Cancer, chemotherapy, and infections all together make changes in blood rheology and may affect the defense mechanisms by changing the thrombocyte function and endothelial cell. We have examined changes of blood rheology on plasma viscosity to put on probable following criteria for starting the treatment of febrile neutropenia immediately. A total of 27 postchemotherapy patients (16 males and 11 females) with febrile neutropenia diagnosed according to international guidelines have been included into the study. The plasma viscosity of the patients whose febrile neutropenia has been successfully treated was also measured to assess the impact of the duration of neutropenia on viscosity. The plasma viscosities of the patients were significantly higher during neutropenic episode than in nonneutropenic state (
Infectious diseases are important factors of morbidity and mortality in patients with hematological malignancies. Even though cancer is a risk factor for infection, neutropenia has been regarded as the main factor for the development of infections in patients undergoing chemotherapy. Although there are so many new developments on diagnosis of infections and antimicrobial treatments, death caused by infections secondary to neutropenia is so common in acute and chronic leukemia patients. For the prevention of infection, early diagnosis and early treatment of infection become important in patients with cancer. Markers for febrile neutropenia are necessary for decision making of prophylaxis or medical treatment.
Cancer, chemotherapy, and infections (all together) make changes in blood rheology and may affect the defense mechanisms by changing the thrombocyte function and endothelial cell [
In this study, we have examined changes of blood rheology on plasma viscosity in order to start treatment of febrile neutropenia immediately.
A total of 27 postchemotherapy patients (16 males and 11 females; mean age
Patient's demographic, clinic, and laboratory results.
Characteristics |
|
---|---|
Gender | |
Male | 16 |
Female | 11 |
MASCC risk index | |
High (<21) | 27 |
Low (≥21) | 0 |
Underlying cancer | |
Hematological | 20 |
Solid tumors | 7 |
Patients status at presentation | |
Inpatients | 17 |
Outpatients | 10 |
Burden of illness | |
Mild signs | 20 |
Severe signs | 7 |
ECOG performance status | |
0–2 | 20 |
3-4 | 7 |
Disease status | |
Controlled | 19 |
Uncontrolled | 8 |
Treatment setting | |
Induction (hematological) | 3 |
Consolidation (hematological) | 17 |
Locally advanced (solid tumors) | 5 |
Adjuvant (solid tumors) | 2 |
Infection documentation | |
Microbiologically documented | 7 |
Fever of unknown origin | 20 |
MASCC: multinational association for supportive care in cancer; ECOG: eastern cooperative oncology group.
The patients had various types of malignancies. Seven of 27 patients had tumor of solid organ, 5 had palliative chemotherapy (two-non-small-cell lung cancer, primitive neuroectodermal tumor (PNET), two of Kaposi’s sarcoma [KS]), and two had adjuvant chemotherapy (gastric cancer) (Table
According to diagnosis used chemotherapy regimens.
Diagnosis | Chemotherapy agents |
|
---|---|---|
AML | High dose cytarabine 3 gr/sqm q12h iv d1, 3, and 5 | 17 |
ALL | Remission induction chemotherapy2 | 3 |
Gastric cancer | 5-Fluorouracil 680 mg/d; folinic acid 40 mg/d (iv d1–5) | 2 |
Lung cancer1 | Paclitaxel 250 mg/d; carboplatin 400 mg/d (iv d1) | 2 |
PNET | Carboplatin 400 mg/d (iv d1); etoposide 140 mg/d (iv d1–3) | 1 |
Kaposi's sarcoma | Vinblastine 8 mg/d (iv d1) | 2 |
2Cyclophosphamide 1000 mg/sqm/d iv d1, daunorubicin 45 mg/sqm/d iv d1-3, vincristine 2 mg/d iv d1, 8, 15, and 22, prednisolone 60 mg/sqm/d po d1-28, and L-asparaginase 6000 IU/sqm/d iv 6 doses.
AML: acute myeloblastic leukemia; ALL: acute lymphoblastic leukemia; PNET: primitive neuroectodermal tumor.
Most patients (78%) were treated with carbapenems (imipenem or meropenem), while six patients (22%) received piperacillin/tazobactam. Patients who failed empiric antibiotic therapy received vancomycin, and those with persistent fever (>5 days) received antifungal therapy (amphotericin B). All patients with prolonged neutropenia received hematopoietic growth factors such as granulocyte colony-stimulating factor (27/27). Success of antimicrobial therapy was defined as resolution of fever and clinical signs of infection, eradication of the microorganism without changing the empiric antibiotic regimen, and maintenance of the response after discontinuation of therapy.
The study protocol was approved and signed by the local ethics committee. Also all the participants were informed of the consent.
The plasma viscosity of the patients whose febrile neutropenia has been successfully treated, also measured to assess the impact of the duration of neutropenia on viscosity. The patients had febrile neutropenia during their clinical treatment (
All tests were performed in the morning, after 8 hours of fasting. All subjects were seated for 5 minutes before collection. Tourniquets were used, and all collections were completed in less than 1 minute. Venous blood was collected into 5 mL ethylenediaminetetraacetic acid tube (anticoagulated tubes) for plasma viscosity analysis. All samples were frozen because immediate measurement of plasma viscosity was not possible. By this method, all samples were studied at the same time, and errors that could be due to calibration of the test machine were minimized. Blood samples taken into anticoagulated tubes were first centrifuged at 3000 rpm for 5 min, and then the separated plasma was frozen at −40°C. On the day of measurement, all samples were melted and recentrifuged (500 rpm for 2 min) and then measured at 37°C in a Brookfield DV-II+ Cone Plate Viscometer (Brookfield, Stoughton, MA, USA) machine, which was calibrated with distilled water (0.69 mPa.s.). Each sample was measured four times, and the average of the measurements was taken into account. Some sources indicate that the normal value of plasma viscosity is between 1.3 and 1.65 mPa.s., while others state that it is 1.10–1.30 mPa.s. at 37°C and independent of age and gender [
Statistical analyses were performed with SPSS software of Windows (Statistical Product and Service Solutions, version 15.0, SSPS Inc, Chicago, IL, USA). Analysis of variance was performed in order to examine the difference between the two groups with respect to viscosity and other laboratory parameters due to the presence of febrile neutropenic episode. Quantitative variables were expressed as mean values ± standard deviation (SD) for normally distributed data and compared with paired
Data from 27 febrile neutropenic episodes were analyzed. The mean age was
Mean duration of febrile neutropenia development from the initiation of chemotherapy was
MASCC risk index score was <21 in all patients (
Positive blood culture was obtained from only 7 AML patients, all of which were sensitive to the initiated antibiotherapy (Klebsiella pneumoniae and Pseudomonas aeruginosa; carbapenems).
There were no differences between duration of exiting febrile neutropenic episode with respect to diagnosis (
The plasma viscosities of the patients were significantly higher during neutropenic episode than nonneutropenic state (
Laboratory results of febrile neutropenic episode and after febrile neutropenic period.
Parameter | Febrile neutropenic episode | After febrile neutropenic period |
|
---|---|---|---|
mean |
|||
Plasma viscosity (mPa.s.) |
|
|
|
Leukocyte ( |
|
|
|
Neutrophil ( |
|
|
|
Hemoglobin (gr/dL) |
|
|
.177 |
Thrombocyte ( |
|
|
.245 |
ESR (mm/h) |
|
|
.323 |
Prothrombin time (second) |
|
|
.283 |
Fibrinogen (mg/dL) |
|
|
.865 |
BUN (mg/dL) |
|
|
.844 |
Creatinine (mg/dL) |
|
|
.213 |
Sodium (mmol/L) |
|
|
.136 |
Potassium (mmol/L) |
|
|
.588 |
Uric acid (mg/dL) |
|
|
.478 |
AST (U/L) |
|
|
.846 |
ALT (U/L) |
|
|
.476 |
ALP (IU/L) |
|
|
|
GGT (U/L) |
|
|
.698 |
Total bilirubin (mg/dL) |
|
|
.927 |
Direct bilirubin (mg/dL) |
|
|
.167 |
Total protein (gr/dL) |
|
|
.268 |
Albumin (gr/dL) |
|
|
.934 |
C reactive protein (mg/L) |
|
|
.948 |
ESR: erythrocyte sedimentation rate; BUN: blood urea nitrogen; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyl transferase.
The duration between chemotherapy initiation to development of febrile neutropenic episode, time to initiation of hematopoietic factor, and duration of exiting febrile neutropenic episodes were similar when compared to plasma viscosities (
Similarly, plasma viscosities were similar in the outpatient (
In the correlation analysis with study parameters and stages, significant correlation was not observed between plasma viscosity alteration and leukocyte-neutrophil alteration.
When patients over and under 60 years old were analyzed separately, duration of febrile neutropenia development, time to initiation of hematopoietic growth factor, choice of first line antibiotherapy, response to antibiotics, and duration of exiting neutropenic episode were not statistically different with respect to plasma viscosities.
The relationship between hemorheological variables, especially plasma viscosity and febrile neutropenia, has not been extensively investigated. It has previously been reported that plasma viscosity is valuable and can be a surrogate marker of erythrocyte sedimentation rate and the other acute-phase reactants [
In our study, plasma viscosity values of the patients during febrile neutropenic episodes were significantly higher compared to values during exiting the neutropenic episode. Compared to other variables, only alkaline phosphatase (ALP) accompanied the white blood cell (WBC)/neutrophil difference between the two stages. Various acute phase reactants known to affect plasma viscosity such as C reactive protein (CRP), fibrinogen, and erythrocyte sedimentation rate (ESR) values were not different between both stages. CRP increases during a number of malignancies, connective tissue disorders and bacterial infections [
Plasma viscosity is influenced by the concentration of plasma proteins and lipoproteins with the major contribution of fibrinogen [
ALP is present in a number of tissues in the body and is particularly concentrated in liver, bile duct, kidney, and bone. Although tissue specific isoenzyme typing is not performed, it is obvious that elevated ALP values in patients who survived neutropenic episode is due to bone marrow activity. However, in the correlation analysis it was shown that ALP elevation was not accompanying viscosity alterations.
In that point the main question is, as acute phase reactants and other main factors known to affect plasma viscosity are similar during both stages, why and by which mechanism is plasma viscosity significantly higher during febrile neutropenic episode compared to following stage?
In this context, it is suggested that host defensive responses and modifications of blood properties are triggered in infectious process, and as a result, thrombocytes and endothelial functions are damaged—endothelial cells affected from infection are known to bind more thrombocytes—and blood flow in the microcirculation is decreased and diseased [
The results of our study failed to demonstrate any differences with respect to electrolytes, kidney function tests and liver enzymes between two stages. Bilirubin and plasma protein values accompany these results in the same direction. Total protein and albumin values were low in both stages without significant difference. Inflammations and tissue injuries affect plasma viscosity by altering plasma protein levels. But the physicochemical or rheological approach states that the contribution of plasma proteins to plasma viscosity depends on their concentration, molecular weight, rigidity, and asymmetrical shape [
In conclusion, we demonstrated significantly elevated plasma viscosity in our patients during febrile neutropenic episode despite normal values of various parameters known to trigger plasma viscosity, particularly fibrinogen. It is suggested that the main mechanism may be the endothelial injury during infectious process and immune response mediated microcirculatory blood flow alterations. Although biochemical variables of this process are not studied, the absence of a study demonstrating the relationship between febrile neutropenia and plasma viscosity in the literature could permit such a speculation. In light of our presented data, it can be concluded that high plasma viscosity is a predictor of febrile neutropenic episode in patients with malignities. Further researches including larger and homogenous patient populations which will investigate microcirculatory mediator cytokines besides acute phase reactants will help to identify the relationship between febrile neutropenia and plasma viscosity.
The authors of this paper have no conflict of interests including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.