Prekallikrein activation

An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture [42-45]. Two different groups have isolated two different proteins, each of which seems to activate the HK-prekallikrein complex. One is heat-shock protein 90 [46] and the other is a prolylcarboxypeptidase [47]. Neither protein is a direct prekallikrein activator as is factor Xlla or factor Xllf because each activator requires HK to be complexed to the prekallikrein. In addition, the reaction is stoichiometric, thus the amount of prekallikrein converted to kallikrein equals the molar input of heat-shock protein 90 (or prolylcarboxypeptidase). These proteins can be shown to contribute to factor Xll-independent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor Xll-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor Xll-dependent [45]. Under normal circumstances (with factor XII present), formation of any kallikrein will lead to factor Xlla formation even if the process were initiated by one of these cell-derived factors. 

Shariat-Madar Z, Mahdi F. Schmaier A Identification and characterization of prolylcarboxypepti-dase as an endothelial cell prekallikrein activator. J Biol Chem 2002 277 17962-17969. 

Pregnancy, exposure to organic solvents during, 23 119 Preheater rotary kiln, 25 53 Preheat trains, 23 221-223 Preinstalled piping system, in fine chemical production, 2 2 428-429 Prekallikrein, 4 86-87 Prekallikrein activator (PKA), 22 145, 146 Pre-liming, in beet juice purification, 23 459... 

Alving BM, Hojima Y, Pisano JJ, Mason BL, Buckingham RE, Mozen MM, et al. Hypotension associated with prekallikrein activator (Hageman factor fragments) in plasma protein fraction. N Engl J Med 1978 299 66-70. 

The pain-producing factor formed by diluting plasma may be identical with activated factor XII (Xlla) and splits into prekallikrein activator with factor XII activity and some fragments (34). Collagen gains kinin-... 

Adverse reactions to human serum albumin are uncommon and usually mild, such as itching and urticaria. Serious reactions are rare. A patient who has reacted violently to albumin on one occasion may tolerate it well on another after being given an antihistamine such as diphenhydramine (1). Aggregates present in protein preparations may be the cause of some reactions. Another postulated cause may be the presence of antibodies against genetic variants of human albumin (2). Hypotensive reactions due to the presence of a prekallikrein activator in some batches of formulations can occur. 

Not fully established, but it is believed that SPPS contains low levels of pre-kallikrein activator, which stimulates the production of bradykinin, which can cause vasodilatation and hypotension. Normally the bradykinin is destroyed by kininase II (ACE), but this is delayed by the ACE inhibitor so that the hypotensive effects are exaggerated and prolonged. In the case with albumin 4%, a sample of the albumin used was analysed, and it was found to contain less prekallikrein activating factor than maximum permissible levels. It was suggested that the infusion of gelatin-based colloids somehow resulted in raised plasma kinin levels associated with inhibition of ACE. ... 

Heinonen J, Peltola K, Himberg J-J, Suomela H (1981) Hypotensive effect of prekallikrein activator (PKA) in plasma protein fractions (PPF). Dev Biol Stand 48 129-130 Henriques W, Andersen AC (1913) Uber parenterale Emahrung durch intravenose Injekti-on. Hoppe Seylers Z Physiol Chem 88 357-369 Hogan JJ (1915) The intravenous use of colloidal (gelatin) solutions in shock. JAMA 64 721-726... 

Lorenz W, Doenicke A, Reimann HJ, Schmal A, Schwarz B, Dorman P (1978) Anaphylactoid reactions and histamine release by plasma substitutes a randomized controlled trial in human subjects and in dogs. Agents Actions 8 397-399 Liiben G, Quast U, Geiger H (1981) Prekallikrein activator levels and side effects with human albumin preparations. Dev Biol Stand 48 123-127 Lund N (1973) Anaphylactic reactions induced by infusion of haemaccel. Br J Anaesth 45 929... 

Factor Xlla is a serine protease that activates FXI to FXIa (Fig. 5). This system is not of physiologic relevance since patients with hereditary deficiencies of factor XII, prekallikrein, and high-molecular weight kininogen do not present with bleeding symptoms. 

HK it can interact with surface-bound factor XII on an adjacent particle thereby disseminating the reaction [25, 28]. As a result the effective kallikrein/factor XII ratio is increased in the presence of HK [25], Finally, in plasma, HK can displace other adhesive glycoproteins such as fibrinogen from binding to the surface [29]. In this sense, HK, like factor XII and prekallikrein, is also a coagulation cofactor because it is required for the generation of kalUkrein (a factor XII activator) as well as the activation of factor XI. 

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

Kaplan AP, Austen KF A pre-albumin activator of prekallikrein. J Immunol 1970 105 802-811. 

Mandle RJ, Kaplan A Hageman factor substrates. Human plasma prekallikrein mechanism of activation by Hageman factor and participation in Hageman factor-dependent fibrinolysis. J Biol Chem 1977 252 6097-6104. 

Wiggins RC. Bouma BN. Cochrane CG. Griffin JH Role of high-molecular-weight kininogen in surface-binding and activation of coagulation factor XI and prekallikrein. Proc Natl Acad Sci USA 1977 74 4636-4640. 

Motta G, Rojkjser R, Hasan AA, Cines DB, Schmaier AH High molecular weight kininogen regulates prekallikrein assembly and activation on endothe- 57 lial cells a novel mechanism for contact activation. 

Kaplan AP, Austen KF A prealbumin activator of prekallikrein. II. Derivation of activators of prekal-likrein from active Hageman factor by digestion with plasmin. J Exp Med 1971 133 696-712. 

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

The intrinsic pathway (Figure 51-1) involves factors XII, XI, IX, VIII, and X as well as prekallikrein, high-molecular-weight (HMW) kininogen, Ca, and platelet phospholipids. It results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). 

---