Effect of Aspirin, Hemodilution and Desmopressin on Platelet Dysfunction

Platelet Dysfunction Clinical Trial

Official title:

Effect of Aspirin, in Vitro Hemodilution and Desmopressin on Platelet Dysfunction Associated With Mild Hypothermia in Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01382134
• Other study ID #: UW 11-075
• Status: Completed
• Phase: N/A
• First received: June 23, 2011
• Last updated: November 14, 2013
• Start date: July 2011
• Est. completion date: September 2013

Study information

• Verified date: November 2013
• Source: The University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hong Kong: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Study hypothesis: Desmopressin (DDAVP) can improve platelet function under influence of aspirin, hemodilution and mild hypothermia

Mild hypothermia (34-35oC) is known to cause platelet dysfunction. This could lead to increased surgical bleeding and increased transfusion requirement during surgery. Although this hypothermia-induced platelet dysfunction seems to be reversible with warming, this is not always possible or desirable.

Desmopressin (DDAVP) is a drug which has proven efficacy in improving platelet function in uraemic and cirrhosis patients, and in reducing blood loss in selected surgeries. In a recent study, we have found that subcutaneous injection of 1.5 mcg (1/10th the usual dose) is already sufficient to fully reverse the platelet dysfunction seen at 32oC. We have demonstrated in another study that prolongation of the bleeding time in a 20% hemodiluted sample predicts increased postoperative bleeding after total knee replacement.

We have therefore designed this study as a follow up to our last two studies on DDAVP and hypothermia, to investigate whether hemodilution affects hypothermia induced platelet dysfunction and the response to DDAVP. In addition, another common cause of perioperative platelet dysfunction is the intake of COX inhibitors, particularly aspirin by patients. Therefor the effect of aspirin on hypothermia induced platelet dysfunction and the response to DDAVP, will also be investigated.

Description:

Mild hypothermia (34-35oC) is known to cause platelet dysfunction. Increased surgical bleeding and increased transfusion requirement at this temperature range has been reported in both cardiac and noncardiac surgeries. This degree of hypothermia is common during any general anaesthesia, particularly during surgeries which invlove major fluid shift and large area exposure of patients, e.g. trauma and burn patients.

Although this hypothermia-induced platelet dysfunction seems to be reversible with warming, warming is not always possible or desirable. During major trauma or burn surgery, surface warming of patient is practically difficult. During surgeries with major blood loss and fluid shift, heat loss usually occurs at a rate that is more rapid than any warming device can catch up with. During neurosurgery, cooling may be beneficial to neurological outcome.

Desmopressin (DDAVP) is a drug which has proven efficacy in improving platelet function in uraemic and cirrhosis patients, and in reducing blood loss in selected surgeries. In a previous in vitro study, we have found that desmopressin significantly improves platelet function at 32oC. The improvement is seen with a very low concentration of desmopressin in vitro, which suggests that probably doses much smaller than the "standard dose" (15 mcg slow iv or subcutaneous) may be useful. In keeping with this in vitro study, in a more recent study, we have found that subcutaneous injection of 1.5 mcg (1/10th the usual dose) is already sufficient to fully reverse the platelet dysfunction seen at 32oC.

One of the limitations of our previous two studies is that the degree of platelet dysfuction observed at 32oC is relatively mild, with only around 20% prolongation of the closure times on the PFA-100® platelet function analyser. The clinical significance of such prolongation remains uncertain. However, we have demonstrated previously in another study that prolongation of the closure time to >188 sec in a 20% hemodiluted sample predicts increased postoperative bleeding after total knee replacement. We have therefore designed this study as a follow up to our last two studies on DDAVP and hypothermia, to investigate whether hemodilution affects hypothermia induced platelet dysfunction and the response to DDAVP.

In addition, another common cause of perioperative platelet dysfunction is the intake of COX inhibitors, particularly aspirin by patients. Therefor the effect of aspirin on hypothermia induced platelet dysfunction and the response to DDAVP, will also be investigated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: September 2013
• Est. primary completion date: July 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• 60 adult Chinese subjects aged 18-60 without known platelet disorder, thrombocytopenia, history of taking drugs that may affect platelet function including herbal preparations.

Exclusion Criteria:

1. Any known platelet or coagulation disorder

2. Expected surgical operation or dental treatment within one week of scheduled drug intake.

3. Known peptic ulcer disease

4. Obesity (BMI >=30)

5. Pregnant or lactating women.

6. Known chronic liver or renal disease.

7. Coronary artery, carotid artery or peripheral artery disease

8. Recent history of taking antiplatelet drugs, anticoagulants or herbal preparations.

9. Smoker or alcohol user

10. Mentally incapable of providing informed consent

11. Students or junior staff members who had direct working relationship with the PI

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Blood Platelet Disorders
• Desmopressin
• Hemodilution
• Hypothermia
• Mild Hypothermia
• NSAID
• Platelet Dysfunction

Intervention

Drug:
• Aspirin, desmopressin
Aspirin 100mg daily for 3 days Desmopressin 15 microgram subcutaneously once only
• Placebo, desmopressin
Placebo 1 tab daily for 3 days Desmopressin 15 microgram subcutaneously once only

Locations

Country	Name	City	State
China	Queen Mary Hospital	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
The University of Hong Kong

Country where clinical trial is conducted

China, 

References & Publications (12)

Cavallini M, Baruffaldi Preis FW, Casati A. Effects of mild hypothermia on blood coagulation in patients undergoing elective plastic surgery. Plast Reconstr Surg. 2005 Jul;116(1):316-21; discussion 322-3. — View Citation

Gallinaro L, Cattini MG, Sztukowska M, Padrini R, Sartorello F, Pontara E, Bertomoro A, Daidone V, Pagnan A, Casonato A. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood. 2008 Apr 1;111(7):3540-5. doi: 10.1182/blood-2007-11-122945. Epub 2008 Feb 1. — View Citation

Hofer CK, Worn M, Tavakoli R, Sander L, Maloigne M, Klaghofer R, Zollinger A. Influence of body core temperature on blood loss and transfusion requirements during off-pump coronary artery bypass grafting: a comparison of 3 warming systems. J Thorac Cardiovasc Surg. 2005 Apr;129(4):838-43. — View Citation

Mannucci PM, Capoferri C, Canciani MT. Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease. Br J Haematol. 2004 Jul;126(2):213-8. — View Citation

Michelson AD, Barnard MR, Khuri SF, Rohrer MJ, MacGregor H, Valeri CR. The effects of aspirin and hypothermia on platelet function in vivo. Br J Haematol. 1999 Jan;104(1):64-8. — View Citation

Ng KF, Lawmin JC, Tsang SF, Tang WM, Chiu KY. Value of a single preoperative PFA-100 measurement in assessing the risk of bleeding in patients taking cyclooxygenase inhibitors and undergoing total knee replacement. Br J Anaesth. 2009 Jun;102(6):779-84. doi: 10.1093/bja/aep091. Epub 2009 May 2. — View Citation

Schmied H, Kurz A, Sessler DI, Kozek S, Reiter A. Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. Lancet. 1996 Feb 3;347(8997):289-92. — View Citation

Schmied H, Schiferer A, Sessler DI, Meznik C. The effects of red-cell scavenging, hemodilution, and active warming on allogenic blood requirements in patients undergoing hip or knee arthroplasty. Anesth Analg. 1998 Feb;86(2):387-91. — View Citation

Todd MM, Hindman BJ, Clarke WR, Torner JC; Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med. 2005 Jan 13;352(2):135-45. — View Citation

Winkler M, Akça O, Birkenberg B, Hetz H, Scheck T, Arkiliç CF, Kabon B, Marker E, Grübl A, Czepan R, Greher M, Goll V, Gottsauner-Wolf F, Kurz A, Sessler DI. Aggressive warming reduces blood loss during hip arthroplasty. Anesth Analg. 2000 Oct;91(4):978-84. — View Citation

Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004 Jun;56(6):1221-8. — View Citation

Ying CL, Tsang SF, Ng KF. The potential use of desmopressin to correct hypothermia-induced impairment of primary haemostasis--an in vitro study using PFA-100. Resuscitation. 2008 Jan;76(1):129-33. Epub 2007 Aug 21. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Platelet function	Venous blood sample will be taken from subjects before and after injection of DDAVP. Blood sample will be subjected to: (i) complete blood count, (ii) PFA-100 platelet function analyzer, (iii) fibrinogen, and (iv) vWF:Ag concentration for analysis.	Day 6 after aspirin intake	No