Hemostasis Defects Associated with Uremia
At a Glance
Uremia is a clinical syndrome that usually evolves in parallel with deterioration of renal function. This syndrome is more common in chronic renal failure, yet it can also be seen in acute renal failure if rapid loss of renal function occurs.
In addition to the fluid, acid-base, and electrolytes imbalance due to the deprived renal function, accumulation of circulating toxins and waste products, in particular the nitrogenous waste products that are normally excreted into the urine, are the main manifestations of uremia.
The relationship between uremia and abnormal hemostasis has long been recognized along with a quite high morbidity rate. Bleeding is one of the main manifestations of the altered hemostasis system in uremia. It is usually presented as a cutaneous type of bleeding, including easy bruising, ecchymosis, mucosal bleeding, and, less commonly, epistaxis and hematuria. Other serious bleeding, such as gastrointestinal and genitourinary bleeding, or subdural hematomas can also occur but do so less frequently.
Thrombotic complications, conversely, may also develop in uremic patients but with higher frequency in patients undergoing hemodialysis in which thrombosis of the arteriovenous fistula is the most common presentation.
Although the underlying pathophysiology of bleeding tendency in uremia is still not fully understood, impaired platelet function is thought to be one of the main causes. This acquired platelet dysfunction is due to both decreased platelet activation and impaired adhesion to vascular subendothelial cells.
In addition, some coexisting factors may intensify bleeding complications in uremic patients, such as coagulopathies, the use of heparin with dialysis, anatomical abnormalities, or comorbidities as in gastritis.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
The degree of renal impairment should be evaluated in all patients with renal disease by assessing renal function by measuring creatinine, blood urea nitrogen (BUN), and glomeruler filtration rate (GFR). Elevated serum levels of creatinine and BUN, along with decreased GFR, are typically detected in renal failure.
Metabolic acidosis, along with abnormal electrolyte levels, can be seen in advanced cases of uremia. Anemia is one of the most common clinical findings in chronic renal failure as well, primarily because of the decreased production of renal erythropoietin.
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal in uremia, unless there is a coexisting coagulopathy.
Normal or only slightly decreased platelet count, along with increased platelet turnover, is a common finding in uremic patients.
Abnormal von Willebrand factor and factor VIII functions have long been described in uremia because of the defective endothelial release. Therefore, evaluating bleeding tendency by performing PFA-100 is essential in these patients. Other coagulation parameters are generally intact in uremia.
Elevated levels of anticardiolipin antibody and antiphospholipid antibody are frequently found in uremic patients with thrombotic complications, as in the arteriovenous fistula thrombosis events.
It is widely accepted that the primary mechanisms of abnormal hemostasis in uremia involve alterations in platelet-endothelial cell interaction and platelet-platelet interaction. The conformational changes in the platelet GPIIb/IIIa receptors and the decreased GPIb receptors recognized in uremia reduce platelet adhesion to the vascular subendothelial wall, which is essential in maintaining normal hemostasis.
This alteration in platelet interaction is mainly caused by several intrinsic and extrinsic factors. Platelet intrinsic factors include altered release of adenosine diphosphate (ADP) and serotonin from alpha-granules, defective arachidonic acid, decreased prostaglandin metabolism, and decreased thromboxane A2 production.
The accumulated uremic toxins (i.e., urea, creatinine, phenol, phenolic acid, and guanidinosuccinic acid), increased nitric oxide (NO) production, von Willebrand factor abnormalities, and renal anemia are the most effective extrinsic factors.
Studies have shown that mixing uremic platelets with normal plasma revealed normal platelet function. This was also consistent with impaired platelet function of mixing normal platelets with uremic plasma. These findings suggest a plasma factor, most likely one or more of the circulating uremic toxins, as the culprit. However, no direct correlation has been recognized between the severities of renal failure or toxin levels in this regard, and platelet dysfunction or bleeding tendency in uremic patients.
Anemia, conversely, seems more correlated to the degree of platelet dysfunction. This is supported by the remarkable improvement in bleeding incidence following the correction of uremic anemia with erythropoietin treatment.
Studies have also shown a possible direct beneficial role of erythropoietin on platelet function by possibly increasing the number of GPIIb/IIIa receptors on the platelet membrane.
The relationship between anemia and impaired platelet function in uremia has been explained by the rheologic effects of red blood cells. At normal hematocrit levels (above 30%), red blood cells mainly fill up the center of the blood vessel pushing platelets toward the endothelial surface. This allows platelets to easily adhere to the endothelium surface at the time of injury to form the initial platelet plug. In contrast, low levels of hematocrit pull platelets away from the endothelium surface impairing their adherence. Therefore, the mere correction of anemia in uremic patients is essential to enhance platelet function and increase their adhesion to endothelial cells, which can be observed clinically by improving bleeding tendency.
It has been proven that platelets and endothelial cells' production of NO, a platelet aggregation inhibitor and an endothelial cells relaxing factor, is increased in uremic patients. This may, somehow, be due to the elevated levels of guanidinosuccinic acid, a uremic toxin that may be a precursor for nitric oxide in this setting.
Correction of the platelet dysfunction is not required in asymptomatic uremic patients; however, in actively bleeding patients or in patients who are about to undergo a surgical or invasive procedure, adjusting platelet function is essential. This can be achieved by several modalities, such as correction of anemia (erythropoietin), administration of desmopressin (DDAVP), cryoprecipitate, estrogen, and/or dialysis.
Although life expectancy improved in uremia following the routine use of dialysis, morbidity and mortality from bleeding remained considerably elevated, despite the significant reduction in the spontaneous mucocutaneous bleeding frequency.
Hemodialysis procedure itself may cause some dysfunction in the coagulation system often seen at the beginning of the dialysis courses. In addition, thrombocytopenia can also be induced by the heparin used during these procedures.
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