Venous Thrombosis in the Nephrotic Syndrome

The Clinical Implications of Basic Research series has focused on highlighting laboratory research that could lead to advances in clinical therapeutics. However, the path between the laboratory and the bedside runs both ways: clinical observations often pose new questions for laboratory investigations that then lead back to the clinic. One of a series of occasional articles drawing attention to the bedsideto-bench flow of information is presented here, under the Basic Implications of Clinical Observations rubric. e hope our readers will en!oy these stories of discovery, and we invite them to submit their own e"amples of clinical findings that have led to insights in basic science. Thrombotic events complicate the nephrotic syndrome in appro"imately #$% of patients.& This association was first recogni'ed in the &(th century by . Howship )ickinson, who pointed out that *when the kidneys themselves are the seat of chronic disease, involving the loss of albumin, . . . the blood in their vessels, as elsewhere, is rendered morbidly coagulable by the drain.+# This observation was refined with the association between a specific renal condition ,the nephrotic syndrome- and venous thrombosis, as reported by )erow and colleagues in &(.(.. /lthough there was considerable debate as to what was cause and what was effect, we now view the nephrotic syndrome as a thrombophilic or hypercoagulable state.0 This conclusion was based on the demonstration of elevated plasma levels of fibrinogen and other clotting factors, accelerated generation of thromboplastin, and thrombocytosis in .$ untreated patients with nephrosis who did not have either a'otemia or clinical thrombosis. 1oon thereafter, 2auffmann and colleagues$ suggested that the thrombophilic state of the nephrotic syndrome is a consequence of a loss of endogenous anticoagulant antithrombin 333 in the urine as a result of altered permselectivity of the glomerular basement membrane. The concept of si'e-selective permeability of the glomerular basement membrane was first proposed in &(45 with the use of an animal model of immune-mediated nephrotic syndrome.4 /fter that initial study, several studies addressed the determinants of molecular e"clusion according to si'e and charge and their modification in nephrosis,5,6 including minimal change disease.( Thus, the mechanistic basis for the permselectivity of the glomerulus was informed by observations that were made with respect to the nephrotic syndrome, and an e"planation for the thrombotic state of nephrosis was derived from a detailed understanding of glomerular permselectivity. 1ince that time, several mechanisms that promote thrombosis in patients with nephrosis have been identified. 3n general, these mechanisms fall into two categories: urinary loss of proteins that prevent thrombosis and increased synthesis of factors that promote thrombosis . ith respect to thrombosis prevention, 07 to 67% of patients with the nephrotic syndrome were found to have reduced circulating levels of antithrombin 333,&7 owing to urinary loss of the anticoagulant.&& 8rotein 9 activity and protein 1 levels also appear to be reduced in patients with the nephrotic syndrome,&# although these findings have not been consistently observed.&. :igure & - ;echanisms of the Thrombophilic 1tate in the <ephrotic 1yndrome.

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/bnormalities in factors that promote thrombosis have been shown both among procoagulant proteins and among fibrinolytic proteins. /ctivation of secondary coagulation in patients with the nephrotic syndrome is accompanied by increased levels of factors = and =333, von illebrand factor, fibrinogen, and >#-macroglobulin, probably owing to increased synthesis.&. 3t is thought that the increase in these higher-molecular-weight species is a reflection of increased acute-phase synthesis.&. Hyperfibrinogenemia, in particular, is a hepatic synthetic response to the hypoalbuminemia of nephrosis. This increase in fibrinogen promotes platelet aggregation, provides substrate for fibrin formation, increases blood viscosity, and promotes erythrocyte aggregation.&0 ;ild thrombocytosis and platelet hyperreactivity also accompany the nephrotic syndrome. 8latelet hyperreactivity, which is found in appro"imately 57% of such patients,&. is multifactorial and can be attributed to increased levels of von illebrand factor, hyperfibrinogenemia, hypercholesterolemia, and hypoalbuminemia.&$ Hypoalbuminemia leads to increased bioavailability of arachidonic acid released by platelets, enhancing the recruitment of other platelets to the growing platelet-rich thrombus with a resulting lowered threshold for aggregation.&4 Hypercholesterolemia enhances agonistdependent sensitivity of platelets, promoting their activation,&5 and cholesterol-lowering therapy with statins reduces platelet aggregation&6 and lowers the risk of venous thrombosis&( in patients with nephrosis. /t the level of fibrinolysis, the nephrotic syndrome is associated with a decrease in circulating plasminogen levels.#7 This decrease in plasminogen is accompanied by an increase in levels of plasminogen activator inhibitor &#& and >#-plasmin inhibitor,&. all of which conspire to impair fibrin clearance and promote thrombus persistence. 3t is important to point out that these changes in factors that contribute to a thrombophilic state in the nephrotic syndrome are glomerulocentric in origin. 9hanges in the permselectivity of the glomerular basement membrane lead to a loss of lower-molecular-weight proteins that regulate hemostasis and thrombosis, and changes in the intraglomerular microenvironment as a consequence of the intrinsic disease process leading to nephrosis promote thrombosis. :or e"ample, inflammatory responses accompanying immune in!ury within the glomerulus may generate procoagulants## and induce e"pression of molecules that impair fibrinolysis.#. The basic clinical observations that showed an association between thrombosis and the nephrotic syndrome have evolved considerably from those of the past century. Once viewed as a cause of nephrosis through pressure-induced in!ury, thrombosis that accompanies the nephrotic syndrome is now viewed as a manifestation of a thrombophilic state that is multifactorial but dependent on the urinary loss of endogenous antithrombotic factors. The evolution in the understanding of these basic thrombotic mechanisms evolved in parallel with a growth in knowledge regarding the selective mechanisms of glomerular protein loss in the nephrotic syndrome, leading to the elucidation of comple" mechanisms by which normal renal function affects hemostasis.

Tromboza venoas n sindromul nefrotic

3mplicaiile clinice ale seriei ba'a de cercetare sa concentrat pe evidenierea laborator de cercetare care ar putea duce la progrese ?n terapeutica clinice. 9u toate acestea, calea de laborator i ?ntre noptiera rulea'@ ?n ambele sensuri: observaii clinice pune de multe ori noi ?ntreb@ri pentru investigaiile de laborator care duc apoi ?napoi la clinica. Anul dintr-o serie de articole oca'ionale care atrag atenia la flu"ul de noptiera-la-bancul de informaii sunt pre'entate aici, sub implicaiile de ba'@ din rubrica observaii clinice. 1per@m c@ cititorii notri se vor bucura de aceste poveti de descoperire, i ?i invit@m s@-i pre'inte propriile e"emple de constat@ri clinice, care au dus la descoperiri ?n domeniul tiinei de ba'@. Bvenimente trombotice complica sindromul nefrotic, ?n apro"imativ #$% din patients.& /ceast@ asociaie a fost recunoscut@ pentru prima dat@ ?n secolul &( de c@tre . Howship )ickinson, care a subliniat c@ Catunci cand rinichii ei ?nii sunt scaunul de boli cronice, care implic@ pierderea de albumina ,. . . sDnge ?n vasele lor, ca pretutindeni, este redat morbida coagulabil de evacuare C#. /ceast@ observaie a fost rafinat, cu asocierea dintre o condiie specific@ renal@ ,sindrom nefrotic- i trombo'@ venoas@, astfel cum raportate de )erow si colegii sai de la &(.(.. )ei e"ist@ o de'batere considerabil@ cu privire la ceea ce a fost cau'a i ceea ce a fost ?n vigoare, vom vi'uali'a acum sindrom nefrotic ca o trombo'@ sau hipercoagulabilitate state.0 /ceast@ conclu'ie sa ba'at pe demonstrarea unor niveluri plasmatice crescute ale fibrinogenului i a altor factori de coagulare, generarea accelerat@ a tromboplastin@, i trombocito'@ la .$ de pacieni netratai cu nefro'a, care nu au avut nici a'otemie sau trombo'@ clinic@. 9urDnd dup@ aceea, 2auffmann i colleagues$ a sugerat c@ starea de trombo'@, sindrom nefrotic este o consecin@ a pierderii de endogene anticoagulant antitrombina 333, ?n urin@, ca urmare a permselectivity alterat@ a membranei ba'ale glomerulare. 9onceptul de m@rime selectiv permeabilitatea membranei ba'ale glomerulare a fost propus pentru prima dat@ ?n &(45, cu utili'area unui model animal de imun-mediate syndrome.4 nefrotic )up@ acest studiu initial, mai multe studii au abordat factorii determinani ai e"clu'iunii molecular@ ?n funcie de m@rime i de ta"a de i modificarea acestora ?n nefro'a, 5,6 inclusiv schimb@ri minime disease.( /stfel, ba'a mecanicista pentru permselectivity a glomerular a fost informat de observaii care au fost f@cute cu privire la sindromul nefrotic, i o e"plicaie pentru starea de nefro'@ trombotice a fost derivat@ dintr-o ?nelegere detaliat@ a permselectivity glomerulare. )in acel moment, mai multe mecanisme care promovea'@ trombo'a la pacientii cu nefro'a au fost identificate. En general, aceste mecanisme se ?mpart ?n dou@ categorii: pierderea urinar@ de proteine care ?mpiedic@ trombo'a i sinte'a crescut@ a factorilor care promovea'@ trombo'a ,&;echanisms &:igure :igura ale statului trombofilice ?n sindromul nefrotic.-. En ceea ce privete prevenirea trombo'ei, 07 la 67% dintre pacientii cu sindrom nefrotic-au dovedit a fi redus nivelurile circulante de antitrombina 333, &7 din cau'a unor pierderi urinare de nivelurile de proteine de activitate anticoagulant.&& 9 i proteinei 1, de asemenea, par a fi reduse ?n pacienii cu sindrom nefrotic, &#, dei aceste re'ultate nu au fost ?n mod constant observed.&. /nomalii ?n factori care promovea'@ trombo'a s-au dovedit atDt ?n rDndul proteine procoagulante i ?ntre proteinele fibrinolitici. /ctivarea coagul@rii secundar@, la pacienii cu sindrom nefrotic este ?nsoit@ de nivelurile crescute de factori = i =333, factorul von illebrand, fibrinogen, i >#macroglobulina, probabil din cau'a la creterea synthesis.&. 1e crede c@ creterea ?n aceste superior molecular@ -greutate specie este o reflectare a crescut de fa'a acuta synthesis.&. Hyperfibrinogenemia, ?n special, este un r@spuns la hepatic@ sintetic hipoalbuminemia de nefro'@. /ceast@ cretere a .

fibrinogenului promovea'a agregarea plachetara, prevede substrat pentru formarea fibrinei, crete vDsco'itatea sDngelui, i promovea'@ eritrocite aggregation.&0 Trombocito'a uoare i hiperreactivitatea trombocitelor ?nsoeasc@, de asemenea, sindrom nefrotic. Hiperreactivit@ii de trombocite, care se gaseste in apro"imativ 57% dintre pacieni, &. este multifactoriala si poate fi atribuit@ la niveluri crescute de factor von illebrand, hyperfibrinogenemia, hipercolesterolemie, i hypoalbuminemia.&$ Hipoalbuminemia duce la creterea biodisponibilit@ii de acid arahidonic eliberat de trombocite, creterea recrutarea de trombocite la creterea altor trombocite bogate ?n tromb, cu un prag care re'ult@ redus pentru aggregation.&4 hipercolesterolemie ?mbun@t@ete agonist-dependente sensibilitate de trombocite, promovarea activarea lor, &5 i reducerea nivelului de colesterol terapia cu statine reduce trombocite aggregation&6 si scade riscul de venoase la pacienii cu thrombosis&( nefro'a. Fa nivelul fibrinoli'ei, sindrom nefrotic este asociat cu o sc@dere a circulant de plasminogen levels.#7 /ceast@ sc@dere a plasminogenului este ?nsoit@ de o cretere a nivelului de inhibitor de activator de plasminogen &#& i >#-plasmina inhibitor, &. toate acestea conspira pentru a afecta fibrin@ clearanceul i de a promova persistena trombilor. Bste important s@ subliniem faptul c@ aceste schimb@ri ?n factorii care contribuie la o stare trombofilic@ ?n sindromul nefrotic sunt glomerulocentric de origine. ;odific@ri ?n permselectivity a membranei ba'ale glomerulare duce la o pierdere de mai mici cu greutate moleculara proteine care reglea'a hemosta'a i trombo'a, i schimb@ri ?n micromediul intraglomerular ca urmare a procesului de boala intrinsec care s@ conduc@ la promovarea nefro'a trombo'a. )e e"emplu, r@spunsurile inflamatorii care ?nsoesc un pre!udiciu ?n cadrul imunitar glomerular poate genera procoagulants## i induce e"presia moleculelor care afectea'@ fibrinolysis.#. Observaiile clinice de ba'@, care au demonstrat o asociere ?ntre trombo'@ i sindrom nefrotic au evoluat ?n mod considerabil de cele ale secolului trecut. Odat@ ce privit ca o cau'@ de nefro'@ prin presiune induse de pre!udiciu, trombo'@ care ?nsoete sindromul nefrotic este acum privit ca o manifestare a unui stat trombofilic@ care este multifactorial@, dar depinde de pierderea urinar@ de factori endogeni antitrombotice. Bvoluie ?n ?nelegerea acestor mecanisme de ba'@ trombotice evoluat ?n paralel cu o cretere a cunotinelor privind mecanismele selective de pierdere de proteine glomerulare, ?n sindromul nefrotic, care s@ conduc@ la elucidarea unor mecanisme comple"e, prin care funcie renal@ normal@ afectea'@ hemosta'a.:orme de pre'entare a informaiilor oferite de autor sunt disponibile cu te"tul integral al acestui articol la <BG;.org.1ursa de informare)e la )epartamentul de ;edicina, 1pitalul Hrigham si :emei, i coala Harvard ;edical - atDt ?n Hoston.