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As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-delta32/delta32 homozygous genotype has phenotypic expressions other than those related to HIV-1.Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-delta32/delta32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-delta32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis.Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-delta32/delta32 study subjects. Based on blood pressure measurement and treatment history, CCR5-delta32/delta32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were approximately 20% higher in CCR5-delta32/delta32 study subjects than in CCR5-+/+ study subjects (p.05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-delta32/delta32 homozygotes (p.05), but serum HCV levels did not differ by CCR5-delta32 genotype. CCR5-delta32/delta32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype.CCR5-delta32/delta32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-delta32/delta32 homozygosity does not provide broad protection against viral infections.

The therapeutic efficacy of prothrombin-complex concentrates in patients with hemophilia and inhibitors (antibodies) to factor VIII has been increasingly debated. We therefore entered 51 hemophiliacs with factor VIII inhibitors into a double-blind randomized crossover study to compare two commercial prothrombin-complex concentrates (Konyne and Proplex) and an albumin placebo. Acute hemarthrosis of the elbow, knee, or ankle was treated with a single dose of a test preparation and assessed six hours later with objective and subjective criteria. In all measurements the concentrates were significantly more effective than the placebo. The data indicate that although prothrombin-complex concentrates, when used in a single dose, are only partially effective in the treatment of joint hemorrhage in hemophiliacs with inhibitors, their continued use for acute hemarthrosis is justified in the absence of any other effective and readily available therapy for this disorder.

In view of uncontrolled observations and anecdotal reports suggesting that the activated PCC, Autoplex, was much more effective than standard (non-activated) PCC in controlling bleeding in hemophiliacs with inhibitors, a controlled double-blind study was designed to compare the effectiveness of Autoplex and Proplex. Acute hemarthrosis was chosen for study as this common but non-life-threatening lesion lends itself well to controlled study. A single dose of “unknown” product (Autoplex 75 FECU/kg; Autoplex 50 FECU/kg; or Proplex 75 FIX U/kg) was given, and effectiveness was judged at 6 hr. By all criteria of efficacy, there were no significant differences between the products. It is noteworthy that a single dose of PCC was judged effective in 50% of episodes, a figure that is consistent with other published clinical trials. In this model, no additional benefit was derived from using the activated PCC, Autoplex, in either dosage.

The association of eosinophilia and Löffler’s endomyocardial fibrosis with acute lymphoblastic leukemia in a 9-yr-old boy is reported. During the illness, there were three leukemic relapses, each preceded by eosinophilia which subsided upon induction of remission. It is suggested that the eosinophilia in this case was not "eosinophilic leukemia," but more likely a nonneoplastic response to an antigenic stimulus from the leukemic process.

A bleeding diathesis is described which is phenotypically indistinguishable from hemophilia A and which has been transmitted as a dominant trait in three generations of women in a North Carolina kindred. The abnormal phenotype is characterized by clinical mildness and slightly abnormal clotting time, prothrombin consumption, and partial thromboplastin time. Bleeding time, platelet count, clot retraction, tourniquet test, and prothrombin time are normal. Concentration of factors I, II, V, VII, IX, X, and XII are normal, while factor VIII activity is reduced to 2%-5% of control values. De novo synthesis of factor VIII does not occur after transfusion; factor VIII-related antigen is normal; patients'plasmas aggregate platelets normally in the presence of ristocetin, and a typical protein pattern is seen when a chymotryptic digest of cryoprecipitate of the proband is examined by SDS-polyacrylamide gel electrophoresis. Six possible genetic explanations are entertained. Balanced X-autosomal translocation of hemophilia A heterozygotes has been excluded by cytogenetic analysis of metaphase chromosomes. Classes von Willebrand's disease (vWd) is probably excluded on the basis of the laboratory data, and extreme lyonization of hemophilia A heterozygotes on probabilistic grounds. The genetic possibilities which cannot be excluded include a previously unrecognized variant mutation at the vWd locus, a dominant mutation at the hemophilia A locus on the X chromosome, and dominant mutation at a hypothetical fourth locus involved in factor VIII synthesis and control.

The association of amyloidosis and factor X deficiency has been reported 18 times. We have added a 19th case and compiled a summary of all previously reported cases. The pathogenesis of this association is discussed and therapeutic recommendations are offered based on the accumulated experience.

The plasma level of naturally acquired inhibitors to clotting Factor VIII activity (F.VIII: C) was assessed by the Bethesda Inhibitor Assay (BIA). At inhibitor concentrations outside the BIA working range (25% to 75% residual F.VIII: C), patient plasmas had to be diluted. However, when a rough estimate of the inhibitor concentration was unavailable, the choice of dilution was arbitrary and testing became tedious and inefficient. In an effort to improve the BIA, a screening test was devised to predict the appropriate plasma dilution. It is based on the partial thromboplastin time (PTT) of the incubated sample and is performed just prior to preparing dilutions for the F.VIII: C assay. Test plasmas were diluted serially in multiples of two, from 1:2 to 1:1024, and then incubated according to the BIA. After 90 min, samples were removed for PTT determinations to screen for the appropriate dilution to use in the F.VIII: C assay. The first two test dilutions to produce PTT values 21 sec (± 4 sec, 95% confidence interval) greater than the control resulted in a residual F.VIII: C for the BIA within the 25% to 75% acceptable range. When the log ratio of patient-to-control PTT determinations (specific PTT) for a given dilution was plotted as a function of log residual F.VIII: C at that test dilution, in 81 Bethesda assays a linear relationship was observed (p> .25; with r2 = .81). The screening test was 89% effective in predicting an appropriate dilution (range 0 to 1020 Bethesda units/ml). The accuracy can be enhanced further if, based on the first of three dilution screen tests in which the specific PTT >21 sec, the F.VIII: C assay is performed using the middle dilution value first. Depending on whether that dilution yields an acceptable residual F.VIII: C, either the higher or lower dilution is chosen in the second F.VIII: C assay.

Antithrombin III (AT III) is a plasma protein that inhibits several activated procoagulants. Hereditary disease or acquired conditions such as severe hepatic dysfunction, nephrotic syndrome and intravascular coagulation may be associated with reduced levels of AT III. Its replacement may be essential in controlling thrombosis. In order to determine the most effective form of replacement, we compared AT III biological activity and antigen levels in conventionally prepared fresh frozen plasma, cryoprecipitate and cryoprecipitate depleted plasma (CDP). Both the activity and antigen levels were comparable in all three products (approximately 100%) and AT III was not concentrated in cryoprecipitate. These results indicate that conventionally prepared CDP, fresh frozen plasma and cryoprecipitate contain equal quantities volume for volume of AT III. On this basis, all products are equally effective as therapy for AT III deficiency, but CDP and fresh frozen plasma are recommended as convenient sources of this factor.

The treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

Immune hemolytic anemia is a recognized complication of the use of factor VIII concentrates. Hemolysis is obscured often by the presence of active bleeding. Where hemolysis has been demonstrated, red blood cell (RBC) destruction has been attributed to anti-A antibodies found in the transfused material. We present two episodes of hemolysis associated with the use of factor VIII concentrate. In the first, a high titer of "immune" anti-A (1:256) was present in the factor VIII. In the second, the patient's RBCs were group B, and the hemolysis was caused by anti-B antibody in the factor VIII concentrate. In addition, the antibody titer in the material that was received was much lower than previously described. The RBC destruction presumably occurred because of the massive dosage of factor VIII concentrate administered on order to overcome a factor VIII inhibitor.

Bleeding episodes in patients with hemophilia A with anti-factor VII antibodies are frequently difficult to treat. Factor VIII concentrates administered by continuous infusion or prothrombin complex concentrates (PCC) have been used for treatment. Hemophilia A patients with inhibitors who respond to factor VIII concentrates generally have low to moderate inhibitor titers (generally less than 20 Bethesda units). Those patients who receive PCC are quite difficult to evaluate but promising clinical responses have clearly been observed. This paper describes our experience with both modalities of therapy and will offer specific guidelines for such therapy.

In patients with coagulation defects, the use of posterior chamber lens implanted within the capsular bag after extracapsular cataract extraction appears to be well suited for the avoidance of long-term hemorrhagic complications. Bleeding tendencies during and following surgery can be managed medically with careful collaboration of a hematologist or coagulationist. This patient's multifaceted coagulopathy was easily manageable by treating each component as a separate entity. It is our present view that the vast majority of patients with severe coagulopathy can safely undergo cataract surgery and can be considered for intraocular lens implantation.

Musculoskeletal bleeding in general and arthropathy in particular are the central problems among many in the two major forms of hemophilia: classic hemophilia, caused by factor VIII deficiency, and Christmas disease, caused by factor IX deficiency. Currently available replacement therapy, if properly used in a multidisciplinary setting, should provide significant benefit to hemophilic patients despite its cost and occasional complications.

Hemophilia B (factor IX deficiency) is an X-linked recessive clotting disorder similar to hemophilia A. In both diseases, phenotypic expression of the disorder may occur in significant numbers of heterozygous carriers. This is presumably due to random inactivation of one of the two X chromosomes of the female carrier as described by the Lyon hypothesis. Described herein is the obstetric care of a severely affected heterozygous carrier of hemophilia B. Predelivery automated plasma exchange was used to raise factor IX levels successfully. Commercial factor concentrates were avoided. The Lyon hypothesis is discussed in detail, and recommendations are made for the care of the clotting factor-deficient gravid woman.

Recent studies in multiply transfused patients with hemophilia A and persistent liver function abnormalities have shown a high incidence of chronic active hepatitis. The purpose of the present study was to determine the severity of liver disease in multiply transfused patients with intermittent liver enzyme abnormalities. Fifteen patients with elevated enzymes on two or three out of four determinations at 6-mo intervals were studied. None had signs or symptoms of chronic liver disease. Thirteen had serologic evidence of prior exposure to the hepatitis B virus. Liver biopsy performed on these patients after replacement therapy with factor VIII showed chronic persistent hepatitis or other mild forms of liver disease in 14 of the 15 patients. Patients with chronic persistent hepatitis had significantly higher mean liver enzymes at time of biopsy than patients with milder forms of hepatic inflammation, but there was no relationship between liver histology and hepatitis B serology or the amount of factor VIII used in the 6 mo preceding biopsy. These findings support the continued use of factor VIII concentrates in patients with hemophilia.

The clinical histories, risk factors, and autopsy findings were reviewed for five deceased hemophiliacs over the age of 40 years to determine the prevalence and severity of arteriosclerosis. The presence of a severe, congenital, hypocoagulative state did not prevent these five men from displaying typical arteriosclerotic vascular disease. One patient actually died of severe, multivessel, coronary artery disease.

A retrospective analysis of 12 patients with the diagnosis of thrombotic thrombocytopenic purpura was undertaken with a review of pathological material. The gingival biopsy was found to be a poor method of diagnosing thrombotic thrombocytopenic purpura. Pathological review also verified chronicity of disease. The pancreas was found to be the most severely involved organ, although serum amylase values did not always reflect pancreatic disease.

One haemophilia A patient with an inhibitor was exposed to a graded surgical procedure and treated with Prothrombin Complex Concentrates (PCC). Hemostasis was not obtained until the inhibitor was neutralized and the patient's factor VIII level was normal. This patient is presented to emphasize that PCC are not nearly as effective as once hoped in producing hemostasis in inhibitor patients. Consequently, major decisions should not be made presuming efficacy of these products in inhibitor patients.

In view of uncontrolled observations and anecdotal reports suggesting that the activated PCC, Autoplex, was much more effective than standard (non-activated) PCC in controlling bleeding in hemophiliacs with inhibitors, a controlled double-blind study was designed to compare the effectiveness of Autoplex and Proplex. Acute hemarthrosis was chosen for study as this common but non-life-threatening lesion lends itself well to controlled study. A single dose of "unknown" product (Autoplex 75 FECU/kg; Autoplex 50 FECU/kg; or Proplex 75 FIX U/kg) was given, and effectiveness was judged at 6 hr. By all criteria of efficacy, there were no significant differences between the products. It is noteworthy that a single dose of PCC was judged effective in 50% of episodes, a figure that is consistent with other published clinical trials. In this model, no additional benefit was derived from using the activated PCC, Autoplex, in either dosage.

A number of inborn errors have recently been associated with a diathesis for collagen vascular disorders. For example, hereditary deficiencies of Clr or C2 components of complement have been associated with certain features of SLE. We wish to record the syndrome of JRA with evolution to SLE associated with a familial deficiency of Factor XI (DTA). The propositus, a 26 year old Sephardic female, presented at age 4 with symmetrical destructive polyarthritis, fever and rash. Progressive renal disease began in her early teens, and she developed multiple diagnostic criteria for SLE beginning at age 25. Three maternal relatives manifest arthritis and two showed mild bleeding after surgery. Physical findings included a deforming arthritis and rash. Low levels of C3 and C4, high titers of antibody to native DNA, positive LE cell preparations and Clq precipitins were present. Skin biopsy showed deposits of IgG, IgM, Clq, C3 and C4 at the dermal-epidermal junction.Factor XI levels were 5 per cent in the propositus and mother, with normal levels in a sister. There was no evidence for a circulating anticoagulant and other clotting factors were normal.We believe the present case represents the first association of an inborn error in the clotting system (Factor XI deficiency) and collagen vascular disease with immune complex deposition.

We report here on a patient whose abnormal fibrin clot was detected via the measurement of clot rigidity with a simple buoyant inner cylinder elastometer. The patient's clinical coagulation studies were all within normal limits except for prolonged thrombin and reptilase clotting times and high level of fibrin split products. The measured rigidity of the patient's clot was approximately ten times lower than that of a clot formed from normal pooled plasma. Light scattering studies indicated that this modified structure was not caused by a gross change in gel fiber morphology. Antithrombin activity was eliminated as a possible cause of the altered clot structure; this suggests the possibility of a modified fibrinogen. Abnormalities in the reptilase time and fibrinogen levels in two siblings support the hypothesis that the modification is an inherited defect. We suggest that the simple measurement of rigidity can be used rountinely to detect abnormalities in plasma clot structure. The screening for such disorders should be of importance to clinician, patient, and biochemical researcher.

Daily administration of large doses of factor VIII concentrate in a hemophiliac with a high titer factor VIII inhibitor resulted in marked reduction in the titer and response of the inhibitor to factor VIII administration and made possible elbow and bilateral knee replacements under conventional factor VIII coverage. Studies performed during the course of treatment indicated that the reduction in the inhibitor was the result of specific tolerance to factor VIII.

In a cooperative study of 1,332 hemophiliacs, the results of a variety of liver function tests were correlated with the intensity and type of exposure to plasma products. After three sets of measurements of six-month intervals, 72% of patients had at least one abnormal transaminase value and 21.1% and 23.6% of patients had persistently elevated SGOT and SGPT levels, respectively, on all three measurements. Patients who had received no factor VIII during the previous year had fewer abnormalities than treated patients. Only those treated patients who received less than 50 units of factor VIII per kilogram per six months had fewer transaminase abnormalities if they used cryoprecipitate than if they used concentrate, but these patient groups are not strictly comparable, in that the cryoprecipitate-treated group contained a higher proportion of patients with mild hemophilia than did the concentrate-treated group.