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Leukocyte adhesion deficiency syndrome

Leukocyte adhesion deficiency, abbreviated LAD, is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. The disorder is often divided into two separate genotypes called type I and type II, with type II being associated with fewer infections but more developmental delay. more...

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LAD is a rare disease; its estimated prevalence is 1 in 100,000 births. There is no described racial or ethnic predilection.

Clinical manifestations

LAD was first recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrent bacterial infections, defects in neutrophil adhesion, and a delay in umbilical cord sloughing. The defects in adhesion result in poor neutrophil chemotaxis and phagocytosis.

Patients with LAD suffer from bacterial infections beginning in the neonatal period. Infections such as omphalitis, pneumonia, gingivitis, abcesses, and peritonitis are common and often life-threatening due to the infant's inability to properly destroy the invading pathogens.

Molecular defect

The inherited molecular defect in patients with LAD is a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule, which is found on chromosome 21. This subunit is involved in making three other proteins (LFA-1, CR3, and Mac-1) This basically means that a gene which creates a protein does not function properly. This results in the lack of important molecules which help neutrophils make their way from the blood stream into the infected areas of the body (ie the lungs in pneumonia). Those neutrophils which do manage to make it to the infected areas have a difficult time "swallowing" the bacteria leading to infection (this is known as impaired phagocytosis). Therefore, the infection is allowed to spread unimpeded and cause serious injury to important tissue.


Typically diagnosis is made after several preliminary tests of immune function are made, including basic evaluation of the humoral immune system and the cell-mediated immune system. Specific diagnosis is made through monoclonal antibody testing for CR3, one of the three complete proteins which fail to form properly as a result of beta-2 integrin subunit deficiency.


Once the diagnosis of LAD is made, bone marrow transplantation is the current standard of care. However, some progress has been made in gene therapy, an active area of research.


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Protein C Levels in Severe Sepsis
From CHEST, 9/1/01 by Steven M. Opal

In this issue of CHEST (see page 915), Yan and colleagues demonstrate that 90% of a population of 70 patients who met the standard clinical criteria for severe sepsis had significantly reduced protein C levels. These investigators examined plasma samples from patients at study entry from a multicenter sepsis trial (the ibuprofen study[1]) and repeated coagulation assays on plasma samples from patients 44 h after study entry. While low baseline levels of protein C portend an unfavorable outcome, the results at 44 h after study entry were more predictive of fatal outcome (p [is less than] 0.05). These results are consistent with a considerable body of literature attesting to the adverse prognostic significance of low protein C levels in patients with severe sepsis.[2-4] In addition to a rather predictable "dose-response" relationship (lower protein C levels, higher mortality rate), this study and several other recent investigations have documented that the failure of low protein C levels to recover in septic patients is highly correlated with a poor prognosis.[4]

In the current investigation, protein C levels were significantly reduced even in those patients (9 of 10 patients) with normal global measures of coagulation activation, such as prothrombin time, partial thromboplastin time, platelet count, and fibrinogen levels. These results indicate that protein C measurement is a highly sensitive marker of coagulation activation and, more importantly, clinically evident severe sepsis. If these results can be replicated in a larger patient population, these results have important clinical implications for clinical trial design. If the vast majority of patients who meet standard clinical criteria for severe sepsis already have low protein C levels, does this obviate the need for actual measurement of protein C before initiating therapy for protein C deficiency? The answer to this question awaits the final answer from the recently completed phase III clinical trial of activated protein C in severe sepsis.[5,6]

It is worth reflecting on the recent history of sepsis research and clinical trials designed to improve the outcome of patients with severe sepsis. For the last 25 years, the main focus of research has been directed against elements of the host immune response to systemic infection. Coagulation activation has been relegated to secondary importance in the pathogenesis and treatment of sepsis. The coagulation activation was assumed to be an epiphenomenon of ongoing systemic inflammation. It was incorrectly expected that regulation of the disordered inflammatory response of sepsis would allow for passive correction of the coagulation abnormalities. It now appears the opposite may be more clinically relevant. Control of disordered coagulation is of primary importance, and the interactions of coagulation and inflammation are central to the pathophysiology of septic shock. Resolution of the systemic inflammatory response may follow therapeutic interventions to re-establish homeostasis of the coagulation and fibrinolytic system.[6]

A number of investigators have systematically dissected the intricate interactions between coagulation, inflammation, and the pathogenesis of sepsis. It is now quite clear that, at least in experimental models, repletion of acquired protein C deficiency in sepsis not only corrects the coagulation abnormality but results in a survival benefit.[7-9] There are tantalizing hints that the same strategy may be true in clinical sepsis as well. Case reports of protein C infusion in patients with meningococcemia have revealed promising results.[4,10] Results of a large phase III clinical trial in severe sepsis also support the value of activated protein C therapy in the treatment of severe sepsis.[5]

Protein C may be uniquely positioned to serve as an essential regulator of the microcirculation in health and disease. Protein C undergoes extensive posttranslational modification, including vitamin K-dependent [Gamma] carboxylation of glutamic acid residues, hydroxylation of aspartic acid, intramolecular cleavage with a single disulfide bridge, and four N-linked glycosylation sites.[2,11] All of these modifications are essential for activity but are insufficient to generate a functional serine protease that inhibits factors Va and VIIIa.

Protein C is a zymogen (proenzyme) that necessitates activation by excision of 12 amino acids off the amino terminus of the heavy chain of protein C. This vital activation process is mediated by thrombin itself in association with an endothelial surface protein known as thrombomodulin. Thrombomodulin is concentrated only on capillary endothelial surfaces.[12] Thus, activated protein C exists precisely in the optimal location within the microcirculation that limits procoagulant activity.[13]

Regrettably, tumor necrosis factor inhibits the expression of thrombomodulin, thereby limiting protein C activation during systemic inflammatory states.[14] Tumor necrosis factor also reduces endothelial protein C receptor on endothelial surfaces, further limiting protein C activation. In this manner, pro-inflammatory cytokines may contribute to microvascular thrombosis, thrombin-mediated endothelial cell, platelet and neutrophil activation, and multiorgan dysfunction.[15-17]

In addition to its anticoagulant properties, activated protein C is distinguished from other antithrombotics by its profibrinolytic activity (inhibition of plasminogen activated inhibitor-1 and reduced activity of thrombin activatable fibrinolysis inhibitor)[18] and significant anti-inflammatory activity (attenuation of leukocyte gene expression)[19] and reduction of neutrophil-endothelial cell interactions.[20] The clinical relevance of the latter two activities to improved outcome in sepsis is unclear at present but a focus of considerable basic research currently.

The results of Yan and colleagues add further evidence in support of the therapeutic rationale for protein C supplementation in severe human sepsis. Activated protein C may be the preferred method of replenishment of protein C levels in patients with severe sepsis. Results of the current phase III trial of activated protein C and subsequent clinical studies with this recombinant human protein should clarify the ultimate role of the protein C pathway in septic shock.

Steven M. Opal, MD Pawtucket, RI


[1] Bernard GR, Wheeler AP, Russel JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997; 336:912-918

[2] Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998; 24:33-44

[3] Mavrommatis AC, Theodoridis T, Orfanidau A, et al. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 2000; 28:451-457

[4] Fisher CJ, Yan SP. Protein C levels as a prognostic indicator of outcome in sepsis anti related diseases. Crit Care Med 2000; 28:S49-S56

[5] Bernard G, LaRosa S, Leterre, PF, et al. The efficacy and safety of recombinant human activated protein C for the treatment of patients with severe sepsis. Presented at Society of Critical Care Medicine 30th International Education and Scientific Symposium, February 10-14, 2001; San Francisco, CA. Abstract 67

[6] Opal SM. Phylogenetic and functional relationships between coagulation in the innate immune response. Crit Care Med 2000; 28:S77-S80

[7] Taylor FB Jr, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79:918-925

[8] Taylor F, Chang A, Ferrell G, et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood 1991; 78:357-363

[9] Esmon CT. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin? Blood 2000; 95:1113-1116

[10] Corbeal LM, Proesmans W. Treatment of meningococcal purpura falminans (Waterhouse-Friederichson Syndrome) with protein C concentrate. Eur J Pediatr 1997; 155:664-665

[11] Esmon CT. The endothelial cell protein C receptor. Thromb Haemost 2000; 83:639-643

[12] Taylor FB Jr, Stearns-Kurosawa DI, Kurosawa S, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95:1680-1686

[13] Rosenberg RD, Aird WC. Vascular-bed-specific hemostasis in hypercoagulable states. N Engl J Med 1999; 340:1555-1564

[14] Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 8:5588-5592

[15] Coughlin SR. Thrombin receptor function and cardiovascular disease. Trends Cardiovase Med 1994; 4:77-83

[16] Lorant DE, Patel KD, McIntyre TM, et al. Co-expression of the GMP-140 and PAF by endothelium stimulated by histamine or thrombin: a juxtacrine system for adhesion and activation of neutrophils. J Cell Biol 1991; 115:223-234

[17] Plabrica T, Lobb R, Furie BC, et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359:848-851

[18] Sakata Y, Loskutoff DJ, Gladson CL, et al. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 1986; 68:1218-1223

[19] Murakami K, Okajima K, Uchiba M, et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997; 272:L197-L202

[20] White B, Schmidt M, Murphy C, et al. Activated protein C inhibits lipopolysaccharide-induced nuclear translocation and nuclear factor [Kappa]B (NF-[Kappa]B) and tumour necrosis factor [Alpha] (TNF-[Alpha]) production in the THP-1 monocytic cell line. Br J Haematol 2000; 110:130-134

Dr. Opal is Professor of Medicine, Brown University School of Medicine.

Correspondence to: Steven M. Opal, Infectious Disease Division, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860

COPYRIGHT 2001 American College of Chest Physicians
COPYRIGHT 2001 Gale Group

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