Back to NephrologyHemostasis in Chronic Renal Failure(Part I -Pathogenesis)
The association of altered hemostasis and uremia has long been recognized, as well as the fairly high morbidity associated with such events. Bleeding is the most common of these manifestations, and is most frequently manifested by epistaxis and ecchymoses. Other bleeding manifestations such as hemopericardium, gastrointestinal hemorrage and subdural hematomas are found less frequently. On the other hand, thrombotic complications also occur with greater frequency in patients undergoing hemodialysis. In this case thrombosis of the arteriovenous shunt is the most common presentation.
The pathogenesis of bleeding disorders is multifactorial and no single explanation is enough to clarify such a complex and confusing matter. It is widely accepted that the primary mechanisms involve alterations in platelet-vessel wall interaction as well as platelet-platelet interaction. Since it reflects the endothelial integrity, platelet number, platelet function and hematocrit, the bleeding time is the best indicator of the alterations found in uremic patients. The reduced mass cell seems to be involved in the genesis of the bleeding tendencies since it alows less time for the platelets to be in contact with the vessel wall. It is further demonstrated by the fact that the mere correction of the hematocrit levels (by the use of rHuEPO ) tends to normalize the bleeding time. The blood cells also enhance platelet function by releasing ADP and by inactivating PGI2 (an inhibitor of platelet aggregation). This increase in adenosine diphosphate is probably due to the hematocrit-dependent rise in the blood shear stress via physiologic intravascular hemolysis (as seen by the raised free plasma hemoglobin).
The platelet count in uremia is usually normal, but platelet function is impaired. The platelet granule content is decreased, a reduction in the storage pool of ADP and serotonin is is present. Calcium content is increased in uremic patients (generally due to secondary hyperparathyroidism) and this increase in serum calcium cause an abnormality in the mobilization of Ca++ in response to stimulation. This observation, coupled with the fact that PTH inhibits platelet function in vitro led to the speculation the PTH might play a role in the genesis of such defects. Despite that, it has been shown that the bleeding time does not correlate well with the levels of serum PTH, making it a very improbable cause of this bleeding tendency.
When considering platelet-platelet interaction, uremic patients also show alterations in this aspect of hemostatic function. This abnormality is independent of plasma factors and seems to be caused by the inability of platelets to produce adequate levels of thromboxane A2 in response to platelet-activating factor.
Another aspect of platelet fuction seems to be altered and this involves the platelet-vessel wall interaction. It is well stablished that this interaction is dependent of two plasma factors ( fibrinogen and Von Willebrand factor) and two platelet adhesion receptors (gpIb and gpIIb-IIIa complex). The activation-dependent receptor function of the gpIIb-IIIa complex is defective in uremia (this is shown by the decreased binding of fibrinogen and vWF to stimulated platelets). The number of these receptors expressed on the platelet membrane is normal but their activation is impaired. On the other hand, the vWF binding activity of gpIb is normal. The removal of uncertain substances from the plasma of uremic patients markedly improve the gpIIb-IIIa defect.
There was a previous belief that some dialysable substances, found in increased concentrations in the plasma of uremic patients, could play a role in the abnormal platelet function seen in chronic renal failure. The substances implicated were mainly urea, creatinine, phenol, phenolic acid and guanidinosuccinic acid. Despite these previous observations, no convincing correlation has been found between bleeding time or platelet adhesion and the serum level of these substances. On the other hand, PGI2 levels (usually increased in uremic patients) seem to have an important role in the genesis of such disorders. Its increased levels might be secondary to the increased levels of PTH.
The observation that cryoprecipitate (rich in factor VIII and vWF) and desmopressin (a synthetic derivative of ADH that releases autologous vWF from storage sites) significantly shorten the bleeding time of uremic patients suggests that a functional defect in vWF-platelet interaction may play a role in the abnormal hemostasis of these patients.
It is always important to bear in mind that the hemodyalisis itself may lead to dysfunction in the coagulation system. It occurs most often at the start of the dialysis program, but may also be associated with thrombocytopenia induced by the heparin used during the procedure. This latter effect can sometimes,but not always, be reversed by the use of low molecular weight heparin (LMWH).
As mentioned above, thrombosis of the arteriovenous fistula is a frequent event in uremic patients undergoing hemodialysis. Platelet aggregation seems to play a major role in such thrombus formation. Arteriovenous grafts show an increased risk when compared with arteriovenous fistulas. Elevated levels of anticardiolipin antibody (IgG-ACA) as well as antiphospholipid antibody are frequently found in these patients, and any kind of thrombotic complication demands a thorough search for these potential causes.
1) Barry M. Brenner - The Kidney 5th Edition
2) Prakash R, Miller CC, Suki WN - Am J Kidney Dis, 26:2,1995 Aug, 347-52
3) Brunet P, Aillaud MF, San Marco M et al. - Kidney Int, 48:3,1995 Sep,794-800
4) Sreedhara R, Itagaki I , Lynn B et al. - Am J Kidney Dis,25:4, 1995 Apr, 555-63
5) Turi S, Soos J, Torday C et al. - Pediatr Nephrol,8:6,1994 Dec,727-32
6) Mahul P, Raynaud J, Favre JP et al. - Ann Fr Anesth Reanim, 14:1,1995,29-32
7) Huraib S, Gader AM, al-Momem AK et al. - Haemostasis,25:6,1995 Nov-Dec,299-304
8) Maurin N, Fitzner S, Fritz H et al. - Clin Nephrol, 43:3,1995 Mar, 196-200
9) Krawczyk W, Dmoszynska A, Marczewski K et al. - Pol Arch Med Wewn, 92:6,1994 Dec, 483-8
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