Search

Fifty-eight previously treated haemophilic subjects were treated exclusively with the recombinant FVIII (rFVIII-KOGENATE) produced by Bayer Corporation (Berkeley, CA) in an international multicentre prospective study of more than 5 years duration. Fifty-four of the 58 had severe haemophilia (< 2% FVIII) and four had moderate haemophilia (2-5% FVIII); 23/58 (40%) were seropositive for HIV, while 35/58 (60%) were HIV seronegative. Patients were monitored for safety and efficacy over a median period of 4.7 years (range 0.9-5.9 years) and received 17 922 infusions totalling 25.7 million units of rFVIII. Of 7107 bleeding episodes reported in home diaries, 5831 (82%) required only one treatment with rVIII. Twenty-five invasive surgical procedures in 17 patients, including eight joint replacements, were successfully accomplished and 13 serious bleeding episodes in eight patients were successfully treated. FVIII recovery performed on 885 occasions using 39 different lots of rFVIII showed mean incremental recovery of 2.48% IU-1 kg-1 (+/- 0.64). Adverse events were associated with 42 infusions (0.2%); none caused discontinuation of therapy. Immunological parameters remained stable in HIV-seronegative subjects treated with rFVIII; a small decrease in CD4 counts was noted in HIV-seropositive individuals (mean - 37.2 cells mm-3 yr-1). No de novo formation of inhibitors to FVIII was noted; and no clinical allergic reactions occurred to murine or hamster proteins. These conclusions from the longest monitored safety study ever performed for a haemophilia treatment product (with more than 5 years of observation) confirm previous interim study reports that rFVIII is well tolerated over the long-term, has biological activity comparable to that of plasma-derived FVIII, and is safe and efficacious for the treatment of haemophilia A.

Hemophilia A is a clotting disorder that is due to reduced or absent coagulation factor VIII (FVIII) activity. In approximately 25% of people with severe hemophilia A, standard treatment with intravenous plasma-derived or recombinant FVIII (rFVIII) induces anti-FVIII antibodies that inhibit FVIII activity (inhibitors). We describe the development of a rat model to study the formation of inhibitors. Immunization of rats with human rFVIII in adjuvant induced an anti-human rFVIII antibody response characteristic of an anti-FVIII inhibitor response in hemophilia A patients. The rats exhibited a rapid, polyclonal secondary antibody response to human rFVIII. These antibodies were reactive against epitopes located in the heavy and light chains. All the rFVIII-immunized rats developed antibodies against the FVIII C2 domain, a region of major reactivity in hemophilia A patients with inhibitors. Furthermore, competition ELISAs demonstrated that rat and human anti-FVIII antibodies recognized identical or overlapping epitopes of the FVIII molecule. The rat anti-FVIII antibodies also functioned as human FVIII inhibitors with titers ranging from 120 to 2048 Bethesda Units (B.U.). We propose that this rat model may be useful to investigate immune responses to FVIII and may lead to better therapies for FVIII inhibitors.

We report an unusual case of extensive spinal epidural hematoma in a seven-year-old male with severe factor IX deficiency. Despite evidence of extensive spinal epidural hematoma on the magnetic resonance imaging scan, aggressive replacement therapy resulted in complete neurologic recovery without the need for surgical decompression. This case also points to the usefulness of serial magnetic resonance imaging scans to monitor progress of the disease.

Purpose: Alpha 2-Antiplasmin (AP) deficiency is a rare congenital bleeding disorder that presents with normal screening tests for platelet function and clotting. We believe that this disorder is frequently overlooked, especially in women with unexplained bleeding., Patients and Methods: We report on two families and one single patient with heterozygous AP deficiency., Results: All patients and most relatives with the defect had a mild bleeding tendency., Conclusions: We suggest the incorporation of the AP assay in all patients who have a bleeding disorder with normal platelet studies and normal clotting profiles.

Background: Although methods of viral attenuation in plasma-derived clotting-factor concentrates have improved, there is still a possibility that such concentrates may transmit certain blood-borne viruses. For this reason, the use of recombinant DNA-derived factor VIII (which is virus-free) to treat hemophilia A has generated considerable interest., Methods: We conducted a multicenter trial in previously untreated children with hemophilia A. They received recombinant factor VIII for all treatment or for prophylaxis and were evaluated at their respective clinics at intervals of no more than three months., Results: Between January 1, 1989, and July 1, 1992, 95 patients who could be evaluated received recombinant factor VIII. By September 1, 1992, they had received the concentrate exclusively for 2.4 months to 3.5 years (median, 1.5 years). All responded well, with no treatment failures. A total of 3315 infusions were administered; there were three reports of minor adverse reactions. Inhibitor antibodies to factor VIII developed in 16 of 81 patients tested for them, after a median of nine days of exposure to factor VIII treatment. Inhibitor titers were or became low in 9 of the 16 patients despite continued episodic treatment with the concentrate. Inhibitors disappeared completely in 4 patients and remained at a low level (< 10 Bethesda units) in 5 patients receiving episodic treatment., Conclusions: Transient or low levels of inhibitor, as observed in this study, may represent part of the natural history of hemophilia in infants. In view of the transient nature and lower concentration of the inhibitors detected and the generally satisfactory response to treatment, the benefits of recombinant factor VIII for the treatment of hemophilia seem to outweigh the risks.

Background: Current treatment of hemophilia A, a hereditary disorder affecting approximately 1 in 10,000 males, relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder., Methods: We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII, assessing the efficacy of recombinant factor VIII for home therapy, and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia, 20 of whom had not been treated previously, enrolled in the investigation., Results: The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program, using recombinant factor VIII for 69 to 807 days (median, 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleeding episodes, 399 (73.9 percent) required only one treatment with recombinant factor VIII. The projected annual consumption of recombinant factor VIII was similar to that of plasma-derived factor VIII concentrate. Twenty-six subjects received recombinant factor VIII for 22 surgical procedures and 10 serious hemorrhages; hemostasis was excellent in all cases. De novo formation of inhibitors occurred in only 1 of 85 previously treated subjects. Inhibitor antibodies also developed in 6 of 21 children, 20 of whom had not previously been treated; 5 had low levels (less than or equal to 7.5 Bethesda units) despite continued treatment with recombinant factor VIII. There was no evidence of new formation of antibody to foreign proteins, and recombinant factor VIII was well tolerated., Conclusions: Recombinant factor VIII has biologic activity comparable to that of plasma factor VIII and is safe and efficacious for the treatment of hemophilia A.

Thirteen hemophilia centers provide comprehensive care to approximately 90 percent of persons with hemophilia in California. For 1987, these centers reported patient human immunodeficiency virus (HIV) antibody status, age group, level of clotting factor deficiency, and hemophilia type on 1,438 persons with hemophilia A and B; HIV serologic status was known for 860 persons (59.8 percent) of whom 537 (62.4 percent) were HIV-antibody-positive. The HIV positivity rate increased with age after taking into account hemophilia type, clotting factor level and treatment center type. The three-year cumulative incidence of reported AIDS (acquired immunodeficiency syndrome) cases based on the number of HIV positive patients, was 11.6 percent. The cumulative incidence rate was 14.6 percent (54 of 370) for those patients over 20 years of age and 4.8 percent (8 of 167) for those under 21 years of age. Although a comparable distribution of the date of diagnoses of AIDS was seen by age group, there appeared to be a bimodal distribution in the rate of AIDS among the age groups, with the 6-12-year-olds and the 21 and older age groups showing higher incidence rates.

Report of two cases of severe idiopathic autoimmune hemolytic anemia (AIHA) in infants who underwent splenectomy and received corticosteroids and cyclophosphamide without benefit. One infant, additionally, was treated with thymectomy and azathioprine without influencing his disease. Experience of therapy for childhood AIHA is reviewed. Four children with AIHA have been thymectomized. Two of these failed to benefit from surgery. There have been fifteen previous trials with immunosuppressive agents in childhood AIHA. About 60% of the children so treated (9 of 15) have shown improvement. Additional clinical trials with this agent are warranted.

We describe a 12-year-old boy with acquired von Willebrand's syndrome, who also had various autoantibodies. He presented with recent hemorrhagic symptoms and a prolonged bleeding time. Hemostatic studies revealed severely reduced levels of factor VIII procoagulant activity (VIII:C), von Willebrand's factor (vWF) antigen (vWF:Ag), and ristocetin cofactor activity (RCoF). An inhibitor that could be detected in the patient's plasma moderately decreased the levels of vWF:Ag in normal plasma, but did not interfere with the measurement of VIII:C or RCoF. Following the infusion of cryoprecipitate, half-lives of VIII:C, vWF:Ag, and RCoF were markedly reduced. 1-Deamino-8-D-arginine vasopressin infusion induced normalization of the prolonged bleeding time and caused a marked increase in VIII:C, vWF:Ag, and RCoF. Prior to treatment, there was a uniform reduction of all the multimers of plasma vWF in sodium dodecyl sulfate agarose gel electrophoresis. Following prednisone therapy, clinical and hemostatic findings were improved, and the multimeric patterns of vWF were normalized. These findings suggest that the low levels of all three parameters of factor VIII and all the multimers of plasma vWF in the patient are caused by rapid elimination of factor VIII complex from the circulation.

Intracranial hemorrhage is a rare but life-threatening complication of childhood idiopathic thrombocytopenic purpura. We present three cases of this complication encountered at our institution, in addition to a tabulation of 15 previously reported cases. Prevention, diagnosis, and management of intracranial hemorrhage in idiopathic thrombocytopenic purpura are discussed. The importance of avoidance of antiplatelet drugs as well as the significance of the location of the intracranial hemorrhage are emphasized. Posterior fossa hemorrhages are especially dangerous because of the possibility of rapid cerebellar herniation and brainstem compression. Management of intracranial hemorrhage should be prompt and aggressive, and splenectomy should always be performed prior to any neurosurgical procedure. It is encouraging that 11 of 18 patients had a favorable outcome.

A multicenter study of various types of von Willebrand's disease (vWD) was conducted in order to compare the different electrophoretic techniques used to evaluate von Willebrand factor multimers in plasma. Seven laboratories participated in the blind study of eight plasma samples from two healthy subjects and six vWD types and subtypes (Ia, Ib, IIA, IIB, IIC and IID). From the results of the multimeric analysis of these samples, it appears that the differential diagnosis of vWD types and subtypes should be first approached by using a low-resolution electrophoretic technique, where each vWF multimer appears as a single band. Low-resolution techniques differentiate type I from type II, subtype Ia from Ib and also subtype IIA from other type II subtypes. When type II subtypes other than IIA are identified with these techniques, samples should be rerun using high resolution techniques that resolve each of the fastest migrating multimers in at least three subbands, and permit the differentiation of subtypes IIB, IIC and IID.

This report describes a patient with thrombocytopenia, microangiopathic hemolytic anemia, proteinuria, and microscopic hematuria that could be transiently improved by the infusion of plasma or various plasma components. An increase in platelet count following the transfusion of normal plasma was predictable and reproducible. In therapeutic trials with commercially available plasma components, factor VIII preparations were effective for inducing an increase in the platelet count and improving hemolytic anemia, but albumin, gamma-globulin, factor IX, and fibronectin preparations were ineffective. Serum from normal donors also relieved the symptoms of this condition in our patient. Partial plasma exchange (1,000 ml/m2 of body surface area) was performed with albumin instead of normal plasma, but there was no significant effect on platelet count or anemia. Large, multimeric von Willebrand factor components of the factor VIII complex (VIII/vWF) were found in the patient's plasma when his platelet count was normal, but their levels were reduced when the platelet count was decreased. The multimers of the patient's plasma were larger than those in normal plasma, but smaller than those in normal platelet lysate. Although the pathogenesis of this disease remains unknown, we conclude that transfusions of normal plasma, serum or factor VIII concentrate provide a factor that causes significant improvement in the thrombocytopenia and hemolytic anemia. Furthermore, large VIII/vWF multimers are possibly directly involved in pathogenesis of this disease.

To evaluate changes in fibrinolytic activity, factor VIII and other hematological variables during and after a progressive step increment in work load, 10 healthy male subjects (22-27 yr of age) were exercised to exhaustion on an electromagnetic bicycle ergometer. Blood samples were drawn serially throughout the experiment. Little change in fibrinolytic activity was observed before 70-80% maximum heart rate (MHR) was achieved. Major changes occurred after 80% MHR. Peak values coincided with maximum exercise. In contrast major changes in factor VIII were observed between 95 and 100% MHR with peak values occurring 5-10 min postexercise. An increase in white blood cell count, platelet count, and retention was observed at maximum exercise. One individual failed to demonstrate an increase in either fibrinolytic or factor VIII activity. Relating the data to either the percent maximal oxygen uptake or percent maximal heart rate demonstrates the importance of the exercise protocol and exerting all subjects to the same relative level of physiological work.

Ontogeny of selected hemostatic system components was studied in 120 bovine fetuses which had been divided into eight monthly gestational age groups. Fetal blood was subjected to the following tests: platelet count, partial thromboplastin time, prothrombin time, thrombin time, fibrinogen quantitation, and assays for prothrombin and factors V and VIII. Platelet numbers corresponding to adult numbers were in fetal blood at least as early as gestation day 60, and their numbers varied only slightly thereafter. Bovine blood was incapable of in vitro coagulation at gestation day 90, with all samples coagulating by gestation day 150. Fetal coagulation screening test times (partial thromboplastin time, prothrombin time, and thrombin time) shortened during gestation and were near times of adults at birth. Of the four individual coagulation factors tested, only factor VIII reached adult values in the fetus in utero. Amounts of fibrinogen, prothrombin, and factors V and VIII in the neonate exceeded that of normal adult cattle.

A peroxidase staining method for von Willebrand factor (vWF) multimer analysis was modified for comparison with an autoradiographic method. This method consists of SDS-agarose electrophoresis followed by blotting to a nitrocellulose membrane and a sensitive peroxidase staining method. The resolution of vWF multimers on the nitrocellulose membrane is comparable to that on the conventional autoradiography. Results can be obtained in 3 days. This nonradioisotopic method will be useful for the determination of the type of von Willebrand's disease in clinical laboratories.

To determine if factor VIII-von Willebrand factor (vWF) complex is involved in the thrombosis associated with asparaginase-prednisone-vincristine induction therapy for acute lymphoblastic leukemia, plasma vWF was analyzed by sodium dodecyl sulfate-agarose gel electrophoresis and crossed immunoelectrophoresis. Five patients with cerebral thrombosis were studied; all had a decreased platelet count following the complication. Sequential studies of three patients disclosed changes in plasma vWF multimer pattern. One patient who was studied serially from 2 days before to 1 day after the event, had an increase in unusually large plasma vWF multimers that disappeared after the complication. The other two patients who were studied at presentation subsequently showed a decrease in plasma large vWF multimers, especially remarkable in the patient having the sharpest decrease in platelet count. No appreciable difference in vWF multimer pattern, when compared to normal pooled plasma, was found in the remaining two patients who were only studied at presentation, or in the seven controls who received the same treatment but did not develop thrombosis. Crossed immunoelectrophoretic analyses of two patients tested disclosed a right shift of immunoprecipitin line in one and a left shift in the other. Our findings suggest that the thrombotic complications resulted from platelet agglutination by plasma vWF.

Two prothrombin complex concentrates, Auto-Factor IX and Proplex, have been reported to be effective in controlling bleeding in hemophilic patients with factor VIII inhibitors. A third PCC, Konyne, was used to treat 64 bleeding episodes (130 infusions) in five hemophilic patients with factor VIII inhibitors. Prompt control of bleeding was observed in each instance with doses of 15 to 100 units of factor IX/kg; no complications were encountered. Konyne resulted in in vivo and in vitro shortening of the partial thromboplastin time of patients with factor VIII inhibitors, but the mechanism of action is unknown. If further studies confirm the efficacy and safety of PCC in the treatment of such patients, its use for this purpose could lead to significant saving of factor VIII concentrates.

We report the case of a 13-year-old boy who was known to have Fanconi's anemia for five years. For treatment of this condition he was given androgens and corticosteroids. Two months before his death, severe varicella developed complicated by pneumonia, jaundice, and prolonged fever; all of which resolved during a five-week hospitalization. Three weeks later he died of Clostridium septicum sepsis caused by necrotizing enterocolitis. At autopsy he was found to have multiple hepatocellular neoplasms. A striking feature of the neoplasms was cholestasis. The liver also showed peliosis hepatis. The association of the use of certain androgenic steroids with hepatic neoplasms histologically resembling hepatocarcinomas, but characterized by lack of metastases and apparent reversibility, suggests the desirability of a new nomenclature for these hepatocellular lesions.

We attempted to characterize the small amounts of factor VIII-related antigen detectable in the severe recessive form of von Willebrand's disease with newly developed radioimmunoprecipitin techniques and radiocrossed immunoelectrophoresis. Previous studies have failed to demonstrate factor VIII-related antigen in most patients tested even with the highly sensitive immunoradiometric assays. Using the newer techniques, we found antigen in the plasma of six of eight patients with severe von Willebrand's disease from different kindreds. Qualitative abnormalities of the trace quantities of factor VIII-related antigen were demonstrated in five of the patients, with absence or relative decrease of the larger, less anodal forms. In addition, five distinct patterns were observed, each suggesting a different molecular abnormality. Heterozygous parents had normal to moderately decreased factor VIII-related antigen, with normal crossed immunoelectrophoretic patterns. This study suggests that severe von Willebrand's disease is a heterogeneous syndrome with various underlying molecular defects.

Dominant transmission of a variant of von Willebrand's disease (vWD) with aberrant polymerization of von Willebrand factor (vWF) has been identified in a Scottish family. Multimer analysis of plasma vWF from the propositus and her father revealed an identical pattern to that previously reported in families designated as type IID vWD. There is loss of the larger multimers and presence of an intermediate subsidiary band not seen in normal subjects or other vWD variants. Platelet/vWF interaction induced by ristocetin is not enhanced in these cases and the platelet vWF shows the same aberrant multimer pattern as plasma vWF. DDAVP infusion in two affected members of the Scottish family and in one of the index cases produced a rise in plasma vWF antigen and factor VIII. Higher molecular weight vWF multimers appeared transiently after infusion of desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) coincident with shortening of the bleeding time. The platelet counts did not change after the DDAVP infusions. DDAVP should be considered for management of bleeding in this variant of von Willebrand's disease.

Excessive growth hormone (GH) secretion and platelet hyperaggregation have been considered to be involved in the development of the vascular complications of diabetes mellitus (DM). Trying to find a common link between GH and platelet hyperaggregation, we measured von Willebrand or ristocetin cofactor activity (VIII R:Rcof), factor VIII-related antigen (VIII R:Ag) and factor VIII coagulant activity (VIII:C) in ten type 2 DM (NIDDM) and seven normal control (C) human subjects. These three parameters were measured before (time 0), and after a one-hour intravenous infusion of 0.1 U/kg bw of GH, (times 1, 4, 6, and 24 hours). The NIDDM subjects were nonobese and without clinical evidence of diabetic vascular complications. Despite remarkably high levels of GH reached during the infusion (average 280 ng/ml), there were no significant changes in the measured parameters in either NIDDM or C group. The baseline levels of factors VIII R:Rcof, VIII R:Ag and VIII:C were also not significantly different in the two groups. Changes in GH serum levels seem to have no effect on the factors VIII:C, VIII R:Ag or VIII R:Rcof levels in normals (C) or in NIDDM subjects without evidence of vascular complications. These results do not preclude the possibility that there may be a different response to GH in DM patients with advanced vascular complications and probable endothelial cell abnormalities.