Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System.

AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. CONCLUSION: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.

Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006).

Haemophilia B is an X-linked disorder resulting in coagulation factor IX deficiency. Patients with severe deficiency (<1% factor IX activity) may have significant bleeding complications similar to patients with haemophilia A or factor VIII deficiency. The development of inhibitory antibodies to the missing coagulation factor is a major complication in patients with haemophilia. While the incidence of inhibitors in patients with haemophilia A is higher than that in haemophilia B, the occurrence of allergic and or anaphylactic reactions with the development of inhibitors is unique to haemophilia B patients. Since haemophilia B is a rare bleeding disorder and the incidence of inhibitors is an even rarer entity, a registry was established by Dr Indira Warrier under the auspices of the FVIII/FIX subcommittee of the International Society of Thrombosis and Haemostasis, to gather information on the occurrence and characteristics of patients with inhibitors and also the incidence of allergic and anaphylactic reactions in this group of patients. This is the first report from this registry and helps us to gather some insight on haemophilia B patients with inhibitors and complications related to inhibitor development and difficulties with immune tolerance.

Ethanol lock therapy for the treatment of catheter-related infections in haemophilia patients.

Central venous access devices (CVAD) are increasingly being used for optimal delivery of clotting factor concentrates in patients with haemophilia with poor peripheral venous access. The utility of CVAD is particularly well recognized in young patients starting factor prophylaxis and in patients with inhibitors undergoing immune tolerance induction (ITI). A catheter-related infection (CRI) remains the most common complication of CVAD in haemophilia patients and is the most frequent indication for its removal. Additionally, in some patients the infection results in significant morbidity and mortality and also contributes to failure of the ITI regimen. Ethanol-lock therapy (ELT) is a treatment modality that has been used to treat CRI in patients with indwelling catheters for home parenteral nutrition and chemotherapy. The aim of this study was to report the success in treating CRI in haemophilia patients using ELT. Three severe haemophilia A patients undergoing ITI regimen who developed CVAD infections resistant to conventional management with antibiotics were treated by ELT according to the institutional technique. All three patients responded well to ELT with clearance of the CVAD infection. There were no adverse side effects. To our knowledge, this is the first report of ELT in patients with haemophilia. The role of ELT needs to be investigated in larger studies for treatment of CRI in patients with bleeding disorders.

The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience.

The response to a highly purified concentrate of porcine factor VIII was evaluated in 45 bleeding episodes in 38 patients with high responding inhibitor antibodies to factor VIII. A total of 437 infusions were given. The patients came from 25 hemophilia centers in the United States. The majority had a life- or limb-threatening hemorrhage for which other modalities had not been successful. In 32 of 45 episodes, a good to excellent response was obtained. Adverse reactions were minimal, occurring in 17 treatment episodes, and were mostly treated with antihistamines and/or hydrocortisone. No clear predictor of clinical response to porcine factor VIII concentrate was identified, including pretreatment human and porcine inhibitor levels, percentage of cross-reactivity between the human and porcine antibodies, and the presence of measurable levels of factor VIII after the porcine factor concentrate was given. Anamnesis to porcine factor VIII did occur in some instances. Porcine factor VIII is a valuable modality in the treatment of serious hemorrhages in patients with inhibitors to factor VIII. Its use should be considered early in the course of severe hemorrhage in these patients.

Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors--benefits and limitations.

In summary, PCCs and APCCs are moderately effective in controlling bleeding in inhibitor patients. However, they are not as effective in controlling or preventing bleeding as factor VIII (or factor IX) concentrates in hemophiliacs who do not have inhibitors. Their precise mechanism of action is still poorly understood, and there is no readily available laboratory test for monitoring patient response. While viral safety is far less of an issue with PCCs than it was a few years ago, and while thrombogenicity is far less of a problem in using PCCs and APCCs in inhibitor patients than it is in persons with hemophilia B, one must keep in mind the risk of acute myocardial infarction. Frequent, repetitive doses may be hazardous. PCCs and APCCs represent a valuable part of one's therapeutic armamentarium in managing bleeding in inhibitor patients. However, one must be aware of their limitations and potential complications, and use them appropriately.

Systemic causes of excessive uterine bleeding.

In assessing a patient with excessive uterine bleeding, the clinician should consider systemic causes in the differential diagnosis. Both hereditary and acquired conditions can result in mucous membrane bleeding, including menorrhagia, epistaxis, and gum bleeding, as well as excessive bruising. Among hereditary conditions, von Willebrand disease (vWD) is by far the most common, affecting an estimated 1% of the population worldwide. It is important to consider the possibility of vWD, and to establish the proper diagnosis (including subtype), as safe, effective, and easy-to-use treatment is available for most persons with this disorder. This review also covers a number of other systemic conditions that can be manifested by excessive uterine bleeding, including congenital deficiency of factor XI, idiopathic thrombocytopenic purpura and other acquired platelet disorders, acquired autoantibodies against factor VIII (FVIII), and vitamin K deficiency states.

Prediction and management of adverse events associated with the use of factor IX complex concentrates.

Among the adverse events that have been associated with the use of F IX CC in inhibitor patients, the likelihood of transmission of blood-borne pathogens is now greatly reduced. However, one must be aware of the possibility of thrombotic complications and acute myocardial infarction when using large, repetitive doses of F IX CC. A greater awareness of such potentially life-threatening complications, and avoidance of frequent, repetitive large doses, should decrease the risk. F IX CC are not always effective in achieving or maintaining hemostasis in hemophiliacs with inhibitors. Thus, in subjects who are responding suboptimally, in those in need of surgical intervention, or in those who have large intramuscular hemorrhages and/or will require a prolonged period of treatment, alternative therapeutic approaches should be considered.

Viral safety and inhibitor development associated with factor VIIIC ultra-purified from plasma in hemophiliacs previously unexposed to factor VIIIC concentrates. The Monoclate Study Group.

A multicenter study evaluated the potential for transmitting non-A/non-B hepatitis, as well as other viruses, with the use of the factor VIIIC product Monoclate. This product is purified from plasma via the monoclonal process that includes heat treatment for ultra-purification as a final step. Twenty different lots of Monoclate were used, and each patient received the assigned lot for the first 6 months of the trial. Nineteen of 38 patients adhered strictly to International Committee on Thrombosis and Hemostasis criteria in that they had normal liver enzymes, no evidence of hepatitis prestudy, and had no previous blood product use. Fourteen hemophilia centers from the United States, the United Kingdom, the Netherlands, and Israel participated in this study. Development of factor VIII inhibitor occurred in six of 38 patients, which was within the statistically expected range. Adverse events were mild, and Monoclate was well tolerated in this group. All 38 patients remained HIV seronegative.

Initial clinical experience with a new pasteurized monoclonal antibody purified factor VIIIC.

Heat treatment of lyophilized factor VIII and factor IX concentrates has been found to eliminate HIV virus infectivity in plasma-derived products. Pasteurization of factor VIII in solution has recently been used to reduce the risk of hepatitis transmission in concentrates prepared by standard fractionation methods. This report presents early experience with factor VIIIC prepared by monoclonal antibody immunoaffinity chromatography following pasteurization of the factor VIIIC/von Willebrand factor complex (Monoclate-P). Twelve patients were treated in three centers with Monoclate-P. Recovery and survival of factor VIII clotting activity were determined and patients were closely monitored for infusion safety. The mean half-life was 14.2 +/- 5.0 while recovery in predicted plasma volume was 72 +/- 12% corresponding to a response of 1.99 +/- 0.66 U/dL for every U/kg administered. These values are very similar to those found for Monoclate in previous studies indicating that pasteurized factor VIIIC purified by immunoaffinity chromatography retains satisfactory pharmacokinetic properties with an added margin of viral safety.

Perspectives on the use of factor IX complex concentrates in the treatment of bleeding in persons with acquired factor VIII inhibition.

In contrast to the type of bleeding encountered in congenital hemophilia with inhibitors, the diathesis toward bleeding exhibited by patients with spontaneously acquired factor VIII (FVIII) inhibitors often is severe and life threatening. Large hematomas and retropharyngeal or central nervous system hemorrhage may appear suddenly. Thus, a high premium is placed on rapid therapeutic intervention. Several treatment options are at the physician's disposal. The role of factor IX (FIX) complex concentrates, both standard and purposely activated, is discussed. The FIX products are also known as prothrombin complex concentrates (PCCs). Prudent choice of any treatment modality requires weighing its benefits and shortcomings. Advantages of PCCs--particularly the activated products--include availability, ease of reconstitution and administration, and at least partial efficacy; control of bleeding episodes can be achieved with PCCs in many (but not all) instances. One salient disadvantage of therapy with FIX complex concentrates is that they are not subjected to such rigorous viral-attenuation processes as are most of the currently marketed FVIII products. Therefore, a small but definite risk of infection with hepatitis B or C (HBV, HCV) remains. An assay that detects antibodies against HCV has been licensed and is being used to screen blood donors. Nevertheless, up to the present time the U.S. Food and Drug Administration (FDA) has ruled that HCV screening of plasmapheresis donors should not be performed for plasma collections destined to be pooled for fractionation and that units of HCV-positive source plasma (e.g., that provided by American Red Cross donors) found to be HCV positive be sent for fractionation. The starting plasma from which FIX complex concentrates and human FVIII concentrates are made thus contains some HCV and may also contain some HBV. Because nonhemophiliacs with acquired antibodies against FVIII are unlikely to have had prior exposure to blood products and are unlikely to have been vaccinated against HBV, they are at risk of viral hepatitis and its sequelae when treated with FIX complex concentrates. Furthermore, therapy with FIX complex concentrates is not always effective in controlling bleeding in persons with FVIII inhibitors, its mechanism of action in bypassing the need for FVIII remains unclear, very large doses are required, and it has an attendant risk of several adverse effects when used in large, repeated doses. These include disseminated intravascular coagulation, thromboembolism, and acute myocardial infarction. Thus, FIX complex concentrates may play a useful role in the treatment of bleeding in nonhemophiliacs with acquired inhibitors against FVIII, but one must carefully consider their disadvantages profile.(ABSTRACT TRUNCATED AT 400 WORDS)

Intravenous gamma globulin treatment for chronic idiopathic thrombocytopenic purpura in children.

Six children, five to 16 years of age, with the chronic, autoimmune form of idiopathic thrombocytopenic purpura were given intravenous gamma globulin (Gamimune, Cutter Biological, Berkeley, California) in a dose of 400 mg/kg per day for five consecutive days as six-hour infusions. Two of the six children had undergone splenectomy but the other four had not. Three of six children had a good or excellent response to the first five-day course of intravenous gamma globulin. The peak platelet count occurred within 12 days of the start of therapy in all. All three have required booster doses of intravenous gamma globulin to maintain platelet counts at a safe level. All children had marked increases in serum IgG following intravenous gamma globulin, except one who had undergone splenectomy and who had chronic idiopathic thrombocytopenic purpura with high baseline levels of immunoglobulin G (IgG). The significance of the observed increase in platelet-associated IgG during treatment is not clear. No untoward reactions necessitating cessation of therapy were encountered during this study. Our short-term observations in six children with chronic idiopathic thrombocytopenic purpura indicate that high-dose intravenous gamma globulin is an effective form of treatment for certain children with this condition.

Severe factor VIII and factor IX deficiency in females.

A survey of 11 hemophilia centers produced data concerning 28 females with extremely low levels of factor VIII or IX coagulant activity. Ten of the 28 have hemophilia A, six have hemophilia B, and 12 have severe von Willebrand's disease. The 16 females who have severe factor VIII or factor IX deficiency as an isolated defect exemplify several of the possible genetic explanations for the occurrence of hemophilia in females. All 16 bruise excessively, and several have had recurrent hemarthroses. Three of these girls, ages five, 10 and 23 years, have evidence of chronic hemophilic arthropathy. The 12 females with severe von Willebrand's disease are either homozygous for von Willebrand's disease or severely affected heterozygotes. All 12 have mucous membrane bleeding. In addition, five of the 12 have recurrent hemarthroses and three have evidence of chronic joint disease. However, the major problem in the adult females with von Willebrand's disease has been extreme menorrhagia. One of the seven adults underwent irradiation sterilization and another had a hysterectomy because of menorrhagia. The others have been managed with anovulatory drugs or plasma infusions and EACA. Despite menorrhagia, five pregnancies and deliveries have been uneventful in three of these women.

Use of intravenous gamma globulin in children and adolescents with idiopathic thrombocytopenic purpura and other immune thrombocytopenias.

Approximately 85 to 90 percent of cases of idiopathic thrombocytopenic purpura (ITP) in children are of the acute, self-limited variety that generally occurs after a viral infection. The remaining 10 to 15 percent of children with this disorder have the chronic (autoimmune) type of ITP. For these patients, splenectomy is often the recommended treatment if severe bleeding occurs and platelet counts remain below 40,000/mm3. However, splenectomy has associated risks and the response to this surgery cannot always be predicted. Intravenous gamma globulin (IVIG) has proven useful as an alternative to splenectomy, especially in children who are considered too young for splenectomy or in those in whom there is no response to splenectomy. It should be noted that booster shots are frequently required and the patient's ITP may become refractory. IVIG may also be useful in preparing a child with ITP for splenectomy and in treating children or adolescents with ITP who have central nervous system or other serious hemorrhages. Although IVIG is not always effective in raising the platelet count, it does provide a very useful alternative method of treating this disorder.

Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders.

The status of human immunodeficiency virus type 1 (HIV-1) infection at the time of transmission to sexual contacts remains poorly defined. Transmission to nonsexual household contacts has appeared to be rare. A total of 505 sexual and nonsexual contacts of HIV-1-infected hemophiliacs in 349 households was observed. At entry, 10% of 201 sexual partners were anti-HIV-1-positive. Follow-up of 151 uninfected partners during a total of 351 person-years of observation showed no sero-conversions, although there were 13 pregnancies during that period. Eighty-seven percent of the seronegative respondents to a detailed questionnaire reported unprotected sexual contact at least occasionally. Among 304 other household members, including 108 parents who helped administer clotting factor concentrates to their children, none was seropositive at entry. Follow-up of 263 showed no seroconversions during a total of 605 person-years of observation. Thus, anti-HIV-1-positive hemophiliacs transmitted to their partners earlier in their course but were not found to do so when prospectively observed. No relationship to level of viremia as indicated by CD4 count, HIV-1 p24 antigenemia, or acquired immunodeficiency syndrome was found. Anti-HIV-1-positive hemophiliacs had not transmitted to their nonsexual household contacts before study entry and did not do so subsequently, indicating that the risk from even close nonsexual contact is extremely low.

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.

Comparison of six commercial plasma references for factor VIII, factor IX and von Willebrand factor. On behalf of the Subcommittee for Factor VIII and IX of the Scientific and Standardization Committee of the ISTH.

Six brands of normal reference plasma produced in the United States, with assigned assay values for factor VII and IX and, in four instances, ristocetin cofactor and van Willebrand antigen, were assayed in nine coagulation laboratories in academic institutions in the same country. Differences in mean assays of reference plasmas, as a percent of labelled potency, were significant and were greater than differences among laboratories. Standard methods of assigning potency to commercial reference plasmas are recommended.

Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors.

OBJECTIVE: To assess the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa; NovoSeven) in the home setting for mild to moderately severe joint, muscle; and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors. DESIGN: Multicentre, open-label, single arm, phase III study of one year duration. METHODS; Patients or their caregivers administered up to three doses of rFVIIa (90 microg/kg i.v.) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode. Once the subject considered that rFVIIa had been "effective" with regard to haemostasis (after 1-3 injections), one further (maintenance) dose of rFVIIa was administered. RESULTS: Of 60 patients enrolled, 56 experienced at least one bleed, and 46 completed the one year study. 614 of 877 bleeds (70%) were evaluable according to protocol definitions. Haemostasis was rated as "effective" in 92% (566/614) of evaluable bleeds after a mean of 2.2 injections. For successfully treated episodes, the time from onset of bleeding until administration of the first injection was 1.1+/-2.0 h (mean+/-SD). Twenty-four hours after initial successful response, haemostasis was reported as having been maintained in 95% of cases. Efficacy was comparable for muscle, joint and target joint, and mucocutaneous bleeding episodes. In an intent-to-treat analysis of all 877 bleeding events, efficacy outcomes were equivalent to the evaluable bleeds, with an effective response in 88% of treated episodes. Treatment-related adverse events occurred in 32 (3% of all) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50% (18/32) of these events. A single episode of superficial thrombophlebitis was the only thrombotic complication encountered, and there were no patient withdrawals due to adverse events. Development of FVII(a) antibodies could not be detected, and hypersensitivity reactions to rFVIIa were not reported. CONCLUSION: rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors.

Management of patients with factor VIII inhibitors.

In summary, while a great deal of information has accumulated concerning the properties and natural history of F VIII inhibitors, management remains frustrating and controversial. While bleeding episodes in those who are low responders can be treated with F VIII concentrates, treatment of bleeding in high responders is often much more difficult. Current therapeutic options include F VIII concentrates of human or porcine origin in high dosage, and PCC or APCC. The choice of treatment depends on the patient's current inhibitor concentration, the type and severity of bleeding, product availability, and the preference of the medical personnel involved. However, none of the available therapeutic modalities work as well as F VIII in a hemophiliac without an inhibitor. Perhaps more promising are the immune tolerance regimens that have been developed and are now being modified and fine tuned by a number of investigators. Such regimens have reportedly eradicated F VIII inhibitors in some hemophiliacs, and have converted others from high responders to low responders, in whom bleeding episodes can be effectively treated with conventional doses of F VIII. In contrast to the F VIII inhibitors developing in hemophiliacs, those developing in nonhemophiliacs can often be eradicated with corticosteroids or immunosuppressive drugs, either alone or in combination with F VIII. Not all respond to such approaches and serious hemorrhage may still occur. Treatment of bleeding episodes has included the use of human or porcine F VIII, APCC and, in two instances, DDAVP.

Platelet-vessel-wall interactions: experiences with von Willebrand platelets.

Adhesion of platelets from 15 patients with von Willebrand's disease was tested in an ex vivo human umbilical vein model. Experiments employed umbilical veins still in their umbilical cords taken from patients undergoing cesarean section and platelets (fetal, adult and vW) either apyrase-washed or used as platelet-rich plasma or whole blood. F VIII R:Ag, F VIII:Rcof, and F VIII:C were measured in initial fresh plasma and in effluents from the umbilical vein segments. F VIII:Rcof increased in most perfusates. Binding of latex-linked specific antihuman F VIII R:Ag demonstrated that F VIII R:Ag existed on subendothelium and on injured endothelial cells. Scanning electron microscopy three-dimensionally displayed vW platelet--vessel-wall interactions. Although vW platelets adhered to injured vein, both qualitative and quantitative differences existed in comparison with adhesion of normal platelets. The differences correlated best with the plasma F VIII:Rcof level. The best adhesion shown by vW platelets was only 51 percent of the adhesion of control fetal or adult platelets. vW platelets had less surface activity, fewer pseudopods, and little ability to spread and pave the exposed subendothelium. Pretreatment of the vein with F VIII R:Ag antibody partly blocked adhesion. Coperfusion of cryoprecipitate with vW platelets improved their adhesivity, state of activation on subendothelium, and ability to form aggregates. ABO differences in blood cell types of fetal material and platelet donors seemed without effect, which further establishes this model's validity for studies of platelet dysfunction and platelet or endothelial reactive agents.