Desmopressin testing in haemophilia A patients and carriers: results of a multi centre survey.

INTRODUCTION: Desmopressin (DDAVP) testing (DT) in patients (pts) with haemophilia A (HA) and carriers (CHA) is up to now not standardized. This prompted us to evaluate results of DT carried out between 1996 and 2011 in centres of the Competence Network Haemorrhagic Diatheses East. PATIENTS AND METHOD: An increase of the factor VIII activity (FVIII) above 50% or at least the two fold of initial values within 120 min after DDAVP was defined as complete response (CR). Data from 80 patients (31 children, 49 adults) of whom 64 suffered from HA (sub-HA: n=48; mild: n=14; moderate: n=2) and 16 patients CHA were evaluated. RESULTS: In 34 patients DDAVP was given i.v. (dose range: 0.26-0.6 µg/kg body weight, mean: 0.33), in 31 intranasally (i.n. 300-600 µg) and in 15 s.c. (15-40 µg). The maximal FVIII increase was reached 60 min after DDAVP. For i.v. application the mean FVIII increase was 3.1-fold, for i.n. 2.1-fold and for s.c. 2.4-fold. A CR was detected in 71 patients, a non-response in 9. Mild side effects such as flush, headaches or nausea were observed in 11 patients (14%). CONCLUSION: For desmopressin testing in patients with haemophilia A and carriers i.v. application at 0.3 µg/kg body weight and the determination of FVIII before and 60 min after desmopressin infusion is recommended.

[Haemophilia A, B or von Willebrand disease type 3. Census of patients in the eastern part of Germany]. / Patienten mit Hämophilie A, B oder von-Willebrand-Syndrom Typ 3. Systematische Erfassung im Osten Deutschlands.

UNLABELLED: Diagnostics and treatment of severe forms of haemorrhagic diatheses (HD), such as haemophilia A, B or type 3 von Willebrand disease (VWD) need high standards in haemophilia treatment centers (HTCs). Due to their generally low incidence, a close cooperation of haemophilia treaters is needed to optimize treatment strategies. For this purpose, the Kompetenznetz Hämorrhagische Diathesen Ost was founded. The first project was the conduction of a survey of epidemiological data of patients with HA, HB and type 3 VWD in all HTCs in the eastern part of Germany. METHOD: The study assessed the data regarding numbers of patients treated with HA, HB or type 3 VWD, disease severity, regime of coagulation factor replacement (CFR) and the frequency of factor VIII and IX inhibitors. RESULTS: Up to now, data of 838 patients from 27 HTCs were evaluated (5-151 per HTCs). Among the included patients, 201 were children or adolescents (<18 years). 81 children suffered from severe HA, 20 from severe HB and 10 from type 3 VWD. In 637 adults we found 246 with severe HA, 51 severe HB and 28 VWD of type 3. The most commonly used treatment of CFR in patients with severe disease was prophylactic modality. 90% of the children received prophylaxis, but also in 64% of the adults an intermittent or long-term secondary prophylaxis was the preferred treatment. At the time of survey conduction, a factor VIII or IX inhibitor was present in 1.9% of the children and in 1.6% of the adults with haemophilia. CONCLUSION: Our data allow an overview of the number of patients and treatment strategies in the eastern part of Germany.

[Drug-induced eosinophilic pneumonia]. / Eosinophile Pneumonie als unerwünschte Arzneimittelwirkung.

Eosinophilic pneumonia is a lung disorder characterized by eosinophilic pulmonary infiltration and blood eosinophilia. It can be caused by a variety of drugs. Especially in mild forms and in chronically neurologically ill patients, it can be difficult to spot. We report the case of a 46-year-old woman suffering from multiple sclerosis who developed nitrofurantoin-induced eosinophilic pneumonia.

Individual dosing of ASA prophylaxis by controlling platelet aggregation.

Acetylsalicylic acid is widely used in the primary and secondary prevention of cardiovascular diseases. In the current study, we used platelet aggregation ex vivo in platelet-rich plasma induced with arachidonic acid as a routine method for the determination of the individual dose of acetylsalicylic acid necessary to inhibit platelet aggregation in 108 patients with cardiovascular diseases. In 40% of all patients studied, a dose of 30 mg/day was sufficient to block the arachidonic acid-induced platelet aggregation nearly completely. In 50% of all patients, a dose of 100 mg/day was necessary. In 10% of all patients, the dose had to be further increased to 300 mg/day or even to 500 mg/day to inhibit platelet aggregation nearly completely. These results demonstrate that platelet aggregation can be used as a simple routine laboratory method to control acetylsalicylic acid treatment in patients with cardiovascular diseases and to determine individual doses of acetylsalicylic acid for a nearly complete inhibition of platelet aggregation. With a standard dose of 100 mg/day, 10% of the patients were nonresponders.

Molecular biology and clinical manifestation of hereditary factor VII deficiency.

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder. Mutations and polymorphisms of the FVII gene were characterized in more than 40 unrelated patients with FVII deficiency. Among the 29 different mutations, the most frequent were Ala294 Val, Ala294Val;404delC, IVS7+7, and Val281 Phe. Four novel mutations (IVS2+1G>C, Arg247 Cys, Glu265 Lys, Asp343 His) were detected. The relationships between genotypes of mutations and polymorphisms of the FVII gene, FVII deficiency, and clinical phenotype were investigated. Homozygosity of the Phe4 Leu, IVS4+1G>A, Cys135 Arg, Ala244 Val, and Ala294 Val;404delC and the double heterozygosity of Tyr68 Cys / IVS3-1G>A, Val252 Met / IVS2+5G>T, Val281 Phe / Cys135 Arg, Ala294 Val / Val281 Phe, Ala294 Val;404delC / Val281Phe, Ala294 Val;404delC / Arg152 stop, Ala294Val;404delC / Gln(-35) stop, Ala294 Val / Val252 Met, Ala294 Val / Gly156 Asp, and Thr359 Met / Asp242 His were related to clinical symptoms. Double heterozygotes for Arg247 Cys / IVS2+1G>C, Ala206 Thr / Pro303 Arg, Leu(-20) Pro / Val252 Met as well as IVS7+7 /Ala294 Val, IVS7+7 /Ala206 Thr, and IVS7+7 / Met298 Ile were asymptomatic. The clinical symptomatology is rather poor in correlation with the FVII activity. Concerning the clinical phanotype, a correlation seems to exist between specific mutations and clinical symptoms.

Female twins with severe Christmas disease (hemophilia B).

Hemophilia B is an X-linked bleeding disorder. We report on female twins, who were conspicious in prolonged bleeding after venipuncture as well as hematomas after intramuscular injections even in the first months of their life. Their father suffering from a severe hemophilia B deceased in 1992. Their mother, half-brother and grandmother from their father's side had no signs of bleeding disorders. Clotting analysis performed in both twins revealed a markedly prolonged partial thromboplastin time (> 100 s). The factor IX levels were below 2%. In order to detect mutations, a general screen using the polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) analysis of the PCR products have been performed. PCR products have been cut into smaller fragments using restriction endonucleases (RE) for an in-depth SSCP screen. A general screen for gross abnormalities in the factor IX gene including deletions, insertions and rearrangements was performed by Southern blot analysis of RE-digests of genomic DNA using the factor IX cDNA as a hybridization probe. Furthermore, we screened for mutations in the CG dinucleotides comprising part of RE-recognition sequences (exon 1, 2, 3, 4, 5, and 8). By all methods applied herein, no mutations have been detected in these twins. On the basis of our results the hemophilia B of these twins might be explained by extreme non-random lyonization.

[Meteorologic effects on hemorrhagic diathesis in hemophilia. 1. Demonstrating weather effects based on a complex weather phase scheme]. / Meteorologische Einflüsse auf die Blutungsneigung bei der Hämophilie.1. Mitteilung: Darstellung der Meteorotropie anhand eines komplexen Wetterphasenschemas.

In haemophilia frequently spontaneous haemorrhages occur without recognition of an evoking cause. Various bleeding-disposing factors are discussed, among others also influences of weather. For the investigation of the meteorotropic relations 1,802 episodes of haemorrhages in 223 haemophiliacs were coordinated to a complex scheme of weather phases. An undisturbed course of the weather was in general connected with a decrease of bleeding, whereas in an influence of low pressure with advection of cold air an increase of the haemorrhages was established. Conspicuous was furthermore the negative biotropism of the radiation-intensive sunny fine weather in summer, which is probably to be traced back to the thermic load in this weather situation.

[Meteorologic effects on hemorrhagic diathesis in hemophilia. 2. Weather effects on hemophilia with special reference to the atmospheric temperature-humidity complex]. / Meteorologische Einflüsse auf die Blutungsneigung bei der Hämophilie. 2. Mitteilung: Die Meteorotropie der Hämophilie unter besonderer Berücksichtigung des atmosphärischen Temperatur-Feuchte-Komplexes.

The meteotropism of haemophilic haemorrhages was investigated for 1,802 episodes of bleeding in 223 patients with the help of selected parameters of the atmospheric temperature-humidity complex and the air pressure. The accumulation of haemorrhages under the influence of tropic air masses was particularly conspicuous. In low blood pressure the frequency of bleeding also increased, whereas high-pressure conditions showed a decrease of bleeding. The study clearly confirms that the haemorrhagic tendency in haemophilia is influenced by weather. Therefore a medico-meteorologic forecast should be taken into consideration for haemophiliacs.

[Multivariate analysis for the understanding of typical diabetic hemostasis criteria. 1: Plasma markers]. / Multivarianzanalyse zur Erfassung diabetestypischer Hämostasekriterien. Teil 1: Plasmatische Merkmale.

In 309 patients investigations were made into the functions of blood coagulation with special consideration of numerous metabolic criteria. They referred to 111 healthy control persons and 198 patients with diabetes mellitus, 67 of them being of type I and 131 of type II. From a variety of metabolic characteristics and haemostasis optimal criteria were determined by means of the statistical method of multivariance analysis, which enables a distinction to be made between diabetics of type I, type II and healthy persons. Among those 13 characteristics detected as optimal amount there were thrombin time, thrombin coagulase time as parameter of haemostasis both before and after venous congestion, reptilase time prior to venous congestion and fibrinogen concentration after it. Thus, these coagulation factors indicate a different behaviour in both types of diabetes and in healthy control persons.

[Multivariate analysis for the understanding of typical diabetic hemostasis criteria. 2. Prevalent thrombocytic markers]. / Multivarianzanalyse zur Erfassung diabetestypischer Hämostasekriterien. Teil 2: Vorwiegend trombozytäre Merkmale.

Various thrombocyte functions and metabolic criteria were investigated in 309 test persons, among them 198 Patients affected with diabetes mellitus, 67 of type I and 131 of type II as well as 111 healthy control persons. From the variety of these factors an optimal amount was determined by means of the statistical method of multivariance analysis separating both types of diabetes and healthy control persons. In addition to haemoglobin A1 concentration, thrombocyte parameters have been found together with the degree of capillary fragility, adrenalin-induced aggregation, platelet aggregation test and clot retraction, which allow individuals to be assigned diagnostically to various groups of test persons. Thus, thrombocyte functions found in both types of diabetes and normal persons exhibit differences which may contribute to a diagnostic classification.

[Multivariate analysis for the understanding of typical diabetic hemostasis criteria. 3. Determination of a typical retinopathy parameter-constellation]. / Multivarianzanalyse zur Erfassung diabetestypischer Hämostasekriterien. Teil 3: Ermittlung einer retinopathietypischen Parameter-Konstellation.

Features of metabolism and haemostasis which are different in diabetics of both types in comparison with normal subjects were covered by the statistical method of multivariance analysis depending on the severity of diabetic retinopathy. In 29 diabetics without retinopathy, 46 patients with stage I or II, and 36 patients with stage III the following parameters could be found as optimal criteria for characterizing the extent of vascular changes: blood sugar concentration, concentration of sialic acid and HDL cholesterol in the serum, serum protein, sialic acid per protein volume, total cholesterol in the serum and capillary fragility and number of large spreading forms of platelets features of hemostasis. Thus, diabetic retinopathy is characterized by a wide spectrum of different features containing the parameters of hemostasis. Thrombocytic vascular interactions are characterized by platelet spreading and capillary fragility which are significant for the development of diabetic retinopathy.

[One-year analysis of bleeding events in 223 hemophiliacs in the DDR]. / Ein-Jahresanalyse von Blutungsereignissen bei 233 Hämophilen der DDR.

The reports of 223 haemophiliacs living in the districts Halle, Leipzig, Karl-Marx-Stadt, and Gera had been analyzed for bleeding events in 1986. There were suffering from haemophilia A 185, from haemophilia B 36 and 2 persons from a complex disorder. In each case 73 patients suffer from a severe and a moderate type of haemophilia. In 55 patients the diagnosis was mild form of haemophilia and in 22 subhaemophilia. Altogether 1802 bleeding episodes had been registered with the following locations: elbow joint 21.0%, knee joint 17.9%, ankle 14.2%, shoulder 4.3%. In 5% of all cases multiple joints had been affected at the same time. Soft tissue bleedings occurred in 16.7% of all cases. For substitution treatment of these 1802 bleeding events altogether 9020 transfusion units were needed, appropriate to 40.4 per year and 52.4 per year and bleeding patient respectively. Expense and duration of treatment depend on the bleeding location. Conclusions for the clinics and the transfusion service are possible.

[Recommendations for a medical-meteorologic prognosis for hemophilia]. / Empfehlungen für eine medizin-meteorologische Vorhersage für Hämophile.

A one year lasting study about the relation between bleedings in haemophiliacs and weather was performed. There had been included 1802 bleeding events. The influence of meteorologic factors to bleeding was proved. The influx of warm air proved inopportune. The decrease in atmospheric pressure as well as winter cold fronts lead to increase of bleeding tendency. Haemophiliacs should avoid physical and psychical stress in such unconvenient atmospheric situations. The replacement therapy should be adapted to the weather situation.

[Platelet spreading in diabetes mellitus]. / Untersuchungen der Thrombozytenausbreitung bei Diabetes mellitus.

In 162 test persons divided into healthy control persons and diabetics of type I and type II the thrombocyte spreading was investigated according to the method of Breddin. Age, sex, degree of seriousness of retinopathy, duration of diseases, present level of blood sugar and HbA1 concentration were taken into account. Spread thrombocyte forms were increasingly found in old age, in diabetics of both types and a close relation to the extent of retinopathy was evident. As diabetic retinopathy became evident and with growing degree of seriousness, spread forms of thrombocytes were increasingly found, so that the increased spreading capacity may be interpreted as a disturbed metabolic and blood vessel situation in diabetes mellitus.

Results of treating stage III and IV malignant non-Hodgkin's lymphomas (NHL).

Malignant non-Hodgkin's lymphoma (NHL) patients were enrolled and analyzed retrospectively in 2 successive study groups. The first group consisted of 57 patients divided into low- and high-grade malignant NHL according to the Kiel classification, the second one included 104 patients divided into low-, intermediate-, and high-grade malignant NHL. The more individualized and more intensive polychemotherapy of the 2nd group yielded clearly better treatment results compared to the first group, especially in high-grade malignant NHL. The complete remissions rose from 32% to 59%, the recurrence rates fell from 62% to 20%, the 5-year survival time of patients under age 30 increased from 0 to 48%. In intermediate-grade malignant NHL, intensive therapy yield results that are as beneficial as those of mild therapy in low-grade malignant NHL (5-year survival rate 62% and 65%, respectively).

[Incidence of hepatitis B in hemophilia patients]. / Hepatitis-B-Häufigkeit bei Häophilen.

Hepatitis represents a serious complication in the transfusion of blood and blood products. In examining patients from the haemophilia centre in Jena HBsAg was identified in no case, HBsAK, however, in 80% of them. The rate of hepatitis infection increased here with the increasing frequency of transfusion. It should be determined by regularly checking HBsAG, HBsAK and transferases within the scope of prophylactic examinations.

[ Fibrinolysis in diabetes mellitus]. / Untersuchungen zur Fibrinolyse bei Diabetes mellitus.

In 198 diabetic patients of type I and type II and in 111 healthy persons of a control group the activity of fibrinolysis was investigated before and after a venous occlusion test of ten minutes. Spontaneous fibrinolysis was significantly diminished in diabetics of both types in comparison to the control group. A relationship to the degree of seriousness of retinopathy could not be identified in type I. The activity of fibrinolysis decreased in all test persons in old age. In diabetics patients of type II as well as in that age group being more than 56 years old there were smaller activities of fibrinolysis at higher stages of retinopathy. A negative linear correlation of this spontaneous activity of fibrinolysis could be found for the duration of the disease as well as for age. Different forms of diabetic therapy and the sex allowed no influence of the activity of fibrinolysis to be recognized. An increase of the activity of fibrinolysis after congestion could be established in diabetics as well as in the control group. After venous congestion the fibrinolytic activity showed no differences any longer in diabetics and in the control group, with age, duration of the disease and form of therapy being taken into consideration. Before and after venous congestion a negative linear correlation could be revealed between the activity of fibrinolysis and the height of blood sugar level. Therefore, the real blood sugar concentration should be taken into account in evaluating the fibrinolytic activity.

[Clinical problems of viral hepatitis B in hematological neoplasms]. / Zur klinischen Problematik einer Virushepatitis B bei hämatologischen Neoplasien.

A virus hepatitis B was observed intercurrently in 8 patients with malignant lymphomas or plasmacytoma respectively. Four of these patients where the therapy of the basic disease was discontinued after manifestations of hepatitis came to death by acute liver dystrophy. The therapy was continued in the remaining four patients without any changes, hepatitis showed a tendency towards an involution with remaining HBsAg carrier status. In our opinion these four cases clearly indicate that, naturally by carefully observing the situation of the liver, a continuation of the envisaged treatment might involve a smaller risk than limiting the treatment.

[Behavior of fibrinogen in diabetic patients in comparison with objective vascular measurements in the ocular fundus]. / Fibrinogenverhalten bei Zuckerkranken im Vergleich mit objektiven Gefässmessungen am Augenhintergrund.

Objective measurements of vessels were performed in vivo in 10 patients affected with diabetes mellitus, the fibrinogen concentrations in the venous blood being determined simultaneously. Whereas the ensured correlations with fibrinogen concentration could be recognized from the diameter of arteries and veins and from the flow velocity, a linear correlation could be found to exist between the fibrinogen level and the volume flowing through a retinal artery. These findings prove that the very existence of a hyperfibrinogen anemia does not justify the assumption of the blood volume flow being decreased. In patients with diabetes mellitus the enhanced volume flowing through retinal arteries is rather connected with an increased fibrinogen level.