Thromboelastometry and Platelet Function during Acclimatization to High Altitude

Abstract

Interaction between hypoxia and coagulation is important given the increased risk of thrombotic diseases in chronically hypoxic patients who reside at sea level and in residents at high altitude. Hypoxia alters the proteome of platelets favouring a prothrombotic phenotype, but studies of activation and consumption of specific coagulation factors in hypoxic humans have yielded conflicting results. We tested blood from 63 healthy lowland volunteers acclimatizing to high altitude (5,200 m) using thromboelastometry and assays of platelet function to examine the effects of hypoxia on haemostasis. Using data from two separate cohorts of patients following identical ascent profiles, we detected a significant delay in clot formation, but increased clot strength by day 7 at 5,200 m. The latter finding may be accounted for by the significant rise in platelet count and fibrinogen concentration that occurred during acclimatization. Platelet function assays revealed evidence of platelet hyper-reactivity, with shortened PFA-100 closure times and increased platelet aggregation in response to adenosine diphosphate. Post-expedition results were consistent with the normalization of coagulation following descent to sea level. These robust findings indicate that hypoxia increases platelet reactivity and, with the exception of the paradoxical delay in thromboelastometry clotting time, suggest a prothrombotic phenotype at altitude. Further work to elucidate the mechanism of platelet activation in hypoxia will be important and could impact upon the management of patients with acute or chronic hypoxic respiratory diseases who are at risk of thrombotic events.

Keywords

hypoxia - high altitude - haemostasis - platelet function - thromboelastometry

• References

• 1 Cucinell SA, Pitts CM. Thrombosis at mountain altitudes. Aviat Space Environ Med 1987; 58 (11) 1109-1111
• 2 Gupta A, Singh S, Ahluwalia TS, Khanna A. Retinal vein occlusion in high altitude. High Alt Med Biol 2011; 12 (04) 393-397
• 3 Fagenholz PJ, Gutman JA, Murray AF. , et al. Arterial thrombosis at high altitude resulting in loss of limb. High Alt Med Biol 2007; 8 (04) 340-347
• 4 Schreijer AJ, Cannegieter SC, Rosendaal FR, Helmerhorst FM. A case of thrombosis at high altitude. Thromb Haemost 2005; 94 (05) 1104-1105
• 5 Anand AC, Jha SK, Saha A, Sharma V, Adya CM. Thrombosis as a complication of extended stay at high altitude. Natl Med J India 2001; 14 (04) 197-201
• 6 Jha SK, Anand AC, Sharma V, Kumar N, Adya CM. Stroke at high altitude: Indian experience. High Alt Med Biol 2002; 3 (01) 21-27
• 7 Ansell JE. Air travel and venous thromboembolism--is the evidence in?. N Engl J Med 2001; 345 (11) 828-829
• 8 Bärtsch P. How thrombogenic is hypoxia?. JAMA 2006; 295 (19) 2297-2299
• 9 Cannegieter SC, Doggen CJ, van Houwelingen HC, Rosendaal FR. Travel-related venous thrombosis: results from a large population-based case control study (MEGA study). PLoS Med 2006; 3 (08) e307
• 10 Schreijer AJ, Cannegieter SC, Meijers JC, Middeldorp S, Büller HR, Rosendaal FR. Activation of coagulation system during air travel: a crossover study. Lancet 2006; 367 (9513): 832-838
• 11 Toff WD, Jones CI, Ford I. , et al. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation. JAMA 2006; 295 (19) 2251-2261
• 12 Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet 2000; 356 (9242): 1657-1658
• 13 Crosby A, Talbot NP, Harrison P, Keeling D, Robbins PA. Relation between acute hypoxia and activation of coagulation in human beings. Lancet 2003; 361 (9376): 2207-2208
• 14 Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in men. Lancet 1990; 336 (8710): 261-264
• 15 Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med 2013; 1 (01) 61-72
• 16 Børvik T, Brækkan SK, Enga K. , et al. COPD and risk of venous thromboembolism and mortality in a general population. Eur Respir J 2016; 47 (02) 473-481
• 17 Roach RC, Bartsch P, Hackett PH. , et al. The Lake Louise acute mountain sickness scoring system. In: Hypoxia and Molecular Medicine. Queens City Printers 1993:272–274
• 18 Hall DP, MacCormick IJ, Phythian-Adams AT. , et al. Network analysis reveals distinct clinical syndromes underlying acute mountain sickness. PLoS One 2014; 9 (01) e81229
• 19 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
• 20 Martin DS, Pate JS, Vercueil A, Doyle PW, Mythen MG, Grocott MP. ; Caudwell Xtreme Everest Research Group. Reduced coagulation at high altitude identified by thromboelastography. Thromb Haemost 2012; 107 (06) 1066-1071
• 21 Modesti PA, Rapi S, Paniccia R. , et al. Index measured at an intermediate altitude to predict impending acute mountain sickness. Med Sci Sports Exerc 2011; 43 (10) 1811-1818
• 22 Hänecke P, Klouche M. Thrombelastography today: practicability and analytical power. Transfus Med Hemother 2007; 34: 421-428
• 23 Sørensen B, Ingerslev J. Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa. J Thromb Haemost 2004; 2 (01) 102-110
• 24 Andrew M, O'Brodovich H, Sutton J. Operation Everest II: coagulation system during prolonged decompression to 282 Torr. J Appl Physiol (1985) 1987; 63 (03) 1262-1267
• 25 Bärtsch P, Haeberli A, Franciolli M, Kruithof EK, Straub PW. Coagulation and fibrinolysis in acute mountain sickness and beginning pulmonary edema. J Appl Physiol (1985) 1989; 66 (05) 2136-2144
• 26 Levett DZ, Fernandez BO, Riley HL. , et al; Caudwell Extreme Everest Research Group. The role of nitrogen oxides in human adaptation to hypoxia. Sci Rep 2011; 1: 109
• 27 Park JW, Piknova B, Nghiem K, Lozier JN, Schechter AN. Inhibitory effect of nitrite on coagulation processes demonstrated by thrombelastography. Nitric Oxide 2014; 40: 45-51
• 28 Nielsen VG. Nitric oxide decreases coagulation protein function in rabbits as assessed by thromboelastography. Anesth Analg 2001; 92 (02) 320-323
• 29 Ramaker AJ, Meyer P, van der Meer J. , et al. Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser. Blood Coagul Fibrinolysis 2009; 20 (06) 436-439
• 30 Jensen AS, Johansson PI, Bochsen L. , et al. Fibrinogen function is impaired in whole blood from patients with cyanotic congenital heart disease. Int J Cardiol 2013; 167 (05) 2210-2214
• 31 Westbury SK, Lee K, Reilly-Stitt C, Tulloh R, Mumford AD. High haematocrit in cyanotic congenital heart disease affects how fibrinogen activity is determined by rotational thromboelastometry. Thromb Res 2013; 132 (02) e145-e151
• 32 Spiezia L, Radu C, Marchioro P. , et al. Peculiar whole blood rotation thromboelastometry (ROTEM) profile in 40 sideropenic anaemia patients. Thromb Haemost 2008; 100 (06) 1106-1110
• 33 Nagler M, Kathriner S, Bachmann LM, Wuillemin WA. Impact of changes in haematocrit level and platelet count on thromboelastometry parameters. Thromb Res 2013; 131 (03) 249-253
• 34 Lang T, Johanning K, Metzler H. , et al. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia. Anesth Analg 2009; 108 (03) 751-758
• 35 Chatterji JC, Ohri VC, Das BK. , et al. Platelet count, platelet aggregation and fibrinogen levels following acute induction to high altitude (3200 and 3771 metres). Thromb Res 1982; 26 (03) 177-182
• 36 Hudson JG, Bowen AL, Navia P. , et al. The effect of high altitude on platelet counts, thrombopoietin and erythropoietin levels in young Bolivian airmen visiting the Andes. Int J Biometeorol 1999; 43 (02) 85-90
• 37 Harrison MT, Short P, Williamson PA, Singanayagam A, Chalmers JD, Schembri S. Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?. Thorax 2014; 69 (07) 609-615
• 38 Lehmann T, Mairbäurl H, Pleisch B, Maggiorini M, Bärtsch P, Reinhart WH. Platelet count and function at high altitude and in high-altitude pulmonary edema. J Appl Physiol (1985) 2006; 100 (02) 690-694
• 39 Tyagi T, Ahmad S, Gupta N. , et al. Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype. Blood 2014; 123 (08) 1250-1260
• 40 Saido TC, Suzuki H, Yamazaki H, Tanoue K, Suzuki K. In situ capture of mu-calpain activation in platelets. J Biol Chem 1993; 268 (10) 7422-7426
• 41 Femia EA, Scavone M, Lecchi A, Cattaneo M. Effect of platelet count on platelet aggregation measured with impedance aggregometry (Multiplate™ analyzer) and with light transmission aggregometry. J Thromb Haemost 2013; 11 (12) 2193-2196
• 42 Müller MR, Salat A, Pulaki S. , et al. Influence of hematocrit and platelet count on impedance and reactivity of whole blood for electrical aggregometry. J Pharmacol Toxicol Methods 1995; 34 (01) 17-22
• 43 Escolar G, Cases A, Viñas M. , et al. Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients using the platelet function analyzer (PFA-100 ): influence of hematocrit elevation. Haematologica 1999; 84 (07) 614-619
• 44 Eugster M, Reinhart WH. The influence of the haematocrit on primary haemostasis in vitro. Thromb Haemost 2005; 94 (06) 1213-1218
• 45 Dai Y, Lee A, Critchley LA, White PF. Does thromboelastography predict postoperative thromboembolic events? A systematic review of the literature. Anesth Analg 2009; 108 (03) 734-742
• 46 Yao X, Dong Q, Song Y, Wang Y, Deng Y, Li Y. Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 2014; 38 (03) 182-190
• 47 Gurbel PA, Bliden KP, Guyer K. , et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46 (10) 1820-1826
• 48 Venema LF, Post WJ, Hendriks HG, Huet RC, de Wolf JT, de Vries AJ. An assessment of clinical interchangeability of TEG and RoTEM thromboelastographic variables in cardiac surgical patients. Anesth Analg 2010; 111 (02) 339-344
• 49 Hincker A, Feit J, Sladen RN, Wagener G. Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Crit Care 2014; 18 (05) 549
• 50 Thompson AA, Dickinson RS, Murphy F. , et al. Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism. Sci Immunol 2017; 2 (08) eaal2861
• 51 Lang T, Bauters A, Braun SL. , et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis 2005; 16 (04) 301-310