The Immunologic Character of Acquired Inhibitors of Antihemophilic Globulin (Factor VIII) and the Kinetics of Their Interaction with Factor VIII*

Shapiro, Sandor S.

doi:10.1172/jci105517

Cited by 131 publications

(59 citation statements)

References 33 publications

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“…These findings contrast strikingly with the accumulating evidence of the monotypic nature of the lightchain types of high titer factor VIII inhibitors, which rarely disappear (35)(36)(37).…”

Section: Discussioncontrasting

confidence: 82%

“…For example, in one experiment one part of 1 u/ml bovine thrombin, prepared as described elsewhere (20), was added to nine parts of oxalated human plasma that had been adsorbed with barium sulfate powder. Clotting times in the factor V assay of diluted subsamples shortened from 45 sec, when barbital buffer was used as the control for the thrombin, to [35][36][37][38] sec. An equal volume of either adsorbed herditary factor V deficiency plasma, as a control, or adsorbed patient's plasma was added to the thrombin-treated factor V, and serial subsamples were removed, diluted, and assayed for factor V activity.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Factor V anticoagulants: clinical, biochemical, and immunological observations

Feinstein¹,

Rapaport²,

McGehee³

et al. 1970

J. Clin. Invest.

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A B S T R A C T A patient who had received multiple transfusions for complications of acute hemorrhagic pancreatitis developed a potent factor V anticoagulant with bleeding due to defective hemostasis. Despite its potency, the anticoagulant disappeared within 15 days of its first manifestation. A second patient with adenocarcinoma of the colon developed an anticoagulant to factor V postoperatively after a single blood transfusion. The anticoagulants appeared to react stoichiometrically with factor V in normal plasma in vitro. They had the physicochemical properties of immunoglobulins, and their activity was neutralized by antihuman immunoglobulin antiserum. One anticoagulant appeared to be slightly more active against homologous than against autologous factor V, but it also inhibited heterologous factor V. Both anticoagulants progressively inactivated intrinsic prothrombin activator formed from normal reagents in the incubation mixture of the thromboplastin generation test, thus confirming that factor V is required for the effective action of the intrinsic prothrombin activator. Since the anticoagulants were immunoglobulins whose activity was consumed in their reaction with factor V, consumption of anticoagulant activity was used to detect factor V antigenic material in test materials. Human serum without factor V clotting activity was found to consume anticoagulant activity, i.e., to contain inactive factor V antigenic material. Plasma from two patients with hereditary factor V deficiency (parahemophilia) failed to consume significant anticoagulant activity. Thus, the lack of factor V activity in these patients represents a deficiency of factor V molecules rather than the synthesis of a defective molecule with impaired clotting activity. INTRODUCTIONAcquired anticoagulants are a well-documented cause of hemorrhagic disease. One relatively common anticoagulant acts against factor VIII (antihemophilic globulin) and has been characterized as an immunoglobulin. It has been found in patients with hereditary factor VIII deficiency after transfusions, in postpartum women, in disorders characterized by immunologic phenomena, e.g. in systemic lupus erythematosus, rheumatoid arthritis, and drug reactions, and in elderly patients without underlying disease. This paper is a report of studies on a much rarer anticoagulant, a potent inhibitor of factor V (proaccelerin), which was found in two patients. The mechanism of action and the properties of each patient's inhibitor were characterized. These inhibitors were used to study further the role of factor V in clotting and to define the defect in two patients with hereditary factor V deficiency (parahemophilia) (1).

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Section: Discussioncontrasting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Factor V anticoagulants: clinical, biochemical, and immunological observations

Feinstein¹,

Rapaport²,

McGehee³

et al. 1970

J. Clin. Invest.

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show abstract

“…Factors VII and X were measured by correction, respectively, of the prothrombin time and Russell's viper venom time of congenitally deficient substrate plasmas. Assays for factors VIII, IX, and XI were done by standard one-stage methods, as previously described (14).…”

Section: Coagulation Methodsmentioning

confidence: 99%

“…To a glass test tube containing 0.3 ml of a standard citrated normal plasma was added 0.33 mg of normal or patient II-7 "step 5" protfhrombin in 0.1-0.2 ml, and the volume brought to 2.75 ml with imidazole-buffered saline, pH 7.2 (14). The mixture was warmed to 370C and recalcified with 0.25 ml of 0.1 is CaCis.…”

Section: Prothrombin Activationmentioning

confidence: 99%

Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin

Shapiro¹,

Martinez²,

Holburn³

1969

J. Clin. Invest.

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“…The isotypic distribution of polyclonal anti-FVIII IgG follows the physiologic profile of IgG subclasses, with a preference, however, for the IgG1 and IgG4 isotypes. [94][95][96] Noticeably, the 2 published human monoclonal FVIII inhibitors, the anti-C2 BO2C11 and anti-C1 LE2E9, are both of the IgG4 isotype. 82,83 Anti-FVIII IgGs are polyclonal in patients and encompass antibodies that are endowed with inhibitory properties toward FVIII procoagulant activity, and antibodies that bind FVIII without affecting its functional activity as measured using the Bethesda assay.…”

Section: Actors Of the Anti-fviii Immune Responsementioning

confidence: 99%

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A

Lacroix‐Desmazes

Navarrete

André

et al. 2008

Blood

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Procoagulant factor VIII (FVIII) is either produced endogenously under physiologic conditions, or administered exogenously as a therapeutic hemostatic drug in patients with hemophilia A. In the circulation, FVIII interacts with a multitude of glycoproteins, and may be used for coagulation at the sites of bleeding, eliminated by scavenger cells, or processed by the immune system, either as a self-constituent or as a foreign antigen. The fate of FVIII is dictated by the immune status of the individual, the location of FVIII in the body at a given time point, and the inflammatory microenvironment. It also depends on the local concentration of FVIII and of each interacting partner, and on the affinity of the respective interactions. FVIII, by virtue of its promiscuity, thus constitutes the core of a dynamic network that links the coagulation cascade, cells of the immune system, and, presumably, the inflammatory compartment. We describe the different interactions that FVIII is prone to establish during its life cycle, with a special focus on players of the innate and adaptive immune response. Lessons The life cycle of FVIII has been described in great detail previously. 1 Here we recapitulate the key steps of the FVIII life cycle, and highlight the different molecules that FVIII may interact with at different stages of its life. In the circulation, FVIII binds to at least 10 different identified proteins, some of them behaving as physiologic chaperones, some that participate in the coagulation cascade, and others being involved in removal of biologic wastes ( Figure 1). While binding to different proteins may involve the same structures on the FVIII molecule, the sequence of FVIII interactions with its physiologic partners is ordered temporally and spatially, depending on the quiescent, activated, or inactivated state of the molecule. Three phases in the life cycle of FVIII may thus be distinguished: transport of FVIII from the site of secretion to the bleeding site; participation of FVIII in the coagulation cascade; and clearance of FVIII from the circulation. Because it is not pertinent for the present discussions, we leave aside the intramolecular interactions of FVIII within the cells that produce it. 2 Transport of FVIII from the site of secretion to the bleeding site. FVIII is synthesized mainly in the liver by sinusoidal endothelial cells 3,4 and possibly by hepatocytes. 5,6 Production of FVIII by human microvascular lung endothelial cells has also been reported. 7 Indeed, transplantation experiments in dogs have indicated that extrahepatic FVIII synthesis suffices for hemostasis. [8][9][10] The mature FVIII is released in the circulation as a heterodimeric glycoprotein that consists of 2332 amino acids and encompasses a heavy chain (HC; domains A1-a1-A2-a2-B, residues 1-1648) and a light chain (LC; domains a3-A3-C1-C2, residues 1649-2332). 1 The molecule contains 25 consensus sequences (Asn-Xxx-Thr/Ser) that allow N-linked glycosylation, of which 19 have been shown to be glycosylated. The overall sugar cont...

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The Immunologic Character of Acquired Inhibitors of Antihemophilic Globulin (Factor VIII) and the Kinetics of Their Interaction with Factor VIII*

Cited by 131 publications

References 33 publications

Factor V anticoagulants: clinical, biochemical, and immunological observations

Factor V anticoagulants: clinical, biochemical, and immunological observations

Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A

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