Liver disease complicating severe haemophilia in childhood

Liver biopsies were performed in 5 boys aged between 2 and 9 years with severe classical haemophilia who had persistently abnormal liver function tests. Abnormal histology was present in all; 4 had chronic persistent hepatitis and the fifth chronic aggressive hepatitis with early cirrhosis. Evidence of previous hepatitis B infection was present in one patient, 3 had antibodies to hepatitis, A, and 2 had subnormal levels of alpha-1-antitrypsin. Haemobilia occurred as a late complication of biopsy in one. The significance of these findings in young boys is discussed, as is the role of exposure to factor VIII containing blood products. It is concluded that cryoprecipitate should be used in preference to large pool factor VIII concentrates in children with haemophilia.     

Liver disease complicating severe haemophilia in childhood.

Liver biopsies were performed in 5 boys aged between 2 and 9 years with severe classical haemophilia who had persistently abnormal liver function tests. Abnormal histology was present in all; 4 had chronic persistent hepatitis and the fifth chronic aggressive hepatitis with early cirrhosis. Evidence of previous hepatitis B infection was present in one patient, 3 had antibodies to hepatitis, A, and 2 had subnormal levels of alpha-1-antitrypsin. Haemobilia occurred as a late complication of biopsy in one. The significance of these findings in young boys is discussed, as is the role of exposure to factor VIII containing blood products. It is concluded that cryoprecipitate should be used in preference to large pool factor VIII concentrates in children with haemophilia.     

Management of severe chronic thrombocytopenia in von Willebrand's disease type 2B

Two patients with a long history of unexplained thrombocytopenia, eventually diagnosed with von Willebrand's disease (vWD) type 2B are reported. In one patient with platelet counts of 80 x 10(9)/l 1-desamino-8-D-arginine vasopressin (DDAVP) had a favourable effect during bleeding episodes. The second patient received intermediate purity von Willebrand's factor (vWF)/factor VIII concentrate (Haemate HS), which helped haemostasis during tooth extraction. It increased platelet counts from 15 to 30 x 10(9)/l, whereas platelet transfusions produced no increase, nor prevented severe bleeding during abdominal surgery. Thus the treatment of vWD type 2B might depend on the degree of thrombocytopenia. It is recommended that in patients with mild to moderately decreased platelet counts, DDAVP treatment can be tried, whereas in patients with severely decreased platelet counts intermediate purity vWF/factor VIII concentrate substitution is preferred. In addition, vWD type 2B should be considered in the differential diagnosis of any child with chronic thrombocytopenia as the treatment strategy is different.     

Management of severe chronic thrombocytopenia in von Willebrand's disease type 2B

Two patients with a long history of unexplained thrombocytopenia, eventually diagnosed with von Willebrand''s disease (vWD) type 2B are reported. In one patient with platelet counts of 80× 10⁹/l 1-desamino-8-D-arginine vasopressin (DDAVP) had a favourable effect during bleeding episodes. The second patient received intermediate purity von Willebrand''s factor (vWF)/factor VIII concentrate (Haemate HS), which helped haemostasis during tooth extraction. It increased platelet counts from 15 to 30 × 10⁹/l, whereas platelet transfusions produced no increase, nor prevented severe bleeding during abdominal surgery. Thus the treatment of vWD type 2B might depend on the degree of thrombocytopenia. It is recommended that in patients with mild to moderately decreased platelet counts, DDAVP treatment can be tried, whereas in patients with severely decreased platelet counts intermediate purity vWF/factor VIII concentrate substitution is preferred.
In addition, vWD type 2B should be considered in the differential diagnosis of any child with chronic thrombocytopenia as the treatment strategy is different.

     

Recombinant factor VIIa in an infant with haemophilia A and inhibitors

Post-traumatic bleeding from the gingiva in a 16-month-old boy with severe haemophilia A did not stop after treatment with factor VIII concentrate and tranexamic acid, and it was demonstrated that he had developed antibodies to factor VIII. Treatment with recombinant factor VIIa 60-90 micrograms/kg body weight four to eight times daily, together with local measures, stopped the bleeding and no complications were seen.     

Immunologic abnormalities in patients with hemophilia A

To assess the immunologic status of healthy persons with hemophilia A, we performed studies of T cell immunity in 21 patients, 10 given only cryoprecipitate and 11 given factor VIII concentrate. Patients in the factor VIII group had significantly decreased helper/suppressor T cell ratios. Both groups had diminished mononuclear cell response to phytohemagglutinin and normal mixed lymphocyte culture, compared with controls. Abnormalities in T cell number or function did not correlate with the presence of antibody to cytomegalovirus, Epstein-Barr virus, or hepatitis B. Physicians caring for patients with hemophilia A should realize that asymptomatic individuals may have early evidence of immunodeficiency.     

Lymphocyte subsets in children younger than 2 years old: normal values in a population at risk for human immunodeficiency virus infection and diagnostic and prognostic application to infected children.

Data were collected prospectively from 116 children younger than 2 years old who were seen at the Duke Pediatric AIDS Clinical Trials Unit for known human immunodeficiency virus seropositivity. Forty-six (40%) of these children were human immunodeficiency virus-infected and 70 were not infected. Using 3-month blocks, 10th, 50th and 90th percentiles were calculated for the CD4+ and CD8+ cell counts, percentage of lymphocytes positive for CD4 and CD8 and T4:T8 ratios. Results from the infected and uninfected children were compared. By 3 to 6 months of age the infected patients had significantly lower CD4+ counts, percentage CD4+ cells and T4:T8 ratios, whereas the percentage of CD8+ lymphocytes was significantly higher. Absolute CD8+ counts were approximately the same in infected and uninfected children through age 2 years. Most infected children had one or more abnormal lymphocyte subset results (less than the 10th percentile for uninfected patients) by age 2: 83% had an abnormal CD4+ percentage; 78% had an abnormal T4:T8 ratio; and 67% had an abnormal CD4+ count. All 13 children who had an opportunistic infection (at any age) had an abnormal CD4+ percentage before age 2 years, and 12 of 13 had a low absolute CD4+ count or T4:T8 ratio. Among patients who died 10 of 11 had 1 or more low CD4+ count, 9 of 11 had an abnormal CD4+ percentage and 8 of 11 an abnormal T4/T8 ratio.     

Inhibitors in the Swedish population with severe haemophilia A and B: a 20-year survey

AIM: To survey the entire population (n = 116) afflicted with severe haemophilia A or B born in Sweden over a 20-y period (1980-1999), and to examine the epidemiological, genetic and clinical aspects of development of inhibitors to factors VIII and IX (FVIII/FIX). METHODS: One hundred of the subjects had haemophilia A and 16 had haemophilia B. All of these subjects had received prophylactic treatment and had a check-up of inhibitor status at least twice a year. Sixty-one were born between 1980 and 1989 and 55 between 1990 and 1999. RESULTS: Nineteen percent (19/100) of those with haemophilia A and 37% (6/16) with haemophilia B developed inhibitors at 12-18 mo of age, after exposure to FVIII/FIX concentrates for an average of 14 d in the case of haemophilia A and 16 d in haemophilia B. All patients with inhibitors carried mutations that impaired protein synthesis. The high incidence of FIX inhibitors may have been due to the large number of complete deletions (13%) in the Swedish haemophilia B population. Patients with haemophilia A showed no significant increase (p = 0.65) in incidence of inhibitors (n = 10/48, total incidence 21%) in the 1990s, when they were treated mainly with recombinant products, as compared to the 1980s (n = 9/52, 17%), when they received intermediate/high-purity plasma-derived concentrates. CONCLUSION: Our population-based study verifies that genotype has a general impact on the incidence of FVIII/FIX inhibitors, and that recombinant FIII/FIX concentrates are not a predisposing factor for inhibitor development.     

Deficient human immunodeficiency virus type 1-specific cytotoxic T cell responses in vertically infected children

Cytotoxic T lymphocyte (CTL) responses to human immunodeficiency virus type 1 (HIV-1) gag proteins were studied prospectively in 17 children (12 infected) born of mothers with HIV-1 seropositivity and in five pediatric patients with hemophilia infected by transfusion of HIV-1-contaminated factor VIII concentrate. B lymphoblastoid cells infected with vaccinia virus vectors expressing HIV-1 gag gene products were combined with autologous peripheral blood mononuclear cells to detect circulating CTLs. Effector cells were defined by monoclonal antibody-mediated, complement-dependent cytolysis. Circulating HIV-1 gag-specific cytotoxic responses were detectable in 4 of 5 HIV-1-infected pediatric hemophilic patients, and were similar in magnitude to those previously described in adults. In contrast, circulating HIV-1 gag-specific cytolysis was detectible in only 3 of 12 vertically infected children. Depletion data revealed that the majority of detectible gag-specific cytolysis was CD8 T cell-mediated. No apparent relationships between CD4 T cell counts, CD8 T cells counts, or serum p24 antigen levels and CTL responses were seen. Deficient CTL development may, in part, explain the more rapid onset of symptomatic disease following vertical HIV infection.     

Hemophiliac immunodeficiency: influence of exposure to factor VIII concentrate, LAV/HTLV-III, and herpesviruses

The relationship between hemophiliac immunodeficiency and exposures to factor VIII concentrate, LAV/HTLV-III retrovirus, and infection with Epstein-Barr virus and cytomegalovirus was examined. Exposure to factor VIII concentrate was significantly correlated with decreased percentages of T helper/inducer cells, decreased T helper/suppressor cell ratios, and decreased proliferative responses to plant mitogens. LAV/HTLV-III seropositivity was the primary predictor of increased percentages of HLA-DR-bearing mononuclear cells and decreased proliferative responses to pokeweed mitogen. Epstein-Barr virus and cytomegalovirus infections acted in a synergistic manner with LAV/HTLV-III to produce immunoregulatory defects. Increased percentages of T suppressor cells and decreased delayed cutaneous hypersensitivity skin test responses were observed in LAV/HTLV-III seropositive hemophiliacs infected with Epstein-Barr or cytomegalovirus. We conclude that hemophiliacs receiving commercial factor VIII concentrate experience several stepwise incremental insults to the immune system: alloantigens in factor VIII concentrate, LAV/HTLV-III infections, and herpesvirus infections.     

Features of whey protein concentrate supplementation in children with rapidly progressive HIV infection

HIV infection is associated with subnormal GSH levels. An increase in glutathione levels has been observed in HIV-infected adults under oral whey protein supplementation. We studied the features associated with a whey protein concentrate supplementation in children with rapidly progressive AIDS. A prospective double-blind clinical trial was carried out for 4 months with 18 vertically HIV-infected children (1.98-6.37 years), under antiretroviral therapy, who had received whey protein, maltodextrin (placebo) or none. Erythrocyte glutathione concentration, T lymphocyte counts (CD4+ and CD8+) and occurrence of associated co-infections were evaluated. Wilcoxon's and Fischer's Exact tests were used to assess differences between whey protein-supplemented and control (placebo and non-supplemented) groups. A significant median increase of 16.14 mg/dl (p = 0.018) in erythrocyte glutathione levels was observed in the whey protein-supplemented group; the TCD4/CD8 lymphocyte ratio showed a non significant increase and lower occurrence of associated co-infections was also observed. In conclusion, whey protein concentrate supplementation can stimulate glutathione synthesis and, possibly, decrease the occurrence of associated co-infections.     

Prospective audit of patients with haemophilia: bleeding episodes and management

Background: Haemophilia is a congenital bleeding disorder that requires replacement of factor VIII (haemophilia A) or factor IX (haemophilia B) via intravenous infusions. Children can either be treated with prophylactic treatment to prevent bleeding or be managed with on‐demand therapy and treat specific bleeding episodes. Aims: The aim of this paper was to prospectively follow a cohort of haemophilia patients to determine the incidence of bleeding, re‐bleeding, re‐treatment and adjunct management over a period of 5 months. Methods: Sixty‐six boys with haemophilia were followed. Age range was 10 months to 19 years; 70% of patients had severe haemophilia and 38 (58%) of all patients were on prophylaxis. Results: Twenty‐nine patients experienced at least one episode of bleeding during study period which included 70 home bleeding episodes and 20 emergency department (ED) presentations. Secondary treatments occurred in 38% of all bleeding episodes. The incidence of re‐bleeds occurring within 3 weeks of the initial bleeding episode was 11%. Conclusions: Further study focusing on optimising treatment regimes for patients with haemophilia presenting with bleeding episodes is necessary.     

Safety trial of heated factor VIII concentrate (8Y).

Seventeen previously untreated boys with haemophilia A were treated with high purity heat treated factor VIII concentrate (8Y) for up to 36 months. Liver function tests were assessed monthly. No boy''s serum has been shown to contain HIV antibodies and no increases in alanine transaminase activity have been detected. In only one patient was a single rise in aspartate transaminase activity noted, and this was without a corresponding rise in alanine transaminase. A second patient''s serum contained hepatitis B core antibody transiently. It was thought likely in both cases that the abnormalities reflected intercurrent infections rather than disease associated with transfusion. The physical treatments used in the production of 8Y seem to inactivate the agent(s) responsible for non-A, non-B hepatitis and HIV transmission by transfusion of factor VIII has been abolished. There are, however, problems associated with conducting safety trials in young haemophiliac patients.     

Portal vein thrombosis in a patient with severe haemophilia A and F V G1691A mutation during continuous infusion of F VIII after intramural jejunal bleeding - Successful thrombolysis under heparin therapy

We report on a 14-year-old boy with severe haemophilia A who developed a portal vein thrombosis during continuous infusion of F VIII. For treatment of a posttraumatic intramural jejunal haematoma with extension into the mesenterium the patient received continuous infusion (CI) of a high purity F VIII concentrate, starting with an initial bolus injection of 100 IU F VIII/kg bw and followed by 4-5 IU F VIII/kg bw/h i.v. F VIII plasma activity ranged between 47 and 88%. Resorption of the haematoma was proven by abdominal ultrasonic follow-ups. After 3 weeks of CI a thrombus formation in the portal vein was detected by ultrasound and confirmed by duplex ultrasound. Subsequent to diagnosis the patient was heparinised with unfractionated heparin (UFH 300-450 IU/kg/d i.v.). In order to induce further resorption of the haematoma, F VIII concentrate was given concomitantly (50 IU/kg bw twice daily) during the initial phase of treatment. After 14 days of anticoagulant therapy with UFH, the regimen was changed to low molecular weight heparin (LMWH; Fraxiparin 0.3™; 2850 IU anti-X activity/d s.c.; bw 60 kg). F VIII dosage was gradually reduced with advanced resorption of the haematoma and thereafter switched to prophylaxis (40 IU/kg bw 3 times weekly). Complete lysis of the thrombus was observed after 6 months of treatment with UFH and LMWH respectively without any further complications. Thereafter LMWH was discontinued. Thrombophilic screening revealed no abnormalities except heterozygous F V G1691A. Conclusion The coexistence of a common prothrombotic risk factor and haemophilia may cause severe complications, in particular if the bleeding disorder has to be corrected temporarily by administration of the concerning deficient agent.     

Transient hypoplastic anemia caused by primary human parvovirus B19 infection in a previously untreated patient with hemophilia transfused with a plasma-derived, monoclonal antibody-purified factor VIII concentrate

BACKGROUND: Modern plasma-derived clotting factor concentrates are produced using various virus-inactivation protocols and are assumed to be safer than they were previously with regard to the risk for transmitting viral infections such as human immunodeficiency virus, hepatitis B, and hepatitis C. The risks from viruses that are relatively resistant to the current inactivation procedures remain uncertain. PATIENT: A 7-year-old with mild hemophilia A who had not been previously infused with any blood products was treated with a plasma-derived, monoclonal antibody-purified factor VIII concentrate to cover orthopedic surgery after traumatic fracture of his left arm. RESULTS: A typical primary human parvovirus (HPV)-B19 infection was observed associated with transient hypoplastic anemia. Retrospective studies including serologic examination and polymerase chain reaction analysis confirmed that the HPV-B19 infection was transmitted by the factor VIII concentrate. CONCLUSIONS: Clotting factor concentrates for the treatment of hemophilia retain a risk for HPV-B19 contamination. HPV-B19 viral infection might induce hypoplastic anemia in these patients, particularly during enhanced hemopoiesis after acute blood loss.     

Haemophilia A in two premature infants

The incidence of prematurity in Germany is about 10% and premature infants with haemophilia A (OMIM 306700) are in fact very rare. We report two new cases, one born in the 28th gestational week, weighing 1200 g with a factor VIII (FVIII) level of 0.03 IU/ml treated with bolus injections of plasma derived FVIII concentrate (pdFVIII), and one born at week 30, weighing only 710 g with a factor level of <0.01 IU/ml and treated with recombinant FVIII concentrate (rFVIII). Recovery of FVIII was 96% in case 1 and 120% in case 2, FVIII half-life was 6 h and 8 h, respectively. During FVIII substitution, neither bleeding, thrombosis nor inhibitor development were noted in both infants. Conclusion:Immediate and frequent factor VIII substitution appears to be safe and effective for prophylaxis and treatment in premature haemophilic neonates.     

Lymphocyte subpopulations in full-term septic neonates

PURPOSE: To estimate the absolute leukocyte and lymphocyte counts and relative and absolute sizes of CD19+ B lymphocytes, CD3+, CD4+, CD8+ and CD3+/HLA-DR+ T lymphocytes in full-term septic neonates and the influence of some perinatal risk factors on these lymphocyte subsets. METHODS: Twenty-one septic and mechanically ventilated full-term neonates (13 boys and eight girls) and 15 healthy full-term neonates born vaginally with an Apgar score > 9 and without hyperbilirubinemia were investigated. Two-color flow cytometric immunophenotyping with appropriate antibody panels using lysed whole vein blood was performed. RESULTS: The mean relative and absolute sizes of CD19+ B lymphocytes, CD3+/CD8+ and CD3+/HLA-DR+ T lymphocytes in septic neonates did not differ significantly from control. In contrast, the mean relative sizes of CD3+ and CD3+/CD4+ T lymphocytes and the CD4+/CD8+ ratio in septic neonates were significantly higher than in healthy neonates. With regard to the absolute size in septic neonates, only CD4+ T cells were significantly higher compared with the control group. Perinatal risk factors (birth asphyxia, gestation and delivery complications) had no significant effect on the relative and absolute counts of all estimated lymphocyte subpopulations in septic neonates. CONCLUSIONS: Increases in the relative sizes of CD3+ and CD3+/CD4+ T lymphocytes and the CD4+/CD8+ ratio in full-term septic neonates provides important information about changes in cell-mediated immunity during the early neonatal period.     

RADIOLOGIC EVALUATION OF PROPHYLAXIS IN SEVERE HAEMOPHILIA

ABSTRACT. Pettersson, H., Nilsson, I. M., Hedner, U., Noréhn, K. and Ahlberg, Å. (Department of Diagnostic Radiology, Coagulation Laboratory and Department of Orthopedics, University of Lund, Malmö General Hospital, Malmö, Sweden). Radiologic evaluation of prophylaxis in severe haemophilia. Acta Paediatr Scand, 70:565,.–The effect of prophylactic treatment of severe haemophilia A and B was evaluated with a recently described radiologic score system for assessing the severity of arthropathy. The severity of the arthropathy was assessed in 50 patients with severe haemophilia receiving prophylaxis with factor VIII or IX (25–30 units factor VIII or IX/kg bodyweight at 4–7 day intervals), and in 9 in whom the condition was complicated by inhibitors and who were thus not receiving prophylaxis. The score values found in a recent investigation of the natural course of haemophilia served as controls in the evaluation of the effect of the prophylaxis. In the group with severe haemophilia receiving prophylaxis changes appeared only exceptionally in joints not affected already before the prophylaxis, and the course of the arthropathy and its severity according to age did not vary to any noteworthy extent from that in the control group with moderate haemophilia. In the cases complicated by inhibitors the joints were most often worse than those in the control group with severe haemophilia. It is concluded that prophylaxis has a considerable effect on the course of the arthropathy and the prophylaxis should be instituted at an early stage of the disease, when the joints are still unaffected.     

Management of haemophilia in children

Haemophilia is an inherited bleeding disorder associated with a reduction or absence of coagulation factor VIII or IX. In severe haemophilia, recurrent, spontaneous bleeding occurs into joints, without treatment this leads to crippling joint deformity. Haemophilia is an X-linked disorder yet there is no family history in approximately one third of cases where haemophilia arises as a result of a new genetic mutation. Without treatment, the prognosis is poor but the development of factor concentrates and ‘non-factor replacement therapy’ has transformed the outlook. This brief review discusses the recent advances in care and provides advice for healthcare professionals involved in the care of children with haemophilia. Recombinant factors are the treatment of choice because they eliminate the risk of viral infection. Prophylactic therapy, where factor is given to prevent bleeds minimises disability. Children in developed countries can now live essentially normal lives with life expectancy that of the general population. Desmopressin and tranexamic acid are useful treatments in mild haemophilia A. Inhibitors to factor VIII or IX arise in about one third of children; vigilance is required in screening for this complication. Bypassing agents such as FEIBA^® and NovoSeven^® may be used to control bleeding in such cases and the regular administration of large doses of factor can eradicate the inhibitor. New molecules including monoclonal antibody therapy, such as emicizumab^® are available. Gene therapy trials are underway in adults with haemophilia.     

Haemophilia prophylaxis in Sweden.

29 boys (4-18 years old) with severe haemophilia A were given prophylactic infusions of AHF concentrate (human fraction I-0) for 2 to 13 years in an attempt to change the haemophilia from a severe to a moderate form and thereby prevent arthropathy and severe bleeding episodes. The sizes of the doses and the intervals at which the doses were given were titrated by AHF survival studies. As a rule, the patients received AHF in amounts sufficient to raise the AHF level to 30-45% at 5-12 day intervals. In about 50% of the infusions the AHF content was not below 1% before the next infusion. During such prophylaxis all patients except one have been in a good general condition. They have had bleeding episodes, which have, however, been much less severe and less frequent. The children have been able to live an almost normal life. The number and duration of stays in hospital have been markedly reduced. 17 of the patients had only minor or no joint defects before the start of the treatment. In this group the joint function was identical with that found in moderate haemophilia in the same age groups. Two patients developed anticoagulants. No other side effects were seen. The prophylactic regimen in Sweden thus reduced severe haemophilia to moderate.