates of allo-immunization and is widely used in hemato-oncology units. Other methods have demonstrated modest effectiveness in some studies, but some of these (HLA- and HPA- matched platelets) are not widely available. There are only a few reports in the literature of continuous platelet transfusion (CPT) as an alternative method for increasing post-transfusion platelet increments. Those reports prompted the current analysis of CPT in platelet refractory patients. Aim: To evaluate the effectiveness of CPT in producing satisfactory platelet increments in refractory patients compared to the standard care of routinely prepared single donor platelet transfusions. Patients and Methods: Patients included in this study were treated for hematological malignancies in our Institution between January 2007 and December 2013. A retrospective analysis of the increment of platelets achieved in refractory patients was performed. Refractoriness was defined as a corrected calculated increment (CCI) less than 10,000 platelets per micro-liter following two successive platelet transfusions. The CCI was calculated as PPI (post-transfusion platelet count minus pre-transfusion platelet count) x BSA (body surface area measured in square meters m2) x 1011/number of platelets transfused. All refractory patients included in this analysis received single donor platelet transfusions. The practice of CPT was adopted by us in March 2008. All refractory patients who received CPT between March 2008 and December 2013 were included. These patients received a continuous 24 hour transfusion of single donor platelet units, each dose given over 4 to 6 hours, comprising of 1.5 x 1011 platelets and equaling to half a single donor platelet unit. Their outcome was compared with that of our refractory patients treated with single donor transfusions in the routine manner, between January 2007 and March 2008 (i.e. before the introduction of CPT). The CCI was used to monitor the effectiveness of each platelet unit at 12 and 24 hours post-transfusion intervals. To account for prior antigen-exposure of the patients, we chose to include for each patient the 11th consecutive platelet transfusion. Factors known to contribute to the development of refractoriness, such as infection, disseminated intravascular coagulation (DIC) and splenomegaly were evaluated for impact on the CCI. The statistical analysis was generated using SAS Software, Version 9.4. Continuous variables were presented as mean ± STD, Categorical variables were presented by (N, %). t-tests and non-parametric Wilcoxon tests were used to compare the value of continuous variables between study groups. Results: Twenty eight patients with hematologic malignancies received at least eleven single-donor platelet transfusions during 2007-2013. Twenty one of the 28 patients received CPT due to refractoriness and seven patients were treated before the introduction of this approach. CPT resulted in a significantly higher post-transfusion mean increment at 24 hours (1.16 vs. 0.37, p<0.05). Increments were higher, albeit not significantly, at 12 hours post-transfusion in the CPT group (2.45 vs. 0.36, p=0.058). Patient's gender, age (younger than 35 years old versus older), renal failure, high grade fever, infection and DIC, splenomegaly or donor-recipient ABO compatibility were not found to significantly influence the increment. Conclusions: CPT results in significantly higher increments at 24 hours post-transfusion, and therefore suggest an effective approach to the treatment of platelet refractoriness in patients treated for hematological malignancies. Disclosures No relevant conflicts of interest to declare.
Endothelial cells (EC) were cultured from the umbilical cord of a male neonate whose mother was p... more Endothelial cells (EC) were cultured from the umbilical cord of a male neonate whose mother was previously diagnosed with type IIA von Willebrand's disease (vWd). The diagnosis of type IIA vWd in the proband was confirmed by low ristocetin activity and the absence of the highest molecular weight (MW) forms of von Willebrand factor (vWf) in his platelet poor plasma. The vWf of EC cultured from the neonate's umbilical cord differed from that of control EC and the cell line EA.hy926 in two respects. Firstly, the full range of molecular weight forms was present in the patient EC lysate and, secondly, vWf:Ag expression was approximately seven‐fold greater than that of control cells, Platelet lysates prepared from other affected members of the type IIA vWd family in the presence or absence of proteolytic inhibitors demonstrated a near normal vWf multimeric distribution. Resistance of these high MW forms to heat degradation was conferred by the presence of proteolytic inhibitors. Moreover, the full plasma vWf multimeric distribution could not be restored by the inclusion of EDTA, N‐ethylmaleimide and leupeptin in the anticoagulant during the rapid preparation of platelet poor plasma. These findings lend support to the heterogeneous nature of type IIA vWd and has possible implications in the understanding of the intracellular processes involved in the biosynthesis and storage of the vWf macromolecular complex as well as the pathogenesis of type IIA vWd.
Seminars in Thrombosis and Hemostasis, Aug 24, 2016
Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with p... more Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with potentially life-threatening consequences. FXIII is composed of two subunits (A and B), and a deficiency or dysfunction of either can result in FXIII deficiency. Traditionally, FXIII deficiency has been managed by infusing plasma-derived products containing FXIII (fresh frozen plasma, cryoprecipitate, and plasma-derived FXIII concentrates), all of which contain both subunits. Despite the increased safety of plasma-derived products, concern remains regarding potential viral safety issues. This review describes the development, from concept to clinical use, of a recombinant FXIII molecule (containing subunit A only; rFXIII-A2) for congenital FXIII-A subunit deficiency. Unmet needs and ongoing challenges in congenital FXIII deficiency are also discussed. Despite the challenges in developing a product for a very rare bleeding disorder, the information gathered on efficacy, safety, and pharmacokinetics of FXIII replacement therapy represents the largest dataset on congenital FXIII-A subunit deficiency in the world. It also provides evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg of rFXIII-A2 in patients with FXIII-A subunit deficiency. The issues encountered and overcome, along with lessons learned, may be applied to and encourage the development of new recombinant products for other rare bleeding disorders.
In order to analyze the interaction of platelets with von Willebrand factor (vWF) and collagen, w... more In order to analyze the interaction of platelets with von Willebrand factor (vWF) and collagen, we studied the binding of glycocalicin (GC) and formalin-fixed platelets to vWF adsorbed onto uncoated or collagen-coated polystyrene surfaces. These studies show that three-fold more vWF binds to collagen-coated polystyrene than to polystyrene coated with fibrin monomer or fibrinogen. At saturation, 37 +/- 2.9 ng vWF bound to the collagen-coated wells, compared to 12.8 +/- 5.4 ng, and 10.9 +/- 2.7 ng of vWF bound to wells coated with fibrin monomer and fibrinogen, respectively. GC also bound significantly more to collagen-coated wells than to wells coated with fibrinogen, and this binding was increased approximately two-fold (from 7 +/- 0.65 ng to 14 +/- 1.1 ng) in the presence of vWF adsorbed to the collagen-coated surface. Only 2 ng of GC was bound to 3000 ng of vWF when the latter was adsorbed directly onto a polystyrene surface. In contrast, GC binding to vWF adsorbed onto a collagen-coated surface was enhanced 600-fold with 7.0 ng of GC bound to 18 ng of immobilized vWF. Formalin-fixed platelets showed little binding to vWF adsorbed onto the microtiter wells. At saturation, 7 x 10(4) platelets bound to 3000 ng of vWF; a 6-fold increase in platelet binding was observed using collagen-coated wells and this binding was increased even further in the presence of vWF, resulting in 250-fold increase in platelet binding to vWF when the latter was adsorbed onto a collagen surface. These studies suggest that (1) GC is involved in platelet binding to collagen and this binding is increased by vWF; (2) GC binding to vWF is enhanced by the collagen-coated surface; (3) the adsorption of vWF onto a collagen surface may induce conformational changes in vWF that promote its interaction with GC or glycoprotein Ib.
We describe a patient with hemophagocytic syndrome resembling malignant histiocytosis which was c... more We describe a patient with hemophagocytic syndrome resembling malignant histiocytosis which was complicating myelodysplastic disease of 3 years duration. Detailed morphological and ultrastructural studies indicate that the histiocytic component did not demonstrate features of malignancy. A review of other known malignancies ending up in the hemophagocytic syndrome is given, and the significance of this syndrome is discussed.
Factor XIII subunit A (FXIII A) is synthesized by megakaryocytes, and monocytes/macrophages. In a... more Factor XIII subunit A (FXIII A) is synthesized by megakaryocytes, and monocytes/macrophages. In addition, the liver has been reported as an extrahaematopoietic source of FXIII A. At present, the extent of contribution of either haematopoietic or extrahaematopoietic sources to the plasma FXIII A level is unknown. We studied the effect of bone marrow aplasia due to high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ASCT) on plasma FXIII A activity and concentration in 20 patients with haematological or solid tumour malignancies. A multiple linear regression model was used to assess the effect of gender, age, malignancy and treatment types, platelet and monocyte counts, abnormal liver function tests, prothrombin time, and number of platelet transfusions on FXIII activity measured in plasma before and following ASCT. Significant correlation between platelet counts and FXIII A activity in plasma was observed (r = 0.51, P = 0.0001), which remained after the adjustment for the aforementioned parameters (multiple R = 0.52, P = 0.0001). In contrast, no significant correlation between FXIII A levels and monocyte counts was observed (r = 0.19), and this lack of correlation persisted after the adjustment. These results suggest that in the ASCT model, following myeloablation, platelets but not monocytes are the haematopoietic cells that contribute significantly to plasma FXIII A levels. In addition, extra-haematopoietic sources of FXIII synthesis may also contribute to FXIII levels in plasma.
Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. ... more Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. With the advent of highly efficacious therapy, the focus has shifted toward managing TKI adverse effects, such as vascular adverse events (VAEs). We used an in vitro angiogenesis model to investigate the TKI-associated VAEs. Our data show that imatinib, nilotinib, and ponatinib reduce human umbilical vein endothelial cells (HUVECs) viability. Pharmacological concentrations of ponatinib induced apoptosis, reduced migration, inhibited tube formation of HUVECs, and had a negative effect on endothelial progenitor cell (EPC) function. Furthermore, in HUVECs transfected with VEGF receptor 2 (VEGFR2), the effect of ponatinib on tube formation and on all parameters representing normal endothelial cell function was less prominent than in control cells. This is the first report regarding the pathogenesis of ponatinib-associated VAEs. The antiangiogenic effect of ponatinib, possibly mediated by VEGFR2 inhibition, as shown in our study, is another piece in the intricate puzzle of TKI-associated VAEs.
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