Download PDF
Hamostaseologie 2019; 39(01): 006-019
DOI: 10.1055/s-0038-1676823
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Microvascular Thrombosis and Ischaemic Limb Losses in Critically Ill Patients

Theodore E. Warkentin
1   Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Transfusion Medicine, Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
3   Service of Clinical Hematology, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario, Canada
4   McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
5   Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

20 September 2018

02 November 2018

Publication Date:
09 January 2019 (online)

Also available at
   Permissions and Reprints

Abstract

Relatively little scientific attention has been given to the small subset of critically ill patients with circulatory shock who develop ischaemic limb losses (symmetrical peripheral gangrene [SPG]). The clinical picture consists of acral (distal extremity) tissue necrosis involving lower limbs in a largely symmetrical fashion and with detectable arterial pulses; in one-third of patients the upper extremities are also affected (potential for four-limb amputations). The laboratory picture includes thrombocytopenia, coagulopathy, and normoblastemia (circulating nucleated red blood cells). The explanation for limb losses is microvascular thrombosis caused by disseminated intravascular coagulation usually secondary to cardiogenic or septic shock. A common myth is that vasopressors cause the ischaemic limb injury. However, the more likely explanation is failure of the natural anticoagulant systems (protein C and antithrombin) to downregulate thrombin generation in the microvasculature. This is because more than 90% of patients with SPG have preceding ‘shock liver’, which occurs 2 to 5 days (median, 3 days) prior to ischaemic limb injury, with impaired hepatic production of protein C and antithrombin.

Zusammenfassung

Die kleine Gruppe kritisch kranker Patienten mit Herz-Kreislauf-Schock und ischämisch bedingter Extremitäten-Gangrän hat bislang relativ wenig wissenschaftliche Aufmerksamkeit erfahren. Das klinische Bild besteht aus ischämischen Gewebsnekrosen der Akren trotz nachweisbarem arteriellen Puls. Die Nekrosen treten typischerweise symmetrisch und vor allem an den unteren Extremitäten auf. Bei ca. einem Drittel der Patienten sind auch die Finger/Hände betroffen (Risiko der Amputation aller vier Extremitäten). Die Laborergebnisse zeigen die Konstellation von Thrombozytopenie, Koagulopathie und zirkulierenden Normoblasten (kernhaltigen Erythrozyten). Der Extremitätenverlust wird verursacht durch mikrovaskuläre Thrombosen bei disseminierter Koagulopathie infolge eines kardiogenen oder septischen Schocks. Ein weit verbreiteter Irrglaube ist, dass Vasopressoren eine Ischämie der Akren/Extremitäten verursachen. Die viel wahrscheinlichere Erklärung dürfte sein, dass ein Versagen der natürlichen antikoagulatorischen Systeme (Protein C, Antithrombin) aufgrund einer Leberschädigung dazu führt, dass die Thrombinbildung in der Mikrozirkulation nicht ausreichend gehemmt wird. Mehr als 90% der Patienten mit symmetrischer Extremitäten-Gangrän haben eine ‘Schockleber’, die 2–5 Tage (im Median 3 Tage) vor Entstehung der Extremitäten-Gangrän auftritt und zu mit eingeschränkter Synthese von Protein C und Antithrombin führt.

Keywords

acute ischaemic hepatitis (‘shock liver’) - antithrombin - disseminated intravascular coagulation - protein C - symmetrical peripheral gangrene - vasopressors

Schlüsselwörter

akute ischämisce Hepatitis (‘Schockleber’) - Antithrombin - Disseminierte intravaskuläre Koagulation - Protein C - Symmetrisches peripheres Gangrän - Vasopressoren
 

  • References

  • 1 Warkentin TE. Ischemic limb gangrene with pulses. N Engl J Med 2015; 373 (07) 642-655
    CrossrefPubMedSearch in Google Scholar
  • 2 Perry CB, Davie TB. Symmetrical gangrene in cardiac failure. BMJ 1939; 1 (4070): 15
    CrossrefPubMedSearch in Google Scholar
  • 3 Caserta SJ, Metz R, Anton M. Symmetrical peripheral gangrene in myocardial infarction; report of a case. N Engl J Med 1956; 254 (12) 568-570
    CrossrefPubMedSearch in Google Scholar
  • 4 Ratnoff OD, Nebehay WG. Multiple coagulative defects in a patient with the Waterhouse–Friderichsen syndrome. Ann Intern Med 1962; 56: 627-632
    PubMedSearch in Google Scholar
  • 5 Rapaport SI, Tatter D, Coeur-Barron N, Hjort PF. Pseudomonas septicemia with intravascular clotting leading to generalized Shwartzman reaction. N Engl J Med 1964; 271: 80-84
    CrossrefPubMedSearch in Google Scholar
  • 6 Corrigan Jr JJ, Ray WL, May N. Changes in the blood coagulation system associated with septicemia. N Engl J Med 1968; 279 (16) 851-856
    CrossrefPubMedSearch in Google Scholar
  • 7 Stossel TP, Levy R. Intravascular coagulation associated with pneumococcal bacteremia and symmetrical peripheral gangrene. Arch Intern Med 1970; 125 (05) 876-878
    CrossrefPubMedSearch in Google Scholar
  • 8 Chaudhuri AK, McKenzie P. Peripheral gangrene after measles. BMJ 1970; 4 (5736): 679-680
    PubMedSearch in Google Scholar
  • 9 Molos MA, Hall JC. Symmetrical peripheral gangrene and disseminated intravascular coagulation. Arch Dermatol 1985; 121 (08) 1057-1061
    CrossrefPubMedSearch in Google Scholar
  • 10 Knight Jr TT, Gordon SV, Canady J, Rush DS, Browder W. Symmetrical peripheral gangrene: a new presentation of an old disease. Am Surg 2000; 66 (02) 196-199
    Search in Google Scholar
  • 11 Musher DM. Cutaneous and soft-tissue manifestations of sepsis due to gram-negative enteric bacilli. Rev Infect Dis 1980; 2 (06) 854-866
    CrossrefPubMedSearch in Google Scholar
  • 12 Robboy SJ, Major MC, Colman RW, Minna JD. Pathology of disseminated intravascular coagulation (DIC). Analysis of 26 cases. Hum Pathol 1972; 3 (03) 327-343
    CrossrefPubMedSearch in Google Scholar
  • 13 Robboy SJ, Mihm MC, Colman RW, Minna JD. The skin in disseminated intravascular coagulation. Prospective analysis of thirty-six cases. Br J Dermatol 1973; 88 (03) 221-229
    CrossrefPubMedSearch in Google Scholar
  • 14 Vincent JL, Nadel S, Kutsogiannis DJ. , et al. Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies. Crit Care 2005; 9 (04) R331-R343
    CrossrefPubMedSearch in Google Scholar
  • 15 Johansen K, Hansen Jr ST. Symmetrical peripheral gangrene (purpura fulminans) complicating pneumococcal sepsis. Am J Surg 1993; 165 (05) 642-645
    CrossrefPubMedSearch in Google Scholar
  • 16 Dünser MW, Mayr AJ, Tür A. , et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003; 31 (05) 1394-1398
    CrossrefPubMedSearch in Google Scholar
  • 17 Russell JA, Walley KR, Singer J. , et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358 (09) 877-887
    CrossrefPubMedSearch in Google Scholar
  • 18 Ghosh SK, Bandyopadhyay D, Ghosh A. Symmetrical peripheral gangrene: a prospective study of 14 consecutive cases in a tertiary-care hospital in eastern India. J Eur Acad Dermatol Venereol 2010; 24 (02) 214-218
    CrossrefPubMedSearch in Google Scholar
  • 19 Davis MD, Dy KM, Nelson S. Presentation and outcome of purpura fulminans associated with peripheral gangrene in 12 patients at Mayo Clinic. J Am Acad Dermatol 2007; 57 (06) 944-956
    CrossrefPubMedSearch in Google Scholar
  • 20 Hayes MA, Yau EHS, Hinds CJ, Watson JD. Symmetrical peripheral gangrene: association with noradrenaline administration. Intensive Care Med 1992; 18 (07) 433-436
    CrossrefPubMedSearch in Google Scholar
  • 21 Joynt G, Doedens L, Lipman J, Bothma P. High-dose adrenaline with low systemic vascular resistance and symmetrical peripheral gangrene. S Afr J Surg 1996; 34 (02) 99-101
    PubMedSearch in Google Scholar
  • 22 Gamper G, Havel C, Arrich J. , et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev 2016; 2: CD003709
    CrossrefPubMedSearch in Google Scholar
  • 23 Warkentin TE. Symmetrical peripheral gangrene: mechanisms for limb loss in the ICU in patients with retained pulses. Clin Pulm Med 2018; 25 (02) 61-66
    CrossrefPubMedSearch in Google Scholar
  • 24 Waseem N, Chen PH. Hypoxic hepatitis: a review and clinical update. J Clin Transl Hepatol 2016; 4 (03) 263-268
    PubMedSearch in Google Scholar
  • 25 Siegal DM, Cook RJ, Warkentin TE. Acute hepatic necrosis and ischemic limb necrosis. N Engl J Med 2012; 367 (09) 879-881
    CrossrefPubMedSearch in Google Scholar
  • 26 Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin Thromb Hemost 2015; 41 (01) 49-60
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Constantino BT, Cogionis B. Nucleated RBCs—significance in the peripheral blood film. Lab Med 2000; 31 (04) 223-229
    CrossrefPubMedSearch in Google Scholar
  • 28 Ward HP, Holman J. The association of nucleated red cells in the peripheral smear with hypoxemia. Ann Intern Med 1967; 67 (06) 1190-1194
    PubMedSearch in Google Scholar
  • 29 Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf 2014; 13 (01) 25-43
    CrossrefPubMedSearch in Google Scholar
  • 30 Warkentin TE. Ischemic limb gangrene with pulses. N Engl J Med 2015; 373 (24) 2386-2388
    PubMedSearch in Google Scholar
  • 31 White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 2000; 96 (12) 3719-3724
    CrossrefPubMedSearch in Google Scholar
  • 32 Powars D, Larsen R, Johnson J. , et al. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 1993; 17 (02) 254-261
    CrossrefPubMedSearch in Google Scholar
  • 33 Hayakawa M, Gando S, Ono Y, Wada T, Yanagida Y, Sawamura A. Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study. Semin Thromb Hemost 2015; 41 (01) 35-42
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Parasnis H, Raje B, Hinduja IN. Relevance of plasma fibrinogen estimation in obstetric complications. J Postgrad Med 1992; 38 (04) 183-185
    PubMedSearch in Google Scholar
  • 35 Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127 (09) 804-812
    Search in Google Scholar
  • 36 Warkentin TE, Cook RJ, Sarode R, Sloane DA, Crowther MA. Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome. Blood 2015; 126 (04) 486-493
    CrossrefPubMedSearch in Google Scholar
  • 37 Warkentin TE, Pai M. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?. J Thromb Haemost 2016; 14 (02) 231-235
    CrossrefPubMedSearch in Google Scholar
  • 38 Safdar H, Cheung KL, Salvatori D. , et al. Acute and severe coagulopathy in adult mice following silencing of hepatic antithrombin and protein C production. Blood 2013; 121 (21) 4413-4416
    CrossrefPubMedSearch in Google Scholar
  • 39 Fijnvandraat K, Derkx B, Peters M. , et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73 (01) 15-20
    Thieme ConnectPubMedSearch in Google Scholar
  • 40 Warkentin TE. Coumarin-induced skin necrosis and venous limb gangrene. In: Marder VJ, Aird WC, Bennett JS, Schulman S, White GC. , eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013: 1308-1317
    Search in Google Scholar
  • 41 Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol 1983; 49 (49) 265-275
    PubMedSearch in Google Scholar
  • 42 Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. ; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-1330
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Takemitsu T, Wada H, Hatada T. , et al. Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation. Thromb Haemost 2011; 105 (01) 40-44
    Thieme ConnectPubMedSearch in Google Scholar
  • 44 Gando S, Iba T, Eguchi Y. , et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 2006; 34 (03) 625-631
    CrossrefPubMedSearch in Google Scholar
  • 45 Gando S, Saitoh D, Ogura H. , et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. Disseminated intravascular coagulation (DIC) diagnosed based on the Japanese Association for Acute Medicine criteria is a dependent continuum to overt DIC in patients with sepsis. Thromb Res 2009; 123 (05) 715-718
    CrossrefPubMedSearch in Google Scholar
  • 46 Singer M, Deutschman CS, Seymour CW. , et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
    CrossrefPubMedSearch in Google Scholar
  • 47 Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open 2017; 7 (09) e017046
    CrossrefPubMedSearch in Google Scholar
  • 48 Iba T, Arakawa M, Di Nisio M. , et al. Newly proposed sepsis-induced coagulopathy precedes International Society on Thrombosis and Haemostasis overt-disseminated intravascular coagulation and predicts high mortality. J Intensive Care Med 2018 (e-pub ahead of print). doi: 10.1177/0885066618773679
    PubMed
  • 49 Umemura Y, Yamakawa K, Hayakawa M, Hamasaki T, Fujimi S. ; Japan Septic Disseminated Intravascular Coagulation (J-Septic DIC) Study Group. Screening itself for disseminated intravascular coagulation may reduce mortality in sepsis: a nationwide multicenter registry in Japan. Thromb Res 2018; 161: 60-66
    CrossrefPubMedSearch in Google Scholar
  • 50 Iba T, Di Nisio M, Thachil J. , et al. A proposal of the modification of Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria for sepsis-associated DIC. Clin Appl Thromb Hemost 2018; 24 (03) 439-445
    CrossrefPubMedSearch in Google Scholar
  • 51 Bell WR, Starksen NF, Tong S, Porterfield JK. Trousseau's syndrome. Devastating coagulopathy in the absence of heparin. Am J Med 1985; 79 (04) 423-430
    CrossrefPubMedSearch in Google Scholar
  • 52 Rhodes A, Evans LE, Alhazzani W. , et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43 (03) 304-377
    CrossrefPubMedSearch in Google Scholar
  • 53 Zarychanski R, Abou-Setta AM, Kanji S. , et al; Canadian Critical Care Trials Group. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med 2015; 43 (03) 511-518
    CrossrefPubMedSearch in Google Scholar
  • 54 Iba T, Thachil J. Present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a perspective from Japan. Int J Hematol 2016; 103 (03) 253-261
    CrossrefPubMedSearch in Google Scholar
  • 55 Allingstrup M, Wetterslev J, Ravn FB, Møller AM, Afshari A. Antithrombin III for critically ill patients. Cochrane Database Syst Rev 2016; 2: CD005370
    PubMedSearch in Google Scholar
  • 56 Warren BL, Eid A, Singer P. , et al. Caring for the critically ill patient. High-dose antithrombin in severe sepsis: a randomized controlled trial. JAMA 2001; 286 (15) 1869-1878
    CrossrefPubMedSearch in Google Scholar
  • 57 Kienast J, Juers M, Wiedermann CJ. , et al; KyberSept investigators. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006; 4 (01) 90-97
    PubMedSearch in Google Scholar
  • 58 Umemura Y, Yamakawa K, Ogura H, Yuhara H, Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost 2016; 14 (03) 518-530
    CrossrefPubMedSearch in Google Scholar
  • 59 Hayakawa M, Saito S, Uchino S. , et al. Characteristics, treatments, and outcomes of severe sepsis of 3195 ICU-treated adult patients throughout Japan during 2011–2013. J Intensive Care 2016; 4: 44
    CrossrefPubMedSearch in Google Scholar
  • 60 Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2014; 12 (09) 1470-1479
    CrossrefPubMedSearch in Google Scholar
  • 61 Yamakawa K, Umemura Y, Hayakawa M. , et al; Japan Septic Disseminated Intravascular Coagulation (J-Septic DIC) Study Group. Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan. Crit Care 2016; 20 (01) 229
    CrossrefPubMedSearch in Google Scholar
  • 62 Umemura Y, Yamakawa K. Optimal patient selection for anticoagulant therapy in sepsis: an evidence-based proposal from Japan. J Thromb Haemost 2018; 16 (03) 462-464
    CrossrefPubMedSearch in Google Scholar
  • 63 Ito T, Maruyama I. Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. J Thromb Haemost 2011; 9 (Suppl. 01) 168-173
    CrossrefPubMedSearch in Google Scholar
  • 64 Saito H, Maruyama I, Shimazaki S. , et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5 (01) 31-41
    CrossrefPubMedSearch in Google Scholar
  • 65 Vincent JL, Ramesh MK, Ernest D. , et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med 2013; 41 (09) 2069-2079
    CrossrefPubMedSearch in Google Scholar
  • 66 ClinicalTrails.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01598831?term=ART-123&rank=2 . Accessed October 21, 2018
    PubMed
  • 67 Yamakawa K, Ogura H, Fujimi S. , et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med 2013; 39 (04) 644-652
    CrossrefPubMedSearch in Google Scholar
  • 68 Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2015; 13 (01) 31-40
    CrossrefPubMedSearch in Google Scholar
  • 69 Yoshimura J, Yamakawa K, Ogura H. , et al. Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Crit Care 2015; 19: 78
    CrossrefPubMedSearch in Google Scholar
  • 70 Burlage LC, Bos S, Adelmeijer J, Sakai T, Porte RJ, Lisman T. Plasma from patients undergoing liver transplantation is resistant to anticoagulant activity of soluble thrombomodulin (ART-123). Liver Transpl 2018 (e-pub ahead of print). doi: 10.1002/lt.25318
    PubMed
  • 71 Wada H, Ohiwa M, Kaneko T. , et al. Plasma thrombomodulin as a marker of vascular disorders in thrombotic thrombocytopenic purpura and disseminated intravascular coagulation. Am J Hematol 1992; 39 (01) 20-24
    CrossrefPubMedSearch in Google Scholar
  • 72 Iba T, Yagi Y, Kidokoro A, Fukunaga M, Fukunaga T. Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure. Surg Today 1995; 25 (07) 585-590
    CrossrefPubMedSearch in Google Scholar
  • 73 Dellinger RP, Schorr CA, Levy MM. A users' guide to the 2016 surviving sepsis guidelines. Intensive Care Med 2017; 43 (03) 299-303
    CrossrefPubMedSearch in Google Scholar