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Treatment of nephrotic syndrome with hypercoagulable state

Dec 26, 2016
The hypercoagulable state of nephrotic syndrome (NS) has long been recognized, it is an objective pathological process, and its degree is often parallel with the severity and activity of glomerular lesions, and has been paid more and more attention. Nephrotic syndrome (NS) complicated with different degrees of hypercoagulable state, especially thrombosis, seriously affect the prognosis of patients with nephrotic syndrome is a common cause of death and disability, anticoagulant therapy has achieved gratifying effect.
First, the incidence of nephrotic syndrome complicated with thrombosis, more common in adult patients, also found in children. Not only in the venous system, but also in the arterial system. Children with nephrotic syndrome complicated with thrombosis incidence is 1.8% ~ 5%, the most common site of renal vein, its incidence is 5 ~ 62%, the average was 35%; followed by deep vein and pulmonary artery, the incidence rates were 25% and 15% to 20% adult patients with nephrotic syndrome complicated with thrombosis incidence about 10% ~ 40%.
Two. Mechanism of hypercoagulable state formation in nephrotic syndrome
Nephrotic syndrome with hypercoagulable state, prone to thrombosis, the relevant factors for the content of blood coagulation factor, anticoagulant and fibrinolytic system changes, platelet function and activation state, abnormal venous stasis, increased blood viscosity, genetic factors and drugs should be used.
(a) abnormal coagulation system
The coagulation factor
The serum factor I and II, V, VII, x increased the content of nephrotic syndrome, and factor I most can reach up to 600mg/dl; and factor IX, Xi, lack of content, the enhancement factor II, III and IV, X and Xi activity; according to the study content of the coagulation factor change is due to increased small molecule protein loss in the urine and liver compensatory protein synthesis.
The anticoagulant
The patients with nephrotic syndrome in the blood of antithrombin III (AT- III) decreased the content of protein, C, protein content of S decreased or normal, decreased activity of protein C, 2- elevated alpha macroglobulin and heparin cofactor II and III decreased AT- content was positively correlated with low albumin levels; according to the research results show that the above anti coagulation a material change is due from the urine and liver compensatory increase in synthesis.
3 fibrinolytic system
Plasmin system includes tissue type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI) and anti plasmin (alpha 2-AP). Tissue type plasminogen activator can activate plasminogen, plasminogen activator inhibitor, plasminogen and tissue type plasminogen activator complexes inhibit the activity of plasmin antiplasmin and can be activated with the original so as to lose its activity.
The patients with nephrotic syndrome at the onset of tissue type plasminogen activator activity decreased, and the serum cholesterol level was negatively correlated; increase the anti plasmin activity, the existence of fibrinolytic function, and blood cholesterol levels were positively correlated. Endothelial cells are the main sites for the synthesis of tissue type plasminogen activator and plasminogen activator inhibitor. Nephrotic syndrome patients with basement membrane damage and a large number of proteinuria, hypoproteinemia as a feature, secondary can cause liver cell cholesterol synthesis, anti plasmin compensatory increase. Lipid metabolism disorder can damage endothelial cells, resulting in endothelial cells synthesis of t-PA / PAI imbalance, leading to hypercoagulability or thrombosis formation.
The patients with nephrotic syndrome in the blood of two D- dimer (D-Dimer) is elevated, two D- dimer is fibrin monomer by activated factor XIII, a specific degradation products of cross-linked followed by plasmin produced by hydrolysis, two D- dimer has strong specificity, sensitive and prethrombotic state molecular markers of thrombosis. In children with renal disease without clinical thrombosis, it can be used as an indirect prognostic factor for the hypercoagulable state and the basis of treatment and prognosis.
The abnormal platelet function and activation state in patients with nephrotic syndrome and to increase the number of platelets, ADP, collagen, four arachidonic acid (AA), thrombin agonist enhanced aggregation. High platelet force and hypoproteinemia, hyperlipemia, hyperfibrinogenemia related. Hypercoagulable state in nephrotic syndrome patients by activated platelet granule membrane to keep the original static platelet cytosolic protein (CD62P), lysosomal granule membrane protein (CD63) and thrombospondin (TSP) degranulation translocation and its expression rate increased significantly with the remission of nephrotic syndrome and gradually returned to normal, suggesting that platelet activation and nephropathy hypercoagulable state relationship is one of the factors that influence the prognosis of dynamic observation of CD62P and CD63, helps to monitor the changes and antiplatelet activity of drugs.
The hemodynamic changes of blood viscosity of patients increased nephrotic syndrome, and elevated blood concentration, hyperlipidemia, high fibrinogen, blood viscosity increased, will lead to erythrocyte aggregation increased.
The genetic factors of the foreign literature reports of patients with nephrotic syndrome, if there exists a coagulation factor and coagulation factor V gene mutation, increased risk of thrombosis.
The other: a strong diuretic, a large number of long-term glucocorticoid use aggravate hypercoagulability.
(two) abnormal coagulation in renal parenchyma
Study on Application of immune fluorescence technique, found in glomerular diseases especially nephrotic syndrome, while fibrinogen / fibrin active antigen, cross-linked fibrin degradation products, factor VIII subunit, alpha -2 and plasmin antiplasmin deposition in glomeruli; by fibrin related antigen and immune electron microscopy revealed that the deposition of vWF membranous nephropathy glomerular endothelial cells, endothelium, basement membrane, by immunohistochemistry in patients with nephrotic syndrome and renal biopsy specimens in glomeruli with coagulation fibrinolysis and platelet protein products deposited; these results suggest that glomerular endothelial cells are local coagulation activation sites, thrombin is generated by exogenous coagulation mechanism of renal vein thrombosis is caused by coagulation in renal parenchyma. Another possible mechanism of activation of coagulation in glomeruli is after the deposition of immune complexes of complement activation in endothelial cells injury, exposure of subendothelial matrix, leading to activation of factor XII, caused by the intrinsic coagulation.
Three, laboratory examination
The clotting activity examination:
The fibrinogen molecules of fibrinogen in large quantity, not easily from the glomerular filtration, as an important component of kidney disease high blood coagulation, high coagulation index commonly used.
The blood and urine fibrin degradation products (FDP): blood and urine determination of fibrin degradation products were increased, and the ratio of urinary FDP fibrin degradation products more meaningful.
The prothrombin time (PT) and white clay in partial thromboplastin time (KPTT) was significantly reduced in high pour point determination.
The blood factor VIII related antigen (8 R:Ag), is a high molecular weight glycoprotein, which is produced by vascular endothelial cells, especially when higher than other glomerular nephropathy.
The anti coagulation function examination
Antithrombin III (AT- III) activity decreased, it is related with the severity of the disease.
3 fibrinolytic system
Tissue type plasminogen activator activity decreased, plasmin activity increased, blood D- two dimer (D-Dimer) increased.
The activation of platelet function and abnormal state
The increase in the number of platelets, platelet granule membrane protein (CD62P), lysosomal granule membrane protein (CD63) and thrombin sensitive protein (TSP) expression rate increased significantly with the remission of nephrotic syndrome and gradually returned to normal, suggesting that platelet activation and nephropathy of hypercoagulable state, is one of the factors affecting the prognosis.
The hemodynamic examination
Blood or plasma specific viscosity increased; red blood cell count and hematocrit increased.
The thrombelastogram:
The dynamic change of coagulation process was observed by changing the blood coagulation power. When the flow of blood R, K nephropathy and M duration was shortened, and the Me value increased Ma.
Check the basic nephropathy
The increase of plasma cholesterol was positively correlated with the degree of hypercoagulability.
The plasma total protein and albumin decreased, which was negatively correlated with the degree of edema, the increase of cholesterol and the hypercoagulable state of blood.
Four, depending on the clinical manifestations of patients with nephrotic syndrome caused by thrombosis or due to coagulation and blockage of blood vessels, the size of the site. The most common pathological types of renal vein thrombosis are membranous nephropathy and membranous proliferative glomerulonephritis. Typical renal vein thrombosis or embolism can be expressed as follows: acute flank pain, costovertebral angle tenderness; the sudden appearance of the urinary protein increased; hematuria; kidney function decreased dramatically; and most likely only mild symptoms, such as pain, swelling of renal region. Confirmed feasible selective angiography, CT, Doppler ultrasound flow pattern, intravenous pyelography. Pulmonary embolism is often lack of typical symptoms, not more than 1/3 of clinical symptoms, such as: the cough, chest pain; hemoptysis; the difficulty breathing; the sudden death of large area embolism. Diagnosed by lung scintigraphy.
Five, treatment of nephrotic syndrome patients with hypercoagulable state, prone to thrombosis.
(a) general treatment
Low fat diet, smoking cessation, weight control, appropriate activities, prevention of long-term bed.
(two) the symptomatic treatment to control blood pressure, diastolic blood pressure <90mmHg, the use of lipid-lowering drugs, such as HMG CoA reductase inhibitors; the correction of hypoproteinemia, such as the application of angiotensin-converting enzyme inhibitors and diuretics and appropriate albumin preparations.
(three) anticoagulation therapy
Nephrotic syndrome treated with anticoagulation indications: edema obviously especially with effusion; the plasma <20g/L or A/G; severe inversion; the obvious hyperlipidemia, especially blood cholesterol? More than 12mmol/L; the higher platelet (more than 300 thousand /mm3); the plasma fibrinogen concentration >6g/L; the antithrombin concentration <70%; D- two concentration of >1mg/L; the pathological type of focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis and crescentic glomerulonephritis; 9 color Doppler and angiography showed renal vein thrombosis or other vascular. One of the above conditions can be selected ordinary heparin or low molecular heparin.
Unfractionated heparin (UFH).
Heparin has strong anticoagulant effect, including heparin, although the "cocktail" mixed therapy in 50s and 60s has been used in the treatment of glomerular disease, but due to lack of understanding on the mechanism of heparin in the treatment of glomerular diseases, and the excessive bleeding to worry too much. Heparin molecular weight is 3000~30000, for the negatively charged acidic polysaccharide, can reduce blood viscosity; except through its anticoagulant effect, prevent the formation of thrombus formation, especially renal glomerular injury in micro thrombosis, thereby reducing glomerular pathological damage process, inhibition of mesangial cells the proliferation of renal and inflammatory mediators release were. In addition, can reduce collagen, fibronectin and other produce, prevent the progression of chronic glomerular lesions. In mesangial proliferative glomerulonephritis animal model, with heparin can inhibit the proliferation of mesangial cells, in addition, can reduce the growth factor and platelet-derived growth factor fibroblast gene expression, thereby inhibiting the expansion of mesangial matrix including laminin, collagen I and IV, and FN, protection glomerular basement membrane negative charge barrier effect.
Usage: for each heparin heparin 1mg/kg (standard weight) with 10%? The glucose solution for intravenous drip, 1 times a day, every 10 to 15 days for a course of treatment for confirmed or highly suspected thrombosis is added 1 times every day, and can take 3 to 5 days after repeated use for 1 ~ 2? A course of treatment. Prothrombin time and prothrombin time were monitored before and after treatment, and prothrombin time was not more than 1 ~ 2 times before treatment. When presented with hemorrhage was associated with severe bleeding when unfractionated heparin with protamine (1mg protamine and heparin 100u).
Our data suggest that heparin combined with other drugs in the treatment of glomerular diseases, has good curative effect in the treatment of refractory nephrotic syndrome cases, the total effective rate was 76.2%, especially on the formation of? With renal vein thrombosis in children, heparin is an effective drug indispensable. Cases with sclerosis and crescent formation were also partially effective. It has been noted in the treatment that many patients without renal micro thrombosis are still effective after heparin treatment. It has been reported that although heparin may have no effect on sclerotic glomeruli, it can protect residual glomerular function and prevent further progress of renal lesions, thus improving clinical symptoms. For patients with acute renal insufficiency nephritis have good effect.
Low molecular weight heparin (LMWH)
Low molecular weight heparin is heparin by chemical or enzymatic depolymerization, decomposed into some by short polysaccharide chain composition, molecular weight ranging from 4000 to 6500 between the Dalton compound, has a long half-life, and derived from the antithrombin III, with significant coagulation factor a clotting enzyme and its biological role use of up to 98%, the half-life of unfractionated heparin 2 ~ 4 times. Cause thrombocytopenia, spontaneous bleeding less than ordinary heparin. Low molecular weight heparin has a strong anticoagulant effect, we first put forward in the domestic refractory nephrotic syndrome in children with low molecular weight heparin dosage and methods. Application method: 100 ~ 120AXaIU/Kg/ times, 1 times a day (0.1ml = 1000AXaIU), abdominal subcutaneous injection, two weeks for 1 courses. Such as bleeding available protamine (low molecular heparin protamine and 0.6ml 0.1ml); application of low molecular weight heparin with unfractionated heparin indications. At the same time were observed in 36 cases of children with nephrotic syndrome with hypercoagulable state. The results show that the use of low molecular weight heparin combination treatment in the primary disease, significantly reduced urinary protein, of which 88.9% of the patients obtained clinical remission; the pathological types of MCNS and MsPGN the best curative effect. Children with refractory hemorheology before and after low molecular weight heparin in the treatment of renal disease, suggesting that children with nephrotic syndrome before treatment with hyperviscosity, after treatment with low molecular weight heparin with high blood viscosity decreased significantly, some patients recovered completely. The use of low molecular weight heparin in 36 cases of nephrotic syndrome patients, all patients had subcutaneous congestion, only 1 cases of hematuria, discontinuation of low molecular weight heparin within 2 weeks after subcutaneous congestion subsides, hematuria 2 days disappear. The long-term application of the drug has no effect on blood lipids, no hair loss, no side effects such as osteoporosis, prolonged APTT is not obvious, no laboratory monitoring.

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