Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey.

Long used in established industrialized nations to treat patients with haemophilia and inhibitors, factor eight inhibitor bypassing activity (FEIBA) has, in recent years, been introduced into more geographically diverse settings. Data are needed on how successfully FEIBA therapy has been implemented in new regions. To determine the efficacy and safety of FEIBA for the treatment of acute bleeding and surgical haemostasis in a newly industrialized country. A multicentre registry of haemophilia A patients with inhibitors receiving FEIBA treatment was established in Turkey. With a standardized case report form, data were collected retrospectively on: patient demographics; characteristics of acute bleeding episodes and surgical interventions; FEIBA regimen; and treatment outcomes. Thirty-seven patients received a total of 112 FEIBA treatment courses, 90 for acute bleeding and 22 for surgical haemostasis. The median FEIBA dose per infusion for acute bleeding was 50 IU kg(-1), and for surgery was 100 IU kg(-1). For both acute joint and muscle/soft tissue bleeding and in surgery, haemostasis was attained in a median of two FEIBA infusions. FEIBA was judged effective in 92% of treatment courses for acute bleeding, with a 95% confidence interval (CI) of 85-97%. Rates of haemostatic efficacy did not differ significantly between anatomical sites of acute bleeding. The haemostatic efficacy rate of FEIBA in surgery was 86% (CI, 65-97%). No thromboembolic complications or other adverse events occurred during any treatment course. FEIBA has been successfully integrated into clinical practice in Turkey, with rates of haemostatic efficacy comparable to those reported in countries with a longer history of FEIBA usage.

Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitors.

The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (< or =50 IU kg(-1) twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0-517), 19.2 BU (range 3.6-515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (< or =10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study.

The usefulness of glycosylated hemoglobin (HbA1C) in discriminating between iron deficiency and thalassemia.

This study assessed whether glycosylated hemoglobin could be used as an index to distinguish between iron-deficiency anemia and thalassemia minor. Glycosylated hemoglobin was measured by high-pressure liquid chromatography in 40 ss -thalassemia minor patients, 20 iron-deficiency anemia patients, and 38 healthy controls, all nondiabetic. Median glycosylated hemoglobin was lower in ss -thalassemia minor than in the iron-deficiency and control groups (p = .000). There was no difference between iron-deficiency patients and healthy controls (p = .095). Glycosylated hemoglobin was not different in iron-replete and iron-deficient traits (p > .05). A cutoff value of 5% has provided a sensitivity of 95% and specificity of 75.7% for distinguishing between these two entities. Positive and negative predictive value were 96.6 and 67.9%. These values were superior to the traditional discriminants' values calculated on the same individuals. Glycosylated hemoglobin could be useful in discriminating between iron-deficiency anemia and thalassemia minor. Further studies are needed, but the point that it can also be used when both conditions exist simultaneously seems to be clinically important.

Candida vertebra osteomyelitis in a girl with factor X deficiency.

Candidal vertebra osteomyelitis is a rare condition which occurs primarily in immunocompromised patients. We report a 14-year-old girl with factor X deficiency who developed candida vertebra osteomyelitis during home therapy. The microorganism was probably from a contaminated peripheral cannula used for infusion of factor concentrate. This is the first such case in bleeding disorders to our knowledge.

Supernumerary nipples in children with hematologic disorders.

The authors report on supernumerary nipples and various hematologic disorders in 7 patients [factor X deficiency (n = 1), factor XI deficiency (n = 2), acute lymphoblastic leukemia (n = 3), and acute myeloblastic leukemia (n = 1)]. They would like to draw attention to the association of supernumerary nipples with hematological disorders, which has not been published before and is considered to be added to the anomalies associated with supernumerary nipples.

Guillain-Barré syndrome in a child with acute lymphoblastic leukemia.

A 4-year-old boy with acute lymphoblastic leukemia receiving maintenance treatment developed quadriparesis, facial palsy, difficulty in swallowing, and hypertension following a respiratory infection and candida septicemia. Examination of the cerebrospinal fluid was normal initially but later showed albuminocytologic dissociation, the characteristic finding of Guillain-Barré syndrome. Complete recovery occurred after treatment with intravenous immunoglobulin. Differential diagnosis of Guillain-Barré syndrome from vincristine toxicity in patients with leukemia and possible association with the infections are discussed.

A novel von Willebrand disease-causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion.

In this report we describe the molecular defect underlying partial and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von Willebrand-disease. Analysis of the VWF gene in affected family members revealed a novel C to T transition at nucleotide 1067 of the VWF complemetary DNA (cDNA), predicting substitution of arginine by tryptophan at amino acid position 273 (R273W) of pre-pro-VWF. Two patients, homozygous for the R273W mutation, had a partial VWF deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked high-molecular weight VWF multimers in plasma. A third patient, also homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag level of less than 0.01 IU/mL) and undetectable VWF multimers in plasma. Recombinant VWF having the R273W mutation was expressed in COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. To identify factors that may function in the intracellular retention of rVWFR273W, we investigated the interactions of VWF expressed in COS-7 cells with molecular chaperones of the ER. The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells. (Blood. 2000;96:560-568)

The effect of steroid and intravenous immunoglobulin on thrombopoietin levels in pediatric patients with immune thrombocytopenic purpura.

Thrombopoietin (TPO), which is the main regulator of megakaryo/thrombopoiesis, has been recently cloned and purified, and shown to be useful in discriminating thrombocytopenia due to decreased production or increased platelet destruction. However, there are no detailed investigations about the drug effects on TPO levels during childhood. This study was conducted to measure the TPO levels of children with immune thrombocytopenic purpura (ITP) during steroid and immunoglobulin treatment. Twelve patients with acute ITP were treated with high-dose methyl prednisolone and five patients were treated with intravenous immunoglobulin. Neither steroids nor immunoglobulin were found to have any effect on TPO levels.

Thrombosis during all-trans-retinoic acid therapy in a child with acute promyelocytic leukemia and factor VQ 506 mutation.

Acute promyelocytic leukemia (APL) is often associated with a severe hemostatic disorder, caused by the release of procoagulant and fibrinolytic substances from leukemic blasts. The coagulation profile may exhibit disseminated intravascular coagulation and fibrinolysis or proteolysis. Therefore, heparin and antifibrinolytic agents alone or in combination have been used to prevent severe bleedings. Remission induction with all-trans-retinoic acid (ATRA) is accompanied with rapid correction of hemostatic abnormalities. Thrombosis is a rare complication of APL and may be due to the alterations in hemostasis caused by the disease itself as well as ATRA and antifibrinolytics. Here, the occurrence of thrombosis during induction treatment with ATRA combined with aprotinin and chemotherapy is described in a patient who is homozygous for factor VQ 506 mutation.

Two novel type 2N von Willebrand disease-causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factor.

Two novel mutations, a T-to-C transition at nucleotide 2612 and a T-to-G transversion at nucleotide 3923 of the von Willebrand factor (vWF) complementary DNA, were detected by analysis of the vWF gene in DNA from members of 2 families with atypical von Willebrand disease. The T2612C transition predicts substitution of cysteine by arginine at amino acid position 788 (C788R), and the T3923G transversion predicts substitution of cysteine by glycine at position 1225 (C1225G) of pre-pro-vWF. The patients homozygous for the C788R and C1225G mutations both had a partial vWF deficiency (0. 18 IU/mL and 0.07 IU/mL vWF antigen, respectively); vWF in plasma from patients homozygous for either the C788R or the C1225G mutation failed to bind factor VIII and lacked high molecular weight multimers. Recombinant (r) vWF molecules having the C788R or C1225G mutation were expressed in COS-7 cells. Both rvWF C788R and rvWF C1225G exhibited significantly impaired secretion and failed to bind factor VIII. Recombinant vWF C788R in COS-7 culture medium showed a severe reduction in high molecular weight multimers, whereas rvWF C1225G showed a very mild reduction in high molecular weight multimers when compared with wild-type rvWF. (Blood. 2000;95:2000-2007)

Diagnosis of von Willebrand disease.

The haemorrhagic diathesis in von Willebrand disease (vWD) is caused by a quantitative deficiency or a qualitative defect in the von Willebrand factor (vWF) in plasma and/or platelets causing insufficient primary haemostasis. Since vWF binds and protects factor VIII (FVIII) towards random proteolysis, coagulation may also be impaired in patients with a low plasma level of vWF, and in instances where vWF displays insufficient binding capacity to FVIII. The entity of vWD displays a vast heterogeneity. Apart from rarely occurring acquired cases, vWD is an inherited disorder of autosomal linkage. The major clinical hallmark in vWD is an increased tendency to mucocutaneous bleeding that rarely reach life-threatening proportions, unless vWF is severely reduced or completely absent. Increased bleeding may also occur in sites such as muscles and joints when the level of FVIII is particularly low. Significant progress has recently been achieved through extensive molecular genetic exploration of various forms of vWD. In order to guide treatment and to form a platform for genetic investigation, however, accuracy in diagnosis and phenotypic characterization is important. By means of various laboratory methods, major subclasses of vWD can be differentiated, as presented in another article of this series. Whereas most of the cases of vWD can quite easily be diagnosed and classified using today's diagnostic methods, the most frequently occurring bleeding disorder of all, vWd type 1 of mild degree, continues to challenge clinicians and diagnostic laboratories. The aim of this paper is to review the laboratory methods most commonly used in diagnostic investigation of the patient suspected of vWD.

Assessment of brain perfusion by 99mTc-HMPAO SPECT in akinetic mutism due to high-dose intravenous methotrexate therapy.

Chemotherapy of the central nervous system may cause neurotoxicity in children with acute lymphocytic leukemia. We evaluated regional blood flow in a 6-year-old child presenting with akinetic mutism, using 99mTc-HMPAO single photon emission tomography (SPECT) following high-dose intravenous methotrexate therapy. While findings in X-ray computerized tomography were decreased density in bilateral basal ganglia and thalamic nuclei with diffusely decreased attenuation of the periventricular white matter, a global, frontal dominant profoundly abnormal perfusion pattern involving both gray and white matter was observed in the SPECT study. Treatment of the central nervous system with high dose intravenous chemotherapy may cause profound abnormalities in white and gray matter blood flow and early assessment of the neurotoxicity may be identified by 99mTc-HMPAO SPECT in the pediatric age group.

Increased serum leukotriene B4 level in the active stage of rheumatoid arthritis in children.

The possible association of leukotriene B4 (LTB4)-like activity with the development of active rheumatoid arthritis was studied in 25 children with the disease and in 15 normal subjects. Serum LTB4-like activity was found to be significantly higher in the active stage of the disease when compared with the values obtained from patients during the inactive stage and from healthy children. No correlation was found between LTB4-activity and other laboratory parameters, e.g. haemoglobin level, white cell count and erythrocyte sedimentation rate.

Bone marrow hemophagocytosis and immunological abnormalities in a patient with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is an inborn error of amino acid transport characterized by a wide spectrum of clinical and biochemical abnormalities. Bone marrow hemophagocytosis in this disorder is an intriguing finding, present mostly in Italian patients. We report a 19-month-old Turkish infant with LPI, bone marrow hemophagocytosis, interstitial lung disease and immunological abnormalities unprecedented in the current literature. Possible etiologic factors responsible for hemophagocytosis and the differential diagnosis of hemophagic syndromes are discussed.

Circulating adhesion molecules ICAM-1, E-selectin, and von Willebrand factor in Henoch-Schönlein purpura.

Adhesion molecules play an important part in leucocyte transendothelial migration and thus may provide a useful marker of surface expression at inflammatory sites. In 20 patients with Henoch-Schönlein purpura serum intercellular adhesion molecule 1 (ICAM-1), E-selectin, and plasma von Willebrand factor (vWF) were determined by ELISA during the active and inactive phase of the disease. Twelve healthy children were studied as a control group. Serum ICAM-1 concentrations increased during the active phase of the disease and differed significantly compared with the inactive phase (p < 0.05). However ICAM-1 in the active phase did not differ significantly compared with controls (p = 0.08). Serum E-selectin concentrations did not differ in the active and inactive phase of the disease. By contrast, vWF increased in the active phase of the disease and differed significantly compared with inactive disease and control groups (p < 0.01). Considering the adhesion molecules and vWF, only vWF correlated well with the C reactive protein measurement in the active phase, which is considered a good marker of disease activity. These data suggest that plasma vWF is a good marker of vascular inflammation and endothelial damage. Circulating ICAM-1 might be an additional parameter in some of the patients.

Association of xeroderma pigmentosum with thrombasthenia.

Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by severe sun-sensitivity, early skin cancers and abnormal DNA repair. XP has a worldwide distribution with an approximate frequency of 1/250,000. It is classified into nine complementation groups, and distribution of patients among the various groups is related to ethnic origin. To our knowledge, the association of XP with thrombasthenia has not been reported previously; here a 12-year-old girl with this combination is reported. She was first noted to have skin erythema on exposure to sunlight at the age of six months and was diagnosed with XP. At the age of one she had the complaints of easy bruising and epistaxis. A diagnosis of thrombasthenia was made based on the absence of platelet aggregation response to ADP, collagen and adrenaline and reduced clot retraction. In clinical management, oral isotretinoin was given in order to suppress tumor formation.

Bernard-Soulier-like functional platelet defect in myelodysplastic syndrome and in acute myeloblastic leukemia associated with trilineage myelodysplasia.

Platelet function was studied in a child with myelodysplastic syndrome (MDS: refractory anemia with an excess of blasts) and a child with acute myeloblastic leukemia (AML-M6) associated with trilineage myelodysplasia (TMDS). An acquired Bernard-Soulier-like platelet defect was considered in both patients with the findings of prolonged bleeding time and abnormally large platelets that failed to aggregate in response to ristocetin. In contrast to findings in von Willebrand's disease, the abnormal response of platelets to ristocetin could not be corrected by the addition of normal flesh plasma. The detection of abnormal platelet aggregation response to ristocetin may be a useful diagnostic finding for clonal disorders causing impaired platelet function in MDS and coexistent TMDS associated with AML. Further studies of ristocetin-induced platelet aggregation in a large number of these patients are required.