Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis: reply

Abstract

We thank Wada and colleagues for commenting on our ‘Forum’ article 1.Warkentin T.E. Pai M. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?.J Thromb Hemost. 2016; 14: 231-5Crossref PubMed Scopus (19) Google Scholar which focused on the pathophysiology of microvascular thrombosis associated with acute disseminated intravascular coagulation (DIC), particularly the subset of patients with critical illness complicated by symmetrical peripheral gangrene (SPG), a distinct syndrome of acral (distal extremity) limb ischemic necrosis despite palpable (or Doppler‐identifiable) arterial pulses 2.Warkentin T.E. Ischemic limb gangrene with pulses.N Engl J Med. 2015; 373: 642-55Crossref PubMed Scopus (61) Google Scholar. In most patients with clinically‐suspected DIC and organ dysfunction, it is difficult to ascertain whether microthrombosis is occurring 3.Wada H. Matsumoto T. Yamashita Y. Hatada T. Disseminated intravascular coagulation: testing and diagnosis.Clin Chim Acta. 2014; 436: 130-4Crossref PubMed Scopus (59) Google Scholar. However, SPG (as well as retiform purpura 4.Lipsker D. Ischemic limb gangrene with pulses (correspondence).N Engl J Med. 2015; 373: 2385-6Crossref Scopus (14) Google Scholar, 5.Warkentin T.E. Ischemic limb gangrene with pulses (correspondence).N Engl J Med. 2015; 373: 2386-8Crossref PubMed Scopus (61) Google Scholar) can be regarded as a cutaneous marker of dermal microthrombosis in DIC 2.Warkentin T.E. Ischemic limb gangrene with pulses.N Engl J Med. 2015; 373: 642-55Crossref PubMed Scopus (61) Google Scholar, 6.Molos M.A. Hall J.C. Symmetrical peripheral gangrene and disseminated intravascular coagulation.Arch Dermatol. 1985; 121: 1057-61Crossref PubMed Scopus (98) Google Scholar. In our paper, we outlined recent observations indicating frequent occurrence of SPG with preceding ‘shock liver’ (also known as ‘acute ischemic hepatitis’, ‘acute hepatic necrosis’ and ‘hypoxic hepatitis’) 7.Warkentin T.E. Heparin‐induced thrombocytopenia in critically ill patients.Semin Thromb Hemost. 2015; 41: 49-60Crossref PubMed Scopus (80) Google Scholar. We also discussed the relevance and importance of acquired severe depletion of the natural anticoagulants, protein C (PC) and antithrombin (AT), and how shock liver could predispose to severely reduced PC and AT levels, concepts supported by the profoundly reduced PC and AT levels observed in patients with acute DIC, shock liver and SPG 2.Warkentin T.E. Ischemic limb gangrene with pulses.N Engl J Med. 2015; 373: 642-55Crossref PubMed Scopus (61) Google Scholar, 8.Siegal D.M. Cook R.J. Warkentin T.E. Acute hepatic necrosis and ischemic limb necrosis.N Engl J Med. 2012; 367: 879-81Crossref PubMed Scopus (19) Google Scholar. In our view, shock liver in the setting of acute DIC represents a plausible explanation for acquired severe depletion of PC and AT, much the same as how warfarin is now recognized as a crucial factor in explaining microthrombosis due to depletion of (vitamin K dependent) PC in the setting of DIC states such as HIT and metastatic adenocarcinoma 9.Warkentin T.E. Elavathil L.J. Hayward C.P.M. Johnston M.A. Russett J.I. Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin‐induced thrombocytopenia.Ann Intern Med. 1997; 127: 804-12Crossref PubMed Scopus (427) Google Scholar, 10.Warkentin T.E. Cook R.J. Sarode R. Sloane D.A. Crowther M.A. Warfarin‐induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome.Blood. 2015; 126: 486-93Crossref PubMed Scopus (32) Google Scholar. Indeed, we referred to shock liver as a ‘coumarin equivalent’ 1.Warkentin T.E. Pai M. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?.J Thromb Hemost. 2016; 14: 231-5Crossref PubMed Scopus (19) Google Scholar, given the striking observation that both coumarin‐induced microthrombosis and SPG complicating DIC and shock liver feature onset of ischemic limb necrosis beginning usually between 2 and 5 days after initiation of coumarin or onset of shock liver, respectively, reflecting the time needed for critical reduction of PC (and AT3, in the setting of shock liver) to occur. Wada et al. list a variety of interesting issues, such as progression of microthrombosis to macrothrombosis, as well as the roles of hypofibrinolysis, vascular endothelial cell injury, decreased blood flow secondary to bed rest or vascular spasm, platelet activation in the setting of decreased ADAMTS‐13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), and congenital hypercoagulable states. We would like to comment on each of these concepts. Progression from micro‐ to macrothrombosis, and vice versa, can be observed in patients with limb ischemic necrosis caused by microthrombosis. Sometimes, the sequence is clearly initiated by macrothrombosis, for example, when a patient with HIT‐ or cancer‐associated DVT develops subsequent microthrombosis and venous limb gangrene complicating warfarin use 9.Warkentin T.E. Elavathil L.J. Hayward C.P.M. Johnston M.A. Russett J.I. Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin‐induced thrombocytopenia.Ann Intern Med. 1997; 127: 804-12Crossref PubMed Scopus (427) Google Scholar, 10.Warkentin T.E. Cook R.J. Sarode R. Sloane D.A. Crowther M.A. Warfarin‐induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome.Blood. 2015; 126: 486-93Crossref PubMed Scopus (32) Google Scholar. However, we have seen patients who initially evince bilateral lower‐ and/or upper‐limb ischemia with palpable pulses, but then the pulses are subsequently lost, sometimes permanently. This occurs presumably as a consequence of thrombotic progression from smaller vessels in a retrograde fashion into larger, more proximal, vessels. Wada and colleagues point out that early diagnosis and treatment of microvascular thrombosis could prevent major (macrovascular) thrombosis; although this is likely to be true, it is important to note that acral microthrombosis itself is sufficient to explain limb loss 2.Warkentin T.E. Ischemic limb gangrene with pulses.N Engl J Med. 2015; 373: 642-55Crossref PubMed Scopus (61) Google Scholar. Disseminated intravascular coagulation is often associated with reactive (secondary) hyperfibrinolysis. However, as Wada and coworkers note, sepsis can lead to increased plasminogen activator inhibitor‐1 (PAI‐1) levels 3.Wada H. Matsumoto T. Yamashita Y. Hatada T. Disseminated intravascular coagulation: testing and diagnosis.Clin Chim Acta. 2014; 436: 130-4Crossref PubMed Scopus (59) Google Scholar, 11.Gando S. Levi M. Toh C.H. Disseminated intravascular coagulation.Nat Rev Dis Primers. 2016; 2: 16037Crossref PubMed Scopus (276) Google Scholar, which could result in microthrombosis in DIC. In our experience, many patients with SPG have cardiogenic shock as a trigger of both DIC and acute shock liver (perhaps reflecting the combined roles of hypotension and right heart dysfunction, with increased right‐sided pressures, predisposing to hepatic ischemia 12.Henrion J. Hypoxic hepatitis.Liver Int. 2012; 32: 1039-52Crossref PubMed Scopus (139) Google Scholar). This raises the issue of whether elevated PAI‐1 and hypofibrinolysis also occur in cardiogenic shock. Dysregulated hypercoagulability could also reflect vascular endothelial cell injury, as can occur in sepsis, including down‐regulation of thrombomodulin (with resulting impaired activation of PC) 13.Faust S.N. Levin M. Harrison O.B. Goldin R.D. Lockhart M.S. Kondaveeti S. Laszik Z. Esmon C.T. Heyderman R.S. Dysfunction of endothelial protein C activation in severe meningococcal sepsis.N Engl J Med. 2001; 345: 408-16Crossref PubMed Scopus (593) Google Scholar and reduction of glycosaminoglycan availability (with resulting impaired AT anticoagulant activity at endothelial surfaces) 14.Henrich M. Gruss M. Weigand M.A. Sepsis‐induced degradation of endothelial glycocalix.ScientificWorldJournal. 2010; 10: 917-23Crossref PubMed Scopus (75) Google Scholar: do these endothelial abnormalities occur too in cardiogenic shock? Studying hemostatic markers in various settings of DIC with SPG could reveal the common key elements. Wada et al. also comment upon decreased blood flow secondary to bed rest and vasospasm as predisposing to macrovascular thrombosis involving larger veins and arteries, respectively. Of course, critically ill patients with acute DIC and shock liver are all bedridden, yet radiologically detectable DVT is seen in only a minority of patients who develop SPG 7.Warkentin T.E. Heparin‐induced thrombocytopenia in critically ill patients.Semin Thromb Hemost. 2015; 41: 49-60Crossref PubMed Scopus (80) Google Scholar. The majority of such patients are hypotensive (triggering physiological vasospasm) and receiving vasopressors (triggering pharmacological vasoconstriction), yet the majority do not develop gangrene. Indeed, we believe it is a ‘myth’ that vasopressors represent a fundamental explanation for SPG 1.Warkentin T.E. Pai M. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?.J Thromb Hemost. 2016; 14: 231-5Crossref PubMed Scopus (19) Google Scholar: although case reports 15.Hayes M.A. Yau E.H.S. Hinds C.J. Watson J.D. Symmetrical peripheral gangrene: association with noradrenaline administration.Intensive Care Med. 1992; 18: 433-6Crossref PubMed Scopus (81) Google Scholar, 16.Colak T. Erdogan O. Yerebakan O. Arici C. Gurkan A. Symmetrical peripheral gangrene and dopamine.Ulus Travma Acil Cerrahi Derg. 2003; 9: 222-4Google Scholar have suggested such a role for vasopressors, these papers have generally not provided sufficient data on hemostatic and chemistry markers, so the roles of acute DIC with ‘hypercoagulation’ and of concomitant shock liver were not considered. We posit that acute DIC with shock liver is a far more plausible explanation for SPG than the mere use of vasopressors. Wada et al. also draw attention to the issue of ADAMTS‐13 deficiency in the setting of sepsis. Studies 17.Aibar J. Castro P. Espinosa G. Fernández S. Hernández C. Rinaudo M. Butjosa M. Tàssies D. Reverter J.C. Nicolás J.M. ADAMTS‐13 in critically ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome.Shock. 2015; 43: 556-62Crossref PubMed Scopus (28) Google Scholar, 18.Peigne V. Azoulay E. Coquet I. Mariotte E. Darmon M. Legendre P. Adoui N. Marfaing‐Koka A. Wolf M. Schlemmer B. Veyradier A. The prognostic value of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) in septic shock patients involves interleukin‐6 and is not dependent on disseminated intravascular coagulation.Crit Care. 2013; 17: R273Crossref PubMed Scopus (48) Google Scholar have shown lower levels of ADAMTS‐13 in patients with severe sepsis or septic shock. In our experience, although ~ 90% of patients with SPG have preceding shock liver 7.Warkentin T.E. Heparin‐induced thrombocytopenia in critically ill patients.Semin Thromb Hemost. 2015; 41: 49-60Crossref PubMed Scopus (80) Google Scholar, the remaining minority have other notable features, including very severe thrombocytopenia (platelet count < 10 × 109 L−1). This suggests that special factors may be operative when very intense platelet activation and consumption is occurring. In this respect, studies of ADAMTS‐13 and other markers might be of relevance. In an analogous fashion, although ~ 90% of patients with HIT‐associated venous limb gangrene have concomitant warfarin therapy as a key pathophysiological determinant of microthrombosis, the remaining minority in whom warfarin cannot be implicated also tend to have exceptionally severe thrombocytopenia or other factors (such as inferior vena cava filter insertion) 7.Warkentin T.E. Heparin‐induced thrombocytopenia in critically ill patients.Semin Thromb Hemost. 2015; 41: 49-60Crossref PubMed Scopus (80) Google Scholar. As always, exceptions to the rule are worth studying for the insights they can reveal. Finally, Wada and coworkers suggest that genetic hypercoagulable states such as congenital AT or PC deficiency could play a role. Here, we have some insights from a study of HIT evaluating the role of factor V Leiden 19.Lee D.H. Warkentin T.E. Denomme G.A. Lagrotteria D.D. Kelton J.G. Factor V Leiden and thrombotic complications in heparin‐induced thrombocytopenia.Thromb Haemost. 1998; 79: 50-3Crossref PubMed Scopus (33) Google Scholar, where it was shown that this congenital hypercoagulable state does not contribute to the marked association between HIT and DVT 19.Lee D.H. Warkentin T.E. Denomme G.A. Lagrotteria D.D. Kelton J.G. Factor V Leiden and thrombotic complications in heparin‐induced thrombocytopenia.Thromb Haemost. 1998; 79: 50-3Crossref PubMed Scopus (33) Google Scholar. Further, congenital hypercoagulable states do not account for the subset of HIT patients who develop venous limb gangrene complicating warfarin therapy 9.Warkentin T.E. Elavathil L.J. Hayward C.P.M. Johnston M.A. Russett J.I. Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin‐induced thrombocytopenia.Ann Intern Med. 1997; 127: 804-12Crossref PubMed Scopus (427) Google Scholar. In other words, the marked procoagulant state of HIT itself explains its high risk of DVT 19.Lee D.H. Warkentin T.E. Denomme G.A. Lagrotteria D.D. Kelton J.G. Factor V Leiden and thrombotic complications in heparin‐induced thrombocytopenia.Thromb Haemost. 1998; 79: 50-3Crossref PubMed Scopus (33) Google Scholar, and the PC‐depleting effects of coumarin account for progression to microthrombosis 9.Warkentin T.E. Elavathil L.J. Hayward C.P.M. Johnston M.A. Russett J.I. Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin‐induced thrombocytopenia.Ann Intern Med. 1997; 127: 804-12Crossref PubMed Scopus (427) Google Scholar, without need for any congenital predisposition. Similarly, we suspect that the hypercoagulable state of acute DIC, together with acquired natural anticoagulant depletion from shock liver alone, is sufficient to create the ‘perfect storm’ underlying microthrombosis in SPG 1.Warkentin T.E. Pai M. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?.J Thromb Hemost. 2016; 14: 231-5Crossref PubMed Scopus (19) Google Scholar, without the need to invoke an additional heritable disorder such as congenital AT or PC deficiency (at least in most patients 20.Kondaveeti S. Hibberd M.L. 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: 893-6Crossref PubMed Scopus (83) Google Scholar). We thank Wada et al. for drawing attention to the various factors that may be operative in DIC‐associated microthrombosis, providing a roadmap for systematic evaluation of affected patients. After all, only when we understand better its pathophysiology through study of affected patients will we be able to identify potential treatments. Our current treatment approach to DIC‐associated microthrombosis (unfractionated heparin with anti‐factor Xa monitoring; AT concentrates; frozen plasma infusion to provide a ‘balance’ of procoagulant and anticoagulant factors 1.Warkentin T.E. Pai M. Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?.J Thromb Hemost. 2016; 14: 231-5Crossref PubMed Scopus (19) Google Scholar) is based upon our current understanding of this limb‐threatening disorder. T. E. Warkentin has received lecture honoraria from Pfizer Canada and Instrumentation Laboratory, has provided consulting services to, and/or has received research funding from, Aspen Global, W.L. Gore, Instrumentation Laboratory, and Medtronic Diabetes, and has provided expert witness testimony relating to thrombocytopenia, coagulopathy, or ischemic limb losses. M. Pai has received lecture honoraria from Bayer and has received advisory board honoraria from BMS/Pfizer and Bayer.