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PubMed2001

The inhibitory effect of IL-1 beta on IL-6-induced alpha 2-macroglobulin expression is due to activation of NF-kappa B.

The cross-talk between the signal transduction of simultaneous acting cytokines largely determines the final impact of cytokines on their target genes. Both NF-kappaB and STAT3 are transcription factors well known to be activated by many stimuli and to mediate transcriptional activation by binding to specific enhancer sequences. In this study, it is analyzed how IL-1beta inhibits IL-6-induced transcriptional activation of the alpha(2)-macroglobulin promoter. It is shown that IL-1beta prevents STAT3 binding to the two STAT3-responsive sites within the alpha(2)-macroglobulin promoter by association of IL-1beta-activated NF-kappaB to this region. The observation that inhibition of IL-6-induced transcriptional activation of this promoter by IL-1beta is reversed by cotransfection with I-kappaBalpha provides evidence that NF-kappaB activation by IL-1beta is responsible for inhibition of IL-6-mediated trans activation of the alpha(2)-macroglobulin gene. Accordingly, cotransfection of the NF-kappaB subunits p50 or p65 themselves inhibited activation of the alpha(2)-macroglobulin promoter by IL-6. Introduction of point mutations in each of the two NF-kappaB sites overlapping the two STAT3 binding sites within the alpha(2)-macroglobulin promoter provides evidence that each of these two sites counteracts transcriptional activation via STAT3. Most interestingly, at least one functional NF-kappaB consensus site is essential for the IL-6-induced transcriptional activation of the alpha(2)-macroglobulin promoter. Additional data are provided indicating that the activation of NF-kappaB by IL-1beta is also responsible for the inhibition of other IL-6-inducible genes, such as the alpha(1)-antichymotrypsin gene as well as the suppressor of cytokine signaling 3 gene, suggesting a more general relevance of this mechanism for transcriptional regulation.

Animals↗

PubMed1990

Interaction of thrombin with endothelial cells in the presence of fibrinogen and alpha 2-macroglobulin.

Binding of thrombin to cultured endothelial cells has been studied in the presence of fibrinogen and alpha 2-macroglobulin. Both fibrinogen and alpha 2-macroglobulin inhibit the interaction of thrombin with endothelial cells. Whereas fibrinogen decreases the rate of activation by the thrombin-thrombomodulin complex of protein C, thrombomodulin inhibits the rate of inactivation by alpha 2-macroglobulin thrombin. alpha 2-macroglobulin also binds to endothelial cells; (Kd = 3 x 10(-7) M with 3 x 10(5) binding sites/cell), and the rate of binding of the alpha 2-macroglobulin to endothelial cells is faster than its complex formation with the thrombin. The data suggest that essentially the cell-bound form of fibrinogen and alpha 2-macroglobulin influences thrombin binding and functions.

Aorta↗

PubMed1986

The acute-phase induction of alpha 2-macroglobulin in rat hepatocyte primary cultures: action of a hepatocyte-stimulating factor, triiodothyronine and dexamethasone.

During inflammation a number of liver-derived plasma proteins increases in concentration. In the rat these so-called acute-phase proteins are mainly proteinase inhibitors, such as alpha 1-proteinase inhibitor, alpha 1-acute-phase globulin and alpha 2-macroglobulin. At present, the mechanisms responsible for the enhanced synthesis of acute-phase proteins are poorly understood. Therefore, we have studied the induction of alpha 2-macroglobulin synthesis in rat hepatocyte primary cultures. Adrenaline, triiodothyronine, estradiol and progesterone were tested for their ability to stimulate alpha 2-macroglobulin synthesis. Only triiodothyronine induced alpha 2-macroglobulin synthesis markedly. However, the presence of dexamethasone was a prerequisite for alpha 2-macroglobulin induction indicating a permissive action of glucocorticoids. Besides glucocorticoids and triiodothyronine a non-dialyzable factor (HSF) derived from rat Kupffer cells or human peripheral blood monocytes was found to be able to stimulate alpha 2-macroglobulin synthesis in hepatocytes. Equal amounts of HSF activity were found in conditioned media from lipopolysaccharide-stimulated and unstimulated rat Kupffer cells as well as in human monocytes. Since the supernatants of unstimulated rat Kupffer cells or human monocytes did not exhibit interleukin 1 activity, HSF activity distinct from interleukin 1 must exist. No HSF activity was found in media conditioned by rat Kupffer cells which had been treated with dexamethasone. Hepatocyte primary cultures were incubated with [35S]methionine-labeled proteins secreted by rat Kupffer cells. A 30 kDa polypeptide was found to be bound to or internalized by rat hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Monoclonal antibodies against a glycoprotein localized in coated pits and endocytic vesicles inhibit alpha 2-macroglobulin binding and uptake.

Eight monoclonal antibodies, all IgG2a, which recognize a 180/90-kDa glycoprotein similar in properties to the receptor for alpha 2-macroglobulin of mouse embryo 3T3 cell plasma membranes, have been tested for their effect on the binding and uptake of alpha 2-macroglobulin by live cells. One antibody directly inhibited binding of 125I-alpha 2-macroglobulin under conditions in which 125I-transferrin binding to the transferrin receptor was unaffected. Another monoclonal antibody decreased alpha 2-macroglobulin binding when preincubated with cells at 37 degrees C. This antibody was also capable of specifically binding to ligand-receptor complexes formed by preincubating 125I-alpha 2-macroglobulin with detergent extracts of Swiss 3T3 cells. Immunoelectron microscopy showed that the 180/90-kDa glycoprotein was localized in coated pits of the cell surface and in intracellular endocytic vesicles (receptosomes/endosomes). The data suggest that the 180/90-kDa glycoprotein is a component of the receptor for alpha 2-macroglobulin.

Animals↗

PubMed1981

Localization of the two protease binding sites in human alpha 2-macroglobulin.

The distance between the two protease binding sites in human plasma alpha 2-macroglobulin has been estimated using singlet-singlet energy transfer experiments. alpha-Chymotrypsin was labeled covalently with donor (dansyl chloride) or acceptor (fluorescein isothiocyanate) groups, and the efficiency of transfer between these dyes was measured within the alpha 2-macroglobulin . (alpha-chymotrypsin)2 complex. The distance between the surface exterior of the protease molecules was calculated to be 4 to 11 A, depending on the assumption made about the equivalence of the binding sites. A catalytically active dimer of alpha-chymotrypsin was prepared using the heterobifunctional reagent N-succinimidyl-3-(2-pyridyldithio)propionate. In contrast with the alpha-chymotrypsin monomer, it binds to alpha 2-macroglobulin with a 1:1 stoichiometry. However, the 1:1 alpha 2-macroglobulin . dimeric alpha-chymotrypsin complex is still able to bind 1 mol of the alpha-chymotrypsin monomer. Energy transfer experiments performed with this ternary complex showed that the distance between the alpha 2-macroglobulin-bound alpha-chymotrypsin molecules is not higher than 4 A, i.e. the two protease binding sites in alpha 2-macroglobulin should be about 44 A apart (center to center) if the anhydrous radius of alpha-chymotrypsin is 20 A.

Animals↗

PubMed1981

Inhibition of alpha 2-macroglobulin-bound trypsin by soybean trypsin inhibitor.

Soybean trypsin inhibitor, a protein of Mr = 20,000, has been used to assess the degree of inaccessibility of porcine trypsin within the alpha 2-macroglobulin-trypsin complex. The interaction between alpha 2-macroglobulin-bound trypsin and the inhibitor was demonstrated by affinity chromatography and trypsin inhibition. Whereas the free trypsin-inhibitor association is very fast (k = 1.2 X 10(7) M-1 s-1), the reaction between complexed trypsin and inhibitor takes 10 h to reach equilibrium. In addition, alpha 2-macroglobulin reduces, by several orders of magnitude, the affinity of trypsin for the inhibitor. Only one of the two trypsin molecules of the ternary (trypsin)2-alpha 2-macroglobulin complex is readily accessible to soybean inhibitor. It is postulated that the recently discovered proximity of the alpha 2-macroglobulin binding sites (Pochon, F., Favaudon, V., Tourbez-Perrin, M., and Bieth, J. (1981) J. Biol. Chem. 256, 547-550) accounts for this behavior. In the light of these results it is concluded that the proteinase binding sites are localized on the alpha 2-macroglobulin surface and that the two subunits of this protein are either not identical or not symmetrically arranged.

Animals↗

PubMed1994

Oxidative dissociation of human alpha 2-macroglobulin tetramers into dysfunctional dimers.

Human alpha 2-macroglobulin is a broad-spectrum, homotetrameric antiproteinase that can maximally bind up to two proteinase molecules in a ternary complex. Proteinases cleave the inhibitor within a peptide stretch termed the bait region and induce the emergence of internal thiol esters whose nucleophilic scission precede a major conformational change which entraps enzymes within molecular cages. In a previous study, leukocyte-generated hypohalous acids and N-haloamines were identified as the first examples of physiologically relevant inactivators of the antiproteolytic activity of alpha 2-macroglobulin (Reddy, V. Y., Pizzo, S. V., and Weiss, S. J. (1989) J. Biol. Chem. 264, 13801-13809), but the mechanisms whereby the oxidants damaged the inhibitor remained undefined. We now demonstrate that N-chloramines (RNCl) destroy the antiproteolytic activity of alpha 2-macroglobulin in an unusual biphasic process that results in the formation of inactive alpha 2-macroglobulin half-molecules. In the first phase, 8 eq of RNCl reacted with each alpha 2-macroglobulin subunit to generate a partially oxidized antiproteinase containing 8 methionyl sulfoxide residues/monomer. Structure-function analyses demonstrated that the oxidized inhibitor retained its homotetrameric structure as well as its ability to entrap proteinases. In marked contrast, the oxidation of an additional 6 methionyl residues and a single tryptophanyl residue fractured the alpha 2 M homotetramer across its non-covalent axis into two pairs of disulfide-linked dimers. Despite the fact that the oxidized dimers displayed normal bait regions whose cleavage by proteinases initiated thiol ester scission, all antiproteolytic activity was lost. Furthermore, the oxidized dimers were unable to undergo the critical conformational changes normally associated with bait region cleavage or thiol ester scission. Together, these results demonstrate that chlorinated oxidants destroy the antiproteolytic activity of alpha 2-macroglobulin by attacking a subset of methionyl and tryptophanyl residues whose oxidation mediates the dissociation of the native homotetramer into conformationally locked dimers.

Amino Acid Sequence↗

PubMed1994

Determination of the synthesis and uptake of alpha 2-macroglobulin by cultured human glioma cells.

Using immunological techniques, the synthesis of alpha 2-macroglobulin was studied in established cell lines derived from human glioblastomas multiforme. alpha 2-Macroglobulin was detected in cytoplasm and in the culture medium of the analyzed cell lines. Radioimmunoprecipitation revealed a protein with M(r) corresponding to alpha 2-macroglobulin in the medium conditioned by U-118MG and U-343MG cells. On the other hand, using immunoblot analysis, alpha 2-macroglobulin was detected in all of the analyzed lines. In immunofluorescence test, alpha 2-macroglobulin was determined also in all four cell lines, but with different staining pattern. Conditioned culture medium (CCM) of U-536MG cells with the lowest level of alpha 2-macroglobulin exerted the lowest mitogenic activity for human fibroblasts.

Blotting, Western↗

PubMed1994

[Expression and secretion of alpha-2-macroglobulin by dust-stimulated alveolar macrophages].

In dust-induced, fibrosing lung processes macrophages are increased activated by foreign body reactions. The release of monokines and proteolytic enzymes, which depends on phagocytosis, may lead to destruction of the extracellular matrix with the consequence of degradation and restitution. Also the transcellular signaling or cell-matrix-interaction may finally result in development of fibrosis. However the proteolytic effect of elastase and collagenase can be inhibited by alpha-2-macroglobulin. Alpha-2-macroglobulin is a protease-inhibitor, which is synthesized by macrophages and has a wide spectrum of inhibitory abilities. Our interest was focused on observation of the production of alpha-2-macroglobulin by alveolar macrophages after stimulation with inorganic dusts of different chemical and physical properties. Rat alveolar macrophages were isolated by bronchoalveolar lavage and exposed to crocidolite, quarz or welder steam dust in vitro. The expression and secretion of alpha-2-macroglobulin was examined by non radioactive in situ hybridization, indirect immunofluorescence and radial immunodiffusion according to Mancini. The stimulated rat alveolar macrophages showed an increased expression of alpha-2-macroglobulin-mRNA and also an enhanced synthesis of alpha-2-macroglobulin-protein. Besides only small differences between the substances used for stimulation were demonstrated.

Animals↗

PubMed1994

Alpha 2-macroglobulin levels in normal human and keratoconus corneas.

PURPOSE: To compare the levels of alpha 2-macroglobulin, one of the major proteinase inhibitors, in corneas with keratoconus to those in normal human corneas and corneas with other diseases. METHODS: An immunoperoxidase technique was used to visualize the presence of alpha 2-macroglobulin in the corneas. Western blot analysis was performed, and the levels of this inhibitor in extracts of keratoconus and normal human corneas were subsequently analyzed by a dot blot assay. RESULTS: alpha 2-Macroglobulin was demonstrated immunohistochemically in the epithelium, stroma, and endothelium of all corneal sections. Compared with normal human control specimens, the staining intensity in the epithelium of keratoconus corneas was markedly reduced. The majority of scarred and other diseased corneas exhibited normal staining intensity for alpha 2-macroglobulin. Dot blot assays showed that the alpha 2-macroglobulin levels in the epithelial and stromal extracts of keratoconus corneas were lower than those found in normal human control counterparts. CONCLUSION: Keratoconus corneas contained a reduced level of alpha 2-macroglobulin. This result lends further support to the hypothesis that degradation processes may be aberrant in keratoconus.

Adolescent↗

PubMed1978

Effects of alpha2-plasmin inhibitor on fibrin clot lysis. Its comparison with alpha2-macroglobulin.

The major plasmin inhibitors namely alpha2-plasmin inhibitor and alpha2-macroglobulin were compared for their effects on lysis of fibrin clot. Plasmin fibrinolytic activity was immediately inhibited by alpha2-plasmin inhibitor, whereas alpha2-macroglobulin inhibited plasmin progressively. Urokinase(plasminogen activator)-induced clot lysis was inhibited efficiently by alpha2-plasmin inhibitor present in the clot. Inhibition of urokinase-induced clot lysis by alpha2-macroglobulin was weak and the molar concentration necessary for alpha2-macroglobulin to achieve the same degree of inhibition as that achieved with alpha2-plasmin inhibitor was about 10 times higher than that of alpha2-plasmin inhibitor. Binding of Lys-plasminogen to fibrin was inhibited by alpha2-plasmin inhibitor but not by alpha2-macroglobulin. Molar concentrations of alpha2-plasmin inhibitor which were effective in inhibiting the binding were 30 times less than that of 6-aminohexanoicacid. alpha2-Plasmin inhibitor was found to interact with Lys-plasminogen to form a weakly-bound complex which is dissociable in the presence of 6-aminohexanoic acid, suggesting that inhibition of binding of Lys-plasminogen to fibrin by alpha2-plasmin inhibitor may be due to interaction of alpha2-plasmin inhibitor with a specific site of the plasminogen molecule and that the site may be 6-aminohexanoic acid-binding site. It is suggested that alpha2-plasmin inhibitor is more reactive and efficient inhibitor of fibrinolysis than alpha 2-macroglobulin.

Aminocaproic Acid↗

PubMed1979

[Heparin inhibition of the antithrombin activity of alpha-2-macroglobulin].

The interaction between thrombin and alpha-2-macroglobulin was studied on human purified materials, either in the presence or in the absence of heparin, by kinetic analysis of thrombin inhibition and polyacrylamide gel electrophoresis. In the absence of heparin, binding of thrombin to alpha-2-macroglobulin, shown by electrophoresis, leads to the loss of the coagulant property of the enzyme. In the presence of heparin the rate of inhibition of thrombin clotting activity by alpha-2-macroglobulin is strongly decreased. Heparin binds to thrombin, impairing the formation of thrombin-alpha-2-macroglobulin complex. These data show that heparin paradoxically protects thrombin from inhibition by alpha-2-macroglobulin whereas it increases the enzyme inhibition by antithrombin III. Such a phenomenon could be of practical interest for treatment of thrombosis in patients with high plasma level of alpha-2-macroglobulin and low level of antithrombin III, such as occurs in the nephrotic syndrome.

Heparin↗

PubMed1997

Studies on proteases and alpha-macroglobulin activity in amphibian blood plasma.

Frog plasma effectively hydrolysed the synthetic chromogenic substrates, H-D-Glu-Gly-Arg-p-nitroanilide (S-2444), benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide (S-2222) and acetyl-Ile-Glu-Gly-Arg- p-nitroanilide (S-2423), all sensitive substrates for trypsin. Moderate hydrolytic activities was observed with H-D-Phe-Pip-Arg-p-nitroanilide (S-2238, substrate for thrombin) and H-D-Pro-Phe-Arg-p-nitroanilide (S-2302, substrate for plasma kallikrein). Frog plasma contained moderate alpha-macroglobulin activity. When plasma was incubated at 37 degrees C, the macroglobulin activity decreased in a time dependent manner while only a moderate decrease in the protease activity was observed. Ten fold dilution of plasma with 0.1 M phosphate buffer, pH 7.6 prevented the inherent loss of macroglobulin activity but it had no effect on protease activity. Dye ligand chromatography of the plasma on red Sepharose revealed that bulk of alpha-macroglobulin activity along with minor proteolytic activity (S-2222 hydrolysis) was present i the washings. On the other hand, about one third of the alpha-macroglobulin activity and bulk of the protease activity was bound to the column and were eluted with 1.5 M NaCl. alpha-Macroglobulin activity in red Sepharose washings and elutions on chromatography on Sephadex G-200, was eluted in two regions with Ve/Vo value of 1.33 and 1.08, respectively.

Animals↗

PubMed1984

Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides.

We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin.

Animals↗

PubMed1988

Purification and characterization of alpha-macroglobulin and ovomacroglobulin of the green turtle (Chelonia mydas japonica).

The plasma alpha-macroglobulin and egg white ovomacroglobulin were purified from the sea turtle, Chelonia mydas japonica, and their structural and functional properties were studied with the aim of clarifying the degree of evolutional divergence of two homologous proteins specific to different tissues of the same animal. The concentration of alpha-macroglobulin in green turtle plasma was about 4 mg/ml. The protein was purified from the plasma by precipitation with polyethylene glycol 6000, followed by zinc chelate chromatography and gel chromatography on Sepharose CL-6B. The concentration of ovomacroglobulin in green turtle egg white was about 0.4 mg/ml. Ovomacroglobulin was purified by gel chromatography on Sepharose CL-6B. The two proteins had similar molecular weights and amino acid compositions, and both inhibited proteinases such as trypsin, chymotrypsin, papain, and thermolysin. The amino terminal sequences of the two proteins were homologous to each other but higher homologies were found between the ovomacroglobulin of turtle and chicken, and between the serum macroglobulins of the same animals. The functional difference between turtle alpha-macroglobulin and ovomacroglobulin became clear when they were treated with methylamine, which is known to destroy the inhibitory activity of human alpha 2-macroglobulin by splitting internal thiolester bonds. The inhibitory activity of the turtle plasma protein was completely destroyed by methylamine but that of ovomacroglobulin was only partially affected. The number of sulfhydryl groups as titrated with 5,5'-dithiobis(2-nitrobenzoate) before and after treatment with proteinases or methylamine was different for the two proteins. The amount of radioactive methylamine that was incorporated was also different between the two proteins. The two proteins purified in this study had no immunological cross-reactivity.

Amino Acid Sequence↗

PubMed1991

alpha 2-Macroglobulin is cleaved by HIV-1 protease in the bait region but not in the C-terminal inter-domain region.

alpha 2-Macroglobulin is cleaved by human immunodeficiency virus-1 protease. The cleavage site is the Phe684-Tyr685 bond in the "bait region", an exposed part of alpha 2-macroglobulin, creating the "F-form". The methylamine derivative of alpha 2-macroglobulin is also cleaved at the same bond. The homologous chicken ovomacroglobulin does not form an F-form structure with the protease, although, F-form generation by other enzymes is known. This is possibly due to the lack of a suitable cleavage sequence in the corresponding region of ovomacroglobulin. In human alpha 2-macroglobulin, the interdomain segment between the main part of the molecule and the receptor-binding C-terminal domain is not cleaved by the HIV protease although typical cleavage sequences occur. In AIDS, therefore, HIV protease from infected cells in unlikely to interfere with receptor-binding of alpha 2-macroglobulin.

Amino Acid Sequence↗

PubMed1998

Inhibition of dopamine and choline acetyltransferase concentrations in rat CNS neurons by rat alpha 1- and alpha 2-macroglobulins.

Previous studies have implicated human alpha-2-macroglobulin (alpha2M) as a potential regulator of neuronal development and function. Rat alpha-1-macroglobulin (alpha1M) and acute-phase alpha-2-macroglobulin (alpha2M) are murine homologues of human alpha2M. In this report, we tested the effect of intracranially infused serotonin-activated rat alpha1M (5HT-alpha1M) on the concentration of dopamine (DA) in the corpus striatum in vivo and the effect of 5HT-activated rat alpha1M and alpha2M on the choline acetyltransferase (ChAT) activity upon embryonic basal forebrain neurons in culture. The results show that direct infusion of 0.65 nmole rat 5HT-alpha1M into the adult rat corpus striatum produced a consistent attenuation upon striatal DA concentrations. This decrease was particularly prominent at 5-7 days post-infusion. In addition, rat 5HT-alpha1M and rat 5HT-alpha2M, like human 5HT-alpha2M, all significantly inhibited ChAT activity of embryonic rat cerebral cortex neurons. Although normal human alpha2M and rat alpha2M were either marginally or insignificantly inhibitory in this preparation, normal rat alpha1M dose-dependently inhibited ChAT activity. These results demonstrate that monoamine-activated alpha-macroglobulins from rat depress dopaminergic and cholinergic neurotransmitter systems in the CNS, and this suggests a potential regulatory role of these alpha-macroglobulins in neurotransmitter metabolism.

Animals↗

PubMed1985

Changes in plasma haptoglobin and alpha-2-macroglobulin in hemophiliacs receiving factor replacement therapy.

Plasma proteins were studied in 84 patients with hemophilia A, who were receiving factor replacement therapy. Compared with age-matched controls, 63 patients (75%) had subnormal haptoglobin and 58 (69%) had elevated alpha-2-macroglobulin. Causes for depressed haptoglobin were sought by correlating ABO blood types, liver function tests, factor VIII procoagulant levels, and intensity of yearly exposure to clotting factor products. Subnormal haptoglobin levels in chronically transfused patients may relate in part to hemolysis from AB incompatability. However, depressed haptoglobin levels were also found in group O hemophiliacs without other evidence of hemolysis. Most patients lacked evidence of active liver disease, making synthetic deficiency unlikely. There was close correlation between depressed haptoglobin and severity of clotting factor deficiency. The degree of alpha-2-macroglobulin elevation correlated with severity of procoagulant deficiency but not with intensity of clotting factor replacement therapy. Since alpha-2-macroglobulin plays a major role in the catabolism of fibrinogen, elevated levels may represent a compensatory increase in response to exogenous fibrinogen contained in the clotting factor concentrates. Alternatively, since alpha-2-macroglobulin has potent immunosuppressive properties, the elevation may represent a response to transfused alloantigens. Whatever the underlying cause, it is likely the elevations are due to endogenous production rather than to transfusions since clotting factor concentrates contain minimal amounts of alpha-2-macroglobulin.

ABO Blood-Group System↗