45F h/o ESRD on dialysis presents ped struck.
Pt is obtunded, intubated for airway protection.
CT head shows subdural hematoma with midline shift.
Neurosurgery is activated.
No antiplatelets or anticoagulants.
Is this person coagulopathic simply by having ESRD?
If so, should we address it with any particular medication?
There is a role for DDAVP in bleeding and concomitant renal failure.
We are cognizant that DDAVP (desmopressin), a vasopressin analog, is often considered/used in the treatment of hemorrhage in the setting of platelet dysfunction, namely patients on ASA/Plavix. The support for this use requires consideration of literature from many specialties and situations (trauma, OR, post-op, various anatomical locations of bleeds, etc), but DDAVP appears to help in patients on ASA, however the evidence is not supportive for Plavix, (likely because ASA half-life is 20 minutes, whereas Plavix half-life is 7 days).
“Uremic Bleeding” is a manifestation of platelet dysfunction as a result of renal failure. The Mechanism is thought to be multifactorial. But first, let us take a look at normal platelet function.
Behold my platelet activation hand-waving synopsis:
Damage to vascular endothelium exposes collagen and tissue factor. Platelets bind to the exposed collagen via glycoprotein receptors or via von Willebrand Factor, which activate cAMP signaling pathways in the platelets, that stimulates platelet integrin to further strengthen the clot. Platelets subsequently release a variety of factors, including TXA2 (through the arachidonic acid cascade) and ADP. ADP and TXA2 both stimulate further platelet activation/aggregation via shape change of the entire platelet, and conformational change of the platelet GIIb/IIIA receptor that promotes binding to fibrinogin or VWF (Plavix is a platelet ADP receptor blocker, and integrilin is a GIIb/IIIA inhibitor). A product of the coagulation cascade, thrombin, also assists in activating platelets.
VWF contributes to this process in multiple ways. First, VWF binds to collagen of the injured vessel wall, and can then bind platelets and link them to the injured wall (using a different GP receptor than other platelet-collagen binding sites), providing an additional mechanism to bind and activate platelets to an injury with shear stress. VWF also facilitates platelet aggregation, assisting in development of a platelet plug. Further, VWF binds to Factor VIII when inactivated, which prevents Factor VIII from being degraded, thus functions as a reservoir.
High levels of urea cause dysfunction directly to VWF; the mechanism is not certain, but affects both the glycoprotein binding of WVF on platelets, and the expression of those sites by platelets. This weakened binding of WVF and platelets diminishes subsequent activation and secretion of TXA2 / ADP secretion, preventing a robust platelet aggregation response. There is not actually a decrease in the amount of VWF-FVIII circulating, further suggesting a dysfunction of circulating factors rather than a decrease. DDAVP administration causes release of stored WVF from endothelium, increasing both the amount of WVF and Factor VIII in the circulation.
A placebo controlled trial in 1983, randomized 24 uremic patients with a history of bleeding to either DDAVP or placebo. The outcomes were bleeding time, and a variety of other laboratory results. There was a significant decrease in bleeding time after 1 hour of DDAVP administration. The medication was well tolerated, with some facial flushing and headache. Subsequently, 9 patients with uremia and platelet dysfunction (elevated bleeding time) were given DDAVP prior to an invasive procedure (e.g. renal biopsy) in 9 patients in an uncontrolled study. The bleeding time in those patients shortened prior to the procedure, and there were no acute bleeding complications during the procedures. This study does not report the extent of uremia qualitatively (aside from prolonged bleeding time), nor does it provide a level of azotemia for reference.
Back to our patient:
There is data to support giving DDAVP to a patient with platelet dysfunction associated with ESRD or “uremic bleeding”. Unfortunately, the data inform us from trials of patients who are clinically uremic, which as a clinical diagnosis distinct from a laboratory diagnosis of azotemia. If we are unable to make the diagnosis of uremia in the ED (such as in our patient) do we assume that patients with ESRD have platelet dysfunction and treat empirically? For additional diagnostic certainty, feel free to perform bleeding time studies in the ED (making a patient bleed and timing how long it takes for bleeding to stop). However, given our patient’s critical condition and the small risk profile of DDAVP, it seems reasonable to give DDAVP empirically to this patient. 0.3micrograms per kg IV.
Beshay JE, Morgan H, Madden C, Yu W, Sarode R: Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients. J Neurosurg 2010, 112:307-318
Beynon C, Hertle DN, Unterberg AW, Sakowitz OW. Clinical review: Traumatic brain injury in patients receiving antiplatelet medication. Crit Care. 2012 Jul 26;16(4):228
Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol. 2007 Mar;3(3):138-53.
Levi M, Eerenberg E, Kamphuisen PW: Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost 2011, 9:1705-1712
Mannucci PM, Remuzzi G, Pusineri F, Lombardi R, Valsecchi C, Mecca G, Zimmerman TS. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med. 1983 Jan 6;308(1):8-12