Thromboembolic Risks and Complications in Nephrotic Children

Abstract

The identification of many biologic anomalies is progressively realized in nephrotic children, thanks to adult studies and to scientific advances. The number of anomalies and the intensity of alterations vary from one patient to another and during flare-ups in the same patient. Their severity is usually a function of the severity of the nephrotic syndrome (NS). The responsibility of each anomaly per se in triggering thrombotic complications is not yet known and today it is understood that the coexistence of several factors is necessary to induce these complications. Thus, the NS presents a true model because it can gather multiple thrombogenic anomalies. It might be more satisfying to characterize all of the mechanisms that could be responsible for a thrombosis rather than to assay all of the biologic components in one patient. When the main balances during the childhood NS are broken-pro- versus anticoagulant forces, pro- versus antifibrinolytic forces, platelet/vessel wall interactions-one cannot evaluate with accuracy the possible impact of acquired interrelations such as a decrease of antithrombin versus an increase of protein C. Among the present unknown factors, a major one is related to the effects, if any, of the proteinuric factor (recently discovered) on the vascular endothelium and the central question is: would it be capable of changing the thromboresistant phenotype to a thrombogenic one? No absolute correlation has been found between the many biologic abnormalities and the occurrence of thromboembolic (TE) complications. However, it is of great interest to have the best evaluation of the TE risks in nephrotic children. The criteria that are commonly used are: albuminuria, and plasma levels of fibrinogen and antithrombin. One can suggest adding to these criteria the D-dimer assay, a molecular marker of coagulation activation, and the factor V Leiden workup because it represents a genetic predisposition for TE complications. As far as prevention of TE complications is concerned, the standard but basic guidelines of nephrotic patients must be followed. Furthermore, vitamin K antagonists should be administered as soon as the risk criteria are gathered, but only after a careful evaluation of the benefits/risks ratio. As to the treatment of TE events, one should follow the present recommendations for children. A better future regarding prevention of TE accidents is based not only on the necessity of multicentric prospective studies but also on basic research that will allow discovery of the "primum movens" of childhood NS.

Disease Severity Correlates with Thrombotic Capacity in Experimental Nephrotic Syndrome

“…[3][4][5][6][7] In this study, we have shown that TGA is highly correlated with proteinuria severity and hypoalbuminemia in two commonly used animal models of NS. Furthermore, these studies show that these animals are also hypercoagulable in a proteinuria-and hypoalbuminemia-dependent fashion, with no apparent threshold effect.…”

“…The coagulation derangements identified in PANnephrotic rats are consistent with previous reports and phenotypically similar to that reported in human NS with respect to hyperfibrinogenemia and AT deficiency. [3][4][5][6]19,20 Thus, the PAN nephrosis model is an excellent preclinical model for the investigation of the acquired hypercoagulopathy of human NS.…”

“…[3][4][5] Interestingly, plasma AT concentration was not significantly altered by proteinuria ( Figure 4A). This finding suggested that the well known AT deficiency may be caused by a qualitative defect in enzymatic activity, which was significantly correlated with proteinuria ( Figure 4B) (R 2 =0.32; P=0.001).…”

“…1,2 As recently reviewed, it is well known that nephrotic-range proteinuria is associated with an acquired complex hypercoagulopathy. [3][4][5][6] The hypercoagulable state is associated with acquired deficiencies of key hemostatic regulatory elements, such as antithrombin (AT) and free Protein S, and elevated levels of high molecular weight procoagulant factors (including factors V and VIII, vWf, and fibrinogen). The predicted overall effect of these coagulation derangements is an enhanced capacity for thrombin generation (conversion of prothrombin to thrombin), which is the key effector enzyme of the hemostatic system.…”

“…The predicted overall effect of these coagulation derangements is an enhanced capacity for thrombin generation (conversion of prothrombin to thrombin), which is the key effector enzyme of the hemostatic system. [3][4][5] However, the effects of these derangements on the dynamics of coagulation system activation are not well understood.…”