Methemoglobin effects on coagulation: a dose-response study with HBOC-200 (Oxyglobin) in a thrombelastogram model.

OBJECTIVES: Because oxidation affects platelet and coagulation factors, hemoglobin auto-oxidation in HBOCs results in the transformation to methemoglobin, which may have additive adverse effects on coagulation. The risk of coagulopathy after different dilutions of HBOC-200 with low and high methemoglobin concentrations was studied. DESIGN: A laboratory study on donor blood using thromboelastography (TEG; Haemoscope, Niles, IL). SETTING: A university laboratory. PARTICIPANTS: Volunteer donor blood. INTERVENTIONS: Blood samples simulated hemodilution during clinical resuscitation of hemorrhagic shock with varying doses of HBOC-200 (Oxyglobin; Biopure Corp, Cambridge, MA). Coagulopathy related to 1:11, 1:5, 1:2, and 1:1 dilution of whole blood with HBOC-200 high methemoglobin concentrations (65%) and HBOC-200 low methemoglobin concentrations (1%) were analyzed. MEASUREMENTS AND MAIN RESULTS: Analysis of fixed effects of dilution on coagulation showed that the progressive dilution of HBOC-200 (low methemoglobin) and HBOC-200 (high methemoglobin) produced significant prolongation in reaction time (R) and clot propagation (K) and significant decreases in clot kinetics (alpha) and clot strength (MA and G). Analysis of fixed effects of treatment group on coagulation showed that clot propagation (K, alpha) and clot strength (MA and G) are significantly different in HBOC-200 (high methemoglobin) compared with HBOC-200 (low methemoglobin). CONCLUSIONS: High methemoglobin concentrations in HBOC-200 cause additive coagulation impairment that likely results from the effects of oxidative substances on platelet function and coagulation proteins. Oxidative products adversely react with coagulation factors and modify redox-sensitive sites in the platelets. Therefore, if methemoglobinemia occurs as a result of HBOC administration and if the levels are significantly elevated (greater than 10%), impairment of coagulation is possible.

HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure (Biopure Corporation).

BACKGROUND: Producing an alternative to human erythrocytes has been one the most exciting dreams of medicine. Hemoglobin-based oxygen carriers (HBOCs) derived from purified human or bovine hemoglobin have been studied for clinical use and one product is currently available in the United States and European Union for veterinary use, and another in South Africa for human use. OBJECTIVE: HBOC-201, bovine purified hemoglobin crosslinked and polymerized with glutaraldehyde, has been studied extensively in patients. We describe HBOC-201's potential market share, the history of HBOCs in general and of this compound, its pharmacology, published studies in patients and HBOCs that are currently being studied. METHODS: A literature review using PubMed listed publications and official product websites. CONCLUSIONS: While HBOC-201 may not replace allogenic blood transfusions, it may serve to allow critically ill patients to be resuscitated in the field or hospital setting until either regeneration of red cell occurs or a transfusion is available.

Does Hextend impair coagulation compared to 6% hetastarch? An ex vivo thromboelastography study.

The objective of this study was to determine if coagulation is different between 6% hetastarch in normal saline (NS) and 6% hetastarch in lactated Ringer's solution (LR), with use of an ex vivo thromboelastography (TEG) model with healthy donated volunteer blood. We simulated hemodilution that occurs during clinical resuscitation of hemorrhagic or hypovolemic shock, using healthy human donor whole blood (WB) ex vivo. Coagulopathy related to low, medium, high, or very high dilution of WB with NS or a high-molecular-weight hetastarch-based plasma expander, 6% hetastarch in NS (HSNS) or 6% hetastarch in lactated Ringer's [Hextend (HSLR)], was analyzed by thromboelastography (TEG). No changes were noted in the TEG profile of undiluted WB controls during the 6-hour period of use (P > 0.95). Dilution with HSNS and HSLR significantly impaired coagulation compared to both WB control and NS. Progressive dilution with NS impaired coagulation but to a lesser extent than colloids (P < 0.01). Low dilution of blood with NS increased clot strength by 12% (not significant; P = 0.097). We conclude that WB containing citrate obtained from healthy donors for TEG analysis yields reproducible data over a minimum of 6 hours. Either hetastarch, when present at concentrations comparable to the manufacturer's maximum recommended dose of 20 mL/kg (equivalent to the high dilution used in these experiments), decreases clot tensile strength to levels associated with an increased risk of bleeding. Substitution of lactated Ringer's for NS in 6% hetastarch appears to offer no advantage in avoiding hemostatic compromise in an in vitro model.

Does OxyVita, a new-generation hemoglobin-based oxygen carrier, or oxyglobin acutely interfere with coagulation compared with normal saline or 6% hetastarch? An ex vivo thromboelastography study.

OBJECTIVES: Because hetastarches have deleterious effects on coagulation that increase with molecular weight (MWt), risk of coagulopathy associated with a high MWt hemoglobin-based oxygen carrier (HBOC) was studied. DESIGN: Preliminary laboratory study of donor blood using thromboelastography (TEG). SETTING: University laboratory. PARTICIPANTS: Volunteer donor blood. INTERVENTIONS: Experiments simulated hemodilution during clinical resuscitation of hemorrhagic shock with varying doses of HBOCs. Coagulopathy related to 1:11, 1:5, 1:2, or 1:1 dilution of whole blood with normal saline, 6% hetastarch (670 kilodaltons [kD]), hemoglobin glutamer-200 (HBOC-200, 200 kD), or OxyVita (OXYVITA Inc, New Windsor, NY) (a new-generation, zero-link polymerized bovine hemoglobin-based oxygen carrier, 33 megadaltons) were analyzed. MEASUREMENTS AND MAIN RESULTS: At 2 lower levels of hemodilution, hetastarch, HBOC-200, and OxyVita produced equivalent reductions in maximum clot strength (TEG-MA and TEG-G) that reached statistical significance compared with whole blood and normal saline. At 2 higher dilutions, OxyVita and HBOC-200 impaired maximum clot strength compared with whole blood, normal saline, and hetastarch. Dilution with hetastarch had a greater effect on clot propagation (K and alpha) than either HBOC. CONCLUSIONS: OxyVita and HBOC-200, HBOCs with different MWt, had similar effects on coagulation as measured by TEG. The impairment of coagulation by HBOCs and hetastarch occurred at doses corresponding to 12 mL/kg or a blood volume replacement of 17%. The use of HBOCs at doses corresponding to 23 mL/kg or a blood volume replacement of 33% significantly decreased coagulation to levels associated with increased clinical bleeding in this preliminary study. Minimal coagulopathic effects are expected with use of OxyVita at the manufacturer's anticipated effective dose of 10 g or 2 to 3 mL/kg.

Fine-needle aspiration cytology of papillary renal cell carcinoma: the association with concomitant secondary malignancies.

Papillary renal cell carcinoma is a rare type of renal malignancy. Cytogenetic findings characteristic for this tumor have been described as well as mutations of the proto-oncogene c-met. Secondary malignancies occurring together with papillary renal cell carcinomas are rare, and are often of genitourinary tract origin. We describe two cases of papillary renal cell carcinoma occurring in association with two other visceral malignancies, gastrointestinal stromal tumor and colon adenocarcinoma.Two cases of papillary renal cell carcinoma diagnosed by fine-needle aspiration (FNA), occurring in association with gastrointestinal malignancies were reviewed. Both aspirates showed cytologic features characteristic for papillary renal cell carcinoma, namely papillary structures, foamy histiocytes, intracytoplasmic hemosiderin, and nuclear grooves. Subsequent histology and immunohistochemical stains supported the cytologic diagnosis. The histologic diagnosis of gastrointestinal stromal tumor and colon adenocarcinoma were confirmed. Papillary renal cell carcinoma is a type of renal carcinoma that can be often accurately diagnosed by FNA. The occurrence of associated visceral malignancies has never been reported. The possible role of the protooncogene c-met in the development of these tumors was explored.

Specimen adequacy and diagnostic specificity of ultrasound-guided fine needle aspirations of nonpalpable thyroid nodules.

Ultrasound-guided fine needle aspiration (USG-FNA) is a safe, effective, and dependable test used to assess thyroid nodules. However, the size of the lesion can adversely affect the outcome of the procedure. The aim of this study was to assess specimen adequacy and diagnostic specificity in USG-FNA of thyroid nodules measuring < or = 1.5 cm. A total of 219 thyroid FNAs were performed in a one year; 26 were obtained by pathologists, 139 by clinicians, and 54 by radiologists under ultrasound guidance. Of the 54 ultrasound-guided aspirates, 19 cases (35%) were performed on nodules < or = 1.5 cm (range 0.8-1.5 cm, mean 1.3 cm). Cytologic material from these 19 cases was reviewed along with corresponding available follow-up surgical material. Standard criteria for specimen adequacy and established morphologic criteria for diagnostic specificity were assessed in each case. All 19 cases met criteria for specimen adequacy, and in 17 cases (89%) specific cytologic diagnoses were made (cellular/adenomatous nodule--2 cases, colloid nodule--10 cases, Hashimoto's thyroiditis--4 cases, and papillary cystic carcinoma--1 case). The diagnoses were confirmed by surgical follow-up in six cases including the case of papillary carcinoma. One case diagnosed as suspicious for a papillary carcinoma subsequently was found to be a follicular adenoma by histology. In one case, a diagnosis of lymphocytic thyroiditis versus intrathyroidal lymphoid tissue was made (See Table I). In majority of cases of USG-FNA of nonpalpable thyroid nodules, adequate material may be obtained for a specific cytopathologic diagnosis.

The significance of the diagnosis of atypia in breast fine-needle aspiration.

The diagnosis of atypia in breast fine-needle aspiration (FNA) continues to be an area of debate in cytology practice. The aim of this study was to assess the clinical significance of this term and to evaluate potential morphological criteria, which would determine the patient's outcome. A computer-based search was carried out to retrieve breast FNAs performed between 1990 and 2000 that were diagnosed as atypical. Cases followed by surgical resection were reexamined for the presence of morphological features potentially differentiating benign and malignant lesions. Out of 1,568 breast FNAs, there were 64 cases (4%) with a diagnosis of atypia. Thirty-eight cases had surgical follow-up material that revealed malignancy in 14 cases (37%) and benign lesions in 24 cases (63%). The benign diagnostic categories included fibrocystic change (12/24), fibroadenoma (3/24), tubular adenoma (2/24), and nonspecific findings (7/24). The malignant diagnoses included ductal carcinoma (9/14), lobular carcinoma (3/14), ductal carcinoma in situ (DCIS; 1/14), and tubular carcinoma (1/14). The evaluation of cytological criteria used to differentiate benign from malignant lesions (i.e., cellularity, loss of cohesion, myoepithelial cells, nuclear enlargement, nuclear overlap, prominent nucleoli) revealed significant overlap between benign and malignant cases, particularly in cases of fibroadenoma, tubular adenoma, and proliferative breast disease. The surgical follow-up of four hypocellular cases revealed lobular carcinoma in two cases and ductal carcinoma in the remaining two cases. Our study confirmed that the diagnosis of atypia is clinically significant because it is associated with a high probability of malignancy. No morphological criterion is able to reliably differentiate benign and malignant lesions in cases diagnosed with atypia. Diagnosis of atypia is particularly significant in hypocellular cases. We recommended that breast FNAs with a diagnosis of atypia be evaluated further histologically.

Pelvic washing cytology of ovarian Sertoli-Leydig-cell tumor with retiform pattern: a case report.

A Sertoli-Leydig-cell tumor is an exceptionally rare neoplasm. We present the pelvic washing cytomorphology of an ovarian Sertoli-Leydig-cell tumor with a retiform pattern in a 24-yr-old female. The cytologic features in this case were tight tissue fragments composed of small, relatively uniform cells with scanty cytoplasm and small rounded or blunt papillary fragments with hyalinized cores lined with small, mildly atypical cuboidal cells. Differential diagnoses included borderline and well-differentiated papillary serous tumors, clear-cell carcinoma, and collagen balls. Correlation of cytologic findings with histomorphology is crucial for correct interpretation of pelvic washings in cases of Sertoli-Leydig-cell tumors.