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CORRESPONDENCE
Year : 2018  |  Volume : 9  |  Issue : 4  |  Page : 198-199
 

Coagulopathy: A possible mechanism of terlipressin-induced peripheral ischemic complications – Evidence from published case reports


1 Department of Pharmacology, PGIMER, Chandigarh, India
2 Department of Neurosurgery, PGIMER, Chandigarh, India
3 Department of Internal Medicine, PGIMER, Chandigarh, India

Date of Submission16-Nov-2018
Date of Decision30-Nov-2018
Date of Acceptance12-Dec-2018
Date of Web Publication1-Feb-2019

Correspondence Address:
Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpp.JPP_127_18

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How to cite this article:
Sarma P, Mahalmani V, Chandel S, Kumar S, Kaur H, Prakash A, Dhibar DP, Medhi B. Coagulopathy: A possible mechanism of terlipressin-induced peripheral ischemic complications – Evidence from published case reports. J Pharmacol Pharmacother 2018;9:198-9

How to cite this URL:
Sarma P, Mahalmani V, Chandel S, Kumar S, Kaur H, Prakash A, Dhibar DP, Medhi B. Coagulopathy: A possible mechanism of terlipressin-induced peripheral ischemic complications – Evidence from published case reports. J Pharmacol Pharmacother [serial online] 2018 [cited 2019 Feb 21];9:198-9. Available from: http://www.jpharmacol.com/text.asp?2018/9/4/198/251386




Terlipressin, a synthetic analog of vasopressin, was introduced in as early as 1990. It is widely used in the treatment of hepatorenal syndrome and bleeding esophageal varices, but is associated with ischemic and other adverse effects.[1] Although common, the mechanism of these ischemic complications is still unknown. The mechanism of these ischemic complications can be summarized into two hypotheses: vasoconstriction hypothesis and V1 receptor adipose tissue hypothesis.

Being a vasopressin analog, it is hypothesized that the ischemic adverse effects of terlipressin are related to its nonselective stimulation of V1 receptors. Few case reports of terlipressin-induced peripheral gangrene reported normal flow and spectral waveform in all major arteries in Doppler.[2],[3] Again, in many cases, fingers and toes were not affected despite affecting the whole limb.[1] Fingers and toes are affected frequently in vasoconstrictor medication-medicated peripheral ischemic complications. Hence, it seems unlikely that vasoconstriction is the sole player in terlipressin-mediated ischemic complications.

Now, coming to V1 receptor adipose tissue hypothesis, many case reports report ischemic peripheral complications, especially in areas with large skin surface and fat, e.g., thigh, breast, and abdominal wall.[4] Some authors have attributed this to greater amount of V1 receptors present in adipose tissue as a responsible factor for ischemic gangrene affecting limbs.[5] Now, coming to normal body physiology, in peripheral limbs, adipose tissue is mainly located in the subcutaneous region of skin. However, in maximum of the cases of terlipressin-induced peripheral gangrene, epidermis and dermis were involved.[1] Subcutaneous tissue was involved in only 16.6% of cases.[1] Again, many of the ischemic complication sites do not have subcutaneous adipose tissue layer, e.g., scrotum.[1] Hence, this finding contradicts the adipose tissue V1 receptor hypothesis.

Another important differential diagnosis of terlipressin-induced gangrene is cutaneous vasculitis, or it can be a manifestation of coagulopathy. In histopathology, a sign of vasculitis was not prominent in most of the case reports. Dermal capillaries also showed thrombosis without inflammatory infiltrate.[6] Again, autoimmune markers were also found to be negative.[3] Hence, a cutaneous autoimmune vasculitis is most unlikely.

Regarding coagulopathy, histopathologically, dermal vessel thrombosis is reported in many cases of terlipressin-induced peripheral ischemic cases.[6],[7],[8] Vasopressin and its analogs are reported to release von Willebrand factor (V2 receptor-mediated action) and factor VIII[1],[9],[10] and which enhances platelet aggregation and subsequently can cause thrombosis.[9],[10] Human platelets express typical V1 vascular vasopressin receptors.[11] Vasopressin causes aggregation of human blood platelets.[12] Vasopressin was able to cause aggregation of washed human platelets suspended in buffered saline in the presence of fibrinogen, calcium, and magnesium ions.[12]

The site of ischemic complication is highly variable which ranged from scalp, tongue, scrotum, abdomen, breast, thigh, feet, toes, and forearm,[1] and there was no site special preference. In few cases, the ischemic complication was reversible after stopping of the drug.[1] Again, heparin[13] is reported (the lesions occur due to alteration of the homeostasis between procoagulant and anticoagulant factors) to cause a similar type of cutaneous lesions, any in many cases, which clears up after some days after stopping, but some progress and can be fatal. The histopathologic findings of both terlipressin and heparin-induced cutaneous lesions are similar.[13]

In two case reports, the ischemic lesions cleared after the use of intravenous alprostadil + oral sildenafil in one case and sildenafil alone in another case,[2],[14] and it was thought that vasodilation may be the main mechanism. However, till now, we do not find any evidence of vasoconstriction in any of the case reports from Doppler studies.[1] Again, both alprostadil and sildenafil have strong antiplatelet action.[15],[16] Hence, antiplatelet action of these agents may be responsible for the improvement of cutaneous lesions.

Hence, to conclude, “coagulopathy” along with “vasoconstriction” seems to be the most likely mechanism of terlipressin-induced ischemic complications [the possible mechanism is shown in [Figure 1] in the settings of current evidence. The coagulopathy may be the result of release of Von willebrand factor (VWF) or direct platelet activation by vasopressin, which may be responsible in addition to other factors for the cutaneous necrotic lesions.
Figure 1: Possible mechanism of terlipressin-induced ischemic complications

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Conflicts of interest

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   References Top

1.
Sarma P, Muktesh G, Singh RS, Mishra A, Singh A, Ruhela RK, et al. Terlipressin-Induced ischemic complications: A systematic review of published case reports. J Pharmacol Pharmacother 2018;9:76-85.  Back to cited text no. 1
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2.
Bañuelos Ramírez DD, Sánchez Alonso S, Ramírez Palma MM. Sildenafil in severe peripheral ischemia induced by terlipressin. A case report. Reumatol Clin 2011;7:59-60.  Back to cited text no. 2
    
3.
Sarma P, Muktesh G, Dhaka N, Ruhela R, Mishra A, Singh R, et al. Terlipressin-induced peripheral ischemic gangrene in a diabetic patient. J Pharmacol Pharmacother 2017;8:148-50.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Salinas M, Herrera I, Guijarro J, Pascual J, Francis L. Extensive cutaneous necrosis induced by terlipressin. J Am Acad Dermatol 2014;70:AB151.  Back to cited text no. 4
    
5.
Iglesias Julián E, Badía Aranda E, Bernad Cabredo B, Corrales Cruz D, Romero Arauzo MJ. Cutaneous necrosis secondary to terlipressin therapy. A rare but serious side effect. Case report and literature review. Rev Esp Enferm Dig 2017;109:380-2.  Back to cited text no. 5
    
6.
Mégarbané H, Barete S, Khosrotehrani K, Izzedine H, Moguelet P, Chosidow O, et al. Two observations raising questions about risk factors of cutaneous necrosis induced by terlipressin (Glypressin). Dermatology 2009;218:334-7.  Back to cited text no. 6
    
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Chandail VS, Jamwal V. Cutaneous complications of terlipressin. JK Sci J Med Educ Res 2011;13:205-7.  Back to cited text no. 7
    
8.
Donnellan F, Cullen G, Hegarty JE, McCormick PA. Ischaemic complications of glypressin in liver disease: A case series. Br J Clin Pharmacol 2007;64:550-2.  Back to cited text no. 8
    
9.
Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: Pharmacology and its clinical relevance. Anaesthesia 2004;59:993-1001.  Back to cited text no. 9
    
10.
Nussey SS, Bevan DH, Ang VT, Jenkins JS. Effects of arginine vasopressin (AVP) infusions on circulating concentrations of platelet AVP, factor VIII: C and von willebrand factor. Thromb Haemost 1986;55:34-6.  Back to cited text no. 10
    
11.
Thibonnier M, Hinko A, Pearlmutter AF. The human platelet vasopressin receptor and its intracellular messengers: Key role of divalent cations. J Cardiovasc Pharmacol 1987;10:24-9.  Back to cited text no. 11
    
12.
Haslam RJ, Rosson GM. Aggregation of human blood platelets by vasopressin. Am J Physiol 1972;223:958-67.  Back to cited text no. 12
    
13.
Katsourakis A, Noussios G, Kapoutsis G, Chatzitheoklitos E. Low molecular weight heparin-induced skin necrosis: A case report. Case Rep Med 2011;2011:857391.  Back to cited text no. 13
    
14.
Lee HJ, Oh MJ. A case of peripheral gangrene and osteomyelitis secondary to terlipressin therapy in advanced liver disease. Clin Mol Hepatol 2013;19:179-84.  Back to cited text no. 14
    
15.
Jaarsma RL, Mohammad SF, Burns GL, Olsen DB. Alprostadil: An effective antiplatelet agent for calves. Artif Organs 1993;17:935-9.  Back to cited text no. 15
    
16.
Gambardella L, Lista P, Pichini S, Pacifici R, Malorni W, Straface E. On the interference of sildenafil on platelet aggregation: An ex vivo pilot study. IJC Metab Endocr 2014;4:73-4.  Back to cited text no. 16
    


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