[Chronic fatigue syndrome].
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Fatigue Syndrome, Chronic↗
Biomedical subjects
U Martinowitz
Publications and source records attributed to U Martinowitz.
Stability of factor VIII concentrates after reconstitution.
Adjusted-dose continuous infusion of factor VIII (F VIII) has recently been shown to reduce the doses of the factor in patients undergoing surgery by 50-75%. The main limitation of this method has been the instability of factor concentrates. All manufacturers are recommending infusion of the concentrate within hours after reconstitution. We studied the stability of 15 different lyophilized F VIII products. Reconstituted samples were stored for periods of 4, 24, and 72 hr and 1, 2, 3, and 4 weeks at temperatures of 4-8 degrees C, 20-23 degrees C, and 37 degrees C in their original glass containers and in plastic tubes and then frozen. Assays were performed in duplicate, using a one-stage clotting method and a chromogenic assay for F VIII, with all samples from a single concentrate in the same run. Activation of the coagulation factor occurred in some concentrates, more often at 4-8 degrees C than at 20-23 degrees C or 37 degrees C. The stability of all products was substantially better than that declared by the manufacturers. Several concentrates maintained factor activities above 80% of baseline for the entire period of 4 weeks at 4-8 degrees C or at 20-23 degrees C. The results demonstrate that many of the F VIII concentrates may be used for continuous infusion.
Drug Packaging↗
Ependymoblastoma in an HIV-positive hemophilic girl.
A case of an HIV-positive hemophilic girl with an ependymoblastoma is presented. The unusual association between the HIV-related condition and her brain tumor is discussed, speculating a viral mechanism involved in the induction of neoplasia.
Adolescent↗
Stability of factor VIII preparation in continuous infusion.
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Drug Stability↗
Combined factor VIII/factor XI deficiency may cause intra-familial clinical variability in haemophilia A among Ashkenazi Jews.
Heterozygous factor XI deficiency occurs very frequently among Ashkenazi Jews. To investigate the potential influence of a co-inherited factor XI deficiency state on the clinical phenotype of mild/moderate haemophilia A, 28 unrelated haemophiliacs of Jewish origin were screened for the two most common factor XI gene mutations. Gene lesions were identified in two out of 14 patients of Ashkenazi origin. In the one family analysed further, co-inheritance of both factor XI and factor VIII deficiencies was associated with a bleeding tendency that was more severe than that associated with either deficiency alone.
Base Sequence↗
High versus ultra-high purity factor VIII concentrate therapy: prospective evaluation of immunological and clinical parameters in HIV seronegative and seropositive hemophiliacs.
This study aimed at evaluation of the immunological status and the clinical course of both HIV seronegative and seropositive hemophiliacs treated with either an ultra-pure factor VIII product (UP-F VIII), or a high-purity F VIII (HP-F VIII) concentrate. Eighteen HIV seronegative patients were divided into two groups of therapy and their immune status was followed for 2 years. During the second year of the study 8 patients of the HP-F VIII and 6 from the UP-F VIII therapy groups were switched to the alternative F VIII concentrates. Eighteen asymptomatic HIV seropositive patients were also divided into therapy groups and their immune status and any development of HIV-related symptoms were followed for 4 years. Evaluation of the HIV seronegative patients during the first year did not reveal any differences between the groups in the CD4 or CD8 cell counts, in natural killer cell (NK) activity, or in the mitogenic responses of T lymphocytes to Phytohemagglutinin (PHA), and of B lymphocytes to Pokeweed mitogen (PWM). The switch of 8 patients from the HP-F VIII and 6 from the UP-F VIII groups to the alternative concentrate did not yield any changes in their immune profile during the second year of the study. The HIV seropositive groups differed in the initial CD4 count, with a lower CD4 count (193 +/- 126 vs 437 +/- 142) and a higher F VIII consumption (63,000 +/- 17,000 vs 26,000 +/- 10,000) in the UP-F VIII group.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Monoclonal purified F VIII for continuous infusion: stability, microbiological safety and clinical experience.
Replacement therapy for patients with hemophilia A postoperatively or for major hemorrhage, administered as a continuous infusion, is efficient and reduces the requirement for factor VIII (F VIII). The convenience of the method is increased by using a minipump and not diluting the concentrate further after reconstitution. A monoclonally purified F VIII concentrate (Monoclate-P), was evaluated for its stability after reconstitution in different infusion systems, for its microbiological safety as well as clinical safety and efficacy in continuous infusion. The F VIII activity was unaffected by 2 of the 3 infusion systems at room temperature during 15 days, whereas in the third (CADD-1) it decreased below 80% of initial value after 3-7 days. Addition of heparin (1 U/ml) or low molecular weight heparin (1 anti-Xa U/ml), which are used to prevent thrombophlebitis at the site of infusion, did not affect the stability. Nine out of 9 samples taken from the infusion systems after 3 days and again after 7 days were sterile. After inoculation with Staphylococcus aureus or Escherichia coli the bacterial growth in samples of the reconstituted concentrate was not different from that in lidocaine in saline or heparin in saline. F VIII was given in continuous infusion with a minipump (Infu-Med) to 12 patients undergoing major surgery and 8 patients with major hemorrhage for a total of 157 days. A progressive decrease of the clearance was seen during the first 5 days of infusion from 3.0 to 1.7 ml/kg/h. Hemostasis was effectively achieved, and no infectious complications were registered.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Coinfection with hepatitis viruses and human immunodeficiency virus in multiply transfused patients.
The prevalence, clinical manifestations and serological markers of hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections were studied in 112 multiply transfused patients (49 hemophiliacs receiving either nonheat-treated factor concentrates or cryoprecipitate, 33 thalassemic, 20 refractory anemia and 10 leukemia patients). Positive serological markers for HCV, HBV and HIV were found to correlate with number of donors and duration of disease (logistic regression P = 0.0001 and 0.01 respectively). Viral infectivity was significantly correlated with type of blood product. HCV seropositivity was more common in hemophiliacs treated with nonheat-treated factor concentrates (93%) compared to those receiving cryoprecipitate (37%) or nonhemophiliacs receiving red packed cells (20%) (P < 0.001). Likewise, HBV seropositivity in patients receiving the above blood products was 83%, 61% and 26% respectively (P < 0.001), and HIV seropositivity was 35%, 6% and 0% respectively (P < 0.001). Acute or chronic liver disease was documented in 4 of 14 (28%) HCV-positive patients. Increased liver enzymes were recorded in sera of 43% HCV-positive patients and 18% HBV-positive patients compared to 22% of HBV and 20% HCV-seronegative patients (P = 0.076). Of 47 HCV-positive patients 24 were coinfected by HBV and 9 had triple infection (HCV, HBV and HIV). No solitary HIV infection was found. HIV seropositivity was always accompanied by serologic evidence for HBV with or without HCV infection.
Blood Component Transfusion↗
Inhibition of integrin-mediated platelet aggregation, fibrinogen-binding, and interactions with extracellular matrix by nonpeptidic mimetics of Arg-Gly-Asp.
The interaction of the activated platelet integrin, glycoprotein IIb-IIIa (GPIIb-IIIa) with fibrinogen and von-Willebrand factor (vWF) is essential for platelet aggregation. The minimal structure required for this integrin's binding to fibrinogen is the Arg-Gly-Asp (RGD) sequence. Inasmuch as normal level of GPIIb-IIIa-RGD interactions are required for maintaining hemostasis, elevated platelet aggregation can cause adverse pathological effects. We have previously reported that nonpeptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear 11-atom spacer, acquired a significant affinity for the GPIIb-IIIa integrin and inhibited platelet aggregation. The structural requirements for the interactions of the RGD sequence with GPIIb-IIIa and the inhibitory potential of a newly designed series of mimetics on platelet aggregation and interactions with extracellular matrix (ECM) were assayed herein. Adenosine-diphosphate (ADP)-induced platelet aggregation was inhibited in a dose-dependent manner by various RGD mimetics, with a maximal inhibition of 80-100% with an IC50 of 3 microM for the most potent inhibitor, NS-11, in which a six-membered ring was introduced into the spacer chain, which exceeded the IC50 attained with the original RGDS peptide. The inhibitory effect of the RGD mimetics was attributed to their specific interaction with the GPIIb-IIIa integrin, since these mimetics inhibited the binding of the PAC-1 mAb to GPIIb-IIIA. Furthermore, the binding of 125I-labeled fibrinogen to platelets was inhibited by the RGD surrogates in a dose-dependent and saturable manner. The RGD-mimetics also inhibited up to 70% the adhesion, aggregation, and deposition of platelets onto ECM.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Platelet aggregation on extracellular matrix: effect of a recombinant GPIb-binding fragment of von Willebrand factor.
Platelets in whole blood incubated on extracellular matrix (ECM) produced by bovine corneal endothelial cells under oscillatory flow conditions demonstrate extensive aggregate formation. Since both platelet-subendothelium and platelet-platelet interactions are mediated by von Willebrand factor (vWF), we used this system to examine the effect of a recombinant GPIb-binding fragment of vWF (designated RG12986), comprising residues 445-733 of the native vWF subunit, on platelet reactivity with ECM. The seven cysteines present in the RG12986 fragment were reduced and alkylated in order to achieve a monomeric conformation. The recombinant vWF fragment binds to unstimulated platelets in the absence of exogenous modulators. When added to platelet-rich plasma, it inhibits ristocetin-induced platelet agglutination. Binding of 51Cr-labeled platelets in reconstituted whole blood to ECM was inhibited by RG12986 in a dose dependent and saturable manner, with IC50 of 4 microM and maximal inhibition (about 70%) at 6 microM. Scanning electron microscope (SEM) analysis showed that addition of RG12986 to whole blood significantly inhibited platelet aggregation on ECM. The extent of inhibition observed with RG12986 at a final concentration of 4 microM was similar to that obtained with the cell adhesion peptide RGDS at the concentration of 0.1 mM. The ability of the RG12986 fragment to inhibit platelet aggregation on ECM is in agreement with the concept that blockade of vWF-GPIb interaction may inhibit further events leading to activation of the glycoprotein IIb/IIIa (GPIIb/IIIa) complex and subsequent thrombus formation.
Amino Acid Sequence↗
Screening for mutations in the antithrombin III gene causing recurrent venous thrombosis by single-strand conformation polymorphism analysis.
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Antithrombin III↗
Response of hemophilic patients to poliovirus vaccination: correlation with HIV serology and with immunological parameters.
Hemophilic patients may present immunological dysfunctions resulting from either human immunodeficiency virus (HIV) infection, or other factors like impure factor VIII concentrate and other viral infections. We evaluated prospectively the serologic response to polio vaccination of Israeli hemophilic patients who were vaccinated during an outbreak of poliomyelitis. Eighty-two hemophilic patients, 43 seronegative and 39 seropositive for human immunodeficiency virus (HIV), were vaccinated with enhanced inactivated poliovirus (eIPV). Titers of antibodies for poliovirus types 1-3 were determined before and 4 weeks after immunization. T helper and suppressor lymphocytes (T4 and T8), B and T lymphocyte mitogenic response, and natural killer cells were tested and correlated with the response to vaccination. Both groups responded to vaccination with increased titers of antibodies to the three viral types, 4 weeks after immunization. HIV-seronegative patients, however, exhibited higher titers than the HIV-seropositive group. The same pattern was found when 21 patients were tested 1 year after the exposure to eIPV. HIV seropositive patients were grouped according to their T4 count (between 16/microliter and 500/microliter). There was no statistically significant difference in the response of these different groups to vaccination. No correlation was found between the response to vaccination and other immune parameters. These results suggest that asymptomatic HIV-seropositive hemophilic patients respond well to eIPV, irrespective of their T4 count.
Adolescent↗
Favorable response of pediatric AIDS-related Burkitt's lymphoma treated by aggressive chemotherapy.
We describe 4 male children infected by the human immunodeficiency virus (HIV) who developed Burkitt's lymphoma during their disease. The clinical picture was characterized by an insidious appearance of symptoms. All the children suffered for several months from abdominal discomfort and a gradual elevation of their blood lactic dehydrogenase (LDH) level prior to diagnosis. Bone marrow involvement was found in 2 of the patients and jaw involvement in the other 2. After confirming the diagnosis of Burkitt's lymphoma, they were treated according to conventional protocols, with no need to reduce the dose intensity. They all went into complete remission and did not suffer from major opportunistic infections during chemotherapy. None of them relapsed. Two patients died from opportunistic infections 1 and 3 years after diagnosis. The other 2 are alive, 7 years and 6 months after diagnosis. The various characteristics of this unique pediatric group are described and the comparison of the clinical picture in adults is made, together with a review of the relevant literature.
Adolescent↗
Dental extractions in patients with bleeding disorders. The use of fibrin glue.
Eighty patients with various bleeding disorders underwent 135 extractions without preventive replacement hematologic therapy. The local hemostatic control involved the use of fibrin glue Beriplast. Secondary bleeding occurred in 9 of 12 patients with severe hemophilia when the concentration of the aprotinin in the fibrin glue was 1,000 KIU/ml. When it was increased to 10,000 KIU/ml and swish and swallow rinses of tranexamic acid before and after the dental extractions were added, only 3 of 25 hemophilia patients suffered from secondary bleeding. Local use of fibrin glue is a safe and cost-effective tool to treat patients with severe bleeding disorders. None of the 43 patients with coagulopathies other than severe hemophilia suffered bleeding after extractions.
Adolescent↗
Evaluation of solvent/detergent treated plasma in the management of patients with hereditary and acquired coagulation disorders.
Haemostatic efficacy and pharmacokinetic analysis of solvent/detergent (S/D) treated, virus inactivated plasma (Octaplas, Germany) was evaluated in eight patients with hereditary factor VII, X and XI deficiency and in three patients with acquired coagulation disorders due to liver disease. The patients received the S/D plasma for treatment of haemarthrosis, menorrhagia or before surgical procedures. In all the patients the S/D plasma was sufficient to prevent or stop bleeding. Side effects included urticaria (one patient) and moderate anaphylactoid reaction (one patient). No evidence of plasma-born viral infections was observed up to 12 months after the treatment (95% confidence limits 0-22%). Calculated mean half-life of coagulation factors VII, X and XI was 4.36 h, 49.21 h and 44.5 h, respectively, similar to that observed with fresh-frozen plasma. Because of retained coagulation factor integrity and improved viral safety, S/D plasma could be considered a superior alternative to standard fresh-frozen plasma.
Adult↗
Fresh blood units contain large potent platelets that improve hemostasis after open heart operations.
Twenty units of fresh whole blood were separated into fresh packed red blood cells (PC) and platelet-rich plasma (PRP) and were transfused to 40 patients immediately after coronary bypass grafting. Patients were preoperatively randomized to receive either PRP (group A, 20 patients) or PC (group B, 20 patients). Platelet number in the PRP group was greater, but not significantly greater, than in the PC group (7.5 +/- 3 versus 5.9 +/- 2.2 x 10(10); p = not significant). However, mean platelet volume in the PC group was significantly greater (8.75 +/- 1.1 versus 6 +/- 0.7 fL). Postoperatively, group A patients bled more than group B (566 +/- 164 versus 327 +/- 41 mL; p less than 0.01) and received more red blood cell units (2.7 +/- 1.2 versus 1.6 +/- 0.7 U; p less than 0.05) and a larger number of blood products (5.9 +/- 3.7 versus 2.6 +/- 1.2 U; p less than 0.05). Transfusion of PRP to group A increased platelet count from 128 +/- 20 to 148 +/- 110 x 10(9)/L; however, platelet functions did not improve. Administration of PC to group B increased platelet count from 139 +/- 22 to 156 +/- 23 x 10(9)/L, improved platelet aggregation (with collagen from 33% +/- 20% to 53% +/- 23%, with epinephrine from 36% +/- 24% to 51% +/- 20%; p less than 0.05), and corrected the prolonged bleeding time. The results suggest that the improved hemostasis observed after fresh whole blood administration is related to the large, potent platelets that remained in the PC and were not separated to the PRP during standard platelet concentrate preparation.
Blood↗
Circumcision in hemophilia: the use of fibrin glue for local hemostasis.
Circumcision can be fatal in hemophilia patients unless they are treated with the missing coagulation factor. We describe 10 severe hemophilia patients in whom circumcision was performed with local fibrin glue instead of infusion of factor concentrate. Of the 10 patients 3 had postoperative bleeding and only 2 of them required infusion of factor VIII concentrate. Fibrin glue is a useful treatment modality for circumcision in patients with bleeding diathesis, and it is safer and cheaper than the infusion of factor concentrate.
Adolescent↗
Adjusted dose continuous infusion of factor VIII in patients with haemophilia A.
Surgical interventions in patients suffering from haemophilia A require infusions of large doses of factor VIII (F VIII) concentrates. These are expensive and may pose a burden on the immune system, which is already compromised in many haemophiliacs. F VIII is usually given as bolus injections, although there are reports on fixed dose continuous infusion. We have developed a continuous infusion programme with dosage adjusted according to daily calculation of the clearance of F VIII. Twenty-four haemophiliacs received a total of 205 d of continuous infusion with F VIII (168 d in hospital, 37 d home therapy). Eighteen patients underwent surgeries (11 elective, seven emergency) and six were treated for serious haemorrhages. We observed a significant, progressive decrease of the clearance of F VIII over the first 5 d from 3.2 (2.8-3.5) to 1.7 (1.3-1.9) ml/kg/h (median and interquartile range). The decrease of the clearance together with the fact that a continuous infusion requires less drug than bolus injections to keep the same minimal concentration, contributed to much lower doses of F VIII than reported in the literature or than required by historical controls, matched for the type of operation. Other advantages of our method are improved safety with stable activities of F VIII, lack of hazardous troughs below the haemostatic range, and the convenience, which permits ambulant therapy even when high doses of F VIII are required.
Adolescent↗