A positive effect of immune suppression on corrected count increment after platelet transfusion at 1 but not at 24h.

The effects of patient characteristics on corrected count increment (CCI) in hemato-oncology patients were studied. CCI values were 13.6 ± 6.5 (1h, n=79) and 6.3 ± 5.3 (24h, n=69). With concomitant immune suppression CCI was higher at 1h (20.0 ± 7.9 versus 13.2 ± 6.3, p=0.023), but not at 24h (5.9 ± 6.7 versus 6.3 ± 5.2; p=0.88). The observed effect is short lived, potentially benefiting bleeding patients, but may not increase intervals between transfusions. Further, CCI1h was lower if fever was present (9.7 ± 3.6 versus 14.3 ± 6.7; p=0.002), and corresponding CCI24h values were 3.7 ± 6.3 versus 6.7 ± 5.0 (p=0.09). At 24h an effect for previous transfusions was observed, 6.7 ± 5.1 (with) versus 1.6 ± 5.4 (without p=0.02).

Bacterial screening of platelet concentrates: results of 2 years active surveillance of transfused positive cultured units released as negative to date.

BACKGROUND: The BacT/ALERT system for bacterial monitoring of platelet concentrates (PCs) was introduced in the Netherlands in 2001. Samples are cultured for 7 days, and as a result of the short shelf-life of PCs, they are usually released as 'negative to date'. Therefore, some of the PCs have already been transfused at the moment of a positive signal in continued cultures in the BacT/Alert. It is unclear, however, whether these PCs are associated with more transfusion reactions. METHODS: During a 2-year period clinical data were collected from all patients who received PCs released as 'negative to date' but with a positive bacterial culture after being transfused. RESULTS: Data of 158 patients who received PCs with confirmed positive bacterial culture tests were analysed. Two patients developed a transfusion reaction. In both PCs, Propionibacterium was cultured. The imputability as related to the transfusion was classified as unlikely in both patients. CONCLUSION: Two of 158 transfusions of PCs released as 'negative to date', but with a confirmed positive BacT/ALERT result, were initially associated with transfusion reactions. However, the imputability of both reactions was low.

Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia.

PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) used in addition to standard inpatient antibiotic therapy shortens the period of hospitalization due to chemotherapy-induced neutropenic fever. PATIENTS AND METHODS: One hundred thirty-four patients with a hematologic (n = 47) or solid tumor (n = 87) who had severe neutropenia (< 0.5 x 10(9)/L) and fever (> 38.5 degrees C once or > 38 degrees C twice over a 12-hour observation period) were randomly assigned to receive GM-CSF 5 micrograms/kg/d (n = 65) or placebo (n = 69) in conjunction with broad-spectrum antibiotics for a minimum of 4 days and a maximum of 14 days. GM-CSF/placebo and antibiotics were stopped if the neutrophil count was greater than 1.0 x 10(9)/L and temperature less than 37.5 degrees C during 2 consecutive days, or for a leukocyte count > or = 10 x 10(9)/L, both followed by a 24-hour observation period (hospitalization period). RESULTS: Compared with placebo, GM-CSF enhanced neutrophil recovery. Median neutrophil counts at day 4 were 2.5 x 10(9)/L (range, 0 to 25) in the GM-CSF arm and 1.3 x 10(9)/L (range, 0 to 9) in the placebo arm (P < .001). No significant difference was observed with regard to median number of days with less than 1.0 x 10(9)/L neutrophils (4 v 4) or days of fever (3 v 3). The median number of days patients were hospitalized while on study was comparable in the GM-CSF and placebo groups at 6 (range, 3 to 14) versus 7 (range, 4 to 14), respectively, according to an intention-to-treat analysis (P = .27). Quality-of-life scores in 90 patients demonstrated significant differences in favor of the placebo group. Hospital costs were significantly higher for GM-CSF-treated patients if GM-CSF was included in the price (median costs, $4,140 [US] for GM-CSF v $590 for placebo; P < .05). CONCLUSION: These results indicate that GM-CSF does not affect the number of days for resolution of fever or the hospitalization period for this patient group, although a significant effect of GM-CSF was observed on neutrophil recovery.

Successful treatment of veno-occlusive disease of the liver with urokinase in a patient with non-Hodgkin's lymphoma.

A 38-year-old man with a non-Hodgkin's lymphoma of intermediate grade malignancy attained partial remission after three courses of CHOP (cyclophosphamide+hydroxydaunorubicin+vincristine+prednisolone). He was assigned to undergo autologous bone marrow transplantation (ABMT). The conditioning regimen consisted of cyclophosphamide and whole body irradiation. Two weeks later he developed veno-occlusive disease (VOD) of the liver. Doppler sonography confirmed the diagnosis showing a reversal of the blood flow in the portal vein. In addition a large thrombus was present in the inferior caval vein. Protein C level was strongly reduced (28%). Because of clinical deterioration intravenous urokinase was started. The transaminases normalised rapidly and the patient showed a dramatic clinical improvement. There were no major bleeding complications. Repeat Doppler sonography showed a normal antegrade flow in the portal vein. This case suggests that a coagulopathy in the hepatic vascular bed might contribute to the development of VOD and that patients with VOD are at risk for other thrombotic complications. Furthermore it shows that urokinase with platelet support can be given safely and effectively to a patient with VOD and severe thrombocytopenia.

The course of preexistent immune abnormalities in HIV negative haemophiliacs treated for two years with a monoclonal purified factor VIII concentrate.

The administration of factor VIII concentrates has been associated with immune abnormalities in patients with severe haemophilia A, even in the absence of HIV infection. The effects of a monoclonal purified factor VIII concentrate, Hemofil M (Baxter), on preexistent immune abnormalities were assessed over a 2 year period in 22 HIV negative haemophiliacs. They were treated previously with other concentrates, and received Hemofil T from 1983 to 1988. No HIV infection was demonstrated. No serologic evidence for other viral (re)-infections was seen. A decrease of HLA-DR expression on non-B lymphocytes in the first year (P = 0.026), and a decrease of T4-T8 ratio over the 2 years were found (P = 0.0016). Skin tests were non-contributive. The decrease in HLA-DR expression is suggestive for an improved immune function, possibly due to a reduced content of protein or virus in this concentrate.

Differences in immune response between HCV positive, HIV negative haemophilia A and B patients.

We measured numbers of lymphocytes and subsets in seven HIV negative, HCV positive severe haemophilia B patients, before and after substitution was changed from prothrombin complex concentrate to monoclonally purified concentrate. Data were compared with controls and our previous findings in haemophilia A. At baseline, haemophilia B patients did not differ from controls. After two years, T helper cells showed an increase (p = 0.028), while a rise in B cells approached statistical significance (p = 0.063). Haemophilia A patients showed increased numbers of activated non-B lymphocytes (p = 0.003) and lowered numbers of B cells (p = 0.001) at baseline. After two years activated non-B lymphocytes decreased (p = 0.004), as did the CD4/CD8 ratio (p = 0.002), due to increasing numbers of CD8 positive cells (p = 0.087). Our data suggest minor inhibition of the immune system in haemophilia B patients, which recovers after changing therapy to a monoclonally purified product. These findings contrast with the excessive immune stimulation in haemophilia A. The observed differences might be due to the administered concentrates.

Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group.

OBJECTIVE: To compare efficacy, safety, and feasibility of adjusted-dose oral anticoagulants (OAC) versus fixed-dose subcutaneous low molecular weight heparin (LMWH) for the prevention of deep venous thrombosis (DVT) in patients who have undergone elective hip or knee replacement. DESIGN: Multicentre, single blind randomised trial. OAC (acenocoumarol, target International Normalised Ratio, 2.0-3.0) and LMWH (nadroparine, 60 aXa IU/kg once daily) were started preoperatively and continued for 10 days. All outcome measures were adjudicated by an independent committee unaware of treatment allocation. SUBJECTS: 672 consecutive patients scheduled for elective hip or knee replacement surgery. All patients wore bilateral graduated compression stockings. MAIN OUTCOME MEASURES: The endpoint for the assessment of efficacy was venography confirmed DVT or confirmed symptomatic pulmonary embolism. The endpoint for the assessment of safety was clinically important bleeding during study treatment or within 48 h of the end of treatment. RESULTS: Among the 517 patients with interpretable venograms, 391 had a hip replacement and 126 had a knee implant. DVT was demonstrated in 50 (20%) of 257 patients allocated to OAC and 43 (17%) of 260 patients allocated to nadroparine (p = 0.45), for an absolute difference in DVT incidence of 2.9% in favour of nadroparine (95% CI, -3.7-9.5). Clinically important bleeding occurred in eight (2.3%) of the 342 oral anticoagulant treated patients and in five (1.5%) of the 330 nadroparine treated patients (p = 0.62), for an absolute difference in favour of nadroparine of 0.8% (95% Cl, -1.3-2.9). CONCLUSION: Patients who undergo major orthopaedic operations have a high risk of venous thromboembolism. Once daily fixed-dose subcutaneous nadroparine is at least as efficacious and safe as daily adjusted OAC for prophylaxis against DVT after hip or knee implantation but is more simple to administer.

Effects of chronic factor VIII substitution on immune parameters in HIV seronegative haemophiliacs: a comparison between cryoprecipitate and factor VIII concentrate.

Chronic substitution therapy of HIV-negative haemophiliacs with factor VIII products can result in abnormalities of ex-vivo measured immune parameters. To assess a possible relation between these abnormalities and product purity, we analyzed two groups of HIV-negative HCV-positive haemophiliacs, one treated with cryoprecipitate exclusively, the other with more purified factor VIII concentrates. Compared to age matched non-transfused male controls, increased numbers of white cells, granulocytes, IgG and IgM levels and decreased CD4+/CD8+ ratios were found in both patient groups. In the concentrate receivers, the numbers of mononuclear cells, CD4+, CD8+ and CD3+/HLA-DR+ cells indicating activated T-cells, were higher than in the cryoprecipitate group. In conclusion, both cryoprecipitate and intermediate/high purity concentrate recipients showed immune parameter abnormalities. These abnormalities tended to be somewhat more pronounced in patients treated with concentrates. By now there is no indication of the clinical relevance of the abnormalities in previously treated HIV seronegative haemophiliacs.

Augmented procoagulant activity in cancer patients, treated with recombinant interferon-gamma in addition to recombinant tumor necrosis factor-alpha and melphalan.

Several investigators have reported that interferon-gamma (IFN gamma) can alter tumor necrosis factor alpha induced effects in vitro. We assessed in vivo effects of recombinant interferon-gamma (rIFN gamma) on recombinant tumor necrosis factor-alpha (rTNF alpha) induced activation of systemic blood coagulation in a non-randomized study in 20 consecutive cancer patients. Eight patients were treated with rIFN gamma prior to and during hyperthermic isolated limb perfusion with rTNF alpha and melphalan (IFN gamma group). They were compared with twelve patients who did not additionally receive rIFN gamma (non-IFN gamma group). Before start of perfusion, higher levels of TNF alpha, F1+2 and TAT levels were found in the IFN gamma group. Fibrinogen and ATIII levels tended to be lower in this group. High TNF alpha levels, due to leakage during perfusion, were associated with activation of coagulation in all patients, that became obvious after the end of perfusion, when heparin treatment had been antagonized. Activation, measured by increased F1+2 and TAT levels, was significantly stronger in the IFN gamma group. Monocytic TF remained low, possibly due to shedding of TF positive vesicles and/or sequestration of TF positive activated monocytes against the vessel wall. In both groups F1+2 and TAT levels declined 24 h after the perfusion, whereas monocytic TF increased to levels that were higher in the IFN gamma group. In conclusion, our data confirm a strong activation of coagulation induced by rTNF alpha in cancer patients. They suggest that rIFN gamma may lead to a slight activation of coagulation and augments TNF alpha induced procoagulant activity. These effects may be due to rIFN gamma induced sustained monocytic TF activity.

Hyperfibrinogenolysis in disseminated adenocarcinoma.

We present the case of a 42-year-old woman with a recently acquired bleeding tendency. Coagulation studies and response to antifibrinolytic therapy suggested primary hyperfibrinogenolysis: markedly low levels of fibrinogen and alpha2-antiplasmin, normal levels of antithrombin III, protein C and protein S combined with an only borderline low number of platelets without evidence of microangiopathic haemolytic anaemia. A suspected causative adenocarcinoma of the lung was demonstrated. She was treated successfully with tranexamic acid and cryoprecipitate, until the tumor progressed and hyperfibrinogenolysis progressed to diffuse intravascular coagulation. Differential diagnosis of these coagulation disorders, with similar etiology, clinical and laboratory findings is reviewed. Therapeutic implications are discussed.

Severe bleeding caused by an inhibitor to coagulation factor V: a case report.

A 67-year-old man with a severe bleeding due to a high level of factor V inhibitor (maximum level of 350 Bethesda units) is described. Coagulation abnormalities improved initially during treatment with prednisolone in combination with cyclophosphamide. Subsequent treatment with either cyclophosphamide or cyclosporin alone was ineffective. After more than 2 years the inhibitor became undetectable after a prolonged period of high dose steroid therapy, but the patient remained steroid dependent. Therapeutic strategies for patients having a factor V inhibitor are discussed.

Octreotide for medullary thyroid carcinoma associated diarrhoea.

Medullary thyroid carcinoma associated diarrhoea can be disabling. A 75-yr-old man with metastatic medullary thyroid carcinoma and refractory diarrhoea is described. Subcutaneous administration of the somatostatin analogue, octreotide, 100 micrograms thrice daily, resulted in a sustained improvement in diarrhoea and disappearance of faecal incontinence without reducing calcitonin levels. Octreotide therapy should be considered as symptomatic treatment for otherwise refractory diarrhoea associated with medullary thyroid carcinoma.

Auto-SCT induces a phenotypic shift from CMP to GMP progenitors, reduces clonogenic potential and enhances in vitro and in vivo cycling activity defined by (18)F-FLT PET scanning.

Autologous SCT (auto-SCT) introduces a reduced tolerance to chemotherapy even in patients with adequate engraftment, suggesting long-term effects of the transplantation procedure on the BM capacity. To study the hematopoietic cell compartment after auto-SCT, CD34(+) BM cells (n = 16) from patients at 6-9 months after auto-SCT were studied with regard to the progenitor subsets, colony frequency and cell cycle status. The BM compartments were studied in vivo using PET tracer 3-fluoro-3-deoxy-L-thymidine (¹8F-FLT PET). BM CD34(+) cells after auto-SCT were compared with normal CD34(+) cells and showed a phenotypic shift from common myeloid progenitor (CMP mean percentage 3.7 vs 19.4%, P=0.001) to granulocyte-macrophage progenitor (GMP mean percentage 51.8 vs 27.6%, P=0.01). In addition, a reduced clonogenic potential and higher cycling activity especially of the GMP fraction (41% ± 4 in G2/S phase vs 19% ± 2, P = 0.03) were observed in BM after auto-SCT compared with normal. The enhanced cycling activity was confirmed in vivo by showing a significantly higher uptake of the ¹8F-FLT PET tracer by the BM compartment. This study shows that auto-SCT results in defects of the hematopoietic compartment at least 6 months after auto-SCT, characterized by changes in the composition of progenitor subsets and enhanced in vitro and in vivo cycling activity.

Renal transplantation in patients with atypical haemolytic uraemic syndrome: a tailor made approach is necessary.

A 33-year-old woman with a history of chronic transplant dysfunction because of repeated bouts of haemolytic uraemic syndrome (HUS) was considered for a second transplant. Extensive genetic investigation of the complement system was executed to rule out known mutations prone to development of HUS. This case illustrates the importance of genetic screening in patients with recurrent HUS.

Metabolic energy reduction by glucose deprivation and low gas exchange preserves platelet function after 48 h storage at 4 degrees C.

INTRODUCTION: We showed earlier that metabolically suppressed platelets (MSP) prepared by incubation in glucose-free, antimycin A medium at 37 degrees C better sustained storage at 4 degrees C than untreated controls at 22 degrees C. However, the use of the mitochondrial inhibitor antimycin A is incompatible with platelet transfusion. OBJECTIVES: The aim of this study was to investigate how energy-reduced (ER) platelets could be prepared in the absence of antimycin A. STUDY DESIGN AND METHODS: Platelets in gas-impermeable bags in glucose-free medium were kept at 22 degrees C for 4 h to reduce energy stores and thereafter stored at 4 degrees C (ER22-4). Controls were energy-reduced platelets without prior incubation at 22 degrees C (ER4), and MSPs in test tubes and untreated platelets in gas-permeable bags with glucose and stored at 22 degrees C (C22) and 4 degrees C (C4). RESULTS: After 48 h storage, ER22-4 were superior to C22 with respect to pH preservation (6 x 4 +/- 0 x 4 vs. 5 x 0 +/- 0 x 4, n= 4), platelet count (800 +/- 225 vs. 650 +/- 150 x 10(9)), thrombin receptor-activating peptide-induced aggregation (50 +/- 15 vs. 10 +/- 5%) and glycoprotein (GP)Ib alpha expression (60 +/- 15% vs. 28 +/- 15). GPIb alpha expression was higher in ER22-4 than in ER4, indicating that energy suppression preserved GPIb alpha during cold storage. CONCLUSION: Metabolic suppression without the use of antimycin A could be mimicked by storage of platelets in glucose-free medium in gas-impermeable bags. Energy suppression preserved GPIb alpha expression during storage at 4 degrees C.

Prolonged platelet preservation by transient metabolic suppression.

BACKGROUND: In this study whether metabolic suppression can be used to preserve platelet (PLT) function during prolonged storage was investigated. STUDY DESIGN AND METHODS: Washed human PLTs were incubated without glucose and with antimycin A to block energy generation. Metabolic suppressed PLTs (MSPs) were stored for 72 hours at different temperatures to find the optimal storage temperature. Controls were incubated with 5 mmol per L glucose and stored at 22 and 4 degrees C. RESULTS: Following metabolic recovery with glucose, MSPs stored at 37, 22, and 4 degrees C showed an increase in basal P-selectin expression (PSE) reaching greater than 40 percent after about 2, 20, and 48 hours; a decrease in thrombin receptor-activating peptide SFLLRN (TRAP)-induced PSE inversely related to the increase in basal PSE; and a decrease in TRAP-induced aggregation reaching less than 30 percent after about 4, 24, and more than 72 hours. When compared with control suspensions, MSPs stored at 4 degrees C better preserved a low basal PSE and in addition showed a better adhesion to surface coated-von Willebrand factor and fibrinogen in a flow chamber. CONCLUSION: Metabolic suppression before storage at 4 degrees C contributes to better preservation of PLT function.

Abnormal immune parameters in HIV-seronegative haemophilic patients.

In HIV-seronegative haemophiliac patients abnormal immune parameters have been demonstrated. In this review data on these abnormalities, their aetiology and clinical consequences are summarized and discussed. The data reviewed show abnormalities at different levels of the adaptive immune system. Most of the reported abnormalities regard lymphocyte subsets and their function, both in vivo and in vitro testing. Strong evidence has not been found for a causal relation between abnormalities and the consumption of factor VIII concentrates nor the purity of the concentrates. It seems likely that certain contaminants in the factor VIII concentrates have an inhibiting effect on lymphocytes and monocytes. Two clinical consequences of the abnormalities have been suggested: a higher susceptibility for infections and a greater risk to develop malignancies. Data on these consequences, however, are contradicting and not in agreement with the good results of long-term treatment of HIV-seronegative haemophiliac patients with factor VIII concentrates. The studies reviewed give no convincing evidence that more pure concentrates are advantageous in HIV-negative haemophiliacs.