Disease relevance of F8

• The knowledge of the porcine fVIII cDNA may be useful to understand functional and immunological differences between human and porcine fVIII and may lead to improved fVIII replacement products for hemophilia [1].
• The physiologic activities concerned with hemostasis and associated with the Factor VIII macromolecular complex were investigated in swine with von Willebrand's disease after infusion of cryoprecipitate, a lyophilized Factor VIII concentrate, or porcine serum [2].
• Since current preparations of animal FVIII:C are not known to transmit infectious agents such as hepatitis or human immunodeficiency virus, they are of potential therapeutic interest [3].
• Five porcine nephroblastomas were examined histologically, and immunohistochemically with antibodies against vimentin (VIM), cytokeratins (CKs), smooth-muscle actin, Factor VIII, and laminin [4].

High impact information on F8

• Blood coagulation factor VIII (fVIII) is a plasma protein that is decreased or absent in hemophilia A [5].
• We isolated a serine protease from Bothrops jararacussu snake venom that catalyzes thrombin-like heavy-chain cleavage but not light-chain cleavage in porcine fVIII as judged by NaDodSO4/PAGE and N-terminal sequence analysis [5].
• Hereditary deficiency of the macromolecular Factor VIII complex results in classic von Willebrand disease in man and animals, a bleeder state characterized by loss of the multiple biologic activities associated with the Factor VIII complex, including the platelet-aggregating von Willebrand factor [6].
• Immediately after each infusion the various activities antihemophilic factor, von Willebrand platelet aggregating factor, and Factor VIII-related antigen, were elevated in approximate proportion to dose and the bleeding time was shortened.There was a late secondary rise in antihemophilic factor [2].
• This indicates that some inhibitor plasmas contain antibodies directed against the fVIII ap segment in addition to A2, A3, and C2 domain epitopes identified in previous studies [7].

Biological context of F8

• The A2 and C2 domains of human blood coagulation factor VIII (fVIII) contain the epitopes targeted by most inhibitory allo- and autoantibodies [8].
• To investigate the basis for the different decay kinetics of human and porcine fVIIIa, hybrid fVIII molecules representing all possible combinations of human and porcine A domains were isolated [9].
• This agrees well with the summed apparent molecular weights of fVIIIA1, fVIIIA2, and fVIIIA3-C1-C2 calculated from SDS-PAGE analysis (148,000) or from the amino acid sequence of human fVIII (159,000) [10].
• Of these preparations, only porcine FVIII:C (0.1-1 U/ml) and porcine fibrinogen (80-600 micrograms/ml) induced a fall in single platelet count of up to 85% due to aggregation [3].
• These results support the hypothesis that PFVIII-induced platelet activation provides a mechanism for enhancing hemostasis, separate from, and additional to, that due to increased circulating Factor VIII, and it is due to residual PvWF in the PFVIII preparation [11].

Anatomical context of F8

• In all plasmas, the substitution of all 3 regions yielded cross-reactivities that were not significantly different from those of porcine fVIII [7].
• Freshly isolated and cultured sinusoidal endothelial cells contained Factor VIII R:antigen, angiotensin I converting enzyme activity, and they synthesized prostaglandins characteristic of other endothelial cells [12].
• The maternal endothelium immunoreacted to IGF-I, to both PDGF-A and PDGF receptors, to vimentin and to von Willebrand factor (Factor VIII) [13].
• Additionally, the labelling of platelets for Factor VIII-related antigen and the ultrastructural study of the sinusoids revealed activation and aggregation of thrombocytes close to Kupffer cells at the beginning of the infection [14].

Associations of F8 with chemical compounds

• We propose that, in addition to catalyzing the inhibition of thrombin and other intrinsic pathway coagulation proteases by antithrombin, heparin functions as an anticoagulant by direct inhibition of the activation of the fVIII-vWf complex by thrombin [15].
• Evaluation of endothelial damage by the catheter (acute, 7 and 14 days) was performed in pig coronaries using Evans Blue, scanning electron microscopy (SEM) and Factor-VIII antibody and compared with normal arteries and arteries that underwent intravascular ultrasound (IVUS) [16].
• NH2-terminal sequence analysis of purified subunits of fVIIIaXa revealed that factor Xa cleaves fVIII at Arg219 within the A1 domain and at Arg490 within the A2 domain, as well as at Arg372, Arg740, and Arg1689 [17].

Other interactions of F8

• We believe that the aggregation of human platelets induced in vitro by porcine FVIII:C is mediated by vWf:Ag which also may be responsible for thrombocytopaenia reported following administration of porcine FVIII:C in vivo [3].
• For the latter method, the antibodies used were those against viral antigen Gp55, porcine myeloid marker SWC3, IL-1alpha, IL-6, TNF-alpha and Factor VIII-related antigen [14].
• The effects of commercial porcine FVIII:C, porcine fibrinogen, porcine fibronectin and the corresponding preparations from human origin on platelet aggregation were studied [3].

Analytical, diagnostic and therapeutic context of F8

• Along with previously determined sequences of the porcine fVIII B domain and the A2 domain, this completes the sequence determination of the cDNA corresponding to the translated protein [1].
• Endothelial cells were characterized by phase-contrast microscopy, electron microscopy and the presence of Factor VIII-related antigen [18].
• Following activation by thrombin, human fVIII was subjected to cation-exchange (Mono S) high performance liquid chromatography at pH 6.0 under conditions that yields stable, heterotrimeric (A1/A2/A3-C1-C2) porcine fVIIIaIIa (Lollar, P., and Parker, C.G. (1990) Biochemistry 28, 666-674) [19].
• In contrast, activation of human fVIII by thrombin followed by Mono S HPLC at pH 5.0 produced a peak with 10-fold greater activity (1.2 x 10(5) unit/mg) than at pH 6.0 and which contained significant amounts of the A2 fragment [19].
• Cell cultures obtained from small microvessels were rich in endothelial cells as identified by the presence of Factor VIII-related antigen [20].

References