Clinical Pearl - Bleeding and Liver Disease

Bleeding is a common complication of liver disease and given that we as nephrologists are sometimes asked to place lines or perform renal biopsies on patients with cirrhosis, it is important to know the physiology behind the reason for excessive bleeding in these individuals. Here is a nice clinical pearl from our Hematology colleagues at MGH:

Endogenous tPA is cleared by the liver and therefore circulating levels of tPA are elevated in patients with cirrhosis. This is the main reason that these patients bleed. Phrased another way, the main hemostatic defect in liver disease is not thrombin generation (defective production of procoagulant clotting factors) but rather accelerated clot lysis. Therefore, an antifibrinolytic treatment (like amiocaproic acid) that inhibits the binding of fibrinolytic molecules (plasmin, plasminogen) to fibrin and thus helps prevent breakdown of existing clots is an elegant and effective way to treat bleeding in cirrhosis. A reduced dose should be given in patients with renal dysfunction and it should be noted that this drug has been associated with AKI in some patients due to urinary tract obstruction and ATN.

Posted by Rebecca Karp Leaf MD and Walter Dzik MD.

Page Kidney

Patient with a history of kidney transplant s/p biopsy 2 weeks prior now undergoing chemotherapy treatment for leukemia develops acute abdominal pain, worsening renal function and hypertension. Renal US followed by CT are shown below:

Renal US with dopplers

Renal US longitudinal view

Abdominal CT with renal tx on right lower quadrant

 

Abdominal CT with red-marked kidney parenchyma

Diagnosis: Page kidney is a condition where extrinsic renal compression from a haematoma or mass results in hypertension and loss of renal function. This condition was initially described by Irwin Page in an animal model with cellophane papers wrapped around the kidney in 1939 and, subsequently, clinically in 1955.Most cases are caused by a subcapsular haematoma following blunt trauma or invasive procedures (eg. renal biopsy). Few cases of spontaneous hematoma have also been reported. Acute renal failure is due to a decreased perfusion of the compressed kidney as a result of pressure exerted by the subcapsular haematoma. In our case, the drop in platelets (4,000) after chemotherapy might have precipitated the bleeding from the previously biopsied site.

Treatment involves relief of the pressure and restoration of blood flow by percutaneous drainage. Nephrectomy is recommended in cases not resolved by interventional nephrology. Conservative course (observation and medical management) has been performed in some case reports.

Noninvasive Control of Uremic Bleeding

We frequently receive requests to dialyze patients with moderate renal failure who are bleeding due to the concern that uremia may be contributing to failure to control blood loss.

Patients with renal failure do have an increased tendency to bleed, usually manifested by prolonged bleeding time. I was recently reminded by one of my colleagues in conference that while dialysis is an option for treatment of uremic bleeding, it is important to recall (ideally prior to placing the large and inflexible central line) that there are several noninvasive medical therapies for uremic bleeding, some of which work quite well and with minimal side effects.

Uremic bleeding is multifactorial, involving dysfunctional Von Willebrand factor, accumulation of many uremic toxins, particularly L-arginine, increased levels of cyclic AMP and cyclic GMP (cGMP) both of which reduce levels of thromboxane A2 (TxA2) and ADP, anemia, which causes platelets to travel midstream through the blood vessels, farther away from the endothelium. Red blood cells also scavenge nitric oxide and release ADP and TxA2. Lower levels of TxA2 and ADP lead to decreased platelet aggregation. Nitric oxide (NO) also plays a central role. L-arginine induces NO synthesis, which stimulates guanylyl cyclase, increasing cGMP levels, and thus decreasing TxA2 and ADP. TNF-alpha and IL 1beta are also increased in uremia, both of which induce NO synthase.

Treatment options for uremic bleeding include: erythropoetin, cryoprecipitate, desmopressin, conjugated estrogens (premarin, explaining the picture associated with the post), and dialysis. Various doses of erythropoetin have been studied, but the success is dependent not on the dosing regimen but the achievement of a hematocrit of 30%. Cryoprecipitate contains factor VIII, vWF, and fibrinogen, likely increasing the proportion of functional clotting factors in uremic patients' plasma. Desmopressin likely releases factor VIII from storage sites, increasing the concentration of factor VIII and minimizing the effect of dysfunctional vWF. The dose is 0.3 to 0.4mcg/kg IV or subcutaneously. It acts within an hour, but tachyphylaxis develops after one dose, likely due to depleted vWF from endothelial stores.

Estrogens can also safely and effectively improve bleeding time in uremic males and females. The dose needed is 0.6mg/kg IV conjugated estrogens over 30-40 minutes once daily for 5 days. The onset of action is about 6 hours, with maximum effect at 5-7 days and a duration of action of 14-21 days. The mechanism is thought to be reduction of L-arginine, which is a precursor to NO. This results in less guanylyl cyclase stimulation and less production of cGMP, leading to increased TxA2 and ADP and improved platelet aggregation. This theory is supported in rat studies. 17beta estradiol given to rats made uremic by reduction of renal mass significantly reduced bleeding time within 24 hours and normalizes plasma concentration of NO metabolites, nitrites and nitrates, and of NO synthase catalytic activity. Endothelial NOS and inducible NOS immunoperoxidase staining in the endothelium of uremic aortas of untreated rats was significantly more intense than in control rats. Uremic rats receiving 17beta estradiol had NOS staining comparable to controls. Estrogens have been used for patients with uremic GI bleeding, with some controversy and a negative RCT in angiodysplasia. Nate Hellman also talked about estrogens in GI bleeding here.

Nature Clinical Practice published a nice review on treatment recommendations for uremic bleeding, with a summary of recommendations and the strength of the evidence behind each recommendation, along with an algorithm for treatment of bleeding patients. Special thanks to Nirupama Ramkumar for finding and summarizing this article in clinical case conference.