Chronic Kidney Disease and Bleeding

Motivation: A man with kidney failure from polycystic kidney disease abruptly bled inside his head.  We blamed it on dysfunctional platelets and used desmopressin (DDAVP) to try to reverse his dysfunctional platelets.  Did not work, and he herniated.  Does desmopressin or other interventions really improve bleeding from dysfunctional platelets?

As way of background, chronic kidney disease increases bleeding time through dysfunction of platelet adhesion and aggregation via a variety of mechanisms including dysfunctional von Willebrand Factor (vWF), anemia, and uremic toxin accumulation.

Paper: Hedges, S.J., Dehoney, S.B., Hooper, J.S. et. al. Evidence-based treatment recommendations for uremic bleeding. Nature Clin. Prac. Neph. (2007); 3: 138-156

Methods: Systematic review of published trials.

Results: 

Cryoprecipitate: Two small controlled trials evaluated cryoprecipitate infusion to replete dysfunctional vWF.  In a prospective trial, seven patients with bleeding time > 15 minutes were infused 10 bags of cryoprecipitate resulting in decreased bleeding time in all patients after 4 hours.  In a retrospective single center analysis, 5 patients were infused with cryoprecipitate resulting in decreased bleeding time in 2 patients and no effect in three others.

Desmopressin (DDAVP): In the one randomized trial with patients on hemodialysis with bleeding time > 15 minutes, one dose of 0.4 ug/kg of DDAVP resulted in normalization of bleeding time in two of eight patients and reduction in seven of eight patients randomized to DDAVP arm.  In another prospective single center trial, one dose of 0.4 ug/kg of DDAVP resulted in normalization of bleeding time in six of twelve patients in one hour.  In two hours, 3 out of 12 had normal bleeding times.  After 24 hours, all patients reverted back to prolonged bleeding time.  Finally, in a retrospective study, one dose of 0.3 ug/kg of DDAVP resulted in normalized bleeding time in 5/12 one hour post-infusion, 2/12 four hours post-infusion, and 1/12 eight hours post-infusion.

Estrogens: Has been tested in three randomized, placebo controlled trials.  In first trial, patients received 0.6 mg/kg of IV conjugated estrogens for five days.  All patients in the estrogen treated group had normalized bleeding time within six hours.  In subsequent randomized trial, the dose used was again 0.6 mg/kg of IV conjugated estrogen for five days.  Patients receiving estrogen had significantly decreased bleeding time at days  seven and fourteen with no significant effects on day 21 and day 28.  In the final trial, patients on HD were randomized to oral conjugated estrogen (50 mg) or placebo for nine days or till normalization of bleeding time.  In the five patients randomized to estrogen, bleeding time normalized in 3 of 5 patients and decreased to less than 50% in remaining 2 patients.  The most common adverse effect was flushing.

Discussion: For the actively bleeding patient with renal failure, dysfunctional uremic platelets can be treated successfully!  In the actively bleeding patient, besides desmopressin, cryoprecipitate can also be helpful.  But, perhaps more intriguingly, conjugated estrogens may be beneficial in the short term even after six hours.  While desmopressin is presumed to induce secretion of Factor VIII from endothelial cells, the mechanism of estrogen is less clear - may work by decreasing NO production or decreasing Factor S concentrations.  I had not really considered estrogen as part of the acute therapy.  In the future, when desmopressin does not appear to stop bleeding, I will turn to cryoprecipitate and conjugated estrogens.

This was a post after a while.  Next posts will appear more frequently.

Drinking Blood

During the medicine sub-i, Dr. Ashar handed us a really interesting paper from 1940s.  I will review this paper here for both the strangeness and the results derived. 

Paper: Schiff, L., Stevens, R.J., Shapiro, N., and Goodman, S.  Observations on the oral administration of citrated blood in man. March, 1941 - Presented at American Society of Clinical Investigation

Objective: In the context of an upper GI bleed, tarry stool or frank blood in stool is assumed to signify sever hemorrhage.  The paper goes about trying to quantify how much blood actually needs to be lost in an upper GI bleed before stool quality changes.

How much blood is necessary to produce tarry stool?
The authors used 18 subjects (3 controls and 15 other patients in hospital for non-GI related diseases), who drank varying amounts of venous blood mixed with 100 to 200 mL of Vichy water (mineral water) to "help disguise the taste."  The result of the study was that grossly tarry stools were detected starting from subjects who drank at least 100 mL of blood (4/7 patients who drank 100 mL of blood had tarry stools).  Everyone who drank 200 mL of blood had tarry stools.

After a bleed in upper GI tract, how long does it take for blood to show up in stool?
On five subjects (unknown identities), 1000 to 2000 mL of blood was poured down nasogastric tubes. To prevent reflex diarrhea from irritation by stored blood products, subjects were pre-treated with codeine and atropine.  After blood was introduced through NG tube, the first bloody stool appeared starting from 4 hours to 12 hours post procedure.  Bloody or tarry stools lasted for three to five days.

After an upper GI bleed, how long does occult blood last in stool?
When two subjects drank anywhere from 75 to 250 mL of blood, the average number of days with guaiac positive stool ranged from three (for 75 mL of blood) to ten days (for 250 mL of blood).  When more than 1000 mL of blood was introduced via the NG tube, guaiac positive stool lasted for five (for 1000 mL of blood) to 12 days (for 2000 mL of blood).

Conclusion: Tarry stools can appear after as little as 100 mL of blood from upper GI bleed - not a massive hemorrhage.  It takes roughly about four to twelve hours for the blood to show up in stool after a big bleed of one to two liters (although patients were pre-treated with anti-motility agents).  Subsequent to a bleed, the occult blood can last for one to two weeks.