IATT iss elycoproten of molecular weight 160,000 Da. Tes concentra tion nonmnally te about §0 mg/dL. IAT dues not rise appreciably a2 an acute phase reactants role im diveace states is probably star co that of ‘the major procease inhibitors in preventing autodigeston of tissues by endogenous cellular enzyrnes Daniels, 1975). [ATS ir of special sinical interest becaure ofthe role plas in neutral izing thrombin, which normally becomes activated intrvarculary from prothtombin during clot formation. This 62,000-Ds protein forms «co- ‘alently banded complex with thrombin over a period of several minutes ‘when mired in solution. On addition of heparin, the comple formation fceuts almost instantaneously (Rosenberg, 1975, 1985, 1987). Although ATS is probably essential for succes therapeutic administration of heparin only those rare individuals with marked deficiencies ceem ta hare thrombotic disorders (Carvalho, 1976). The action of ATS extends to other coagulation factors (IX, X, XI XI, and kallikrein). Serum levels of AT maybe depressed in severe liver disease or in proteinlosing disorders ‘when the stile sized molecule albumin i lost, snd aso in diseminated Intravascular coagulopathy (DIC). Anew experimental protocol for teat- ing DIC snvolves replacing ATS by infusion of concentater when the patient ATS lve fills to very low concentrations as part of the consump- tive coagulopathy: Presumably, return to normal levels of ATS has the sffect of blocking further thrombosis sytemicaly. ATS levels ae ler in heparin therapy and slightly elevated in oral anticoagulane therapy owing to increased and reduced tumover, respectively. ‘Although AAT, AMG, and ATS provid the bulk ofplasmin-neutralizing activity in serum (Harpe, 1976), 2 distinct antiplasmin migrates as an {lobule (3jnen, 1985). This eos reactivity of serum protease inhibitors for plain illustrates the difculty in sorting out the recite physiologic function of each molecular specie, Because cach one appeats capable of| substituting for another in diferent instances. However, aniplasmn binds ‘quansitatively to the majority of plasmin that is generated from plasmino- fem in human plasma that undergoes clotting. Antplarin thus serves 36 fae ofthe crteal checks within the joint coagulation-ibrnolytic system, ‘which maintain hemostasis by Balancing clot formation agunst dsslu” ‘aon. By this mechanism, clot formation and breakdown are generally contained within local regions of the vasculature without extending tothe tntire circulation. Hereditary deficiency of antplanmin reslts ins Bled ing disorder due to relatively unlimivedlibrinalyi, PALL acts to prevent actrationof plasminogen, thereby blocking fibt- nnlysis at an catly step. Deficiency of PALI resuke in less inhibition leading to greater Hbrinolysis and potentally a bleeding disorder. Elevated levels of PAI-T prevent fbrinolyss, leading to thrombote disorders and to the progresion of atherosclerosis. Protein C (with ie cofactor protein S) inactivates acurated coagulation factor V and VII. Deficiency of protein C oS (Grifin, 1989) allows prolonged activity in vivo of proco- Egulantfictors leading to thrombotic disorders ‘The C1 esterase inhibitor is eapable of inbting activated complement components Clr and Cle phos some other cosgsltion and Abrinolytie factors, Tt rses ae an acute phase reactant. Hereditaty deicency of Cl ‘scerae inhibitor allows acation of complement to proceed telaively ‘unabated, a disorder termed hereditary angioedema. ‘The complement syrtem and its inhibitor are described in depth in Chapter 47 ACUTE PHASE REACTANTS. “The soute phase reactant proteins share the property of showing levtione in concentrations in responce to sresfl or infammatory states that occur ‘was infection, injury, surgery, trauma, or other Uasue necrors (Dani's, 1974; Laurell, 1975; Dowion, 1988) They include AAT, a-aci glycopeo™ tein, haptoglobin, ceruloplasmin, bsinogea, serum ammyoid A protein, and CRE Others are fctor VII, ferritin, lipoproteins, complement pro- teins, and immunoglobulins, Tt is easy to see Row such a response of the plasma proteins would be advantageous to the body Inflammation causes Felease from leukocytes af protealycie enzymes in tissue that must be neutralized by enayte inhibitors cole thew extent of derruction,scav- ‘enger proteins haptoglobin, CRP) help collect and sransport cellular debris and breakdown products to phagocytic ells (reticuloendothelial stem) to process them and conserve sital substances (e.g, iron); and Inealing of wounds requires a large amount of Sri, which stives via the circulation ae fibrinogen. ‘Thus, the humoral response of the acute phase Feactants can be viewed a a phenomenon thai geared to handle exensive insult each time itis wiggered, even though not all components will be needed om every ocesion. The elevation of acute phae reactants likely 2 response tothe cytokines, including inerlevkin-1,romor necrosis factor, incerferony, and inteleukin-6, The total physiologic response includes 270 induction of fever, rersitment of leukocytes, cataboliam of muscle, and a shifcin protein syntheis patterns with reduction in albumin production. "For clinical use in diagnosis, other parameters in fact may be as seasi- tive a5 these and far easier to measure (eg, fever, leukocytosis, ESR). However, these proteins provide another dimension of quantitation that an be uteful for monitoring the eaurse of 2 patient by serial determina Uons (van Oss, 1975) OF course, those patient with congenial deficien- cies (Gitlin, 1975), those wih other impairment of synthesis du to drugs tor organ disease, and newborns who normally have lower levels of many onsttuent (Gitlin, 1969) may not show the dramatic increaer expected However» generally urefol acute phate reactant for monitoring response is CRP, which she fastest sing acute phase reactant and one that returns ‘to normal quickly following successful therapies (Fischet, 1976). CRP i frequently applied tothe detection and preliminary clasficatin of cult infections, becanee haste infections can stimulate mic higher levels of| CRP than viral ones. Tei also widely used for assessing disease activity in autoimmune disorder, becaue i it rarely clevated persistently without ‘continued inflammatory response, Elevations of CRP ean be up to 1000 ‘umes noraial levels, which greatly assist an detecting sbnorinal sates compared with the other acute phase reactants, which may rise at most nly several-fold in such responses, although ferritin levels may occasion ily rise co values greater than 20,000 ng/tl, PATTERNS OF PROTEIN ABNORMALITIES Some of the mast frequently encountered patterns of protein abnormalities in electrophoresis are shown ar denaitometrc scans tn Figure 19-8. Scat ning allows quantitation of each faction, but vival snepection of the slectrophorete stip provides more detailed information about individual proteins separated in high-resolution sytem (Ritzman, 1975). Tnterpreta- tion of electrophoretic result depends on visual inspection to identify slnormal patterns or aberrant bands, and on quantitation by san to gauge ‘he relative quantities of individ fractone Patcers of hypoproteinemis die to mmalnstniton oF gross lose of protein show decreases in all factions, but the most dramatic reduction i Sften seen in albumin compared with ite normaly high value atthe most sbundane serum protein (Fg. 19-9, ane 3). Severe aration, malabeorp- tion, or ination associated with severe chronic disease will show marked reduction in albumin to levele below 20 g/L. The other serom proteins, including AAT, AMG, haptoglobin, transferin, and C3, appear even Ginter on electrophoresis, Reduction in stxining intensity for the B-lipoprocein parallels a mated decreate in serum cholesterol concentea- tion. ‘The immune system is strongly affected by severe starvation, with decreased synthesis of imamenoglobulins resuking in hypogammaglobu- Tinemis and impaired resistance to bacterial and ather infections: Protein losing enteropathy Fig 19 8,1) shows a variation i the hypoproteinensia pattern, in which most fractions are diminished owing tothe combination Of decreased synthesis and increased loss, although ty may be relatively hhgher owing to 2 cocusting acute phase response (haptoglobin) oF tO preferential retention of larger moleccles(ay-mactoglobulin) Specific os of proteins snto the rine a in nephrotie symdrome acears om a molecular weight basis, with smaller proteins being lst more rapidly than larger ones. Accordingly, albumin appears catly in the course Of protein-losing nephropathies, fllowed by smaller quantities of AAT, transferrin, and, ultimately, immunoglobulins (Fig, 19-10, lanes t and 2). “The very large molecele AMG is retained, ar are the lige micelles of B-lipoprocein, The resule i complementary patterns of proteins in the serum (decreases in albumin and a, Pp, and y-globulins increased o~ macroglobulin and clevated (lipoprotein) versus those in rine eee Fig. 15-4, B) (glomerslir proteinarin woth albumin, i, hy and /ractione present but without ay-macroglabulin inthe urine sample). Tobslar pro- feinuria that is due to iapaired renal tubular eeabsorption of smal protein shows a pattern of 8 andi the wrine with only minimal albums lose inco the urine (Killngsworth, 1982) (Ge Fig. 19-10 ane 4). Inadaition 0 glomerular and tubular patterns of proteinuria (Maachi, 2004), itis impor tant to recognize the important patter of s monoclonal gammopathy in urine (ee Fig 19-10, le 3, and Fig 19). A simular pater of a single large band occurs in hemoglobinuria (se Fig. 19-10, lane 5), which anise be distinguished from a monoclonal immunoglobulin ot fre light chains ‘Acute phase or immediate response pastems have greatest effect on scram protein electrophoresis by increasing the amount of haptoglobin while sighdly decreasing the concentration of albumin, Increases in hsp toglobin usually indicate come form of responce, whether acute or chronic,J_| _Slobuins aa LY tease \Ngiioe is rove garmonatyy Normal pattern A E | | LALA Paraprotein “Immesiate response pattern’ (¢monoelonal gammopathy’) 8 F 4 4 t + t lbwee”>—\ Ww “onayarpre ters Nepean c G Fa 4 ‘ Lanrt_ ynogemmaghoainen Pratencsng etrpaty H Figure 19-8. Serum protein slertophoresis nicopthalogieconltons. (oun 8 De KE Reg) to steesfl stimel Pig. 19-9) Other proteins suchas AAT can contibute to thir response, minor components such ar CRP do not contabute sig- pieanty to this proteim stain pattern, although immunologic messure- sent of CRP may show up to 1000- fold elevations. T the haptoglobin hae been depleted in s patient ssa real af setive hemolysis, an independent band of hemoglobin may be migrating inthe f- or avregion. Hemolysis cof a sample in vitro may show a red band (on the unstained gel) of the baptoglobin-hemoglobin complex that migrates diferenly fom hemo- slobis alone. The pattern of delayed response or chronie pattern is 38 fxtenson ofthe scat phase response (high haptoglobin, slight reduction Jn albumin) with greater decreae in albumin and polyclonal increase in linmanogiobuline broadening the +-egion. ‘Astring elevation oftraneferrn mn che region sometimes occurs in patents suffering from iton deficiency anemia. The increase in transferrin ‘Corresponds to ineressed TBC, an the percent saturation ie low (Koerper, 1977)."This variation may be eamfaed with a myeloma protein beestxe the transferrin band forms 4 narrow, conal-sppesting band Cathosis of the liver creates protein patrerm tac recognizable (Fig 19-8, aj. Hepatocelllar damage from cirthoris results im diminished capacity to synthesize albumin. Furthermore, the imbalance of hemody- ‘amie pressures in portal hypertension secondary to cirshoss lad to the formation of sete uid, which contains almost exlusivey albumin. This - _ — . 1 2°53) Figure 19:9, Serum preven patens (1) conic islammation wth decreased albumin and inrensedeslobulns, (2) acute iarnmation wth increase ‘racuon hapten) and decreased C3 sue to acvaton and consumption amplement (3) nation pesesinal cord nuty with hypoproseinema ef evra — << Alb i ;- eee) ae) Figure 18-10 Paters of urn poten elcvophoress in dierent disorders. 1) Severe lomerurprovemurn ths aor hand of sburon plas secon one ctrastemn ) () ace pratenura wth font bard f bmn ardether are proteins (3) Inmunoglabsin hgh chans() (2) Tubur preter eth maple Esra tht aa not corespend te major serum pres (3) Nemavirs th 3 mor of hearin (ak be conned wh nederal grmapay ecreased symthess, coupled with increased loss, greatly reduces serum slbumin concentrations, The loss of albumin is balanced to some extent bby marked polyclonal increase in maminogiobuline with 2 fraction that ‘may contribute signfianty co ancoti presses The increae in globulin {involves all immunoglobulins, the increase in immunoglobulin A (ig) in the slow Geregion shows a contingum with the 7 (lea termed [eY bridging) Th contrast co polyclonal increses, oligoclonal bande conse of only 3 few clones af distinct immunoglobulins tha migrate in defined portions. This pater i sen in serum in eats in which an immunologic disorder fs present, or in some patente tested with chronic immunosupprestion for organ transplantation (Mars, 1991), Ohgoclonal ban in the CSP are ‘wed to indicate imamologic activity in the central nervous system and ‘occur in infectious diseases of autoimmene or demyelinating disorders (Gee Chapter 46). 2Albumin Light chains ee Serum Urine Figure 19-11. serum and uine protein eectvophretic patterns ina patient ith ‘raltele myeloma. Serum demonstrates »prederanance 0 the loge complete Imsineglosin the wane hae rge amaunt ofthe mabersael hgh chine th {nina smal mount ofthe whole mmunogtebuln SELECTED REFERENCES Pee ladle! fre Sagan of seal te Update aan fhe a of brary ering in ngnsng Wo’ diner Hypogammaglobolinemia is manifested at neatly to completely absent fraction. I occuts normally in neonates before maturation of the immune sper, Iealeo accursin some congenital itumunodefiiency states such a¢ Broton’ agammaglobulinemia and other sates involving B cell function. Perhaps more commonly, this pattern is seen in adults with Iymmphoreiclar ditorders in whom normal plasma eels have been dis- placed by iymphoeyte proliferations, and to some extent after chemo- therapy for eradication of malignancies, az well asin hypoproteinemic states (6ee Fig. 19-9, lane 3). “Thesingle most important and widespread clinical application of serum protein electrophoresis wed for the detection af monoclonal gammopa- thies. This very explicit patern comes from a paaprotein(immunogioba. lin) secreted by « monoclonal proliferation of plasma celle and i generally found without normal amounts of polyclonal ae normal plasma cele are replaced by the malignant clone (se Fg. 19-11). The pretence of para- protein with normal polylonal 7 suggests a possible plasmacytoma that thse not yet spread throughout the bone marrow Laboratory evlation of nelona should include serum and urine protein clectrophoreses to detect aberrant clonal bands, snmunoelectophoresis or immunofiation to Ope the heavy and light chains of che paraproten, and quanttation of imu inoglobstine to provide a baseline for monitoring the patent reponse to therapy or disese progression. Other proteins that may sometimes be tmisaken for monoclonal bands of immunoglobulin on serum protein slectrophoresis include haptoglobin-hemoglobin compleacs, C3 and ite ‘arian, Bipoproten, wansfernn, Sbrinogen, immune complexes, CRE, aa occasionally, o- macroglobulin Tmmunoglobilng, disorders ofthe immune system, and abnormalities of complement are discussed further in Chapters 6,47, and 50, Thc gaper pets pater of psn and nev mitt the dcr, hd entrap absimnce Mohan Res, Cinprebnioe rice of anys for carydae eer wane ond rate fo tbr Borghors JA Protas Mt Messows Gta Eran tka ntratte siagnovtealgorton for fe soe ‘estos of people re or ramsey fee Am Clin Publ 20072683090, "Tho ale Sate the mars spac dag of AAT een ng the ome msi of Smmansaney Pmagng by tars fing, and neh Ainge FR Lancet MR. open: review of ‘logical ypc andthe ole inborn niin (Gin Chon Aes 200,312 12-2, see ere pea oops eign sf te nbemry of ome tt os fats le — Win dae: Ames Pharmacl Tht S04, REFERENCES Hilton NE, Gin JD, Corlplnnin metabo an ‘onaon. Ana Rey No 200225 8958 "hail a lent mary f serpleie lem a nl mpi Lisi), Roper ME, Wee TW, Above RI. Loli Se primary churacrtion a = ation ‘bin inser ht Sly Lund eo protein Cl Chem nanan, Hany ovat of Bbirabin ond ds ration to erie andthe reaing protein” Math ney! spars lal pape pate meee Mase M, Feubt 3) Regoner Ac Pane of proteins wnary serum dod tie lc net erserimrnonsfosamet protein ar fresacenent followed ip erection wi the Enowledge beet sem MIDI Lion Cin Che Accs the complete reference i oline a p/w empertcnsale com 272 inch Glin ght U, ete "Mtatene sd polymorphs of the gene of the tor henan led yr sem ian, Ha ‘Ms tom ao tor-fe Th atk prods» ome bing of no prt nt ne Pome aaa pe door E Ses dbo ren popes ike de tandng ois stutas soca Co Gem inate grin veo ay pt rae font rnp of sb lone E Alou Hepen: ewe, ton, ‘hinepsnton BNA Cal Bl 0) a1 i inbred fe ety to bs of ‘at is Moeisen N, Gulbrnson R, Keten DF. isons oy bs wera ene {orn fd des blag cap ed ‘om sal jury. Cn Chem 1990 38190812 "Bar of yr pcm CSP sk ™