Protein C and S and inflammation in sickle cell disease.

Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCD. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels.

Sickle cell disease; a general overview.

Sickle cell disease (SCD) is a heterogeneous disorder, with clinical manifestations including chronic haemolysis, an increased susceptibility to infections and vaso-occlusive complications often requiring medical care. Patients with SCD can develop specific and sometimes life-threatening complications, as well as extensive organ damage reducing both their quality of life and their life expectancy. Proven effective treatment options for sickle cell patients are limited to hydroxyurea, blood transfusions and bone marrow transplantation. With the increasing prevalence of SCD in the Netherlands, a fundamental understanding of its pathophysiology and clinical syndromes is of importance for local medical practitioners.

Erythropoiesis and serum sVCAM-1 levels in adults with sickle cell disease.

Sickle cell patients are characterized by stress erythropoiesis involving cytokines, growth factors, and adhesion molecules. We set out to determine whether serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, which are inversely related to red blood cell counts in sickle cell disease (SCD), reflect erythropoietic activity in adult HbSS patients. Serum levels of sVCAM-1 were compared to erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and soluble transferrin receptor (sTfR) levels in 29 adults with HbSS, and their respective levels were also compared to 29 race- and age-matched HbAA controls. EPO and sTfR levels were increased as compared to healthy controls, whereas IL-3 and GM-CSF were not. No significant correlation of sVCAM-1 levels could be detected with any of the measured erythropoietic markers. Patients, but not controls, with detectable IL-3 levels had lower sTfR and GM-CSF levels as compared to patients with undetectable IL-3 levels. Even though a link of sVCAM-1 to erythropoiesis could not be established, it cannot be ruled out that sVCAM-1 levels reflect the release of young red blood cells into the circulation. IL-3 and GM-CSF levels suggest that different rates of erythropoiesis may be characterized by specific cytokine profiles in SCD. Further research should focus on the potential cytokines and adhesion molecules involved in sickle cell erythropoiesis, as this may increase our understanding of sickle cell complications and may provide us with potential markers for risk assessment in sickle cell disease as well.

Steady-state sVCAM-1 serum levels in adults with sickle cell disease.

Cytokines and adhesion molecules play an important role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), and their in vivo profiles are potential tools for assessing SCD severity. We compared steady-state soluble vascular cell adhesion molecule-1 (sVCAM-1) serum levels to clinical (painful crisis frequency, occurrence of acute chest syndrome, leg ulcers, and cerebrovascular disease) and related hematological parameters of SCD severity (such as HbF%, hemoglobin levels, and leukocyte counts) in 29 HbSS adults. Serum sVCAM-1 levels were not related to clinical severity, but an inverse correlation was demonstrated between sVCAM-1 and hemoglobin levels (r=-0.71, p<0.001) with a positive correlation to serum lactate dehydrogenase levels (r=0.59, p=0.008). Based upon these results, steady-state serum sVCAM-1 levels do not seem to reflect clinical disease severity. However, as VCAM-1 is involved in hematopoiesis, sVCAM-1 levels might reflect bone marrow activity in SCD. This underlies the pleiotropic nature of adhesion molecules in vivo and the need for further research in this area, especially since therapies targeting (cellular) adhesive interactions involving the endothelium are emerging for SCD.

No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease.

Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.

Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study.

Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of low-adjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6-2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20-59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical benefit (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing specific events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study.

Duffy phenotype does not influence the clinical severity of sickle cell disease.

The red blood cell Duffy antigen receptor for chemokines serves as a sink for the clearance of chemokines such as interleukin-8 (IL-8) from the circulation. We analyzed the impact of the Duffy phenotype on sickle cell disease (SCD) severity and serum IL-8 levels in 15 Duffy-positive and 36 Duffy-negative sickle cell patients. There was no difference in clinical severity between Duffy-positive and Duffy-negative sickle cell patients. In asymptomatic sickle cell patients the upward deviation of mean serum IL-8 levels was significantly greater in Duffy-negatives (n = 20) than in Duffy-positives (n = 8) (P = 0.011). However, during a vasoocclusive episode, serum IL-8 levels were similar between Duffy-negatives (n = 11) and Duffy-positives (n = 3). Although the Duffy phenotype seems to influence steady-state serum IL-8 levels, it does not seem to have an effect on SCD severity.

Elevated IL-8 levels during sickle cell crisis.

The vaso-occlusive process (VOC) in sickle cell disease is of a complex nature. It involves intricate interactions between sickle red blood cells, endothelium and probably also leukocytes. As these interactions are regulated by cytokines, we analyzed the role of the potent neutrophil chemokine IL-8 by measuring serum levels in sickle cell patients during sickle cell crisis. These results were compared to nonsymptomatics and healthy controls. In patients having a vaso-occlusive crisis both HbSS and HbSC patients showed significantly enhanced serum IL-8 levels compared to healthy controls. Several of these patients showed extremely elevated serum IL-8 levels which were independent of the crisis inducing factor. Furthermore, a sickle cell patient with VOC as a complication of rhGM-CSF treatment similarly showed high IL-8 serum levels at crisis onset. Nonsymptomatic sickle cell patients serum IL-8 levels were comparable to healthy controls. These results implicate a role for IL-8 at or during (the initiation of) sickle cell crisis.

New concepts in assessing sickle cell disease severity.

Vasoocclusion leads to pain, chronic organ damage, and a decreased life expectancy in patients with sickle cell disease. Therapeutic options for sickle cell disease have usually been evaluated according to their capacity for reducing the frequency of vasoocclusive crises requiring clinical attention. However, the frequency of vasoocclusive crises is not representative for the rate of accumulating organ damage in most sickle cell patients. This implies that the frequency of vasoocclusive crises needn't correlate with disease severity and, although being of importance, cannot solely serve as a parameter of treatment efficacy. Therefore, additional new objective parameters are needed to effectively study the vasoocclusive process in sickle cell disease. Several studies show that intricate adhesive interactions between (red) blood cells, plasma components, and endothelium play a crucial role in the pathophysiology of sickle cell vasoocclusion, offering new potential parameters to effectively assess disease severity as well as new therapeutical targets in the near future. Whether these adhesive mechanisms involve the causes or the effects of vasoocclusion will be determined if their inhibition, by interventive measures, results in therapeutic benefits.

[Ascites due to hypothyroidism]. / Ascites door hypothyreoïdie.

A 77-year-old man presented with ascites which was due to hypothyroidism. After the ascites had been brought into remission by salt restriction, diuretics and paracentesis, monotherapy with levothyroxine prevented recurrence. Ascites reappeared as soon as levothyroxine was withdrawn due to the patient's non-compliance. Distinctive aspects of this type of ascites are the high concentration of total protein in the ascites and the high serum-to-ascites albumin gradient (SAAG). The pathogenesis of ascites in hypothyroidism is unknown. Possible hypotheses include increased capillary permeability, obstruction to lymphatic flow caused by hyaluronic acid-albumin complexes, and diminished water diuresis due to excess antidiuretic hormone. A patient with unexplained ascites should be tested for hypothyroidism, especially when the SAAG is high (> 11 g/l).

Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific increment during vasoocclusive crisis.

Adhesion of sickle erythrocytes to vascular endothelium plays a central role in sickle cell disease complications. Cytokines and adhesion molecules are critically involved in the regulation of these adhesive processes. To analyze their role, IL-6, GM-CSF, sVCAM-1, sICAM-1, sE-Selectin, and sP-Selectin serum levels were determined in sickle cell patients under basic conditions and during vasoocclusive crisis. In nonsymptomatic patients a high serum level of sVCAM-1 was observed compared to controls. In patients having vasoocclusive crisis sVCAM-1 levels increased even more and seemed to correlate with crisis evolution.

Prophylaxis of delayed nausea and vomiting after cancer chemotherapy.

OBJECTIVE: To compare ondansetron and domperidone for treatment of delayed nausea/vomiting (DN/V) following highly emetogenic chemotherapy, after attaining total suppression of emesis on the day of chemotherapy by mean of ondansetron (combined with dexamethasone in the case of cisplatin-treated patients). METHODS: Domperidone (3 x 20 mg daily) was compared with ondansetron (3 x 8 mg daily) in a randomized double-bind placebo-controlled study. Out of 65 consecutive patients who received a first course of either cyclophosphamide and cisplatin for advanced stage ovarian cancer or cyclophosphamide, doxorubicin and 5-fluoro-uracil for metastatic breast carcinoma, 60 patients were eligible for entering the study. According to data from the literature these chemotherapeutic regimens with induce DN/V to a comparable degree. The patients were questioned daily from day 2 through day 5 by the same investigator and the severity of nausea or vomiting was scored on a numerical scale. RESULTS: Emesis was totally suppressed in all patients on the day of chemotherapy. As to DN/V, 16 out of 20 patients receiving placebo required "rescue" medication versus none in the other two groups (p < 0.001). Only 2 (10%) patients were symptomatic with domperidone versus 9 (45%) symptomatic patients in the ondansetron-treated group (p < 0.05). CONCLUSIONS: Both drugs are effective, but domperidone (3 x 20 mg) is more effective than ondansetron (3 x 8 mg) for the prevention of the delayed nausea and/or vomiting which occur after highly emetogenic chemotherapy (p < 0.05).

Successful chemotherapy with deoxycoformycin in adult T-cell lymphoma-leukaemia.

A patient from the Caribbean area with active T-cell lymphoma-leukaemia was primarily treated with deoxycoformycin (DCF), 5 mg/m2 i.v. on 3 consecutive days, followed by 5 mg/m2 i.v. weekly. A complete remission was attained and maintained during several weeks with DCF. A single consolidation course with other cytostatics was then given. The patient continues in complete remission without further therapy, 24 months after diagnosis, 17 months after the last cytostatic drugs. T-cell lymphoma-leukaemia has a bad prognosis with conventional anti-lymphoma therapy but was exquisitely sensitive to DCF in this patient.

Response to pyridoxine hydrochloride in refractory anemia due to myelofibrosis.

Eleven of 14 patients with primary myelofibrosis were given a therapeutic trial with 250 mg of pyridoxine hydrochloride daily because of refractory anemia. The effect on the hemoglobin level and the hematocrit value was studied and compared to that in a group of untreated patients with the same degree of anemia. Six of 11 treated patients responded within three months with a rise in the hemoglobin level (at least 3 g/100 ml) and/or an increase in the hematocrit value (at least 10 per cent), and transfusions were no longer required. Deliberate discontinuation of pyridoxine treatment in one responding patient was followed by a relapse of the anemia; resumption of therapy once again induced an erythropoietic response. Spontaneous remissions of anemia were not observed in the untreated group. It is concluded that a trial with pyridoxine is warranted in patients with myelofibrosis and refractory anemia.

'Classic' and 'acute' myelofibrosis. A retrospective study.

In a retrospective study of 38 patients with histologically proven myelofibrosis, 5 parameters (recorded on the first admission) were investigated as to their usefulness to predict the course of the disease. In 9 patients the development of 'acute' myelofibrosis could be predicted by the finding of pancytopenia, low reticulocyte counts (median 20,500/mul), extremely elevated SRE (median 125 mm) and normal serum levels of LDH and uric acid on the first admission. In 28 patients the development of classic fibrosis with splenomegaly could be predicted by the finding of high reticulocyte counts (median 133,200/mul) and increased levels of serum LDH (median 547 U) and uric acid (median 8 mg/dl in males and 6.8 mg/dl in females) on the first admission, even when splenomegaly was initially absent. The relationship between classic and acute myelofibrosis and the significance of the mentioned parameters is discussed.

Analysis of extramedullary erythropoiesis in the spleen by a semiquantitative method using indium-111.

A semiquantitative method for evaluating the splenic uptake of 111In is described. With this method the uptake of indium in the spleen was significantly higher in seven patients with extramedullary erythropoiesis (EME) than in a control group of seven patients with comparable degrees of splenomegaly but without clinical and/or histological signs of EME. The discrimination between these groups could be further improved by also taking the degree of splenomegaly into account. It is concluded that the described technique is a valuable non-invasive aid for establishing the presence of EME in the spleen.