Blood Coagulation and the Nephrotic Syndrome: Deficiency or Excess?

Abstract

Special CommunicationBlood Coagulation and the Nephrotic Syndrome: Deficiency or Excess? Ramon R. Duarte, MD, FACP Tariq I. Mughal, and MD(Lond), FACP Abdullah Al-RogiMB, BS Ramon R. Duarte Address reprint requests and correspondence to Dr. Duarte: Department of Medicine, King Fahad Hospital, P.O. Box 22490, Riyadh 11426, Saudi Arabia. From the Department of Medicine, King Fahad Hospital, Riyadh Search for more papers by this author , Tariq I. Mughal From the Department of Medicine, King Fahad Hospital, Riyadh Search for more papers by this author , and Abdullah Al-Rogi From the Department of Medicine, King Fahad Hospital, Riyadh Search for more papers by this author Published Online:1 Mar 1990https://doi.org/10.5144/0256-4947.1990.187SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractNormal hemostasis can be disrupted in patients with nephrotic syndrome. More commonly a thrombotic diathesis is seen but there are also sporadic reports of abnormal bleeding. These abnormalities appear to result from the abnormal protein loss, hypoalbuminemia, and hyper-lipidemia that characterize the condition. Hemoconcentration, enhanced platelet aggregation, increased activity of several coagulation factors, and defective fibrinolysis collectively predispose to thrombotic complications. An acquired deficiency of some clotting factors is usually responsible for the bleeding diathesis.IntroductionPatients with nephrotic syndrome tend to suffer from a spectrum of hemostatic disorders, ranging from an increased incidence of thromboembolism to an increased bleeding tendency.1-3 Although the association between nephrotic syndrome and thromboembolic complications has been recognized for more than a century, the precise causal relationship is not entirely understood.4-6 Moreover, the association between the increased bleeding tendency and nephrotic syndrome is also somewhat unclear.2-7 In this review, we present a current synopsis on the subject and discuss some of the controversial aspects that have emerged during the past decade.8,9 An in-depth understanding of the underlying pathogenesis should pave the way to better clinical methods for preventing these grave complications.In discussing the diverse hemostatic abnormalities associated with the nephrotic syndrome, it is preferable to divide these abnormalities into two categories: first, alterations that predispose to a hypercoagulable state, and second, abnormalities that lead to a bleeding tendency (Table 1).Table 1. Factors with potential to affect hemostasis in the nephrotic syndrome.Table 1. Factors with potential to affect hemostasis in the nephrotic syndrome.FACTORS PREDISPOSING TO A HYPERCOAGULABLE STATEIt is well known that the thromboembolic complications seen, in the nephrotic syndrome are preceded by a hypercoagulable state which until recently has proved relatively difficult to diagnose, largely due to lack of reproducible techniques for detecting and monitoring the various changes in the coagulation cascade.10,11 It is known that there is a major biochemical imbalance between procoagulant and anticoagulant mechanisms in the presence of a hypercoagulable state. The precise pathophysiology has recently been summarized by Bauer and Rosenberg9 and is beyond the scope of this review. Pursuant to this and other observations, it was discovered that four major abnormalities can lead to a hypercoagulable state, with its dire consequences. These are: (1) profound abnormalities in the coagulation cascade with substantial alterations in zymogens and co-factors; (2) alterations in the coagulation inhibitors; (3) alterations in the fibrinolytic system; and (4) defects in the molecular functions of platelets.Zymogens and Co-FactorsAmong the zymogens of patients with nephrotic syndrome, most investigators have demonstrated decreased plasma concentrations of factors II, VII, IX, XII, and XIII.2,5,12-15 Conversely, increased plasma concentrations of co-factors I, V, and VIII have also been consistently observed in other studies.16,17 Alterations in other zymogens such as factor X remain controversial, with some investigators reporting an increase and others a decrease or no change in the plasma levels.16,18 It is generally assumed, but without major supportive evidence, that such elevated plasma levels of zymogens and co-factors are usually caused by an increased rate of synthesis or, perhaps, a decreased volume of distribution.19Coagulation InhibitorsSeveral components of the coagulation inhibitors have been found to be altered in the nephrotic syndrome. The major inhibitors appear to be antithrombin III, protein C, and protein S.20-24 Antithrombin III appears to be the most important and perhaps the best studied. It is the principal inhibitor of thrombin, activated factors IX, X, XI and XII, and plasmin.25,26 More than 90% of patients with nephrotic syndrome and documented thromboembolic phenomena have been shown to have antithrombin III levels that are less than 75% of normal.20 The mechanism responsible for the subnormal serum or plasma levels of this protein has not yet been clarified. Because antithrombin III has been detected in the urine of nephrotic patients,26 it is conceivable that either increased urinary losses or enhanced renal tubular catabolism of this protein could play an important role in this regard.Although an increased in vivo consumption of antithrombin III by an ongoing generation of thrombin may also reduce its concentration, at least one study20 has not revealed any further reductions in the serum antithrombin III levels after the development of venous thrombosis, therefore excluding such a possibility. To date, there have been no studies addressing the possibility of a reduced rate of synthesis of antithrombin III in patients with the nephrotic syndrome.Recently the importance of two other coagulation inhibitors has been recognized. A deficiency of activated protein C, normally an inhibitor of co-factors V and VIII, was noted to have a role in the thrombotic tendency observed in a familial protein C deficiency state.27 It was found that a protein C level below 50% resulted in an increased tendency to thrombosis. It has since been well established that activated protein C and antithrombin III activity are complementary.28 The precise alteration of protein C in patients with nephrotic syndrome remains unclear, with some studies demonstrating an increased urinary loss of this glycoprotein while others have shown significantly higher levels than those seen in controls.23,24 It has also been noted that the activity of protein S, a plasma protein that normally serves as a co-factor for activated protein C, may also be compromised in patients with nephrotic syndrome. Some studies have recently shown that the levels of free protein S are significantly reduced in nephrotic patients, resulting in an increased predisposition to thrombosis.23,29FibrinolysisDysfunction of the fibrinolytic system may also be involved in the various mechanisms contributing to the disordered hemostatic process observed in the nephrotic syndrome. The regulatory role of the generation of plasmin in the coagulation process is suggested by the known actions of plasmin in degrading not only fibrin, but also fibrinogen and factors V and VIII.30 These effects may help to localize the thrombus to the site of vascular injury.The conversion of plasminogen to plasmin requires the presence of activators. The nature of such activators is unknown, although kallikrein, activated factor XII, protein C, and other tissue or endothelial factors may constitute some of them.31 Unlike plasma, for which the activity of plasmin is readily neutralized by alpha2-antiplasmin, alpha2-macroglobulin, alpha1antitrypsin, and other inhibitors, the in vivo activation of plasmin in the matrix of the thrombus wall8,32 generally results in a locally uninhibited fibrinolysis. Therefore, if the activators are deficiently released or the inac-tivators abnormally increased, the hemostatic process could be disturbed. The latter may in turn predispose to either the inefficient removal of an already formed thrombus or to an inappropriate inhibition of the clotting process. Several abnormalities of the fibrinolytic process have been described in patients with nephrotic syndrome.19,33-35 It appears that, except for one report, the most consistent pattern has been decreased fibrinolytic activity.5,17,34,35 The mechanism, or mechanisms, leading to decreased fibrinolysis remain uncertain. Defective formation or release of plasminogen activator, or an increase in antiplasmin activity, or both mechanisms, have been suggested.34,35 Abnormal urinary losses of plasminogen activators, or the presence of abnormal inhibitors of these activators, could similarly contribute to such an abnormality.Physical exercise is known to result in increased fibrinolytic activity of blood after venous occlusion,36 an effect not usually observed in hyper-lipidemic subjects.37 It is therefore possible that nephrotic individuals who are sedentary and frequently hyperlipidemic could have similar reductions in the release of plasminogen activator. One preliminary study documented such a deficient activator release after venous occlusion in nephrotic patients.38Findings suggesting an increased rather than decreased fibrinolytic activator release have also been reported.5 These conflicting reports may reflect variations in the degree of in vivo depletion of endothelial stores of the activator by an ongoing activation of coagulation factors or platelets. In this regard, the increased platelet aggregability along with the activation of coagulation factors described in nephrotic patients could promote a relative depletion of activators from endothelial cells,39 thereby explaining such a variability. It is also conceivable that the lack of appropriate identification of the fibrinolytic events might well be related to technical inadequacies in the currently available laboratory methods.Several other studies have also documented an increased inhibition of plasmin in the basal state, after venous occlusion, or both.5,8,34 Only one study actually disclosed opposite findings.17 This contradictory report can probably be explained by the fact that it documented a marked urinary loss of alpharantitrypsin and an inadequate increase in the plasma concentration of alpha2-macroglo-bulin. Since the above-mentioned proteins are important inhibitors of plasmin,32,40 their deficiency could, therefore, lead to a lack of inhibition of the enzyme.Platelet FunctionThe alterations in platelet-vascular interactions and the consequental propensity to develop thrombosis have been well described. Recently some studies described in depth the pathophysiological changes underlying these interactions and the function of arachidonic acid metabolites, the prostaglandins, and thromboxane in the regulation of such interactions.9,41 Thrombocytosis is often present in patients with nephrotic syndrome.6,42 Although thrombocytosis in itself may not predispose to an enhanced platelet-vessel wall interaction, in vitro evidence indicates that platelets from patients with nephrotic syndrome frequently show an increased tendency to adhere, aggregate, and release their contents.9,42,43 Findings from additional clinical studies have also suggested that platelet aggregation and the release reaction appear to occur in vivo, as reflected by an increased plasma level of beta-thromboglobulin and platelet factor IV, respectively.43,44 In addition, nephrotic patients with renal vein thrombosis displayed a more accentuated tendency for in vitro and in vivo platelet aggregation compared to those without thrombosis. During remission of the nephrotic proteinuria, such enhanced parameters of platelet function have been noticed to return to the normal range,44 suggesting an important relationship between the abnormal losses of protein and platelet behavior (vide infra).The various factors responsible for such increased platelet adhesion and aggregation have not been definitely clarified. Because the adhesion of platelets to the subendothelial structures requires the binding of von Willebrand factor to a platelet receptor, it is possible that the high levels of factor VIII observed in patients with nephrotic syndrome could be responsible for promoting the initial attachment of platelets to the subendothelial structures.5 In addition, it appears that the presence of hyperlipidemia and hypoal-buminemia may also be pathogenetically important. In this regard, increased plasma levels of beta-thromboglobulin and platelet factor IV have been documented in hyperlipidemic patients compared to age-matched and sex-matched nor-molipidemic control subjects.45 Given the fact that cholesterol has been shown to enhance the production of thromboxane A2 by the platelets,46 it is conceivable that the accentuated platelet aggregation and release observed in hyperlipidemic subjects, including nephrotic patients, is caused by an increased rate of thromboxane A2, and/or endoperoxide, generation by the platelets. This, in turn, may be a consequence of an alteration in the platelet membrane cholesterol-phospholipid ratio precipitated by the hyperlipidemia.47In patients with cirrhosis and nephrotic syndrome, the presence of hypoalbuminemia has also been shown to be associated with an exaggerated platelet aggregation and release reaction.44,48 These proaggregatory effects of hypoalbuminemia could, therefore, be synergistic with those resulting from the hyperlipidemia. The abnormal platelet activation caused by hypoalbuminemia can be prevented or corrected by the normalization of the plasma albumin level, or by simply adding albumin to plasma either in vitro or in vivo.6,41,49 The mechanism, or mechanisms, leading to such an enhanced platelet aggregation as a result of hypoalbuminemia still remain unexplained. There is, however, some evidence to indicate that the abnormal platelet behavior might be caused by an increased rate of endoperoxide and thromboxane A2 production by the platelets.50 In this regard, the release of 14Clabeled arachidonic acid from platelet membranes and its subsequent conversion to endoperoxides and thromboxane A2 is apparently stimulated by a low albumin concentration, while it is inhibited by a normal albumin level.41,51Because albumin will naturally bind the arachidonic acid that is released from platelets,41,52 thereby preventing its subsequent metabolic degradation by means of platelet cyclo-oxygenase, the low albumin levels observed in nephrotic patients could make more arachidonic acid available for thromboxane A2 or endoperoxide generation by the platelets.41 In addition, because beta-thromboglobulin released from platelets during aggregation has been reported to inhibit prostacyclin I2 production by endothelial cells, it is possible that an acquired deficiency of this autacoid could also contribute toward maintaining the hyperaggregatory state.53 Furthermore, the aggregated platelets usually express factor XI-like activity in their membranes and provide a substrate for the activation of factors XII, X, and V.42 These latter actions may also be synergistic with the effects of hypoalbuminemia and hyperlipidemia in promoting or supporting a hypercoagulable state in nephrotic patients.Blood ViscositySome patients with nephrotic syndrome and a normal hematocrit have displayed increased in vitro red cell aggregation caused by the high fibrinogen concentration in their plasma.54 This high fibrinogen concentration can cause an increase in the blood viscosity and reduce the rate of blood flow through the blood vessels, particularly the veins.54 In addition, the venous stasis can result in local hypoxemia, which in turn can lead to endothelial cell damage and disruption of the lining, with subsequent surface-mediated platelet activation and formation of a platelet plug.55 The recent observation of a reduced red blood cell surface change in nephrotic patients may also be contributory.56 Together these factors can provoke circumstances favorable for the formation of a thrombus.Factors Favoring a Bleeding TendencyAbnormal bleeding in nephrotic patients who are uremic may not be uncommon, but it is exceedingly rare to witness an increased hemorrhage tendency in the nonuremic nephrotic patient.19 The principal factors favoring such an eventuality include decreased concentration or activity of some plasma coagulation cascade factors, as well as thrombocytopenia, which can rarely occur.6 Furthermore, it is possible that the vascular production of prostacyclin I2 is increased, while the production of thromboxane A2 decreases, resulting in an increased bleeding tendency.9The reduced plasma levels of the coagulation factors, in particular II, V, VII, IX, and XII, have already been discussed in detail. Defects of adenosine diphosphate-induced platelet aggregation and platelet factor III availability have also been noted.9 With the exception of a reported case of severe deficiency of factor VII, which resulted in a prolonged prothrombin time and associated spontaneous subcutaneous and muscle hematomas,2 most other deficiencies reported have been characterized by an asymptomatic prolongation of the prothrombin time or partial thromboplastin time.13,14,19PATHOPHYSIOLOGICAL HYPOTHESISBased on the available evidence, the thrombotic tendency observed in patients with nephrotic syndrome could result from a combination of several procoagulant alterations, such as hemocon-centration, increased platelet function, enhanced activity of coagulation factors, and reduced fibrinolysis (Figure 1). The abnormal permeability of the glomerular filtration membrane is not only responsible for the increased urinary losses of albumin, but also for the escape of antithrombin III, protein C, protein S, and plasminogen activator from the circulation. The increased urinary losses of the latter could contribute to a defective inhibition of thrombin and the activated forms of factors V and X, while the escape of anti-thrombin III could lead to a decreased fibrinolysis. In addition, the hypoalbuminemia that usually develops as a result of the abnormal proteinuria could simultaneously lead to enhanced platelet aggregation, a reduced volume of distribution of several coagulation factors, and hyperlipidemia. These three conditions in turn could further enhance platelet aggregation and the fibrinolytic defect. At the same time, the aggregated platelets could facilitate activation of the coagulation cascade, and by means of the release of beta-throm-boglobulin, impair vascular prostacyclin I2 production, thereby leading to defective control of the platelet procoagulant properties. Hemocon-centration can similarly predispose to local thrombosis by inducing venous stasis and endothelial damage.Figure 1. Probable pathogenesis of the thrombotic tendency in the nephrotic syndrome. ATIII = antithrombin III; VD = volume of distribution; AA = amino acids; TXA2 = thromboxane A2; PGI2 = prostaglandin I2; BTG = beta-thromboglobulin.Download FigureFinally, the accumulation of plasmin inhibitors, such as alpha2-macroglobulin and beta-lipopro-tein, could also bring about further impairment of the plasma fibrinolytic activity. Whether hypoalbuminemia and hyperlipidemia are responsible for a decrease in vascular prostacyclin synthesis (PGI2) remains to be demonstrated.CONCLUSIONThe nephrotic syndrome has occasionally been associated with a deficiency of factors II, VII, IX, XII, and XIII. Although these abnormalities were frequently asymptomatic (factors IX and XII), very rarely spontaneous bleeding (factor VII) occurred. In general, a spontaneous or steroid-induced remission of the nephrotic proteinuria has usually resulted in a resolution of such abnormalities. When surgical procedures, including renal biopsy, are contemplated in cases of severe deficiency, specific replacement therapy could be instituted.More frequently, however, nephrotic patients are at risk or actually suffer thromboembolic phenomena. A combination of enhanced platelet aggregation, procoagulant changes in the clotting cascade, and decreased fibrinolytic activity is usually responsible. The risk of thrombotic complications seems to vary in direct proportion with the degree of proteinuria, hypoalbuminemia, and hyperlipidemia. There seems to be no specific factor, or factors, that identify patients at risk of thromboembolic phenomena, but sedentary activity, hemoconcentration, severe edema, and hyperlipidemia may constitute some of them. Although no prospective studies have yet been done, agents that inhibit thromboxane A2 synthesis (e.g., aspirin) or that stimulate prostacyclin I2 synthesis (e.g., dipyridamole) could constitute a potential prophylaxis against recurrence in high-risk patients.ARTICLE REFERENCES:1. Robert A, Olmer M, Sampol J, et al.. "Clinicaf correlation between hypercoagulability and thrombo-embolic phenomena" . Kidney Int. 1987; 31(3):830-5. Google Scholar2. Epstein O, Bevan G, Siddiqui N, Ardeman S. "Factor VII deficiency associated with nephrotic syndrome" . Br Med J. 1976; 2(6048):1361. Google Scholar3. Llach F. 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