In order to firmly establish a normal range for von Willebrand factor antigen (vWF:Ag), we determined plasma vWF:Ag concentrations in 1,117 volunteer blood donors by quantitative immunoelectrophoresis. The presence of the ABO blood group has a significant influence on vWF:Ag values; individuals with blood group O had the lowest mean vWF:Ag level (74.8 U/dL), followed by group A (105.9 U/dL), then group B (116.9 U/dL), and finally group AB (123.3 U/dL). Multiple regression analysis revealed that age significantly correlated with vWF:Ag levels in each blood group. We then performed reverse ABO typing on stored plasma from 142 patients with the diagnosis of von Willebrand disease (vWd). Of 114 patients with type I vWd, blood group O was found in 88 (77%), group A in 21 (18%), group B in 5 (4%), and group AB in none (0%), whereas the frequency of these blood groups in the normal population is significantly different (45%, 45%, 7% and 3%, respectively) (P less than .001). Patients with type II or III vWd had ABO blood group frequencies that were not different from the expected distribution. There may be a subset of symptomatic vWd patients with decreased concentrations of structurally normal vWf (vWd, type I) on the basis of blood group O. Some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood type.

We identified a consecutive series of 12 children with noncyanotic congenital cardiac lesions with loss of the largest plasma von Willebrand factor (vWF) multimers determined by SDS-agarose electrophoresis. Seven had previous histories of mucocutaneous hemorrhage; ten had a prolonged bleeding time. Analysis of the factor VIII molecular complex revealed that six patients had reduced vWF measured both immunologically (vW:Ag) and by ristocetin cofactor assay (vW:rist). All had normal or borderline normal factor VIII procoagulant (F VIII) concentrations. Three children had prolonged partial thromboplastin times due to concurrent factor XII deficiency; none had laboratory evidence of intravascular coagulation. Five of the children were restudied after surgical correction of their cardiac lesions. Four had normalization of vWF multimers; the fifth, whose vWF was abnormal postoperatively, had a residual pressure gradient across a previous pulmonary artery banding site. Multimeric abnormalities were not found in the parents of three patients. Thus some patients with noncyanotic congenital heart disease may have an acquired abnormality of vWF that is normalized with correction of the abnormal hemodynamic state.

This study was undertaken to determine the levels of protein C antigen and activity and protein C inhibitor in sequential plasma samples of disseminated intravascular coagulation (DIC) patients. Our normal range for both protein C antigen and activity is 70 to 130 U/dL, and protein C inhibitor is 65 to 135 U/dL. A decreased level of protein C activity was found in 96% of the plasma samples from individuals with DIC; the protein C antigen was decreased in 73%. The inhibitor of protein C was decreased in all samples. Analysis of serial samples from patients with DIC reveals that protein C activity and antigen and protein C inhibitor decrease progressively during the initial stages of DIC and remain at a low level for 24 to 48 hours before gradually returning toward normal in nonfatal cases. The protein C activity decreases in parallel with protein C inhibitor and is lower than protein C antigen. In a fatal case of DIC, protein C activity and protein C inhibitor rapidly decreased to undetectable levels; however, protein C antigen was gradually decreasing but still detectable at time of death. In DIC, a discrepancy initially occurs between the activity and antigen of protein C, suggesting a complex with the inhibitor or other inactive forms of protein C. Protein C appears to play a major role in the control of DIC.

This study was undertaken to evaluate the precision and sensitivity of three different commercial APTT reagents containing the activators kaolin, micronized silica, or ellagic acid. These reagents varied greatly in their ability to detect mild coagulopathies. The ellagic acid reagent was able to detect the mildest deficiencies for the most common coagulopathies. This reagent was sensitive to 50% levels of Factor VIIIC, whereas the APTT with the kaolin reagent was not prolonged until levels of 35% or less were attained. The micronized silica reagent was the least sensitive to Factor IX deficiency, detecting levels of 12% or less. Precision was similar for all reagents when tested with normal and slightly abnormal plasmas. Since methods and instrumentation vary, each laboratory should evaluate their APTT reagent to determine its precision and sensitivity.

Previous s t u d i e s by o t h e r s have demonstrated p r e f e r e n t i a l l o s s of t h e high molecular weight vWf multimers a f t e r i n f u s i o n of p u r i f i e d 1251-radiolabeled vWf but t h i s abnormality might be t h e r e s u l t of p u r i f i c a t i o n and r a d i o l a b e l i n g t h e vWf. We studied plasma f a c t o r VIII molecular complex s e r i a l l y i n a p a t i e n t with s e v e r e vWd a f t e r t r a n s f u s i o n with c r y o p r e c i p i t a t e (cryo) and determined t h e multimeric composition of vWf by SDS-agarose e l e c t r o p h o r e s i s . S t u d i e s before and a f t e r i n f u s i o n of 1 donor u n i t cryo per 5 kg body weight were a s follows: Multimeric a n a l y s i s of vWf showed progressive l o s s of t h e l a r g e r multimers. A v W antigen fragment was i d e n t i f i e d following subsequent infusions. Thus, with i n f u s i o n of vWf from cryo, we have confirmed t h e p r e f e r e n t i a l l o s s of l a r g e multimers. The v W antigen f r a g may be t h e r e s u l t of i n vivo o r i n v i t r o p r o t e o l y s i s . Plasma samples from 8 c h i l d r e n with v e n t r i c u l a r s e p t a 1 d e f e c t (VSD) were previously found t o l a c k t h e high molecular weight vWf multimers by e l e c t r o p h o r e s i s i n SDS-agarose followed by s t a i n i n g with 1251-radiolabeled anti-vWf and autoradiography. Low vWf by a n t i g e n i c and r i s t o c e t i n c o f a c t o r a s s a y s were found i n 4 whereas a l l had normal VII1:C; none had evidence of i n t r a v a s c u l a r coagulation. To determine i f t h e s e c h i l d r e n were d i f f e r e n t from o t h e r s with VSD, c a r d i a c c a t h e t e r i z a t i o n f i n d i n g s were evaluated. All had a sealed foramen ovale and high o r high normal end d i a s t o l i c pulmonary a r t e r y pressure. To d a t e , 3 of t h e c h i l d r e n have been re-studied a f t e r s u r g i c a l c o r r e c t i o n of t h e i r VSD. Two had normalization of vWf multimers; t h e t h i r d , whose vWf was abnormal postoperatively, had a r e s i d u a l pressure g r a d i e n t a c r o s s a previous pulmonary a r t e r y banding s i t e . Multimeric abnormalities were not found i n t h e p a r e n t s of 3 p a t i e n t s . Thus, some p a t i e n t s with VSD and an abnormal hemodynamic s t a t e may have an "acquired" l o s s of t h e high vWf multimers t h a t i s normalized with c~r r e c t i d~ of t h e hemodynamic d e f e c t . COMPARATIVE ACTIVITY OF ADENOSINE DEAMINASE (ADA)909 AND OR~T~DINE DECARBOXYLASE (oDc) i N RED BLOOD CELLS (RBC) FROM PATIENTS WITH DIAMOND-BLACKFAN SYNDROME (DBS). B e r t i l E. Glader and Karen Backer. Department of P e d i a t r i c s , Stanford University School of Medicine, Stanford California.W e previously reported t h a t ADA a c t i v i t y i s increased i n RBC from p a t i e n t s with DBS, but not i n RBC from p a t i e n t s with o t h e r RBC-hypoplastic d i s o r d e r s (NEJM 307:1486(NEJM 307: , 1983). I t a l s o has been ...

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Previous s t u d i e s by o t h e r s have demonstrated p r e f e r e n t i a l l o s s of t h e high molecular weight vWf multimers a f t e r i n f u s i o n of p u r i f i e d 1251-radiolabeled vWf but t h i s abnormality might be t h e r e s u l t of p u r i f i c a t i o n and r a d i o l a b e l i n g t h e vWf. We studied plasma f a c t o r VIII molecular complex s e r i a l l y i n a p a t i e n t with s e v e r e vWd a f t e r t r a n s f u s i o n with c r y o p r e c i p i t a t e (cryo) and determined t h e multimeric composition of vWf by SDS-agarose e l e c t r o p h o r e s i s . S t u d i e s before and a f t e r i n f u s i o n of 1 donor u n i t cryo per 5 kg body weight were a s follows: Multimeric a n a l y s i s of vWf showed progressive l o s s of t h e l a r g e r multimers. A v W antigen fragment was i d e n t i f i e d following subsequent infusions. Thus, with i n f u s i o n of vWf from cryo, we have confirmed t h e p r e f e r e n t i a l l o s s of l a r g e multimers. The v W antigen f r a g may be t h e r e s u l t of i n vivo o r i n v i t r o p r o t e o l y s i s . Plasma samples from 8 c h i l d r e n with v e n t r i c u l a r s e p t a 1 d e f e c t (VSD) were previously found t o l a c k t h e high molecular weight vWf multimers by e l e c t r o p h o r e s i s i n SDS-agarose followed by s t a i n i n g with 1251-radiolabeled anti-vWf and autoradiography. Low vWf by a n t i g e n i c and r i s t o c e t i n c o f a c t o r a s s a y s were found i n 4 whereas a l l had normal VII1:C; none had evidence of i n t r a v a s c u l a r coagulation. To determine i f t h e s e c h i l d r e n were d i f f e r e n t from o t h e r s with VSD, c a r d i a c c a t h e t e r i z a t i o n f i n d i n g s were evaluated. All had a sealed foramen ovale and high o r high normal end d i a s t o l i c pulmonary a r t e r y pressure. To d a t e , 3 of t h e c h i l d r e n have been re-studied a f t e r s u r g i c a l c o r r e c t i o n of t h e i r VSD. Two had normalization of vWf multimers; t h e t h i r d , whose vWf was abnormal postoperatively, had a r e s i d u a l pressure g r a d i e n t a c r o s s a previous pulmonary a r t e r y banding s i t e . Multimeric abnormalities were not found i n t h e p a r e n t s of 3 p a t i e n t s . Thus, some p a t i e n t s with VSD and an abnormal hemodynamic s t a t e may have an "acquired" l o s s of t h e high vWf multimers t h a t i s normalized with c~r r e c t i d~ of t h e hemodynamic d e f e c t . COMPARATIVE ACTIVITY OF ADENOSINE DEAMINASE (ADA)909 AND OR~T~DINE DECARBOXYLASE (oDc) i N RED BLOOD CELLS (RBC) FROM PATIENTS WITH DIAMOND-BLACKFAN SYNDROME (DBS). B e r t i l E. Glader and Karen Backer. Department of P e d i a t r i c s , Stanford University School of Medicine, Stanford California.W e previously reported t h a t ADA a c t i v i t y i s increased i n RBC from p a t i e n t s with DBS, but not i n RBC from p a t i e n t s with o t h e r RBC-hypoplastic d i s o r d e r s (NEJM 307:1486(NEJM 307: , 1983). I t a l s o has been ...

We previously reported the presence of an acquired von Willebrand factor (vWF) abnormality characterized by absence of the highest molecular weight (raw) multimers in 12 children with non-cyanotic congenital cardiac lesions. In order to determine the prevalence and define the mechanism of the vWF defect, a prospective series of 17 children were studied at the time of cardiac catheterization. In addition to standard coagulation and vWF assays, vWF multimeric patterns were determined by SDS agarose electrophoresis using two agarose concentrations, low concentration (0.65%) and high concentration (3.0%). Nine of the 17 children had absence of high mw vWF multimers on 0.65% agarose gels as follows:Of 5 children with absence of high mw vWF multimers on 0.65% agarose gels, 4 had 3% agarose gel patterns similar to that seen in patients with Type IIA von Willebrand disease (vWd). Two of 3 studied had the presence of vWF:frag on crossed immunoelectrophoresis. The patterns were not different when samples were drawn into a "cocktail" of proteolytic inhibitors. There was no correlation of abnormal vWF multimers with elevated B thromboglobulin, low dose ristocetin induced platelet aggregation or abnormal platelet vWF subunits. Thus, abnormal vWF multimers are commonly associated with non-cyanotic congenital cardiac lesions, particularly VSD. The lack of abnormality in platelet vWF multimers, absent low dose ristocetin aggregation, and presence of vWF:frag suggests that these alterations may be secondary to fragmentation or are of endothelial cell origin.