Severe Classic Hemophilia Research Articles

More Information on Patients with Factor XI Deficiency

It has been called to our attention that our recent Clinical Concepts and Commentary article, “Current Concepts of Hemostasis: Implications for Therapy,” contains a statement that implies that postoperative bleeding in patients with factor XI deficiency is usually mild.1We wish to clarify this implication. Patients with factor XI deficiency over a lifetime are mild bleeders who do not usually experience the chronic, crippling hemarthrosis or other severe bleeding episodes so typical of severe classic hemophilia or hemophilia B. Nonsurgical bleeding episodes in factor XI–deficient patients are usually mild over a lifetime. We wish to make it clear, however, that it is quite possible for patients with factor XI deficiency undergoing surgery to bleed severely unless they are pretreated. The replacement therapy for factor XI deficiency in the United States usually consists of plasma replacement therapy before an operation. More recently, recombinant factor VIIa has been used for factor XI deficiency, and it has been found to be effective, although it is not yet approved by the US Food and Drug Administration for this indication.2One of the readers of the journal pointed out to one of us via e-mail that patients with factor XI deficiency undergoing cardiopulmonary bypass may bleed excessively. We agree with this statement, and at our institution, such patients would be treated, preoperatively and postoperatively, with recombinant factor VIIa or with plasma replacement therapy, which may require plasma exchange transfusions to increase factor XI to 50% or greater. Factor XI concentrates are available in Europe but not in the United States, and these concentrates have occasionally been associated with thrombotic side effects. In summary, we wish to emphasize that even though patients with factor XI deficiency usually have mild bleeding episodes over a lifetime, this does not mean that they may not experience extensive hemorrhage after severe trauma or surgery. Although some patients with factor XI deficiency do not bleed after operative procedures, a family history of bleeding after surgery is suggestive that relatives of such patients will also bleed during surgery.It has been recommended that replacement therapy for factor XI deficiency also include the use of antifibrinolytic agents such as tranexamic acid because it seems that one function of factor XI is to boost thrombin generation to the extent that the “thrombin activatable fibrinolytic inhibitor” (TAFI) can be activated.3Adding tranexamic acid enhances the antifibrinolytic effect.We are grateful to the reader who called this potential interpretation of factor XI deficiency to our attention.* The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. hrr@med.unc.edu

Immunological dysfunction and persistent lymphadenopathy in patients with classic hemophilia.

Thirty‐four asymptomatic heterosexual adults with severe classic hemophilia without inhibitors receiving more than 40,000 units of factor VIII concentrate per year were studied and compared to 10 heterosexuals receiving cryoprecipitate and to 22 age matched controls. Anergy was noted in 68 percent of the patients treated with factor VIII concentrates, 57 percent of those treated with cryoprecipitate and 5 percent of the controls. The lyophilized factor VIII treated group had a significant elevation of serum IgG, decreased mitogen responses, high nonstimulated background activity, and altered T cell subsets with an increase in total T lymphocytes, T suppressor cells and decreased Th/Ts ratios.Four of the patients with cellular immune dysfunction developed fatigue, night seats, dyspnea, weight loss, neuropathic pain and rashes. They had diffuse, peripheral, non‐tender lymphadenopathy. Two had splenomegaly. All four were anergic, had inverted Th/Ts ratios, with an increase in suppressor cells. Three had lymph node biopsies which demonstrated reactive follicular hyperplasia. All had elevated serial titers to EBV. The systemic symptoms resolved as these titers returned towards normal. The lymphadenopathy is persistent although all four patients have gained weight and feel well. The persistent lymphadenopathy syndrome in hemophilia is a distinct entity which occurs in a subset of hemophiliacs with severe cellular immune dysfunction.

Impaired cell-mediated immunity in patients with classic hemophilia.

THREE cases of Pneumocystis carinii pneumonia, two of which were fatal, have recently been observed in patients with severe classic hemophilia who had been treated with lyophilized preparations of ...

T-Cell Alterations in Hemophiliacs Treated with Commercial Clotting Factor Concentrates

Various immunological parameters were determined in 46 patients with severe hemophilia A and in 9 patients with severe hemophilia B. All patients were treated over many years with commercial factor VIII or IX concentrates. Patients with severe classic hemophilia had a significantly reduced relative and absolute number of T-helper cells and a significantly increased relative and absolute number of T-suppressor cells. About half of these patients had an inverse T-helper/suppressor cell ratio. Patients with moderate hemophilia A and severe hemophilia B did not show these abnormalities. Hemophiliacs with an inverse ratio had a significantly higher concentration of serum total protein, IgG and IgM. No relationship between the amount of factor VIII concentrate administered, the HLA-type of the patient, the presence or absence of CMV-antibodies, hepatitis markers, thrombocytopenia and abnormal liver function tests to the T-cell abnormalities could be established. Lymphadenopathy was frequently associated with an inverse ratio. Indirect evidence suggests that the alterations of the immune system began in 1979/80.

In vitro detection of mild inhibitors to factor VIII in hemophilia.

Plasma samples from patients with severe classic hemophilia, suspected of having mild inhibitors not detected in the standard Bethesda inhibitor test, were examined in modified Bethesda tests and in a screening test based on the activated partial thromboplastin time (APTT). The APTT test was more sensitive to mild inhibitors than any modification of the Bethesda method. Increasing the ratio of patient to normal plasma in either the APTT or the Bethesda test improved the sensitivity to mild inhibitors. If a patient's plasma is used as its own control in the APTT test, results are more consistent as minor fluctuations in the APTT occur over time.

Behavioral treatment of disease-related chronic insomnia in a hemophiliac

Hemophilia represents a congenital chronic disorder characterized by recurrent unpredictable internal hemorrhages with accompanying acute bleeding pain. The medical management of a 38-year-old hemophiliac with severe classic hemophilia was further complicated by a high titer Factor VIII antibody, increasing the life-threatening status of a severe hemorrhage. The patient had a one-year history of less than 2 hours of sleep per night as a result of daily chronic tension and intrusive cognitions about the dangers of his illness. A treatment package consisting of progressive muscle relaxation, meditative breathing, cognitive refocusing, and stimulus control procedures resulted in an average of 6 hours per night of uninterrupted sleep; improvement was maintained over a 27-week follow-up period. The treatment is discussed within the context of the behavioral medicine approach in hemophilia comprehensive care.

Immunoradiometric measurement of the factor VIII procoagulant antigen.

A fluid-phase immunoradiometric assay has been developed which identifies an antigen on the Factor VIII (antihemophilic factor) procoagulant protein. This sensitive and quantitative assay is not influenced by levels of Favor VIII-related antigen (von Willebrand factor) or other plasma proteins. There is a close correlation of procoagulant activity and immunologically detectable protein in normal and von Willebrand's disease plasmas. In contrast, several different patterns have been identified in hemophilic plasmas. Neither procoagulant activity nor procoagulant antigen is detectable in plasmas from patients with severe classic hemophilia. Patients with mild and moderate hemophilia have either comparable plasma concentrations of procoagulant activity and procoagulant antigen or relatively greater levels of immunologically detectable protein.

Use of Prothrombin Complex Concentrates in Hemophiliacs with Inhibitors: Clinical and Laboratory Studies

Nine patients with severe classic hemophilia and inhibitors against factor VIII were treated for 156 bleeding episodes with 503 infusions of Proplex, Konyne, or Auto-Factor IX, three preparations of prothrombin complex concentrates (PCCs). Approximately two thirds of the bleeding episodes were managed successfully. Although the prothrombin time (PT) and partial thromboplastin time (PTT) were shortened after most PCC infusions, there was no evidence of disseminated intravascular coagulation. The degree of shortening of PT or PTT was not related to the particular PCC preparation used, dose, or cessation of hemorrhage. All PCC preparations contained activated clotting factors, as manifested by their ability to shorten the PTT of normal plasma, factor-VIII-deficient plasma, and factor-IX-deficient plasma. Shortening, which was greater with Auto-Factor IX than with the other products, was inhibited partially by a factor IX antibody and blocked completely by prolonged incubation with plasma. Although the nature of the procoagulant material in PCCs is uncertain, these products are of proven benefit to hemophilic patients with high-titer inhibitors. Side effects have been minimal and inhibitor titers have not risen.

Ocular Enucleation in a Patient with Severe Classic Hemophilia a

A 27-year-old man with severe classic hemophilia A (antihemophilic globulin level: 1.5% of normal) had blunt trauma to his left eye that produced a corneoscleral laceration with prolapse of the intraocular contents. His left eye was enucleated under management with factor VIII replacement. This consisted of sufficient cryoprecipitate to increase the calculated circulating factor VIII level to 125%, sufficient factor VIII every 12 hours to increase peak postinfusion levels from 100 to 120%, and to maintain minimum levels of 30% immediately before infusion. Because he had developed a gingival hematoma when he was placed on epsilon amino caproic acid after only one day of factor VIII replacement following extraction of mandibular molars, we continued the high level of factor VIII replacement for five days and then began antifibrinolytic epsilon amino caproic acid therapy. His surgical and postoperative course were uneventful on this regimen.

Heckathorn's disease: variable functional dificiency of antihemophilic factor (factor VIII)

A family is described in which a syndrome resembling moderately severe classic hemophilia was apparently inherited as an X chromosome-linked trait. In two affected individuals, the titer of functional antihemophilic factor varied dramatically from time to time, while the conversion of prothrombin to thrombin was impaired in no apparent relationship to AHF functional activity. A transfusion of 200 ml of fresh-frozen plasma did not correct the serum prothrombin times in either patient. In vitro, the additions of 10% of normal plasma or serum or washed plain or frozen platelets also did not normalize the serum prothrombin times. No inhibitor could be demonstrated in the blood of either patient. In one patient, RH, dissipation of infused cryoprecipitated AHF was abnormally slow, and, after an intensive course of transfusion of cryoprecipitate and whole blood, the titer of functional AHF remained at normal levels for at least 1 wk. The plasma of RH inhibited a human antibody against AHF in proportion to its titer of functional AHF (i.e., the defect was CRM-) despite the presence of relatively greater amounts of antigenic material recognized by heterologous antiserum. No qualitative abnormality of the AHF-like material in RH's plasma was identified. Inheritance of the abnormality appears superficially to be X chromosome-linked; on this assumption, three of four obligate carriers of the disorder were recognized by the presence of excess amounts of AHF-like antigens relative to AHF functional activity. This coagulation disorder has been designated Heckathorn's disease and may presage the discovery of other examples of hemophilia-related syndromes.

Heckathorn's Disease: Variable Functional Deficiency of Antihemophilic Factor (Factor VIII)

Abstract A family is described in which a syndrome resembling moderately severe classic hemophilia was apparently inherited as an X chromosome-linked trait. In two affected individuals, the titer of functional antihemophilic factor varied dramatically from time to time, while the conversion of prothrombin to thrombin was impaired in no apparent relationship to AHF functional activity. A transfusion of 200 ml of fresh-frozen plasma did not correct the serum prothrombin times in either patient. In vitro, the additions of 10% of normal plasma or serum or washed plain or frozen platelets also did not normalize the serum prothrombin times. No inhibitor could be demonstrated in the blood of either patient. In one patient, RH, dissipation of infused cryoprecipitated AHF was abnormally slow, and, after an intensive course of transfusion of cryoprecipitate and whole blood, the titer of functional AHF remained at normal levels for at least 1 wk. The plasma of RH inhibited a human antibody against AHF in proportion to its titer of functional AHF (i.e., the defect was CRM-) despite the presence of relatively greater amounts of antigenic material recognized by heterologous antiserum. No qualitative abnormality of the AHF-like material in RH's plasma was identified. Inheritance of the abnormality appears superficially to be X chromosome-linked; on this assumption, three of four obligate carriers of the disorder were recognized by the presence of excess amounts of AHF-like antigens relative to AHF functional activity. This coagulation disorder has been designated Heckathorn's disease and may presage the discovery of other examples of hemophilia-related syndromes.

Incidence and Course of Inhibitors among Patients with Classic Hemophilia

SummaryThe incidence of known inhibitors among patients with severe classic hemophilia seen at Orthopaedic Hospital, Los Angeles, increased from 4.8 percent in 1967 to 7.8 percent in 1972. Possible reasons for the increase may include : 1. selective referral of patients with inhibitor to this center and 2. a three-fold increase in the frequency of plasma product infusion and an eight-fold increase in the factor VIII units infused per year per patient. The incidence of inhibitors was highest among young children; in 1972, 14.6 percent of children under age 10 years and 6 percent of older patients had inhibitors. Several patients developed inhibitors in late adolescence or adulthood, some after little exposure to blood products, and others after many more than a hundred accumulated days of exposure. Anamnestic responses to plasma product infusions occurred in all children under age 4 with inhibitors and all older patients with pre-infusion inhibitor titers of at least two units. Some adolescent or adult patients with low-titer inhibitors received plasma products on several occasions without developing higher titers but later responded to another infusion with a marked rise in titer.

Hemophilia Prophylaxis With Factor VIII Concentrate

Antihemophilic factor concentrate was given on fixed schedules to adults with severe classic hemophilia who had very frequent hemorrhages. While receiving 250 factor VIII units a day, the subjects had almost half as many bleeding episodes as during a baseline period; on a regimen of 500 factor VIII units a day, bleeding episodes occurred about one fourth as often as during the baseline period. When a large dose, 2,000 factor VIII units, was given once a week, no bleeding episodes occurred in the first 48 hours, but occurred again in midweek when factor VIII levels had returned to baseline values. Prophylaxis in hemophilia with factor VIII concentrate is feasible and beneficial; the expense may not be much greater than that of treating random hemorrhages.