Limb Ischemic Necrosis Secondary to Microvascular Thrombosis: A Brief Historical Review

Abstract

Ischemic limb injury can be broadly classified into arterial (absent pulses) and venous/microvascular (detectable pulses); the latter can be divided into two overlapping disorders—venous limb gangrene (VLG) and symmetrical peripheral gangrene (SPG). Both VLG and SPG feature predominant acral (distal) extremity ischemic necrosis, although in some instances, concomitant nonacral ischemia/skin necrosis occurs. Historically, for coagulopathic disorders with prominent nonacral ischemic necrosis, clinician-scientists implicated depletion of natural anticoagulants, especially involving the protein C (PC) system. This historical review traces the recognition of natural anticoagulant depletion as a key feature of nonacral ischemic syndromes, such as classic warfarin-induced skin necrosis, neonatal purpura fulminans (PF), and meningococcemia-associated PF. However, only after several decades was it recognized that natural anticoagulant depletion is also a key feature of predominantly acral ischemic microthrombosis syndromes—VLG and SPG—even when accompanying nonacral thrombosis is not present. These acquired acral limb ischemic syndromes typically involve the triad of (a) disseminated intravascular coagulation, (b) natural anticoagulant depletion, and (c) a localizing explanation for microthrombosis occurring in one or more limbs, either deep vein thrombosis (helping to explain VLG) or circulatory shock (helping to explain SPG). In most cases of VLG or SPG there are one or more events that exacerbate natural anticoagulant depletion, such as warfarin therapy (e.g., warfarin-associated VLG complicating heparin-induced thrombocytopenia or cancer hypercoagulability) or acute ischemic hepatitis (“shock liver”) as a proximate factor predisposing to severe depletion of hepatically synthesized natural anticoagulants (PC, antithrombin) in the setting of circulatory shock.

Keywords

acute ischemic hepatitis (“shock liver”) - disseminated intravascular coagulation - heparin-induced thrombocytopenia - natural anticoagulants - symmetrical peripheral gangrene - venous limb gangrene

Publikationsverlauf

Artikel online veröffentlicht:
30. April 2024

• References

• 1 Warkentin TE. Ischemic limb gangrene with pulses. N Engl J Med 2015; 373 (07) 642-655
• 2 Hueter C. Fall von Gangrän in Folge von Venenobliteration. Virch Arch Pathol Anat 1859; 17: 482-488
• 3 Guelliot A. Note sur trois cas de purpura infectieux foudroyant. Un Med Sci Nord Est 1884; 8 (02) 25-37
• 4 Hutchinson J. Notes of uncommon cases. BMJ 1891; 2 (1592) 8-9
• 5 Sanarelli G. De la pathogenie du cholera. . Le cholera experimental. Ann Inst Pasteur 1924; 37: 11-80
• 6 Shwartzman G. A new phenomenon of local skin reactivity to B. typhosus culture filtrate. Proc Soc Exp Biol Med 1928; 25 (07) 560-561
• 7 Apitz K. A study of the generalized Shwartzman phenomenon. J Immunol 1935; 29 (03) 255-266
• 8 Gregoire R. La phlébite bleue (phlegmatia caerulia dolens). Press Med 1938; 46 (71) 1313-1315
• 9 Fishberg AM. Redistribution of blood in heart failure. J Clin Invest 1938; 17: 510
• 10 Perry CB, Davie TB. Symmetrical peripheral gangrene in cardiac failure. BMJ 1939; 1 (4070) 15
• 11 Schneider CL. Fibrin embolism (disseminated intravascular coagulation) with defibrination as one of the end results during placenta abruptio. Surg Gynecol Obstet 1951; 92 (01) 27-34
• 12 Seegers WH, Johnson JF, Fell C. An antithrombin reaction to prothrombin activation. Am J Physiol 1954; 176 (01) 97-103
• 13 Verhagen H. Local haemorrhage and necrosis of the skin and underlying tissues, during anti-coagulant therapy with dicumarol or dicumacyl. Acta Med Scand 1954; 148 (06) 453-467
• 14 Greenbaum D. Gangrene of the extremities following cardiac infarction and noradrenaline therapy. Lancet 1958; 1 (7030) 1103-1104
• 15 Egeberg O. Thrombophilia caused by inheritable deficiency of blood antithrombin. Scand J Clin Lab Invest 1965; 17: 92
• 16 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530
• 17 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
• 18 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
• 19 Stenflo J. A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J Biol Chem 1976; 251 (02) 355-363
• 20 Seegers WH, Novoa E, Henry RL, Hassouna HI. Relationship of “new” vitamin K-dependent Protein C and “old” autoprothrombin II-a. Thromb Res 1976; 8 (05) 543-552
• 21 Mammen EF, Thomas WR, Seegers WH. Activation of purified prothrombin to autoprothrombin I or autoprothrombin II (platelet cofactor II or autoprothrombin II-A). Thromb Diath Haemorrh 1960; 5: 218-249
• 22 Owen WG, Protein C. . In: Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 2nd ed. Philadelphia, PA: J.B. Lippincott Co.; 1987: 235-241
• 23 DiScipio RG, Davie EW. Characterization of protein S, a γ-carboxyglutamic acid containing protein from bovine and human plasma. Biochemistry 1979; 18 (05) 899-904
• 24 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68 (05) 1370-1373
• 25 Branson HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 2 (8360) 1165-1168
• 26 Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG. Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 1983; 49 (03) 251
• 27 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311 (24) 1525-1528
• 28 Molos MA, Hall JC. Symmetrical peripheral gangrene and disseminated intravascular coagulation. Arch Dermatol 1985; 121 (08) 1057-1061
• 29 Powars DR, Rogers ZR, Patch MJ, McGehee WG, Francis Jr RB. Purpura fulminans in meningococcemia: association with acquired deficiencies of proteins C and S. N Engl J Med 1987; 317 (09) 571-572
• 30 Mahasandana C, Suvatte V, Marlar RA, Manco-Johnson MJ, Jacobson LJ, Hathaway WE. Neonatal purpura fulminans associated with homozygous protein S deficiency. Lancet 1990; 335 (8680) 61-62
• 31 Mahasandana C, Suvatte V, Chuansumrit A. et al. Homozygous protein S deficiency in an infant with purpura fulminans. J Pediatr 1990; 117 (05) 750-753
• 32 Adcock DM, Hicks MJ. Dermatopathology of skin necrosis associated with purpura fulminans. Semin Thromb Hemost 1990; 16 (04) 283-292
• 33 Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990; 16 (04) 293-298
• 34 Marlar RA, Neumann A. Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies. Semin Thromb Hemost 1990; 16 (04) 299-309
• 35 Francis Jr RB. Acquired purpura fulminans. Semin Thromb Hemost 1990; 16 (04) 310-325
• 36 Brozna JP. Shwartzman reaction. Semin Thromb Hemost 1990; 16 (04) 326-332
• 37 Adcock DM, Brozna J, Marlar RA. Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis. Semin Thromb Hemost 1990; 16 (04) 333-340
• 38 Levin M, Eley BS, Louis J, Cohen H, Young L, Heyderman RS. Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr 1995; 127 (03) 355-363
• 39 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
• 40 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
• 41 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). Thromb Haemost 2001; 86 (05) 1327-1330
• 42 Siegal DM, Cook RJ, Warkentin TE. Acute hepatic necrosis and ischemic limb necrosis. N Engl J Med 2012; 367 (09) 879-881
• 43 Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin Thromb Hemost 2015; 41 (01) 49-60
• 44 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
• 45 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
• 46 Levy JH, Ghadimi K, Faraoni D. et al. Ischemic limb necrosis in septic shock: What is the role of high-dose vasopressor therapy?. J Thromb Haemost 2019; 17 (11) 1973-1978
• 47 Warkentin TE, Ning S, Lim W. Colloid transfusion, natural anticoagulant depletion, and symmetric peripheral gangrene. N Engl J Med 2020; 383 (16) 1592-1594
• 48 Warkentin TE, Ning S. Symmetrical peripheral gangrene in critical illness. Transfus Apheresis Sci 2021; 60 (02) 103094
• 49 Heit J. Thrombophilia: clinical and laboratory assessment and management. In: Kitchens CS, Kessler CM, Konkle BA. eds. Consultative Hemostasis and Thrombosis. 3rd ed. Philadelphia, PA:: Elsevier; 2013: 205-239
• 50 Tsuchida T, Hayakawa M, Kawahara S, Kumano O. Thrombin generation capacity is enhanced by low antithrombin activity and depends on the activity of the related coagulation factors. Thromb J 2022; 20 (01) 29
• 51 Marlar RA, Endres-Brooks J, Miller C. Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Blood 1985; 66 (01) 59-63
• 52 Dreyfus M, Masterson M, David M. et al. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost 1995; 21 (04) 371-381
• 53 Estellés A, Garcia-Plaza I, Dasí A. et al. Severe inherited “homozygous” protein C deficiency in a newborn infant. Thromb Haemost 1984; 52 (01) 53-56
• 54 Ido M, Ohiwa M, Hayashi T. et al. A compound heterozygous protein C deficiency with a single nucleotide G deletion encoding Gly-381 and an amino acid substitution of Lys for Gla-26. Thromb Haemost 1993; 70 (04) 636-641
• 55 Long GL, Tomczak JA, Rainville IR, Dreyfus M, Schramm W, Schwarz HP. Homozygous type I protein C deficiency in two unrelated families exhibiting thrombophilia related to Ala136→Pro or Arg286→His mutations. Thromb Haemost 1994; 72 (04) 526-533
• 56 Soria JM, Brito D, Barceló J. et al. Severe homozygous protein C deficiency: identification of a splice site missense mutation (184, Q→H) in exon 7 of the protein C gene. Thromb Haemost 1994; 72 (01) 65-69
• 57 Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood 1985; 65 (01) 15-20
• 58 Hartman KR, Manco-Johnson M, Rawlings JS, Bower DJ, Marlar RA. Homozygous protein C deficiency: early treatment with warfarin. Am J Pediatr Hematol Oncol 1989; 11 (04) 395-401
• 59 Minford AM, Parapia LA, Stainforth C, Lee D. Treatment of homozygous protein C deficiency with subcutaneous protein C concentrate. Br J Haematol 1996; 93 (01) 215-216
• 60 Smith OP, White B, Vaughan D. et al. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997; 350 (9091) 1590-1593
• 61 Faust SN, Levin M, Harrison OB. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345 (06) 408-416
• 62 Kondaveeti S, Hibberd ML, Booy R, Nadel S, Levin M. Effect of the Factor V Leiden mutation on the severity of meningococcal disease. Pediatr Infect Dis J 1999; 18 (10) 893-896
• 63 Lerolle N, Carlotti A, Melican K. et al. Assessment of the interplay between blood and skin vascular abnormalities in adult purpura fulminans. Am J Respir Crit Care Med 2013; 188 (06) 684-692
• 64 Theron A, Dautremay O, Boissier E. et al. Idiopathic purpura fulminans associated with anti-protein S antibodies in children: a multicenter case series and systematic review. Blood Adv 2022; 6 (02) 495-502
• 65 D'Angelo A, Della Valle P, Crippa L, Pattarini E, Grimaldi LME, Viganò D'Angelo S. Brief report: autoimmune protein S deficiency in a boy with severe thromboembolic disease. N Engl J Med 1993; 328 (24) 1753-1757
• 66 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: Lippincott Williams & Wilkins; 2013: 1308-1317
• 67 Veith FJ, Ascher E. Obituary. A tribute to Henry Haimovici. September 7, 1907–July 10, 2001. J Vasc Surg 2001; 34 (06) 1135-1136
• 68 Haimovici H. Gangrene of the extremities of venous origin; review of the literature with case reports. Circulation 1950; 1 (02) 225-240
• 69 Haimovici H. The ischemic forms of venous thrombosis. 1. Phlegmasia cerulea dolens. 2. Venous gangrene. J Cardiovasc Surg (Torino) 1965; 5 (06) 164-173
• 70 Haimovici H. Ischemic forms of venous thrombosis. Phlegmasia cerulea dolens. Venous gangrene. Springfield, IL: Charles C. Thomas;; 1971. . (230-page book)
• 71 Haimovici H, Suffness G. Gangrene of the extremities of venous origin; report of a case. Am J Med Sci 1948; 215 (03) 278-281
• 72 Harvison PJ. Dicumarol. xPharm: The Comprehensive Pharmacology Reference. Elsevier; 2007: 1-4
• 73 Warkentin TE. Heparin-induced thrombocytopenia-associated thrombosis: from arterial to venous to venous limb gangrene. J Thromb Haemost 2018; 16 (11) 2128-2132
• 74 Towne JB, Bernhard VM, Hussey C, Garancis JC. White clot syndrome. Peripheral vascular complications of heparin therapy. Arch Surg 1979; 114 (04) 372-377
• 75 Srinivasan AF, Rice L, Bartholomew JR. et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164 (01) 66-70
• 76 Grim Hostetler S, Sopkovich J, Dean S, Zirwas M. Warfarin-induced venous limb gangrene. J Clin Aesthet Dermatol 2012; 5 (11) 38-42
• 77 Cuker A, Arepally GM, Chong BH. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018; 2 (22) 3360-3392
• 78 Warkentin TE. Venous limb gangrene during warfarin treatment of cancer-associated deep venous thrombosis. Ann Intern Med 2001; 135 (8 Pt 1) 589-593
• 79 Ng HJ, Crowther MA. Malignancy-associated venous thrombosis with concurrent warfarin-induced skin necrosis, venous limb gangrene and thrombotic microangiopathy. Thromb Haemost 2006; 95 (06) 1038-1039
• 80 Klein L, Galvez A, Klein O, Chediak J. Warfarin-induced limb gangrene in the setting of lung adenocarcinoma. Am J Hematol 2004; 76 (02) 176-179
• 81 Haimovici H, Bergan JJ. Coumadin-induced skin necrosis versus venous gangrene of the extremities. J Vasc Surg 1987; 5 (04) 655-656
• 82 Abrahams DG. Incipient symmetrical peripheral gangrene complicating paroxysmal tachycardia. Br Heart J 1948; 10 (03) 191-194
• 83 Tölle KH. Symmetrical gangrene complicating cardiac defect. [ in German]. Frankf Z Pathol 1953; 64 (01) 120-132
• 84 Swan WGA, Henderson CB. Peripheral gangrene in myocardial infarction. Br Heart J 1951; 13 (01) 68-73
• 85 Bird T, Leithead CS, Lowe KG. Symmetrical peripheral gangrene in low-output heart-failure. Lancet 1954; 264 (6842) 780-782
• 86 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
• 87 Selzer A. The hypotensive state following acute myocardial infarction. I. Clinical observations. Am Heart J 1952; 44 (01) 1-11
• 88 Guest Jr JL, Hall DP, Ellison RG. Symmetrical gangrene following insertion of a ball-valve mitral prosthesis in a patient with giant left atrium. A case report. J Thorac Cardiovasc Surg 1965; 49 (04) 550-556
• 89 MacAdam HG. Purpura hemorrhagica fulminans. Arch Pediatr 1903; 20 (12) 943
• 90 Storstein O. Incipient symmetrical peripheral gangrene complicating pneumonia. Br Heart J 1951; 13 (03) 411-414
• 91 Bettigole RE. Symmetric peripheral gangrene in pneumococcal sepsis. Ann Intern Med 1961; 54 (02) 335-342
• 92 Rahal Jr JJ, MacMahon HE, Weinstein L. Thrombocytopenia and symmetrical peripheral gangrene associated with staphylococcal and streptococcal bacteremia. Ann Intern Med 1968; 69 (01) 35-43
• 93 Stossel TP, Levy R. Intravascular coagulation associated with pneumococcal bacteremia and symmetrical peripheral gangrene. Arch Intern Med 1970; 125 (05) 876-878
• 94 Goodwin JN, Berne TV. Symmetrical peripheral gangrene. Arch Surg 1974; 108 (06) 780-784
• 95 Tripodi A, Primignani M, Chantarangkul V. et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009; 137 (06) 2105-2111
• 96 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
• 97 Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf 2014; 13 (01) 25-43
• 98 Warkentin TE. Ischemic limb gangrene with pulses. N Engl J Med 2015; 373 (24) 2386-2388
• 99 Warkentin TE. Microvascular thrombosis and ischaemic limb losses in critically ill patients. Hamostaseologie 2019; 39 (01) 6-19
• 100 Warkentin TE. Heparin-induced thrombocytopenia (and autoimmune heparin-induced thrombocytopenia): an illustrious review. Res Pract Thromb Haemost 2023; 7 (08) 102245
• 101 Baskaran J, Lopez RA, Cassagnol M. Prothrombin complex concentrate. StatPearls; 2022
• 102 Product Monograph. Beriplex® P/N 500 / Beriplex® P/N 1000. CSL Behring Canada, Inc. 2019 . Accessed March 26, 2024 at: https://labeling.cslbehring.ca/PM/CA/Beriplex-PN/EN/Beriplex-PN-Product-Monograph.pdf
• 103 Product Monograph. octaplex®; Octapharma Canada, Inc. 2017 . Accessed March 26, 2024 at: https://pdf.hres.ca/dpd_pm/00041970.PDF
• 104 Bendapudi PK, Whalen MJ, Lahoud-Rahme M, Villalba JA. Case 7–2021: a 19-year-old man with shock, multiple organ failure, and rash. N Engl J Med 2021; 384 (10) 953-963
• 105 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