Impaired function of platelet membrane glycoprotein IIb-IIIa in end-stage renal disease.

Impaired platelet function and a bleeding tendency are well-recognized complications of chronic renal failure. Because the fibrinogen receptor GPIIb-IIIa plays a central role in platelet aggregation and adhesion to the subendothelium, it was reasoned that a defect in this receptor may underlie the impaired platelet function in uremia. To test this hypothesis, the function of this receptor in the platelets of 11 uremic patients was studied. Aggregation studies were performed with flow cytometric techniques with anti-GPIIb-IIIa conformation-specific monoclonal antibodies (mAb) (anti-LIBS1 and anti-PMI-1). Antifibrinogen and antithrombospondin mAb were used to characterize fibrinogen binding to GPIIb-IIIa and the release of alpha-granules, respectively. Platelets from patients with chronic renal failure showed significantly decreased binding of conformation-dependent anti-LIBS1 mAb after ADP, phorbol myristate acetate, or RGD-peptide stimulation compared with normal controls, suggesting a defect related to the ability of the fibrinogen receptor to undergo a conformational change. Moreover, antifibrinogen and antithrombospondin binding to activated platelets were reduced in uremic patients, implying impairment of both ligand-binding and alpha-granule release. Hemodialysis partially restored GPIIb-IIIa function, which may account for the observed effects of this therapy in restoring platelet aggregation. These findings indicate that platelets of patients with chronic renal failure reveal an aggregation defect at least partially due to an intrinsic GPIIb-IIIa dysfunction and the presence of a putative uremic toxin that inhibits fibrinogen binding to GPIIb-IIIa.

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Prostaglandin-Endoperoxides and Cyclic 3′-5′-AMP in Platelets of Patients with Uremia

10.1055/s-0039-1680416 ◽

1977 ◽

Author(s):

F. R. Matthias ◽

W. Palinski

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Adenylate Cyclase ◽

Prostaglandin E1 ◽

Cyclase Activity ◽

Adenylate Cyclase Activity ◽

Bleeding Tendency ◽

Prostaglandin Endoperoxide ◽

Uremic Patients

In platelets of normal donors and of patients with chronic renal failure the following determinations were performed: 1. prostaglandin-endoperoxide-formation after N-ethylmaleimide stimulation measured as malondialdehyde; 2. the c-AMP level according to the Gilman-method; 3. the adenylate-cyclase activity in response to prostaglandin E1; 4. aggregation in response to collagen.In comparison to’normal donores the prostaglandin-endoperoxide production was reduced in uremic patients. Plasma of uremics depresses the endoperoxide formation of normal platelets. The basal c-AMP level of platelets of’ patients with renal failure was not significantly changed, whereas the plasma c-AMP level was increased; the activation of the platelets adenylate-cyclase was impaired. The adenylate-cyclase activity of platelets from normal donors was reduced by uremic plasma.. The results are of interest as to the explanation of the bleeding tendency of uremic patients.

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Tranexamic Acid Inhibits Fibrinolysis, Shortens the Bleeding Time and Improves Platelet Function in Patients with Chronic Renal Failure

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614370 ◽

1999 ◽

Vol 82 (10) ◽

pp. 1250-1254 ◽

Cited By ~ 23

Author(s):

Olga Panes ◽

Blanca Muñoz ◽

Edgar Pais ◽

Rodrigo Tagle ◽

Fernando González ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Platelet Aggregation ◽

Tranexamic Acid ◽

Platelet Function ◽

Bleeding Time ◽

Degradation Products ◽

Severe Disease ◽

Plasmin Activity ◽

Primary Hemostasis

Summary Background: A defect in platelet function is the main determinant of the prolonged bleeding time in chronic renal failure (CRF). We previously reported a significant correlation between platelet abnormalities and elevated plasma markers of plasmin and thrombin generation. Our aim was to explore the effect of inhibiting both plasmin action with tranexamic acid (TA) and thrombin production with low molecular weight heparin (LMWH), on the bleeding time (BT) and platelet function in patients with CRF. Methods: 37 patients with CRF (mean creatinine 8.6 ± 4.4 mg/dl) under conservative treatment, with prolonged BT, entered this study and received TA during 6 days, with (n = 24) and without LMWH (n = 13). BT, platelet aggregation/secretion, platelet granule contents, von Willebrand factor and parameters of coagulation and fibrinolysis were recorded before and at the end of treatment. Results: The BT was shortened in 26/37 (67%) patients. This effect was associated with significant improvement of platelet aggregation and secretion, with decrease to a normal range of fibrin/fibrinogen degradation products, mild increase in plasmin-antiplasmin complexes and pronounced reduction of circulating plasminogen. No differences were seen among patients with or without LMWH. No serious side effects or complications were observed. Interpretation: These findings indicate that the activation of fibrinolysis plays a significant role in the defect of primary hemostasis in patients with CRF. Inhibition of plasmin activity with TA shortens the BT and improves platelet function in the majority of patients with severe disease.

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Platelet Function and the Bleeding Time in Progressive Renal Failure

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647640 ◽

1988 ◽

Vol 60 (01) ◽

pp. 083-087 ◽

Cited By ~ 30

Author(s):

M P Gordge ◽

R W Faint ◽

P B Rylance ◽

G H Neild

Keyword(s):

Renal Failure ◽

Platelet Aggregation ◽

Platelet Function ◽

Bleeding Time ◽

C Reactive Protein ◽

Severe Renal Failure ◽

Reactive Protein ◽

Thromboxane Production ◽

Von Willebrand ◽

Willebrand Factor

SummaryBleeding time and platelet function tests were performed on 31 patients with progressive chronic renal failure (CRF) due to non-immunological (urological) causes, and compared with 22 healthy controls. Patients were classified as mild (plasma creatinine <300 μmol/l), moderate (300-600 μmol/l) or severe renal failure (>600 μmol/l). Bleeding time was rarely prolonged in mild and moderate CRF and mean bleeding time significantly elevated only in severe CRF (p <0.005). Haematocrit was the only index which correlated with bleeding time (r = -0.40). Platelet counts, collagen stimulated thromboxane generation, and platelet aggregation responses to ADP, collagen and ristocetin were all either normal or increased in all three CRF groups, but thromboxane production in clotting blood was reduced. Plasma fibrinogen, C reactive protein and von Willebrand factor (vWF) were elevated in proportion to CRF. We found no evidence that defects in platelet aggregation or platelet interaction with vWF prolong the bleeding time in patients with progressive CRF.

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A Comparison of the Effect of Decorsin and Two Disintegrins, Albolabrin and Eristostatin, on Platelet Function

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649933 ◽

1995 ◽

Vol 74 (05) ◽

pp. 1316-1322 ◽

Cited By ~ 13

Author(s):

Mary Ann McLane ◽

Jagadeesh Gabbeta ◽

A Koneti Rao ◽

Lucia Beviglia ◽

Robert A Lazarus ◽

...

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Sequence Similarity ◽

Platelet Aggregation Inhibitors ◽

Antiplatelet Drug ◽

Rgd Sequence ◽

Fibrinogen Receptor ◽

Activated Platelets

SummaryNaturally-occurring fibrinogen receptor antagonists and platelet aggregation inhibitors that are found in snake venom (disintegrins) and leeches share many common features, including an RGD sequence, high cysteine content, and low molecular weight. There are, however, significant selectivity and potency differences. We compared the effect of three proteins on platelet function: albolabrin, a 7.5 kDa disintegrin, eristostatin, a 5.4 kDa disintegrin in which part of the disintegrin domain is deleted, and decorsin, a 4.5 kDa non-disintegrin derived from the leech Macrobdella decora, which has very little sequence similarity with either disintegrin. Decorsin was about two times less potent than albolabrin and six times less potent than eristostatin in inhibiting ADP- induced human platelet aggregation. It had a different pattern of interaction with glycoprotein IIb/IIIa as compared to the two disintegrins. Decorsin bound with a low affinity to resting platelets (409 nM) and to ADP-activated platelets (270 nM), and with high affinity to thrombin- activated platelets (74 nM). At concentrations up to 685 nM, it did not cause expression of a ligand-induced binding site epitope on the (β3 subunit of the GPIIb/IIIa complex. It did not significantly inhibit isolated GPIIb/IIIa binding to immobilized von Willebrand Factor. At low doses (1.5-3.0 μg/mouse), decorsin protected mice against death from pulmonary thromboembolism, showing an effect similar to eristostatin. This suggested that decorsin is a much more potent inhibitor of platelet aggregation in vivo than in vitro, and it may have potential as an antiplatelet drug.

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Color Doppler Indices of Orbital Arterial Flow in End-Stage Renal Disease Patients; Are the Changes Related to Chronic Hemodialysis or Chronic Renal Failure?

Iranian Journal of Radiology ◽

10.5812/iranjradiol.6730 ◽

2012 ◽

Vol 9 (1) ◽

pp. 12-6

Author(s):

Hadi Rokni Yazdi ◽

Safoura Faraji ◽

Farokhlegha Ahmadi ◽

Reza Shahmirzae

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Renal Disease ◽

End Stage Renal Disease ◽

Color Doppler ◽

Chronic Hemodialysis ◽

Arterial Flow ◽

Doppler Indices ◽

Stage Renal Disease ◽

End Stage

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Parathyroid hormone metabolism and its potential as a uremic toxin

AJP Renal Physiology ◽

10.1152/ajprenal.1980.239.1.f1 ◽

1980 ◽

Vol 239 (1) ◽

pp. F1-F12 ◽

Cited By ~ 3

Author(s):

E. Slatopolsky ◽

K. Martin ◽

K. Hruska

Keyword(s):

Renal Failure ◽

Parathyroid Hormone ◽

Chronic Renal Failure ◽

Biological Effects ◽

Uremic Toxin ◽

Terminal Portion ◽

Single Chain ◽

Biochemical Alterations ◽

Amino Terminal ◽

Carboxy Terminal

Secondary hyperparathyroidism is a universal complication of chronic renal failure. It has been proposed that the markedly elevated levels of immunoreactive parathyroid hormone (i-PTH) in uremia may represent a “uremic toxin” responsible for many of the abnormalities of the uremic state. Plasma i-PTH consists of a mixture of intact hormone, a single-chain polypeptide of 84 amino acids, and smaller molecular weight hormonal fragments from both the carboxy- and amino-terminal portion of the PTH molecule. The hormonal fragments arise from metabolism of intact PTH by peripheral organs as well as from secretion of fragments from the parathyroid glands. The structural requirements for the known biological actions of PTH reside in the amino-terminal portion of the PTH molecule. Carboxy-terminal fragments, biologically inactive at least in terms of adenylate cyclase activation, hypercalcemia, or phosphaturia, depend on the kidney for their removal from plasma, and thus accumulate in the circulation in chronic renal failure. It is unknown at the present time if other biological effects of these carboxy-terminal fragments may contribute to some of the biochemical alterations observed in uremia. The most significant consequence of increased PTH levels in uremia is the development of bone disease characterized by osteitis fibrosa. In addition, it would appear that PTH plays an important role in some of the abnormal electroencephalographic patterns observed in uremia. This may be due to a potential role of PTH in increasing calcium content of brain. Parathyroid hormone also has been implicated as a pathogenetic factor in many other alterations present in uremia, i.e., peripheral neuropathy, carbohydrate intolerance, hyperlipidemia, and other alterations. Unfortunately, outstanding clinical research is lacking in this field and conclusive experimental data are practically nonexistent. Further studies are necessary if one is to accept the concept of PTH being a significant “uremic toxin.”

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Recent Advances in the Management of the Infant, Child, and Adolescent With Chronic Renal Failure

Pediatrics in Review ◽

10.1542/pir.11.9.277 ◽

1990 ◽

Vol 11 (9) ◽

pp. 277-282

Author(s):

Richard N. Fine

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Renal Disease ◽

End Stage Renal Disease ◽

Quarter Century ◽

Irreversible Reduction ◽

Age Limits ◽

Stage Renal Disease ◽

End Stage

The prognosis of the infant, child, or adolescent with chronic renal failure, defined as an irreversible reduction in glomerular filtration rate, has improved during the past quarter century because of the use of dialysis and renal transplantation. These have prolonged lives in previously fatal situations. Because the potential not only to sustain life but also to effect full rehabilitation exists with the introduction of these treatments, it is now imperative that the multisystem consequences of uremia be either minimized or totally avoided in the pediatric patient with chronic renal failure. The role of the pediatrician in managing the infant, child, or adolescent with chronic renal failure should be directed toward minimizing the potentially devastating consequences of uremia so that the patient is in optimal clinical condition when end stage renal disease occurs. INCIDENCE It is difficult to know the incidence and prevalence of chronic renal failure and end stage renal disease in children. Surveys in Europe and North America have been conducted to obtain precise information regarding these issues; not only have the definitions included in these surveys differed, but the upper and lower age limits defining pediatric patients have not been uniform. The available data suggest a prevalence of chronic renal failure of 18.5 per 1 million child population and an incidence of end stage renal disease of from 3 to 6 children per 1 million total population.

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Platelet Function in Various Haemorrhagic Disorders

10.1055/s-0039-1689499 ◽

1975 ◽

Author(s):

T. Mandalaki ◽

C. Dimitriadou

Keyword(s):

Platelet Aggregation ◽

Density Gradient ◽

Platelet Function ◽

Factor Xiii ◽

Platelet Rich Plasma ◽

Bleeding Tendency ◽

Factor Xiii Deficiency ◽

Haemorrhagic Diathesis

Platelet aggregation by ADP, collagen, thrombin and ristocetin was studied systematically both in citrate platelet rich plasma and isolated platelets by density gradient using albumine (according to Nicholls and Hampton) in various cases of congenital haemorrhagic diathesis, namely v. Willebrand disease, Glanzmann disease (thrombasthenia), Thrombopathy (PF3, defect), Factor XIII deficiency and in unclassified hereditary haemorrhagic disorders as well as in acquired bleeding tendency. According to the platelet abnormalities found during this study a classification of “Thrombopathies” observed in Greece is attempted.

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