An Inhibitor Selectively Directed Against Factor VIII-AHF In A Patient With Von Willebrand’S Disease (vWD)

1981 ◽  
Author(s):  
A Castella ◽  
J L Miller ◽  
R W Neuberg ◽  
H S Friedman
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Replacement Therapy ◽  
Thrombin Time ◽  
Excessive Bleeding ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
History Of ◽  
Molecular Variant ◽  
Work Up

We have studied a 17 month old boy with previously diagnosed vWD who presented with intracerebral hemorrhage. There was a history of excessive bleeding from circumcision, after corrective surgery for pyloric stenosis, and from an upper lip cut. He had received multiple units of cryoprecipitate from the first month of life until the present admission. Work-up demonstrated prolonged bleeding time and prolonged PTT, normal prothrombin time, thrombin time, and platelet aggregation with ADP, epinephrine and collagen. Ten days after cessation of factor VIII replacement therapy he had undetectable F VIII-AHF, F VIII-Ag of 86% by the Laurell technique and F VIII-RCo of 18%. We could demonstrate a time- dependent inhibitor directed against F VIII-AHF measuring 92 Bethesda units. In mixing studies with normal plasma, little or nor inhibitory activity directed against F VIII-RCo could be identified. The patient’s platelets showed increased ristocetin-induced platelet aggregation (RIPA) at doses as low as 0.5 mg/ml.There was no evidence of a bleeding disorder in the maternal side of the family. All of the paternal family members studied showed prolonged bleeding times, decreased F VIII-RCo, and increased RIPA with low doses of ristocetin, findings similar to those patients recently characterized as having type IIb vWD. Although other members of the patient’s family had previously received cryoprecipitate replacement therapy, no inhibitors appear to have developed in these persons.Factor VIII inhibitors in vWD are uncommon, with those reported usually showing little or no inhibition of F VIII-AHF. These findings appear to represent a unique pattern of inhibitor development that may be related to a molecular variant of vWD in this patient.

scholarly journals "Impotent" Platelets in Albinos With Prolonged Bleeding Times

Blood ◽  
1972 ◽  
Vol 39 (4) ◽  
pp. 490-499 ◽  
Author(s):  
Harold M. Maurer ◽  
James A. Wolff ◽  
Sue Buckingham ◽  
Arthur R. Spielvogel
Keyword(s):  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Bleeding Tendency ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Tryptophan Metabolites ◽  
History Of

Abstract Functional, biochemical, and morphologic platelet abnormalities are reported in four children with the syndrome of albinism, mild bleeding tendency, prolonged bleeding time, and normal platelet count. In these children, primary platelet aggregation with adenosine diphosphate occurred normally, but secondary aggregation was impaired. Collagen and norepinephrine produced almost no platelet aggregation. Platelet content of serotonin (5-HT) was markedly reduced, and uptake and retention of 5-HT by the platelets in vivo and in vitro was poor. In one child who was given a tryptophan load, urinary tryptophan metabolites were normal, suggesting that there was no evidence of a block in the 5-HT synthetic pathway in the gastrointestinal tract. Electron microscopy revealed an absence of densely osmophilic granules in 5-HT poor platelets. Platelets from other albinos with no history of bleeding contained normal amounts of 5-HT and densely osmophilic granules.

Circulating anticoagulant in a family with prolonged bleeding time and factor VIII deficiency

Blood ◽  
1977 ◽  
Vol 49 (5) ◽  
pp. 799-806 ◽  
Author(s):  
M Diez-Ewald ◽  
EC Lian ◽  
R Nunez ◽  
D Deykin ◽  
DR Harkness
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Factor Viii Activity ◽  
Clot Retraction ◽  
Factor Viii Related Antigen ◽  
Factor Viii Deficiency ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Aggregation Activity

Abstract A circulating anticoagulant against factor VIII activity was demonstrated in the plasma of a boy from a family with both factor VIII deficiency and prolonged bleeding time. However, the factor VIII- related antigen, ristocetin-induced platelet aggregation activity, platelet retention in glass bead columns, platelet aggregation with adenosine 5′-diphosphate, collagen and epinephrine, and clot retraction among affected members were normal. The electrophoretic mobility of factor VIII-related antigen on crossed immunoelectrophoresis was normal. The inactivation of factor VIII activity by the inhibitor was time dependent and was nonlinear as the concentration of the inhibitor was increased. Immunotyping showed that the inhibitor was IgG with k light chains.

scholarly journals Circulating anticoagulant in a family with prolonged bleeding time and factor VIII deficiency

Blood ◽  
1977 ◽  
Vol 49 (5) ◽  
pp. 799-806
Author(s):  
M Diez-Ewald ◽  
EC Lian ◽  
R Nunez ◽  
D Deykin ◽  
DR Harkness
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Factor Viii Activity ◽  
Clot Retraction ◽  
Factor Viii Related Antigen ◽  
Factor Viii Deficiency ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Aggregation Activity

A circulating anticoagulant against factor VIII activity was demonstrated in the plasma of a boy from a family with both factor VIII deficiency and prolonged bleeding time. However, the factor VIII- related antigen, ristocetin-induced platelet aggregation activity, platelet retention in glass bead columns, platelet aggregation with adenosine 5′-diphosphate, collagen and epinephrine, and clot retraction among affected members were normal. The electrophoretic mobility of factor VIII-related antigen on crossed immunoelectrophoresis was normal. The inactivation of factor VIII activity by the inhibitor was time dependent and was nonlinear as the concentration of the inhibitor was increased. Immunotyping showed that the inhibitor was IgG with k light chains.

Increased Ristocetin Induced Binding of Factor VIII to Platelets in Von Willebrand’s Disease (vWd)

1979 ◽  
Author(s):  
Z.M. Ruggeri ◽  
F.I. Pareti ◽  
P.M. Mannucci ◽  
T.S. Zimmerman
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Bleeding Time ◽  
Human Platelet ◽  
Bleeding Tendency ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Prolonged Bleeding Time ◽  
Crossed Immunoelectrophoresis ◽  
Ristocetin Cofactor

Initial reports of ristocetin-induced platelet aggregation (RIPA) demonstrated it to be decreased in some patients with vWd. We now report 20 patients (from five unrelated families) in whom RIP A was increased, apparently as the result of an increased ristocetin-induced binding of Factor VIIIrelated antigen (VIIIR:Ag) to platelets. All the patients had a life-long bleeding tendency, with prolonged bleeding time, and an abnormal two-dimensional crossed immunoelectrophoresis (2DCIE). Increased RIPA was demonstrated by measuring the minimum ristocetin concentration necessary to induce platelet aggregation. This was 0.42 mg/ml á 0.11 SD in the patients, and 0.91 á 0.097 SD in 17 normals (t = 13.83; P < 0.001). VIIIR:Ag binding to platelets occurred at ristocetin concentrations (0.4 mg/mI) which were ineffective in normals (who required >0.6 mg/mI). In contrast, the VIIIR:Ag of other patients with abnormal 2DCIE and markedly decreased RIP A did not bind to platelets at ristocetin concentrations as high as I mg/ml. It has been previously demonstrated that 30% to 60% of normal VIIIR:Ag binds to isolated human platelet membranes in the absence of ristocetin or any other agent, and that binding is restricted to the larger forms of VIIIR:Ag. However, VIIIR:Ag from the patients with increased RIPA, including two with normal ristocetin cofactor activity, showed decreased or undetectable binding as did all other patients with abnormal 2DCIE. This study suggests that ristocetin induced platelet Factor VIII interaction does not accurately reflect the “bleeding time factor” defect in vWd.

ANTI-THROMBINneo IgG IN AN ASYMPTOMATIC PATIENT WITH A BENIGN MONOCLONAL GAMMOPATHY

1987 ◽  
Author(s):  
B S Coller ◽  
J Jesty
Keyword(s):  
Monoclonal Gammopathy ◽  
Asymptomatic Patient ◽  
Protein A ◽  
Thrombin Time ◽  
X Rays ◽  
Excessive Bleeding ◽  
Bone Marrow Histology ◽  
Benign Monoclonal Gammopathy ◽  
History Of ◽  
And Control

A 68 year old male hospitalized for cardiac disease was found to have an elevated prothrombin time (18.5/12.4 s) and aPTT (59.6/25.9s). He had no history of excessive bleeding or bruising. Subsequent evaluation revealed: thrombin time >500/34.1 s; fibrinogen 260 mg/dl functional and 522 mg/dl immunologic; reptilase 25.6/18.1 s; thrombin-induced platelet release of ATP (patient=0 and control=14.6 nmoles/109 platelets at 0.5 U/ml); AT-III 89% functional and 36.5 mg/dl immunologic; and prothrombin 167%. Mixing experiments showed the presence of an inhibitor of the thrombin time, and purification of IgG by protein A affinity chromatography showed the inhibitor of fibrin formation to reside in the IgG fraction. When coupled to Affi-gel 10, patient IgG (but not control IgG) removed purified thrombin from solution; the same gel did not remove prothrombin. The patient's IgG did not inhibit thrombin’s cleavage of a chromogenic substrate (Chromozym TH). Studies on the patient's serum revealed: IgG 2,360 mg/dl, IgA 371 mg/dl, and IgM 107 mg/dl. Serum protein electrophoresis and immunoelectrophoresis showed a monoclonal IgG lambda protein with probably normal amounts of normal IgG. Other parameters (hematocrit, albumin, calcium, bone marrow histology, bone X-rays) indicated that the patient has a benign monoclonal gammopathy, not multiple myeloma. We conclude that our patient is producing an IgG inhibitor that reacts with a neo-antigen produced by the cleavage of prothrombin to thrombin; the IgG can prevent the interaction of thrombin with fibrinogen and the thrombin receptor on platelets, but not small synthetic substrates. We suspect that his monoclonal IgG is the inhibitor and find it remarkable that he has no increase in bleeding.

Fibrinogen New Orleans: An Inherited Variant with Abnormal Peptide Release

1979 ◽  
Author(s):  
S.I. Chavin ◽  
W.A. Andes ◽  
W.G. Beltran ◽  
W.J. Stuckey
Keyword(s):  
Laboratory Finding ◽  
Polyacrylamide Gel Electrophoresis ◽  
Complete Fusion ◽  
Thrombin Time ◽  
Clotting Time ◽  
Excessive Bleeding ◽  
Normal Limits ◽  
Peptide Release ◽  
Mother And Daughter ◽  
History Of

An inherited fibrinogen abnormality is described in a 30-year old woman with a history of several episodes of excessive bleeding. The initial laboratory finding was a prolonged thrombin time, and a comparable prolongation was present in the plasmas of her mother and daughter, but not of her father. The abnormal fibrinogen gave a reaction of complete fusion with normal fibrinogen in an Ouchterlony plate, and by immunoelectrophoresis, it had a slightly faster than normal anodal migration. The patient’s plasma and purified fibrinogen were able to prolong the clotting time of normal plasma. Using SDS-polyacrylamide gel electrophoresis, we have detected a marked delay in release of a major proportion of the A peptide and a lesser delay in release of the B peptide, after thrombin treatment. B peptide release appeared to be completed before that of A peptide release, in contrast to the situation with normal fibrinogen. Cross-linking of the resulting fibrin was delayed but eventually complete. The rate and extent of monomer aggregation, measured by spectrophotometry, were within normal limits.

Studies on a Variant of Factor VIII Resulting in ’von Willebrand’s Disease»

1975 ◽  
Author(s):  
F. G. H. Hill ◽  
M. C. K. Chan ◽  
R. M. Hardisty
Keyword(s):  
Factor Viii ◽  
Bleeding Time ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time

A variant of von Willebrand’s disease in a 14-year-old girl is described, characterised by a prolonged bleeding time and defective ristocetin aggregation (VIIIWF 6%), with VIIIRAg 70-110% and VIIIC 40-60%. The electrophorotic mobility of her VIIIRAg in agarose at pH 9.2 was intermediate between normal VIIIRAg and that of the patient of Kernoff et al, (1), and identical with that of Case 4 of Peake et al. (2). Further characteristics of the factor VIII molecule in this patient’s plasma and platelets will be presented, including antigenic, physicochemical and functional propeertis.1. Kernoff, P. B. A. et al. (1974). Brit. J. Haemat. 26, 435.2. Peake, I. R. et al. (1974). N. Engl. J. Med. 291, 113.

Intracranial Hemorrhage in a Patient with Osteogenesis Imperfecta Due to Inherited and Acquired Platelet Dysfunction.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3960-3960
Author(s):  
Arash Rezazadeh ◽  
Sandra C. Hollensead ◽  
Damian A. Laber ◽  
Goetz H. Kloecker
Keyword(s):  
Platelet Aggregation ◽  
Osteogenesis Imperfecta ◽  
Factor Viii ◽  
Platelet Dysfunction ◽  
Multiple Fractures ◽  
Vascular Abnormality ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Abnormal Bleeding

Abstract A 42 year-old man with Osteogenesis Imperfecta (OI) had three episodes of spontaneous Subdural Hematoma (SH) after binge drinking. There is no remote history of abnormal bleeding or easy bruising despite multiple fractures. Medications included Aspirin (ASA). The first and second SH occurred within the preceding year and were treated conservatively. The third SH occurred while on ASA and drinking more than 500cc liquor/day. The Platelet Function Assay (PFA-100) was significantly abnormal (see table). After platelet transfusions the SH was surgically evacuated without complications. An MRA of the head showed no vascular abnormality. CBC, serum chemistries, PT, PTT, factor VIII and von Willebrand factor were normal. The patient stopped taking ASA, but continued to drink. The PFA-100, although abnormal, had improved. After a month-long alcohol abstinence his PFA-100 normalized. He has been without SH ever since. However the platelet aggregation study still shows a lack of second wave response to ADP. EVENT ASA ETOH Collagen/Epi Collagen/ADP Platelet Count SH3 (+) (+) &gt;300 112 266 Plt transfusion n/a n/a 122 51 347 Follow up (−) (+) 219 108 231 Follow up (−) (−) 117 80 276 Reference Range 118–162 Seconds 59–103 Seconds 140–370 Discussion: Both OI and ETOH are known factors of causing intrinsic platelet defect. The Framingham Offspring Study showed that alcohol consumption is inversely associated with both platelet activation and aggregation, particularly in men. ETOH is capable of inhibiting collagen induced platelet aggregation, secretion, arachidonate mobilization, and TXA2 formation. Also it has been suggested that intracellular Ca2+ homeostasis and aggregation in platelets are impaired by ethanol through the generation of H2O2 and oxidation of sulphydryl groups. OI causes vascular fragility and intrinsic platelet defect. In one study the most frequent abnormalities were increased capillary fragility (35%), decreased platelet retention (33%) and reduced factor VIII R:Ag (23%). Reduced ristocetin cofactor, deficient platelet aggregation induced by collagen and prolonged bleeding time were less common findings. The combination of vascular, platelet related and plasmatic defects may reflect that OI is a heterogeneous group of disorders with common clinical expression. Conclusion: Patients with OI are at risk for intracranial bleeding due to vascular fragility and intrinsic platelet defect. Our patient had a normal PFA-100, off ASA and ETOH. The platelet aggregation study -a more sensitive test- was able to detect a platelet secretion defect in our patient. The abnormal platelet aggregation study was likely due to his OI, which never caused abnormal bleeding by itself. The additional affect of ASA and ETOH on his platelets led to recurrent episodes of SH. Many OI patients are on NSAID/ASA due to chronic bone pain. Special attention should be paid to alcohol abuse in this group of patients. Normal platelet counts and coagulation tests may not be sufficient to evaluate the risk of bleeding. We suggest performing a PFA-100 or a platelet aggregation study, when platelet dysfunction is suspected.

Sustained Bleeding after a leech Bite in the Apparent Absence of Hirudin

1989 ◽  
Vol 61 (03) ◽  
pp. 366-369 ◽  
Author(s):  
R Munro ◽  
F O P Hechtel ◽  
R T Sawyer
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Medicinal Leech ◽  
Bite Wound ◽  
Apparent Absence ◽  
Coagulation Parameters ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Human Volunteers

SummaryThe bite of the medicinal leech bleeds for many hours. For decades it has been assumed that the remarkably prolonged bleeding time of a leech bite wound is due to hirudin, a specific anti-thrombin secreted by the leech during feeding. By measuring haematological parameters of blood oozing from a leech bite wound on 15 different occasions in 7 human volunteers, we demonstrate that the hirudin-sensitive coagulation parameters, including thrombin-induced platelet aggregation, are prolonged for only 15 min, after which they return to normal. This suggests that excess hirudin secreted by the leech is washed out during this period. However, bleeding from the leech bite wound persists for a mean of 10 h. Platelets in smears of exuding blood show no evidence of spontaneous aggregation, but in vitro platelet aggregation can be induced by exogenous collagen at any time. In view of sustained bleeding in the apparent absence of hirudin, attention is focussed onto an unsuspected factor or factors which may better explain the prolonged bleeding phenomenon.

Variant von Willebrand’s Disease

1980 ◽  
Vol 43 (01) ◽  
pp. 002-005 ◽  
Author(s):  
David Green ◽  
K J Philip
Keyword(s):  
Factor Viii ◽  
Bleeding Time ◽  
Excessive Bleeding ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Crossed Immunoelectrophoresis ◽  
The Family ◽  
History Of ◽  
Autosomal Dominance ◽  
Ristocetin Cofactor

Summary30 members of an Illinois kindred were studied with a battery of haemostatic tests including the template bleeding time, platelet retention by glass beads (PRGB), measurement of activities related to factor VIII, and crossed-immunoelectrophoresis (CIEP). 9 family members had a history of excessive bleeding, and all 9 had prolonged bleeding times and increased migration of their factor VIII-related antigen (VIIIR:Ag) on CIEP. Of the other tests performed, the VIII: Ristocetin Cofactor and the PRGB showed the best correlation with the bleeding time. 3 subjects who were not bleeders, but who came from a branch of the family where there were several affected members, also had an abnormal VIIIR: Ag. The pattern of inheritance of the altered VIIIR: Ag in this family was one of autosomal dominance with full penetrance. The CIEP is a valuable screening test for the detection of variant von Willebrand’s disease and the recognition of silent heterozygotes.

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