EXPLORAREA HEMOSTAZEI SECUNDARE CALEA INTRINSEC 1.

Timpul de coagulare (TC): Timpul de coagulare reprezint timpul necesar coagulrii, in vitro, a unei probe de snge, recoltat n absena anticoagulantelor, i care vine n contact cu o suprafa nesiliconat. Testul investigheaz calea intrinsec i calea comun a coagulrii. Rezultate: Valori normale: Metoda Lee-White: 8-10min. Valori crescute: Defecte grave ale factorilor de coagulare ai cii intrinseci. Prezena anticoagulantelor. Valori sczute: Contaminare accidental cu substane procoagulante (trombin, resturi organice). Tehnic incorect. 2. Timpul Howell = Timpul de recalcificare a plasmei: Timpul Howell (TH) msoar timpul necesar coagulrii plasmei citrate/oxalate, bogat n trombocite, peste care s-a adugat o cantitate optim de clorur de calciu (CaCl2). Testul investigeaz calea intrinsec (coagularea factorilor: XII, XI, IX, VIIc), calea comun (coagularea factorilor: X, V, II, I) i eliberarea factorului 3 plachetar (fp3). Scop: monitorizarea tratamentului cu anticoagulante. Rezulatate: Valori normale: 1-2 minute Valori crescute: Deficit al factorilor de coagulare din calea intrinsec sau calea comun. Deficit cantitativ i/sau calitativ al factorului 3 plachetar. 3. Timpul de Cefalin = Timpul parial de tromboplastin (PTT): Timpul parial de tromboplastin (PTT) msoar timpul necesar coagulrii unei plasme citrate peste care se adaug: cefalin (pentru activarea factorilor XII i XI) i clorur de calciu (CaCl2) ca iniiatori ai reaciei. PTT este o variant a TH, mult mai sensibil dect acesta. PTT investigheaz calea intrinsec i calea comun a coagulrii (ns sensibilitatea testului pentru aceasta din urm este mai mic), independent de factorii plachetari ai coagulrii. Altfel spus, este un test de coagulare plasmatic global, care implic n desfurarea sa toi factorii plasmatici mai puin F VII, F XIII. PTT are dezavantajul c variaz mult n funcie de tehnica laboratorului i de reactivii folosii, motiv pentru care n prezent se prefer folosirea aPTT sau KPTT, care este mai bine standardizat. Timpul parial de tromboplastin activat (aPTT), care mai este denumit i timpul partial de tromboplastin cu kaolin (KPTT), reprezint varianta standardizat a PTT. Kaolinul are rolul de a activa suplimentar de factori de contact (XII i XI). Este adugat la plasma sarac n trombocite nainte de adugarea cefalinei, cu scopul de a crete sensibilitatea i exactitatea testului. Scop: monitorizarea terapiei cu heparin n caz de antecedente clinice i familiale, care sugereaz un deficit al unuia din factorii de coagulare sau prezena unui inhibitor al factorilor de coagulare sau a anticoagulantului lupic. Rezultate: Valori normale: PTT = 60-120 secunde aPTT= 25-35 secunde. n cazul pacienilor, care primesc terapie anticoagulant, rezultatele testului sunt de 1,5-2,5 ori mai mari dect n cazul pacienilor care nu iau anticoagulante Valori crescute (peste 40 secunde):

a) cu antecedente personale sau familiare hemoragice: Boal von Willebrand. Hemofilia A (deficit de factor VIII). Hemofilia B (deficit de factor IX). Hemofilie C (deficit de factor XI). Prezena inhibitorilor specifici ai factorului VIII. b) fr antecedente personale sau familiare hemoragice: Deficit de factor XII. Deficit de prekalicrein. Deficit de kininogen. Prezena de anticoagulant lupic. Ciroza. Hipofibrinogenemie dobndit. Hipoprotrombinemie. Malabsorbie. Valori scazute: CID [este o situaie patologic, declanat de ptrunderea n circulaie a substanelor tromboplastin-like (toxine bacteriene, lichid amniotic, etc.), dar i de perturbri morfofuncionale ale microcirculaiei (arsuri, traumatisme, intervenii chirurgicale, complicaii obstetricale, hemopatii maligne, etc.). Acest tip de coagulare, care se produce haotic i difuz, se caracterizeaz printr-un consum masiv de factori de coagulare, care devin insuficieni la nivelul injuriei vasculare, conducnd concomitent att la tromboze ct si la hemoragii, ceea ce d aspectul caracteristic de sngerare cu cheaguri de snge.]

CALEA EXTRINSEC 1. Timpul de protrombin (TP) = Timpul Quick (TQ): Timpul de protrombin = Timpul Quick reprezint timpul necesar coagulrii unei mostre de snge recoltat pe citrat de sodiu, peste care se adaug calciu i tromboplastin tisular (factor 3 tisular). Testul investigheaz n principal calea extrinsec a coagularii, n care intervin urmtorii factori: V, VII, X, i secundar calea comun (este mai sensibil pentru aceasta din urm dect aPTT): I (protrombina), II (fibrinogen). Valoarea TP se poate exprima n secunde sau se poate exprima printr-un raport (TQmartor fa de TQpacient), care se numete indice de protrombin (IP) sau activitate protrombinic (AP): TQmartor IP (AP) = x 100 TQpacient Din cei 5 factori ai coagulrii implicai n acest test, 3 sunt dependeni de vitamina K (II, VII, X). Acest test este mai sensibil n cazul deficitului de factori I, II, VII, X. Scop: n principal pentru monitorizarea tratamentului cu anticoagulante orale cumarinice (Sintrom = Trombostop) sau warfarinice. Pentru o anticoagulare eficace IP (AP) trebuie meninut la 30%. este folosit att ca test screening ct i ca metod de diagnostic pentru defectele factorilor de coagulare dependeni de vitamina K. este util n evaluarea funciei hepatice Rezultate: Valori normale: a) TQ = 12-16 secunde (10-15sec.) b) IP (AP) = 85-100% Atentie: La o persoan aflat sub terapie anticoagulant, TP trebuie sa fie de 2-3 ori mai mare dect valoarea TP a unei persoane care nu ia anticoagulante!!! Atentie: TP este normal n hemofilie!!! Valori crescute: IP < 70% indic disfuncie hepatic medie IP < 50% indic insuficien hepatic sever IP 30% indic - hipocoagulabilitate franc - risc vital prin hemoragii prelungite la traumatisme minore - evoluie spre o form fulminant de hepatit acut IP < 10% indic risc de hemoragii cerebrale amenintoare de via a) fiziologic: nou-nscuii b) patologic: Defecte congenitale sau dobndite ale factorilor I, II, V, VII, X. Cancer de cap pe pancreas. Prezena de anticoagulant circulant de tip antitrombinic (ex: heparin). Caren de vitamin K. Hepatopatii (hepatite acute, n special fulminante; ciroze). Hipervitaminoz A. Medicamente hepatotoxice.

2. INR (International Normalised Ratio): INR este abrevierea denumirii anglo-saxone "International Normalised Ratio". OMS recomand utilizarea INR, deoarece acesta este expresia standardizat a timpului Quick (TQ) pentru remedierea variaiilor constantelor datorate diferitelor tipuri de tromboplastine folosite n diferite laboratoare, permind astfel compararea rezultatelor. TQpacient INR = x ISI TQmartor n care TQmartor este determinat cu ajutorul tromboplastinei de referin. Scop: INR este folosit pentru monitorizarea tratamentului cronic cu anticoagulante orale deoarece ne permite s avem o idee mai precis asupra activitii acestor medicamente. Rezultate: Valoarea normal: ct mai aproape de 1 (IP = 75-100%), la un individ fr terapie anticoagulant. Valori crescute: 2 - 4,5 la persoanele aflate sub terapie anticoagulant, n funcie de scopul tratamentului, preventiv sau curativ. Cu ct valoarea este mai mare, cu att sngele este mai fluid. O valoare prea mare se asociaz cu risc crescut de hemoragii, iar o valoare prea mic cu risc crescut de tromboz. Se recomand meninerea: a) INR = 2 - 3 (IP = 30-40%) pentru profilaxia trombozei venoase profunde sau a trombembolismului pulmonar. b) INR = 3 - 4,5 (IP = 20%) pentru tratamentul accidentelor trombotice n caz de protezare cardiac sau pentru tratamentul trombozei venoase profunde recidivante.

CALEA COMUN 1. Timpul de Trombin (TT): Timpul de trombin reprezint timpul necesar transformrii fibrinogenului n fibrin (adic a formrii cheagului sanghin) ntr-o mostr de snge recoltat pe citrat, peste care s-a adugat trombin i clorur de calciu (CaCl2). El se msoar din momentul adugrii trombinei i pn n momentul n care se formeaz coagulul. Valoarea obinut este influenat de: concentraia fibrinogenului, prezena antitrombinei i activitatea heparinei, streptokinazei sau a urokinazei (utilizate n scopuri terapeutice). Timpul de trombin investigheaz calea comun a coagularii. Testul este utilizat pentru a face diferenierea ntre o alterare a fazei iniiale a coagulrii i o alterare a fazei finale a coagulrii. n cazul unui aPTT sau TP anormale, dac adugm peste plasm o soluie de trombin i obinem coagul n 10-20 de secunde, putem s presupunem c este vorba de insuficien de protrombin i nu de factori implicai n faza iniial a coagulrii. Dac TT este mai mare de 20 de secunde, trebuie s ne gndim la o insuficien a fibrinogenului sau la existena unui inhibitor al trombinei (antitrombina III stimulat de heparin, cnd se utilizeaz acest anticoagulant n terapeutic). Scop: Detectarea bolior hepatice. Monitorizarea terapiei cu heparin, streptokinaz sau urokinaz. Ca test screening de coagulare pentru detectarea produilor de degradare a fibrinogenului i a fibrinei (stabilete diagnosticul de CID difuz) i pentru detectarea anticoagulantului lupic. Acest test are dezavantajul c trebuie confirmat prin alte teste, care stabilesc nivelul fibrinogenului. Rezultate: Valori normale: 10-20 secunde (ntotdeauna trebuie comparat aceast valoare cu o prob martor) Valori crescute: a) fiziologic: nou-nascui b) patologic (se consider patologic alungirea cu peste 5 secunde fa de valoarea martor): Terapia cu heparin sau alte anticoagulante. Terapia fibrinolitic. Prezena anticorpilor anti-trombin. Prezena inhibitorilor circulani ai antitrombinei. Boli hepatice. Hipofibrinogenemii. Disfibrinogenemii. Suspiciune de CID (trebuie confirmat prin teste ce pun n eviden produii de degradare a fibrinei = PDF). Medicamente: heparin, streptokinaz, urokinaz.

2. Timpul de Reptilaz (TR): Timpul de reptilaz reprezint timpul necesar coagulrii plasmei oxalate sau citrate n prezena reptilazei. Testul investigheaz transformarea fibrinogenului n fibrin in absena trombinei, deci calea comun. Cauzele care l altereaz sunt aceleai care altereaz TT, cu excepia inhibitorilor trombinei (prezena heparinei n plasm produce un TT alungit cu un TR normal). Scop: Timpul de reptilaz este folosit ca investigaie de baz a coagulrii pentru detectarea hipofibrinogenemiilor, disfibrinogenemiilor, dar i a prezenei globulinelor anormale (mielom), care pot provoca o polimerizare anormal a monomerilor de fibrin. Ajut la stabilirea cauzei care a determinat alungirea timpului de protrombin (TP): prezena unui anticoagulant de tipul heparinei sau prezena produilor de degradare a fibrinogenului (suspiciune de CID), care au aciune antitrombinic. Rezultate: Valori normale: 10-14 secunde Valori crescute: Dac coagul de fibrin apare n 14-21 de secunde, nseamn ca trombina era inhibat. Dac apariia coagulului ntarzie mai mult de 22 de secunde, trebuie s ne gndim c exist un deficit de fibrinogen. 3. Dozarea fibrinogenului: Fibrinogenul Este alctuit din 3 lanuri polipeptidice: (A), (B), reunite prin puni disulfurice.

Sub aciunea trombinei, fibrinogenul se transform n monomeri de fibrin, care prin polimerizare vor forma fibrina solubil. Factorul XIIIa stimuleaz conversia fibrinei solubile n fibrin insolubil, stabiliznd cheagul sanghin. Rezultate: Valori normale: 200-400 mg/dL Valori crescute: Sarcin. Infecii acute (cu excepia febrei tifoide). Infarct miocardic acut. Stri post-hemotagice. Valori scazute: Defecte de producere a fibrinogenului (congenitale sau dobndite). CID. Hemofilie A. Hemofilie B. Insuficien hepatic grav. Fibrinoliz. Dezlipire prematur de placent. Tratament fibrinolitic. Afibrinogenemie congenital. 4. Evaluarea deficitului de factor XIII: Dopul hemostatic iniial nu este suficient pentru a preveni pierderea de snge, dac nu este stabilizat sub aciunea factorului XIII plasmatic. Deficitul de factor XIII este o tulburare ereditar, care se manifest prin hemoragii postoperatorii tardive i insuficien cicatrizrii plgii operatorii. Testul investigheaz procesul de polimerizare a fibrinei i este indicat n cazurile n care TQ i PTT sunt normale, dar exist antecedente personale de sindrom hemoragic. Diagnosticul deficitului de factor XIII se bazeaz pe investigarea solubilitii coagulului de fibrin n soluie de uree 5M. n mod normal, coagulul format n prezena factorului XIII devine solubil n aproximativ 24 de ore, spre deosebire de coagulul format n absena factorului XIII, care se dizolv n uree n cteva minute.

RETRAC IA CHEAGULUI = TIMPUL TROMBO-DINAMIC Acest proces ncepe imediat dup formarea cheagului rou fibrinoplachetar. Rolul sau const n apropierea marginilor breei vasculare n timpul reparrii peretelui vascular. Retracia cheagului depinde de: concentraia fibrinogenului, a factorului XIII (FSF), de numrul i valoarea funcional a trombocitelor, precum i de numrul eritrocitelor prinse n cheagul sanghin. Acest test este o prob diagnostic foarte important, care const n msurarea cantitii de ser eliminate (exprimat n procente) de cheagul sanghin dup contracia proteinei contractile din citoscheletul trombocitului (trombostenina). n acest mod, dopul fibrino-plachetar i reduce dimensiunile, i crete consistena si devine mai rezistent. Rezultate: Valori normale: n mod normal procesul ncepe dup aproximativ 20-30 minute, cnd se constat apariia unei picturi de ser pe suprafaa trombusului, i se termin n aproximativ 240 minute (4 ore), cnd majoritatea serului este expulzat. Dup acest interval trombusul trebuie s fie de consisten ferm, iar volumul lui trebuie s fie retractat la aproximativ jumtate fa de volumul iniial. Trombusul va fi in continuare examinat periodic timp de 24 de ore, determinnd procentual cantitatea de ser eliminat. Valori alterate: a) retracia cheagului ntarzie mai mult de 4 de ore sau chiar este absent: trombocitopenii, trombocitopatii (trombastenia Glanzmann), hepatopatii (ciroza hepatica), disproteinemii b) retracia cheagului se produce ntr-un interval mai scurt de 4 de ore: hiperfibrinoliz

EXPLORAREA FIBRINOLIZEI Definiie: Fibrinoliza este un proces fiziologic, care const n dezagregarea i dizolvarea cheagurilor sanghine, sub aciunea unei enzime numit plasmin sau fibrinolizin. Aceasta este o enzim plasmatic cu rol n degradarea (prin hidroliz) att a fibrinei, ct i a fibrinogenului. n plus, ea mai poate degrada factorii de coagulare IX, VIII, V, II. Fibrinoliza fiziologic sau tromboliza este un proces declanat de fibrinogeneza fiziologic, strict localizat la nivelui dopului fibrino-plachetar, care are ca scop repermeabilizarea vaselor de snge dup repararea peretelui vascular. Fibrinoliza patologic este declanat n condiiile creterii nivelului de activatori ai fibrinolizei sau scderii nivelului de inhibitori ai fibrinolizei. Plasmina lizeaza progresiv reeaua de fibrin, rezultnd produi de degradare a fibrinei (PDF) de dimensiuni din ce n ce mai mici: iniial X i Y, ulterior D i E. Aceste fragmente rmn legate prin legaturi covalente (fragmente D-D, D-E-D ) i au primit denumirea de D-dimeri. Degradarea fibrinogenului se produce numai n caz de fibrinoliz patologic sau n cazul utilizrii terapeutice a unui agent fibrinolitic i nu determin formarea de D-dimeri. Mecanismele declanatoare ale fibrinolizei sunt reprezentate de: coagulare; activitatea motorie; catecolaminele n exces; mediatori chimici i amine biogene; hipoxia i necroza celular; staza venoas; circulaia extracorporeal; traumatismele vasculare. A) Teste globale de fibrinoliz: 1. Timpul de liz a cheagului sanghin = TLCS msoara timpul necesar disoluiei cheagului sanghin. Rezultate: Valori normale: 48-72 de ore Valori crescute: hipofibrinoliz Valori scazute: hiperfibrinoliz subacut: TLCS 48 ore acut: TLCS 1 ora supraacut: TLCS nu se produce. Atenie: Cnd TLCE nu se produce trebuie investigat eventuala prezen a unor anticoagulani circulani!!! 2. Timpul de liz a cheagului de euglobuline (TLCE) este cea mai rapid metod de investigare a fibrinolizei i, n plus, are avantajul c poate fi efectuat i pe snge heparinizat. Este un test global, care msoar aciunea activatorilor plasminogenului i plasminei. Este un test mult mai sensibil dect TLCS i const n evaluarea activitii fibrinolitice a unei plasme de cercetat, prin precipitarea n mediu acid (pH = 5,9). Rezultate: Valori normale: liza cheagului euglobulinic se face n aproximativ 3 ore Valori sczute: n hiperfibrinoliz (cnd cantitatea de tPA circulant este crescut) Cauze de hiperfibrinoliz: Complicaii obstetricale (desprindere precoce de placent, retenie de ft mort). Ciroz hepatic. Cancer de prostat. Discrazii sanghine. n timpul i dup realizarea circulaiei extracorporeale n cadrul chirurgiei cardiovasculare. n moarte subit cauzat de traumatisme i de oc electric. B) Teste analitice de fibrinoliz: 1. Determinarea PDF (produii de degradare a fibrinei). PDF sunt fragmente rezultate sub aciunea plasminei asupra fibrinei, care vor fi ndeprtate din circulaie de ctre macrofagele din ficat. Prezena lor semnific fibrinoliz. PDF inhib polimerizarea fibrinei i agregarea plachetar. Valorile normale: 5g/ml.

 Valori crescute: Postoperator. Eclampsie. Hepatopatii. CID. Hiperfibrinoliz primar. Carcinoame. Nefropatii. Embolism pulmonar. Tromboz venoas. Tratament fibrinolitic. Traumatisme recente.

Determinarea D-dimerilor. D-dimerii sunt o subpopulaie de PDF, specific degradrii coagulului de fibrin deja stabilizat, ceea ce crete specificitatea testului. Rezultate: Valori normale: 0,5g/ml Valori crescute: n situaii de hiperactivare a coagularii (tromboz venoas profund, CID, hiperfibrinoliz primara, tromboembolism pulmonar, trombembolism arterial, sarcina mai ales postpartum , maligniti, postoperator, terapie trombolitic). 2. Determinarea produilor de degradare a fibrinogenului = Testul monomerilor de fibrin (TMF) = Testul cu etanol pentru evidenierea monomerilor de fibrin Produii de degradare a fibrinogenului sunt fragmente rezultate sub aciunea plasminei asupra fibrinogenului, care vor fi ndeprtate din circulaie de ctre macrofagele din ficat. Prezena monomerilor de fibrin sugereaz o hiperfibrinoliz secundar (CID).

'''Insulin-like growth factor 1 (IGF-1)''', which was once called somatomedin C, is a [[polypeptide]] [[protein]] [[hormone]] similar in [[molecular structure]] to [[insulin]]. It plays an important role in childhood growth and continues to have [[Anabolism|anabolic effects]] in adults. ==Production and circulation== IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7649 daltons. IGF-1 is produced primarily by the [[liver]] as an [[endocrine]] hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by [[growth hormone]] and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5b. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.

In rat experiments the amount of IGF-1 mRNA in the liver was positively associated with dietary [[casein]] and negatively associated with a protein free diet.<ref>{{cite doi|doi:10.1079/BJN19920029}}</ref> ==Action== Its primary action is mediated by binding to its specific receptor, the [[Insulin-like growth factor 1 receptor]], abbreviated as ""[[IGF1R]]"", present on many cell types in many tissues. Binding to the IGF1R, a [[receptor tyrosine kinase]], initiates intracellular signaling; IGF-1 is one of the most potent natural activators of the [[AKT]] [[Signal transduction|signaling pathway]], a stimulator of cell growth and proliferation, and a potent inhibitor of [[Apoptosis|programmed cell death]]. IGF-1 is a primary mediator of the effects of [[growth hormone]] (GH). [[Growth Hormone]] is made in the [[pituitary]] gland, is released into the blood stream, and then stimulates the [[liver]] to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every [[cell (biology)|cell]] in the body, especially skeletal [[muscle]], [[cartilage]], [[bone]], [[liver]], [[kidney]], [[nerve]]s, [[skin]], [[hematopoietic]] cell, and [[lungs]]. In addition to the [[insulin]]-like effects, IGF-1 can also regulate [[cell growth]] and development, especially in nerve cells, as well as cellular [[DNA]] synthesis. Deficiency of either [[growth hormone]] or IGF-1 therefore results in diminished stature. GH-deficient children are given [[recombinant]] GH to increase their size. IGF-1 deficient humans, who are categorized as having [[Laron's disease]], or Laron's dwarfism, are treated with recombinant IGF-1. ==IGF-2 and Insulin; related growth factors== IGF-1 is closely related to a second protein called "[[Insulin-like growth factor 2|IGF-2]]". IGF-2 also binds the IGF-1 Receptor. However, IGF-2 alone binds a receptor called the "IGF II Receptor" (also called the Mannose-6 phosphate receptor). The insulin growth factor-II receptor (IGF2R) lacks signal transduction capacity, and its main role is to act as a sink for IGF-2 and make less IGF-2 available for binding with IGF-1R. As the name "insulin-like growth factor 1" implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin. ==IGF-1, daf2 and Regulation of Aging== The [[daf-2]] [[gene]] encodes an [[insulin]]-like [[receptor (biochemistry)|receptor]] in the worm ''[[C. elegans]]''. [[Mutation]]s in ''daf-2'' have been shown by [[Cynthia Kenyon]] to double the lifespan of the worms.<ref>See publications documenting series of experiments at [http://wormworld.ucsf.edu/publications.html Cynthia Kenyon lab], in particular, Jennie B. Dorman, Bella Albinder, Terry Shroyer & Cynthia Kenyon, "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans," ''Genetics'', volume 141, number 4, pages 1399-1406 (1995); and Javier Apfeld & Cynthia Kenyon, "Cell non-autonomy of C. elegans daf-2 function in the regulation of diapause and lifespan," ''Cell'', v. 95, n.2, pp.199-210 (1998).</ref> The gene is known to regulate reproductive development, aging, resistance to [[oxidative stress]], thermotolerance, resistance to [[Hypoxia (medical)|hypoxia]], and also resistance to bacterial [[pathogens]].<ref>{{cite journal| author = Minaxi S Gami and Catherine A Wolkow | year = 2006 | title = Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16441841 | journal = Aging Cell | volume = 5 | issue = 1 | pmid = 16441841 | doi = 10.1111/j.1474-9726.2006.00188.x | pages = 31}}</ref> DAF-2 is the only insulin/[[IGF-1]] like receptor in the worm. Insulin/[[IGF-1]]-like signaling is conserved from worms to [[human]]s. DAF-2 acts to negatively regulate the forkhead [[transcription factor]] DAF-16 through a [[phosphorylation]] cascade. Genetic analysis reveals that DAF-16 is required for ''daf-2''-dependent lifespan extension and dauer formation. When not phosphorylated, DAF-16 is active and present in the [[Cell nucleus| nucleus]]. ==Receptors== IGF-1 binds to at least two cell surface receptors: the [[IGF-1 receptor]] (IGF1R), and the [[insulin receptor]]. The [[IGF-1 receptor]] seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than IGF-1 is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor [[tyrosine kinase]] meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the

insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).. IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age. ==Use as a diagnostic test== IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a [[screening test]] for [[growth hormone deficiency]] and [[acromegaly|excess]]. Interpretation of IGF-1 levels is complicated by the wide normal ranges, and variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems. ==Diseases of deficiency and resistance== Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed [[Laron dwarfism]] does not respond at all to [[growth hormone treatment]] due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below -3 standard deviations (SD), and IGF-1 levels below -3SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment. The IGF signaling pathway appears to play a crucial role in cancer. Several studies have shown that increased levels of IGF lead to an increased risk of cancer. Studies done on lung cancer cells show that drugs inhibiting such signaling can be of potential interest in cancer therapy.<ref>{{cite journal |author=Velcheti V, Govindan R | title=Insulin-like growth factor and lung cancer |journal=Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer |volume=1 |issue=7 |pages=60710 |year=2006 | pmid=17409926 |doi= |url=http://www.jto.org/pt/re/jto/fulltext.01243894-200609000-00002.htm}}</ref> ==Factors influencing the levels of IGF-1 in the circulation== Factors that are known to cause variation in the levels of [[growth hormone]] (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and [[xenobiotic]] intake.<ref>{{cite journal |author=Scarth J | title=Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review |journal=Xenobiotica |volume=36 |issue=2-3 |pages=119218 |year= 2006 | pmid=16702112}}</ref> The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also [[endocrine disruptor]]. ==IGF-1 as a therapeutic agent== [[Image:IGF-1.GIF|thumb|right|3-d model of IGF-1]] IGF-1 has been manufactured recombinantly on a large scale using both yeast and ''E. coli''. Several companies have evaluated IGF-1 in clinical trials for a variety of indications, including growth failure, type 1 diabetes, type 2 diabetes, [[amyotrophic lateral sclerosis]] (ALS aka "Lou Gehrig's Disease"), severe burn injury and myotonic muscular dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the sponsor, [[Genentech]], discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards oncology. Cephalon and Chiron conducted two pivotal clinical

studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA. However, in the last few years, two additional companies [[Tercica]] and [[Insmed]] compiled enough clinical trial data to seek FDA approval in the United States. In August 2005, the FDA approved Tercica's IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved Iplex, [[Insmed]]'s IGF-1/IGFBP-3 complex. The Insmed drug is injected once a day versus the twice-a-day version that Tercica sells. By delivering Iplex in a complex, patients might get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia{{Fact|date=September 2008}}. This medication might emulate IGF-1's endogenous complexing, as in the human body 97-99% of IGF-1 is bound to one of six [[IGF binding proteins]]{{Fact|date=September 2008}}. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding. Insmed was found to infringe on patents licensed by Tercica, which then sought to get a U.S. district court judge to ban sales of Iplex. [http://www.nytimes.com/2007/02/17/business/17patent.html?ref=health] To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 agreed to withdraw Iplex from the U.S. market, leaving Tercica's Increlex as the sole version of IGF-1 available in the United States. [http://www.nytimes.com/2007/03/07/business/07patent.html?ref=health] On 18 November, 2008, Merck announced that their investigational compound MK-677, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms. [http://www.hayspharma.com/news/clinical-research/merck-researchers-growth-hormone-may-not-helpalzheimers/18880973] On 25 November, 2008, results of a new study were released showing that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients. Previous shorter studies had conflicting results. [http://www.newswise.com/articles/view/546591/] ==Terminology== IGF-1 has been known as "sulfation factor"<ref>{{cite journal |author=Salmon W, Daughaday W |title=A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro |journal=J Lab Clin Med |volume=49 |issue=6 |pages=82536 |year=1957 |pmid=13429201}}</ref> and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s. It was also known as "somatomedin C" in the 1980s. ==Interactions== Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 Binding Proteins (IGFBPs), of which there are six (IGFBP1-6). Specific references are provided for [[Protein-protein_interaction|interact]]ions with [[IGFBP7]],<ref name=pmid14521955>{{cite journal | quotes = yes |last=Ahmed |first=Sanjida |authorlink= | coauthors=Yamamoto Kazuhiro, Sato Yuichiro, Ogawa Takashi, Herrmann Andreas, Higashi Shouichi, Miyazaki Kaoru |year=[[2003]]|month=Oct. |title=Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity |journal=Biochem. Biophys. Res. Commun. | volume=310 |issue=2 |pages=6128 |publisher= |location = United States| issn = 0006-291X| pmid = 14521955 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid8939990>{{cite journal | quotes = yes |last=Oh |first=Y |authorlink= |coauthors=Nagalla S R, Yamanaka Y, Kim H S, Wilson E, Rosenfeld R G |year=[[1996]]|month=Nov. |title=Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II |journal=J. Biol. Chem. |volume=271 |issue=48 |pages=303225 |publisher= | location = UNITED STATES| issn = 0021-9258| pmid = 8939990 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[IGFBP3]]<ref name=pmid12735930>{{cite journal | quotes = yes |last=Liu |first=Bingrong |authorlink= |coauthors=Weinzimer Stuart A, Gibson Tara Beers, Mascarenhas Desmond, Cohen Pinchas |year=|month= |title=Type Ialpha collagen is an IGFBP-3 binding protein |journal=Growth Horm. IGF Res. |volume=13 |issue=2-3 |pages=8997 |publisher= | location = Scotland| issn = 1096-6374| pmid = 12735930 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid10823924>{{cite journal |

quotes = yes |last=Ueki |first=I |authorlink= |coauthors=Ooi G T, Tremblay M L, Hurst K R, Bach L A, Boisclair Y R |year=[[2000]]|month=Jun. |title=Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system |journal=[[PNAS| Proc. Natl. Acad. Sci. U.S.A.]] |volume=97 |issue=12 |pages=686873 |publisher= |location = UNITED STATES| issn = 0027-8424| pmid = 10823924 |doi = 10.1073/pnas.120172697 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid11600567>{{cite journal | quotes = yes |last=Buckway |first=C K |authorlink= |coauthors=Wilson E M, Ahlsn M, Bang P, Oh Y, Rosenfeld R G |year=[[2001]]|month=Oct. |title=Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding |journal=J. Clin. Endocrinol. Metab. |volume=86 | issue=10 |pages=494350 |publisher= |location = United States| issn = 0021-972X| pmid = 11600567 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid1383255>{{cite journal | quotes = yes |last=Cohen |first=P |authorlink= | coauthors=Graves H C, Peehl D M, Kamarei M, Giudice L C, Rosenfeld R G |year=[[1992]]|month=Oct. | title=Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma |journal=J. Clin. Endocrinol. Metab. |volume=75 |issue=4 |pages=104653 |publisher= |location = UNITED STATES| issn = 0021-972X| pmid = 1383255 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid9497324>{{cite journal | quotes = yes | last=Twigg |first=S M |authorlink= |coauthors=Baxter R C |year=[[1998]]|month=Mar. |title=Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit | journal=J. Biol. Chem. |volume=273 |issue=11 |pages=60749 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 9497324 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid9446566>{{cite journal | quotes = yes |last=Firth |first=S M |authorlink= |coauthors=Ganeshprasad U, Baxter R C |year=[[1998]]|month=Jan. |title=Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3 |journal=J. Biol. Chem. |volume=273 |issue=5 |pages=26318 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 9446566 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> and [[IGFBP4]].<ref name=pmid7683646>{{cite journal | quotes = yes |last=Bach |first=L A |authorlink= | coauthors=Hsieh S, Sakano K, Fujiwara H, Perdue J F, Rechler M M |year=[[1993]]|month=May. |title=Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6 |journal=J. Biol. Chem. |volume=268 |issue=13 |pages=924654 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 7683646 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid9722589>{{cite journal | quotes = yes |last=Qin |first=X |authorlink= | coauthors=Strong D D, Baylink D J, Mohan S |year=[[1998]]|month=Sep. |title=Structure-function analysis of the human insulin-like growth factor binding protein-4 |journal=J. Biol. Chem. |volume=273 |issue=36 |pages=23509 16 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 9722589 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref>. <p> [[IGFBP-3]] is a carrier for IGF-1, meaning that IGF-1 binds [[IGFBP-3]], creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to [[IGFBP-3]], IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to [[IGFBP-3]], IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF1 has for its receptor, [[IGFR]], its binding does not interfere with IGF-1 function. For these reasons, an IGF-1/ [[IGFBP-3]] combination approach was approved for human treatment... brought forward by a small company called [[Insmed]]. However, Insmed fell afoul patent issues, and was ordered to desist in this approach. <p> Other IGFBPs are inhibitory. For example, both [[IGFBP-2]] and [[IGFBP-5]] bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.