Microvascular Thrombosis: A Serious and Deadly Pathologic Process in Multiple Diseases

ABSTRACT

Much of our understanding of the pathogenesis of thrombosis has long been based on observations made on large blood vessels. Nevertheless, there has been a recent shift in our attention to the microvasculature and to how microcirculatory occlusion affects function of various organs in diseases. This article provides an overview of microthrombosis in small blood vessels, with discussion of the progressive stages of its development. The initial event is triggered by a variety of diseases, followed by a second phase when multiple contributory factors amplify the process with the final phase of microvascular occlusion and microvascular thrombosis. The outcome is either recovery or injury to the affected organ. If the process is generalized, it is often associated with catastrophic or fatal outcomes. Our current knowledge of the major role of contributory factors leads to a new paradigm. A therapeutic approach limited to a single target of the underlying pathogenic factor, such as the use of anticoagulants, is insufficient and too often unsuccessful. Simultaneous management of all the contributory factors should therefore be considered.

KEYWORDS

Thrombosis - disseminated intravascular coagulation - inflammation - hypercoagulable state - sepsis

REFERENCES

• 1 Aird W C. Spatial and temporal dynamics of the endothelium.  J Thromb Haemost. 2005;  3 (7) 1392-1406
• 2 Lipowsky H H. Microvascular rheology and hemodynamics.  Microcirculation. 2005;  12 (1) 5-15
• 3 Baskurt O K, Meiselman H J. Blood rheology and hemodynamics.  Semin Thromb Hemost. 2003;  29 (5) 435-450
• 4 Aird W C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.  Circ Res. 2007;  100 (2) 158-173
• 5 Aird W C. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.  Circ Res. 2007;  100 (2) 174-190
• 6 Pries A R, Kuebler W M. Normal endothelium.  Handb Exp Pharmacol. 2006;  176 (176 Pt 1) 1-40
• 7 Kwaan H C, Samama M M. The significance of endothelial heterogeneity in thrombosis and hemostasis.  Semin Thromb Hemost. 2010;  36 (3) 286-300
• 8 Ishii H, Salem H H, Bell C E, Laposata E A, Majerus P W. Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain.  Blood. 1986;  67 (2) 362-365
• 9 Esmon C T, Gu J M, Xu J, Qu D, Stearns-Kurosawa D J, Kurosawa S. Regulation and functions of the protein C anticoagulant pathway.  Haematologica. 1999;  84 (4) 363-368
• 10 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over.  Semin Thromb Hemost. 2008;  34 (8) 747-761
• 11 Lippi G, Franchini M, Favaloro E J. Unsuspected triggers of venous thromboembolism—trivial or not so trivial?.  Semin Thromb Hemost. 2009;  35 (7) 597-604
• 12 Virchow R. Phlogose und Thrombose in Gefabsystem. In: Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Germany: Von Meidinger Sohn; 1856: 458
• 13 Levi M, Schultz M, van der Poll T. Disseminated intravascular coagulation in infectious disease.  Semin Thromb Hemost. 2010;  36 (4) 367-377
• 14 Galindo M, Gonzalo E, Martinez-Vidal M P et al.. Immunohistochemical detection of intravascular platelet microthrombi in patients with lupus nephritis and anti-phospholipid antibodies.  Rheumatology (Oxford). 2009;  48 (8) 1003-1007
• 15 Nagy J A, Chang S H, Shih S C, Dvorak A M, Dvorak H F. Heterogeneity of the tumor vasculature.  Semin Thromb Hemost. 2010;  36 (3) 321-331
• 16 Rubin D B, Drab E A, Ward W F. Physiological and biochemical markers of the endothelial cell response to irradiation.  Int J Radiat Biol. 1991;  60 (1-2) 29-32
• 17 Kloner R A, Ganote C E, Jennings R B. The “no-reflow” phenomenon after temporary coronary occlusion in the dog.  J Clin Invest. 1974;  54 (6) 1496-1508
• 18 Brands M T, van den Bosch S C, Dieleman F J, Bergé S J, Merkx M A. Prevention of thrombosis after microvascular tissue transfer in the head and neck. A review of the literature and the state of affairs in Dutch Head and Neck Cancer Centers.  Int J Oral Maxillofac Surg. 2010;  39 (2) 101-106
• 19 Lecoq J P, Senard M, Hartstein G M, Lamy M, Heymans O. Thromboprophylaxis in microsurgery.  Acta Chir Belg. 2006;  106 (2) 158-164
• 20 Kwaan H C, Bongu A. The hyperviscosity syndromes.  Semin Thromb Hemost. 1999;  25 (2) 199-208
• 21 Esmon C T. The impact of the inflammatory response on coagulation.  Thromb Res. 2004;  114 (5-6) 321-327
• 22 Esmon C T. The interactions between inflammation and coagulation.  Br J Haematol. 2005;  131 (4) 417-430
• 23 Levi M. The coagulant response in sepsis and inflammation.  Hamostaseologie. 2010;  30 (1) 10-12, 14–16
• 24 Bevilacqua M P, Pober J S, Majeau G R, Fiers W, Cotran R S, Gimbrone Jr M A. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1.  Proc Natl Acad Sci U S A. 1986;  83 (12) 4533-4537
• 25 Coughlin S R. Thrombin signalling and protease-activated receptors.  Nature. 2000;  407 (6801) 258-264
• 26 Bevilacqua M P, Nelson R M. Endothelial-leukocyte adhesion molecules in inflammation and metastasis.  Thromb Haemost. 1993;  70 (1) 152-154
• 27 Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome.  Crit Care Med. 2010;  38 (2, Suppl) S35-S42
• 28 Lee C C, Marill K A, Carter W A, Crupi R S. A current concept of trauma-induced multiorgan failure.  Ann Emerg Med. 2001;  38 (2) 170-176
• 29 Hertig A, Rondeau E. Role of the coagulation/fibrinolysis system in fibrin-associated glomerular injury.  J Am Soc Nephrol. 2004;  15 (4) 844-853
• 30 Welty-Wolf K E, Carraway M S, Ortel T L, Piantadosi C A. Coagulation and inflammation in acute lung injury.  Thromb Haemost. 2002;  88 (1) 17-25
• 31 Dhainaut J F, Marin N, Mignon A, Vinsonneau C. Hepatic response to sepsis: interaction between coagulation and inflammatory processes.  Crit Care Med. 2001;  29 (7, Suppl) S42-S47
• 32 Papadopoulos M C, Davies D C, Moss R F, Tighe D, Bennett E D. Pathophysiology of septic encephalopathy: a review.  Crit Care Med. 2000;  28 (8) 3019-3024
• 33 Stegmayr B G. Apheresis as therapy for patients with severe sepsis and multiorgan dysfunction syndrome.  Ther Apher. 2001;  5 (2) 123-127
• 34 Levi M, Ten Cate H. Disseminated intravascular coagulation.  N Engl J Med. 1999;  341 (8) 586-592
• 35 ten Cate H, Timmerman J J, Levi M. The pathophysiology of disseminated intravascular coagulation.  Thromb Haemost. 1999;  82 (2) 713-717
• 36 Lippi G, Cervellin G. Disseminated intravascular coagulation in trauma injuries.  Semin Thromb Hemost. 2010;  36 (4) 378-387
• 37 Kojima M, Shimamura K, Mori N, Oka K, Nakazawa M. A histological study on microthrombi in autopsy cases of DIC.  Bibl Haematol. 1983;  (49) 95-106
• 38 Shimamura K, Oka K, Nakazawa M, Kojima M. Distribution patterns of microthrombi in disseminated intravascular coagulation.  Arch Pathol Lab Med. 1983;  107 (10) 543-547
• 39 Schouten M, Wiersinga W J, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis.  J Leukoc Biol. 2008;  83 (3) 536-545
• 40 Osterud B. Tissue factor expression by monocytes: regulation and pathophysiological roles.  Blood Coagul Fibrinolysis. 1998;  9 (Suppl 1) S9-S14
• 41 Meziani F, Delabranche X, Asfar P, Toti F. Bench-to-bedside review: circulating microparticles—a new player in sepsis?.  Crit Care. 2010;  14 (5) 236
• 42 Soriano A O, Jy W, Chirinos J A et al.. Levels of endothelial and platelet microparticles and their interactions with leukocytes negatively correlate with organ dysfunction and predict mortality in severe sepsis.  Crit Care Med. 2005;  33 (11) 2540-2546
• 43 McEver R P. GMP-140: a receptor for neutrophils and monocytes on activated platelets and endothelium.  J Cell Biochem. 1991;  45 (2) 156-161
• 44 Klintman D, Li X, Thorlacius H. Important role of P-selectin for leukocyte recruitment, hepatocellular injury, and apoptosis in endotoxemic mice.  Clin Diagn Lab Immunol. 2004;  11 (1) 56-62
• 45 Ward P A. Role of the complement in experimental sepsis.  J Leukoc Biol. 2008;  83 (3) 467-470
• 46 Laudes I J, Chu J C, Huber-Lang M et al.. Expression and function of C5a receptor in mouse microvascular endothelial cells.  J Immunol. 2002;  169 (10) 5962-5970
• 47 Esmon C T, Fukudome K, Mather T et al.. Inflammation, sepsis, and coagulation.  Haematologica. 1999;  84 (3) 254-259
• 48 Levi M, Lowenberg E, Meijers J C. Recombinant anticoagulant factors for adjunctive treatment of sepsis.  Semin Thromb Hemost. 2010;  36 (5) 550-557
• 49 Bernard G R, Vincent J L, Laterre P F Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group et al. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 (10) 699-709
• 50 Ely E W, Laterre P F, Angus D C PROWESS Investigators et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.  Crit Care Med. 2003;  31 (1) 12-19
• 51 Dhainaut J F, Yan S B, Joyce D E et al.. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.  J Thromb Haemost. 2004;  2 (11) 1924-1933
• 52 Abraham E, Laterre P F, Garg R Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.  N Engl J Med. 2005;  353 (13) 1332-1341
• 53 Levi M, Levy M, Williams M D Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated).  Am J Respir Crit Care Med. 2007;  176 (5) 483-490
• 54 Costa V, Brophy J M. Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis.  BMC Anesthesiol. 2007;  7 5
• 55 Barie P S. “All in” for a huge pot: the PROWESS-SHOCK trial for refractory septic shock.  Surg Infect (Larchmt). 2007;  8 (5) 491-494
• 56 Barie P S. Current role of activated protein C therapy for severe sepsis and septic shock.  Curr Infect Dis Rep. 2008;  10 (5) 368-376
• 57 Bernard G R, Margolis B D, Shanies H M Extended Evaluation of Recombinant Human Activated Protein C United States Investigators et al. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis.  Chest. 2004;  125 (6) 2206-2216
• 58 Leitner J M, Firbas C, Mayr F B, Reiter R A, Steinlechner B, Jilma B. Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia.  Clin Pharmacol Ther. 2006;  79 (1) 23-34
• 59 Warren B L, Eid A, Singer P KyberSept Trial Study Group et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.  JAMA. 2001;  286 (15) 1869-1878
• 60 Ott I, Miyagi Y, Miyazaki K et al.. Reversible regulation of tissue factor-induced coagulation by glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor.  Arterioscler Thromb Vasc Biol. 2000;  20 (3) 874-882
• 61 Brandtzaeg P, Sandset P M, Joø G B, Ovstebø R, Abildgaard U, Kierulf P. The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease.  Thromb Res. 1989;  55 (4) 459-470
• 62 Abraham E, Reinhart K, Opal S OPTIMIST Trial Study Group et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.  JAMA. 2003;  290 (2) 238-247
• 63 van der Poll T, Levi M, Büller H R et al.. Fibrinolytic response to tumor necrosis factor in healthy subjects.  J Exp Med. 1991;  174 (3) 729-732
• 64 Carmeliet P, Schoonjans L, Kieckens L et al.. Physiological consequences of loss of plasminogen activator gene function in mice.  Nature. 1994;  368 (6470) 419-424
• 65 Bajzar L, Jain N, Wang P, Walker J B. Thrombin activatable fibrinolysis inhibitor: not just an inhibitor of fibrinolysis.  Crit Care Med. 2004;  32 (5, Suppl) S320-S324
• 66 Leung L L, Nishimura T, Myles T. Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).  Adv Exp Med Biol. 2008;  632 61-69
• 67 Kwaan H C, Gordon L I. Thrombotic microangiopathy in the cancer patient.  Acta Haematol. 2001;  106 (1-2) 52-56
• 68 Elliott M A, Letendre L, Gastineau D A, Winters J L, Pruthi R K, Heit J A. Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration.  Eur J Haematol. 2010;  85 (1) 43-50
• 69 Zakarija A. Thrombotic microangiopathy syndromes.  Cancer Treat Res. 2009;  148 115-136
• 70 Gordon L I, Kwaan H C. Cancer- and drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.  Semin Hematol. 1997;  34 (2) 140-147
• 71 Kwaan H C, Boggio L N. The clinical spectrum of thrombotic thrombocytopenic purpura.  Semin Thromb Hemost. 2005;  31 (6) 673-680
• 72 Karpman D, Sartz L, Johnson S. Pathophysiology of typical hemolytic uremic syndrome.  Semin Thromb Hemost. 2010;  36 (6) 575-585
• 73 Baronzio G, Freitas I, Kwaan H C. Tumor microenvironment and hemorheological abnormalities.  Semin Thromb Hemost. 2003;  29 (5) 489-497
• 74 Brat D J, Van Meir E G. Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma.  Lab Invest. 2004;  84 (4) 397-405
• 75 Wang J, Weiss I, Svoboda K, Kwaan H C. Thrombogenic role of cells undergoing apoptosis.  Br J Haematol. 2001;  115 (2) 382-391
• 76 Rak J. Microparticles in cancer.  Semin Thromb Hemost. 2010;  36 (8) 888-906
• 77 Kwaan H C, Rego E M. Role of microparticles in the hemostatic dysfunction in acute promyelocytic leukemia.  Semin Thromb Hemost. 2010;  36 (8) 917-924
• 78 Key N S, Kwaan H C. Microparticles in thrombosis and hemostasis.  Semin Thromb Hemost. 2010;  36 (8) 805-806
• 79 Myhre-Jensen O, Hansen E S, Butrago B. Renal microthrombosis. Incidence in 500 consecutive autopsies. Clinico-pathological relations.  Acta Pathol Microbiol Scand [A]. 1972;  80 (3) 403-411
• 80 Shih H M, Lin C C, Shiao Y W. Pulmonary tumor thrombotic microangiopathy.  Am J Emerg Med. 2011;  29 (2) 241, e3-e4
• 81 Chinen K, Tokuda Y, Fujiwara M, Fujioka Y. Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: an analysis of 6 autopsy cases and review of the literature.  Pathol Res Pract. 2010;  206 (10) 682-689
• 82 Tehrani M, Friedman T M, Olson J J, Brat D J. Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma.  Brain Pathol. 2008;  18 (2) 164-171
• 83 Hallahan D, Clark E T, Kuchibhotla J, Gewertz B L, Collins T. E-selectin gene induction by ionizing radiation is independent of cytokine induction.  Biochem Biophys Res Commun. 1995;  217 (3) 784-795
• 84 Jahroudi N, Ardekani A M, Greenberger J S. Ionizing irradiation increases transcription of the von Willebrand factor gene in endothelial cells.  Blood. 1996;  88 (10) 3801-3814
• 85 Verheij M, Dewit L G, van Mourik J A. The effect of ionizing radiation on endothelial tissue factor activity and its cellular localization.  Thromb Haemost. 1995;  73 (5) 894-895
• 86 Hauer-Jensen M, Fink L M, Wang J. Radiation injury and the protein C pathway.  Crit Care Med. 2004;  32 (5, Suppl) S325-S330
• 87 Astedt B, Bergentz S E, Svanberg L. Effect of irradiation on the plasminogen activator content in rat vessels.  Experientia. 1974;  30 (12) 1466-1467
• 88 Dropcho E J. Neurotoxicity of radiation therapy.  Neurol Clin. 2010;  28 (1) 217-234
• 89 Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment.  Br J Oral Maxillofac Surg. 2008;  46 (8) 653-660
• 90 Madrid C, Abarca M, Bouferrache K. Osteoradionecrosis: an update.  Oral Oncol. 2010;  46 (6) 471-474
• 91 Kwaan H C. Miscellaneous secondary thrombotic microangiopathy.  Semin Hematol. 1987;  24 (3) 141-147
• 92 Kwaan H C. Thrombotic thrombocytopenic purpura: a diagnostic and therapeutic challenge.  Semin Thromb Hemost. 2005;  31 (6) 615-624
• 93 Mitra D, Jaffe E A, Weksler B, Hajjar K A, Soderland C, Laurence J. Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells.  Blood. 1997;  89 (4) 1224-1234
• 94 Laurence J, Mitra D. Apoptosis of microvascular endothelial cells in the pathophysiology of thrombotic thrombocytopenic purpura/sporadic hemolytic uremic syndrome.  Semin Hematol. 1997;  34 (2) 98-105
• 95 Zipfel P F, Heinen S, Skerka C. Thrombotic microangiopathies: new insights and new challenges.  Curr Opin Nephrol Hypertens. 2010;  19 (4) 372-378
• 96 Louise C B, Obrig T G. Shiga toxin-associated hemolytic-uremic syndrome: combined cytotoxic effects of Shiga toxin, interleukin-1 beta, and tumor necrosis factor alpha on human vascular endothelial cells in vitro.  Infect Immun. 1991;  59 (11) 4173-4179
• 97 Louise C B, Obrig T G. Human renal microvascular endothelial cells as a potential target in the development of the hemolytic uremic syndrome as related to fibrinolysis factor expression, in vitro.  Microvasc Res. 1994;  47 (3) 377-387
• 98 Dragon-Durey M A, Sethi S K, Bagga A et al.. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome.  J Am Soc Nephrol. 2010;  21 (12) 2180-2187
• 99 Le Quintrec M, Roumenina L, Noris M, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome associated with mutations in complement regulator genes.  Semin Thromb Hemost. 2010;  36 (6) 641-652
• 100 Heinen S, Hartmann A, Lauer N et al.. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation.  Blood. 2009;  114 (12) 2439-2447
• 101 Kwaan H C. Miscellaneous secondary thrombotic microangiopathy.  Semin Hematol. 1987;  24 (3) 141-147
• 102 Kelton J G, Warkentin T E. Heparin-induced thrombocytopenia: a historical perspective.  Blood. 2008;  112 (7) 2607-2616
• 103 Kwaan H C, Sakurai S. Endothelial cell hyperplasia contributes to thrombosis in heparin-induced thrombocytopenia.  Semin Thromb Hemost. 1999;  25 (Suppl 1) 23-27
• 104 Baskurt O K, Meiselman H J. Blood rheology and hemodynamics.  Semin Thromb Hemost. 2003;  29 (5) 435-450
• 105 Kwaan H C, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities.  Semin Thromb Hemost. 2003;  29 (5) 451-458
• 106 Newton C R, Marsh K, Peshu N, Kirkham F J. Perturbations of cerebral hemodynamics in Kenyans with cerebral malaria.  Pediatr Neurol. 1996;  15 (1) 41-49
• 107 Beare N A, Harding S P, Taylor T E, Lewallen S, Molyneux M E. Perfusion abnormalities in children with cerebral malaria and malarial retinopathy.  J Infect Dis. 2009;  199 (2) 263-271
• 108 Buffet P A, Safeukui I, Deplaine G et al.. The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology.  Blood. 2011;  117 (2) 381-392
• 109 Grau G E, Mackenzie C D, Carr R A et al.. Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria.  J Infect Dis. 2003;  187 (3) 461-466
• 110 Cox D, McConkey S. The role of platelets in the pathogenesis of cerebral malaria.  Cell Mol Life Sci. 2010;  67 (4) 557-568
• 111 Baruch D I, Gormely J A, Ma C, Howard R J, Pasloske B L. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1.  Proc Natl Acad Sci U S A. 1996;  93 (8) 3497-3502
• 112 Chakravorty S J, Hughes K R, Craig A G. Host response to cytoadherence in Plasmodium falciparum.  Biochem Soc Trans. 2008;  36 (Pt 2) 221-228
• 113 García F, Cebrián M, Dgedge M et al.. Endothelial cell activation in muscle biopsy samples is related to clinical severity in human cerebral malaria.  J Infect Dis. 1999;  179 (2) 475-483
• 114 Francischetti I M, Seydel K B, Monteiro R Q et al.. Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes.  J Thromb Haemost. 2007;  5 (1) 155-165
• 115 Francischetti I M, Seydel K B, Monteiro R Q. Blood coagulation, inflammation, and malaria.  Microcirculation. 2008;  15 (2) 81-107
• 116 Combes V, Taylor T E, Juhan-Vague I et al.. Circulating endothelial microparticles in malawian children with severe falciparum malaria complicated with coma.  JAMA. 2004;  291 (21) 2542-2544
• 117 Milner Jr D A. Rethinking cerebral malaria pathology.  Curr Opin Infect Dis. 2010;  23 (5) 456-463
• 118 Kato G J, Hebbel R P, Steinberg M H, Gladwin M T. Vasculopathy in sickle cell disease: biology, pathophysiology, genetics, translational medicine, and new research directions.  Am J Hematol. 2009;  84 (9) 618-625
• 119 Morris C R. Mechanisms of vasculopathy in sickle cell disease and thalassemia.  Hematology (Am Soc Hematol Educ Program). 2008;  177-185
• 120 Morris C R, Kato G J, Poljakovic M et al.. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease.  JAMA. 2005;  294 (1) 81-90
• 121 Francis Jr R B. Platelets, coagulation, and fibrinolysis in sickle cell disease: their possible role in vascular occlusion.  Blood Coagul Fibrinolysis. 1991;  2 (2) 341-353
• 122 Peters M, Plaat B E, ten Cate H, Wolters H J, Weening R S, Brandjes D P. Enhanced thrombin generation in children with sickle cell disease.  Thromb Haemost. 1994;  71 (2) 169-172
• 123 Key N S, Slungaard A, Dandelet L et al.. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease.  Blood. 1998;  91 (11) 4216-4223
• 124 Kurantsin-Mills J, Ofosu F A, Safa T K, Siegel R S, Lessin L S. Plasma factor VII and thrombin-antithrombin III levels indicate increased tissue factor activity in sickle cell patients.  Br J Haematol. 1992;  81 (4) 539-544
• 125 Nsiri B, Gritli N, Bayoudh F, Messaoud T, Fattoum S, Machghoul S. Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease.  Hematol Cell Ther. 1996;  38 (3) 279-284
• 126 Kurantsin-Mills J, Ibe B O, Natta C L, Raj J U, Siegel R S, Lessin L S. Elevated urinary levels of thromboxane and prostacyclin metabolities in sickle cell disease reflects activated platelets in the circulation.  Br J Haematol. 1994;  87 (3) 580-585
• 127 Ataga K I, Orringer E P. Hypercoagulability in sickle cell disease: a curious paradox.  Am J Med. 2003;  115 (9) 721-728
• 128 Gladwin M T, Kato G J. Hemolysis-associated hypercoagulability in sickle cell disease: the plot (and blood) thickens!.  Haematologica. 2008;  93 (1) 1-3
• 129 Gladwin M T, Vichinsky E. Pulmonary complications of sickle cell disease.  N Engl J Med. 2008;  359 (21) 2254-2265
• 130 Bunn H F, Nathan D G, Dover G J et al.. Pulmonary hypertension and nitric oxide depletion in sickle cell disease.  Blood. 2010;  116 (5) 687-692
• 131 Gordeuk V R, Campbell A, Rana S et al.. Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease.  Blood. 2009;  114 (21) 4639-4644
• 132 Machado R F, Martyr S, Kato G J et al.. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension.  Br J Haematol. 2005;  130 (3) 445-453
• 133 Rose V L, Kwaan H C. Anti-Pr cold hemagglutination associated with livedo reticularis.  Am J Hematol. 1985;  19 (4) 419-421
• 134 Ruch J, McMahon B, Ramsey G, Kwaan H C. Catastrophic multiple organ ischemia due to an anti-Pr cold agglutinin developing in a patient with mixed cryoglobulinemia after treatment with rituximab.  Am J Hematol. 2009;  84 (2) 120-122
• 135 Blum W, Porcu P. Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome.  Semin Thromb Hemost. 2007;  33 (4) 350-354
• 136 Porcu P, Danielson C F, Orazi A, Heerema N A, Gabig T G, McCarthy L J. Therapeutic leukapheresis in hyperleucocytic leukaemias: lack of correlation between degree of cytoreduction and early mortality rate.  Br J Haematol. 1997;  98 (2) 433-436
• 137 Vaughan W P, Kimball A W, Karp J E, Dragon L H, Burke P J. Factors affecting survival of patients with acute myelocytic leukemia presenting with high wbc counts.  Cancer Treat Rep. 1981;  65 (11-12) 1007-1013
• 138 Creutzig U, Ritter J, Budde M, Sutor A, Schellong G. Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia. Associations with hyperleukocytosis and acute monocytic leukemia.  Cancer. 1987;  60 (12) 3071-3079
• 139 Cuttner J, Conjalka M S, Reilly M et al.. Association of monocytic leukemia in patients with extreme leukocytosis.  Am J Med. 1980;  69 (4) 555-558
• 140 Scott C S, Stark A N, Limbert H J, Master P S, Head C, Roberts B E. Diagnostic and prognostic factors in acute monocytic leukaemia: an analysis of 51 cases.  Br J Haematol. 1988;  69 (2) 247-252
• 141 Biondi A, Cimino G, Pieters R, Pui C H. Biological and therapeutic aspects of infant leukemia.  Blood. 2000;  96 (1) 24-33
• 142 Stucki A, Rivier A S, Gikic M, Monai N, Schapira M, Spertini O. Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination.  Blood. 2001;  97 (7) 2121-2129
• 143 An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators.  N Engl J Med. 1993;  329 (10) 673-682
• 144 Beek A M, Nijveldt R, van Rossum A C. Intramyocardial hemorrhage and microvascular obstruction after primary percutaneous coronary intervention.  Int J Cardiovasc Imaging. 2010;  26 (1) 49-55
• 145 Patel B, Fisher M. Therapeutic advances in myocardial microvascular resistance: unravelling the enigma.  Pharmacol Ther. 2010;  127 (2) 131-147
• 146 Bhavsar J, Rosenson R S. Adenosine transport, erythrocyte deformability and microvascular dysfunction: an unrecognized potential role for dipyridamole therapy.  Clin Hemorheol Microcirc. 2010;  44 (3) 193-205
• 147 Bekkers S C, Yazdani S K, Virmani R, Waltenberger J. Microvascular obstruction: underlying pathophysiology and clinical diagnosis.  J Am Coll Cardiol. 2010;  55 (16) 1649-1660
• 148 Buja L M. Myocardial ischemia and reperfusion injury.  Cardiovasc Pathol. 2005;  14 (4) 170-175
• 149 Khouri R K. Free flap surgery. The second decade.  Clin Plast Surg. 1992;  19 (4) 757-761
• 150 Ashjian P, Chen C M, Pusic A, Disa J J, Cordeiro P G, Mehrara B J. The effect of postoperative anticoagulation on microvascular thrombosis.  Ann Plast Surg. 2007;  59 (1) 36-39, discussion 39–40
• 151 Radomski M W, Palmer R M, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium.  Lancet. 1987;  2 (8567) 1057-1058
• 152 Azizzadeh B, Buga G M, Berke G S, Larian B, Ignarro L J, Blackwell K E. Inhibitors of nitric oxide promote microvascular thrombosis.  Arch Facial Plast Surg. 2003;  5 (1) 31-35
• 153 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 (2) 295-306
• 154 Cervera R, Piette J C, Font J Euro-Phospholipid Project Group et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.  Arthritis Rheum. 2002;  46 (4) 1019-1027
• 155 Espinosa G, Cervera R. Antiphospholipid syndrome: frequency, main causes and risk factors of mortality.  Nat Rev Rheumatol. 2010;  6 (5) 296-300
• 156 Mehdi A A, Salti I, Uthman I. Antiphospholipid syndrome: endocrinologic manifestations and organ involvement.  Semin Thromb Hemost. 2011;  37 (1) 49-57
• 157 Cervera R, Asherton R A. Catastrophic antiphospholipid syndrome.  Pathophysiol Haemost Thromb. 2006;  35 (1-2) 181-186
• 158 Asherson R A, Cervera R, Piette J C et al.. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients.  Medicine (Baltimore). 1998;  77 (3) 195-207
• 159 Asherson R A, Cervera R, Piette J C et al.. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients.  Medicine (Baltimore). 2001;  80 (6) 355-377
• 160 Cervera R, Khamashta M A, Shoenfeld Y Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies) et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients.  Ann Rheum Dis. 2009;  68 (9) 1428-1432
• 161 Bucciarelli S, Erkan D, Espinosa G, Cervera R. Catastrophic antiphospholipid syndrome: treatment, prognosis, and the risk of relapse.  Clin Rev Allergy Immunol. 2009;  36 (2-3) 80-84
• 162 Stein S C, Smith D H. Coagulopathy in traumatic brain injury.  Neurocrit Care. 2004;  1 (4) 479-488
• 163 Astrup T. Assay and content of tissue thromboplastin in different organs.  Thromb Diath Haemorrh. 1965;  14 (3-4) 401-416
• 164 Goodnight S H, Kenoyer G, Rapaport S I, Patch M J, Lee J A, Kurze T. Defibrination after brain-tissue destruction: A serious complication of head injury.  N Engl J Med. 1974;  290 (19) 1043-1047
• 165 Jacoby R C, Owings J T, Holmes J, Battistella F D, Gosselin R C, Paglieroni T G. Platelet activation and function after trauma.  J Trauma. 2001;  51 (4) 639-647
• 166 Nekludov M, Antovic J, Bredbacka S, Blombäck M. Coagulation abnormalities associated with severe isolated traumatic brain injury: cerebral arterio-venous differences in coagulation and inflammatory markers.  J Neurotrauma. 2007;  24 (1) 174-180
• 167 Dietrich W D. Morphological manifestations of reperfusion injury in brain.  Ann N Y Acad Sci. 1994;  723 15-24
• 168 Dietrich W D, Alonso O, Halley M. Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats.  J Neurotrauma. 1994;  11 (3) 289-301
• 169 Maeda T, Katayama Y, Kawamata T, Aoyama N, Mori T. Hemodynamic depression and microthrombosis in the peripheral areas of cortical contusion in the rat: role of platelet activating factor.  Acta Neurochir Suppl (Wien). 1997;  70 102-105
• 170 Stein S C, Graham D I, Chen X H, Smith D H. Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury.  Neurosurgery. 2004;  54 (3) 687-691, discussion 691
• 171 Kaufman H H, Hui K S, Mattson J C et al.. Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury.  Neurosurgery. 1984;  15 (1) 34-42
• 172 Kushimoto S, Yamamoto Y, Shibata Y, Sato H, Koido Y. Implications of excessive fibrinolysis and alpha(2)-plasmin inhibitor deficiency in patients with severe head injury.  Neurosurgery. 2001;  49 (5) 1084-1089, discussion 1089–1090
• 173 Grenander A, Bredbacka S, Rydvall A et al.. Antithrombin treatment in patients with traumatic brain injury: a pilot study.  J Neurosurg Anesthesiol. 2001;  13 (1) 49-56
• 174 Wahl F, Grosjean-Piot O, Bareyre F, Uzan A, Stutzmann J M. Enoxaparin reduces brain edema, cerebral lesions, and improves motor and cognitive impairments induced by a traumatic brain injury in rats.  J Neurotrauma. 2000;  17 (11) 1055-1065
• 175 Dudley R R, Aziz I, Bonnici A et al.. Early venous thromboembolic event prophylaxis in traumatic brain injury with low-molecular-weight heparin: risks and benefits.  J Neurotrauma. 2010;  27 (12) 2165-2172
• 176 Roos Y B, de Haan R J, Beenen L F, Groen R J, Albrecht K W, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands.  J Neurol Neurosurg Psychiatry. 2000;  68 (3) 337-341
• 177 Vergouwen M D, Vermeulen M, Coert B A, Stroes E S, Roos Y B. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia.  J Cereb Blood Flow Metab. 2008;  28 (11) 1761-1770
• 178 Romano J G, Forteza A M, Concha M et al.. Detection of microemboli by transcranial Doppler ultrasonography in aneurysmal subarachnoid hemorrhage.  Neurosurgery. 2002;  50 (5) 1026-1030, discussion 1030–1031
• 179 Giller C A, Giller A M, Landreneau F. Detection of emboli after surgery for intracerebral aneurysms.  Neurosurgery. 1998;  42 (3) 490-493, discussion 493–494
• 180 Crompton M R. The pathogenesis of cerebral infarction following the rupture of cerebral berry aneurysms.  Brain. 1964;  87 491-510
• 181 Stein S C, Browne K D, Chen X H, Smith D H, Graham D I. Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study.  Neurosurgery. 2006;  59 (4) 781-787, discussion 787–788
• 182 Wurm G, Tomancok B, Nussbaumer K, Adelwöhrer C, Holl K. Reduction of ischemic sequelae following spontaneous subarachnoid hemorrhage: a double-blind, randomized comparison of enoxaparin versus placebo.  Clin Neurol Neurosurg. 2004;  106 (2) 97-103
• 183 Roos Y. STAR Study Group . Antifibrinolytic treatment in subarachnoid hemorrhage: a randomized placebo-controlled trial.  Neurology. 2000;  54 (1) 77-82
• 184 Chwajol M, Starke R M, Kim G H, Mayer S A, Connolly E S. Antifibrinolytic therapy to prevent early rebleeding after subarachnoid hemorrhage.  Neurocrit Care. 2008;  8 (3) 418-426
• 185 Starke R M, Kim G H, Fernandez A et al.. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage.  Stroke. 2008;  39 (9) 2617-2621
• 186 Pabinger I, Karnik R, Lechner K, Slany J, Niessner H. Coumarin induced acral skin necrosis associated with hereditary protein C deficiency.  Blut. 1986;  52 (6) 365-370
• 187 McGehee W G, Klotz T A, Epstein D J, Rapaport S I. Coumarin necrosis associated with hereditary protein C deficiency.  Ann Intern Med. 1984;  101 (1) 59-60
• 188 Rose V L, Kwaan H C, Williamson K, Hoppensteadt D, Walenga J, Fareed J. Protein C antigen deficiency and warfarin necrosis.  Am J Clin Pathol. 1986;  86 (5) 653-655
• 189 Sallah S, Abdallah J M, Gagnon G A. Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency.  Haemostasis. 1998;  28 (1) 25-30
• 190 Dahlbäck B. New molecular insights into the genetics of thrombophilia. Resistance to activated protein C caused by Arg506 to Gln mutation in factor V as a pathogenic risk factor for venous thrombosis.  Thromb Haemost. 1995;  74 (1) 139-148
• 191 Kiehl R, Hellstern P, Wenzel E. Hereditary antithrombin III (AT III) deficiency and atypical localization of a coumarin necrosis.  Thromb Res. 1987;  45 (2) 191-193
• 192 Fluri S, Kaczala G W, Leibundgut K, Alberio L. Chickenpox is not always benign: postvaricella purpura fulminans requires prompt and aggressive treatment.  Pediatr Emerg Care. 2010;  26 (12) 932-934
• 193 Sharma V K, Dubey T N, Dave L, Agarwal A. Postvaricella purpura fulminans with no evidence of disseminated intravascular coagulation (DIC) or protein S deficiency.  J Indian Med Assoc. 2010;  108 (8) 529-530
• 194 Francis Jr R B. Acquired purpura fulminans.  Semin Thromb Hemost. 1990;  16 (4) 310-325
• 195 Josephson C, Nuss R, Jacobson L et al.. The varicella-autoantibody syndrome.  Pediatr Res. 2001;  50 (3) 345-352
• 196 Manco-Johnson M J, Nuss R, Key N et al.. Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis.  J Pediatr. 1996;  128 (3) 319-323
• 197 Busuttil D P, Hay C R, Lewis M A, Wynn R F. Aggressive multiple modality therapy for varicella-associated purpura fulminans.  Br J Haematol. 2000;  110 (4) 1012-1013