Coagulation factor activity in units of leukoreduced and nonleukoreduced canine fresh-frozen plasma

Michelle L. Foote 1Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.

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Marjory B. Brooks 3Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Todd M. Archer 1Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.

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Robert W. Wills 2Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.

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Andrew J. Mackin 1Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.

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John M. Thomason 1Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.
1Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.
2Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.
3Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Abstract

OBJECTIVE

To evaluate coagulation factors in units of leukoreduced (LR) and nonleukoreduced (non-LR) canine fresh-frozen plasma (cFFP).

ANIMALS

8 healthy research dogs.

PROCEDURES

In a crossover study, dogs were randomly assigned to 1 of 2 groups from which blood was collected and either did or did not undergo leukoreduction. After a recovery period of ≥ 28 days, the dogs were switched between protocols. After each collection, blood samples were centrifuged, and cFFP was stored frozen for later comparative analysis of coagulation factors, antithrombin, and protein C activities (reported as comparative percentages of the corresponding activities determined in a canine pooled plasma standard); prothrombin and activated partial thromboplastin times; and fibrinogen concentration.

RESULTS

There were no significant differences detected between results for LR cFFP, compared with those for non-LR cFFP.

CONCLUSIONS AND CLINICAL RELEVANCE

Although there was variation among residual activities of coagulation factors in LR and non-LR cFFP, the variations and differences were considered unlikely to impact the efficacy of LR cFFP transfused for coagulation factor replacement in dogs. However, owing to the small sample size and high variability of results in the present study, additional research with a larger sample size is required for definitive conclusions on the effects of leukoreduction on coagulation factors in cFFP and to develop treatment guidelines for LR cFFP use in dogs with congenital and acquired coagulopathies.

Abstract

OBJECTIVE

To evaluate coagulation factors in units of leukoreduced (LR) and nonleukoreduced (non-LR) canine fresh-frozen plasma (cFFP).

ANIMALS

8 healthy research dogs.

PROCEDURES

In a crossover study, dogs were randomly assigned to 1 of 2 groups from which blood was collected and either did or did not undergo leukoreduction. After a recovery period of ≥ 28 days, the dogs were switched between protocols. After each collection, blood samples were centrifuged, and cFFP was stored frozen for later comparative analysis of coagulation factors, antithrombin, and protein C activities (reported as comparative percentages of the corresponding activities determined in a canine pooled plasma standard); prothrombin and activated partial thromboplastin times; and fibrinogen concentration.

RESULTS

There were no significant differences detected between results for LR cFFP, compared with those for non-LR cFFP.

CONCLUSIONS AND CLINICAL RELEVANCE

Although there was variation among residual activities of coagulation factors in LR and non-LR cFFP, the variations and differences were considered unlikely to impact the efficacy of LR cFFP transfused for coagulation factor replacement in dogs. However, owing to the small sample size and high variability of results in the present study, additional research with a larger sample size is required for definitive conclusions on the effects of leukoreduction on coagulation factors in cFFP and to develop treatment guidelines for LR cFFP use in dogs with congenital and acquired coagulopathies.

Blood transfusions are commonly used for the treatment of life-threatening anemia in veterinary patients. Unfortunately, transfusion recipients are at risk for developing severe and potentially life-threatening reactions. In veterinary medicine, 3% to 13% of blood transfusion recipients develop a transfusion reaction.1–3 A potential cause of transfusion reactions is the interaction between naturally occurring or induced antibodies in recipient plasma and the antigens on transfused RBCs, WBCs, and platelets.3–5 The transfusion of WBCs and platelets has been associated with adverse reactions in human6,7 and canine recipients.8 In an attempt to reduce inflammatory responses and the risk of some types of transfusion reactions, WBCs (and potentially other cells, particularly platelets) can be extracted from the blood by leukoreduction before transfusion.6–10

Between blood collection and storage, whole blood is typically centrifuged to create specific fractionated blood products, usually consisting of a unit of packed RBCs and a unit of plasma. The plasma can be immediately transfused as fresh plasma or stored as fresh-frozen plasma, both of which contain therapeutic levels of functional coagulation factors and transfusion of which is an essential component of treatment for many congenital and acquired coagulopathies.11,12

In humans, leukoreduction procedures can decrease the residual concentration and function of coagulation factors in hFFP, thereby reducing the therapeutic benefit of the transfusion product.12–15 Compared with non-LR hFFP, LR hFFP has substantially lower concentrations of coagulation factors VII, VIII, and XI. Additionally, LR hFFP has a substantially longer aPTT than does non-LR hFFP, whereas the aPTT for LR hFFP remains within reference limits.12 Currently, it is unknown how leukoreduction affects the residual concentration and function of coagulation factors in cFFP.

The purpose of the study reported here was to evaluate coagulation factors in units of cFFP prepared from canine whole blood that did versus did not undergo leukoreduction. Similar to the effects that leukoreduction has on human blood products, we hypothesized that LR cFFP would have lower concentrations of coagulation factors, compared with non-LR cFFP, but that the clotting times would not differ between LR cFFP and non-LR cFFP.

Materials and Methods

Animals

Eight healthy adult research dogs that had not been exposed to any medications or vaccines for at least 2 weeks before study initiation were included. Animal use was approved by the Mississippi State University Institutional Animal Care and Use Committee and was in compliance with the requirements of the American Association for Accreditation of Laboratory Animal Care.

Blood donation, leukoreduction, and sample collection

Dogs were randomly allocated into 1 of 2 groups: the LR group, from which collected blood underwent leukoreduction, and the non-LR group, from which collected blood did not undergo leukoreduction. For blood collection, dogs were positioned in right or left lateral recumbency, the hair overlying the nondependent jugular vein was clipped, and the skin was aseptically prepared. A 16-gauge needle, attached to a connecting tube, was inserted into the jugular vein, and under negative pressure, approximately 450 mL of blood was collected into a standard triple blood-banking baga for the non-LR group and a quadruple blood-banking bag containing an in-line leukoreduction filterb for the LR group. The bags contained a citrate phosphate dextrose solution as an anticoagulant.

For the LR group, WBCs and platelets were removed by passage of the blood through the leukoreduction filter within 30 minutes after collection. Samples of blood were collected from the in-line tubing system before and after the leukoreduction filter and analyzed with an automated hematologic analyzerc to determine the total WBC and platelet counts. For both groups, the RBCs and plasma were then separated by centrifugation. Once separated, external pressure was applied to the unit of plasma, and the plasma passed through a connecting tube into an attached empty satellite bag. Within 3 hours after collection, the plasma samples were aliquoted and stored at −20°C until analysis. After a recovery period of ≥ 28 days following completion of the blood collection, the dogs were switched between protocols, and both protocols were repeated.

Coagulation testing

Frozen plasma samples were shipped overnight on dry ice to the Comparative Coagulation Laboratory at the Cornell University Animal Health Diagnostic Center. The hemostatic proteins and indices measured included coagulant activities of coagulation factors V, VII, VIII, X, and XI; clotting times (PT and aPTT); anticoagulant factors (antithrombin and protein C); and clottable fibrinogen. All factor assays were performed with a single lot of commercial PT and aPTT reagents, substrate-deficient plasmas, and a canine standard plasma (pooled from 20 healthy dogs and stored frozen in single-use aliquots). The standard plasma was assigned a factor activity of 100%, equivalent to 1 U/mL.16,17 Results of the coagulant and anticoagulant activity assays were reported as comparative percentages of the corresponding assays of the canine pooled plasma standard. As previously described,16,18 intrinsic factor coagulant activity assays (coagulation factors VIII and XI) were performed with a 1-stage aPTT technique configured with a rabbit brain cephalin and ellagic acid aPTT reagentd and canine plasma deficient in factor VIII or human plasma deficient in factor XI. Coagulation activity assays for factors V, VII, and X were performed with a modified 1-stage PT technique with a rabbit thromboplastin reagente and human (factor V) or canine (factor VII) substrate-deficient plasma or factor X-depleted bovine plasma. Clottable fibrinogen was measured in an automated coagulation instrument by the Clauss method18,19 with human thrombin reagent (100 NIH U/mL) as described. Antithrombin and protein C activities were measured with synthetic chromogenic substrate kitsf,g modified from the manufacturer's instructions by the use of a canine, rather than human, plasma standard.

Statistical analysis

A sample size calculation was performed on the basis of data from a previous study12 that detected a significant difference in coagulation factor VII activity in units of hFFP without leukoreduction (98%) and with leukoreduction (87%). With α set to 0.05, power set to 0.65, and the expected difference between means set to 11% (ie, 98% −87%), that calculation revealed that a total of 8 dogs/treatment group would be required to detect a significant difference between groups. With a statistical computer programh that incorporated a residual maximum likelihood procedure, separate linear mixed models were fixed for aPTT, PT, fibrinogen, antithrombin, protein C, and coagulation factors V, VII, VIII, X, and XI. Histograms were then assessed for normality. Period, sequence, and filter were included as fixed effects, and dog identity was included as a random effect with a variance component covariance structure specified. The distribution of the conditional residuals was evaluated for each outcome to ensure the assumptions of the statistical model had been met. Values of P ≤ 0.05 were considered significant.

Results

Eight healthy adult research Treeing Walker Coonhounds (5 males and 3 females) were used in the study. Mean age was 1.5 years (range, 1.5 to 6.5 years), and mean body weight was 27.4 kg (range, 20.5 to 30.5 kg). Dogs were deemed healthy on the basis of results of physical examination, CBC (including a manual platelet count), serum biochemical analyses, urinalysis, and testing for heartworm antigen. In addition, none of the dogs had been exposed to any medications or vaccines for at least 2 weeks before study initiation. No adverse events were detected in the donor dogs during or after blood collection.

Leukoreduction

The median WBC count before leukoreduction was 5.2 × 103 WBCs/μL (range, 3.4 × 103 WBCs/μL to 8.9 × 103 WBCs/μL; reference range, 7.0 × 103 WBCs/μL to 22.0 × 103 WBCs/μL). After leukoreduction, the total WBC count was 0 WBCs/μL in all samples. The median platelet count before leukoreduction was 232 × 103 platelets/μL (range, 112 × 103 platelets/μL to 340 × 103 platelets/μL; reference range, 160 × 103 platelets/μL to 650 × 103 platelets/μL). After leukoreduction, the median platelet count was 4 × 103 platelets/μL (range, 0 to 137 × 103 platelets/μX).

Coagulation testing

Hemolysis was detected in 1 unit of non-LR cFFP (from dog 5), and fibrin clot fragments were identified in 1 unit of LR cFFP (from dog 8). Both of these units were excluded from statistical analysis, leaving 7 units of non-LR cFFP and 7 units of LR cFFP. Compared with the coagulation factor VIII activity established as 100% in a canine pooled plasma standard, the coagulation factor VIII activity was 1,000% in the unit of non-LR cFFP with hemolysis and 663% for the unit of LR cFFP with clot fragments.

In non-LR and LR cFFP, the mean ± SD activities, reported as percentages of the corresponding coagulation factor activities determined in a canine pooled plasma standard, were 79% ± 11% and 74% ± 21%, respectively, for coagulation factor V; 78% ± 21% and 82% ± 32%, respectively, for factor VII; 162% ± 133% and 196% ± 110%, respectively, for factor VIII; 85% ± 10% and 63% ± 22%, respectively, for factor X; and 105% ± 27% and 124% ± 31%, respectively, for factor XI (Table 1; Figure 1). For each evaluated coagulation factor, the mean activity was > 60% in all units of LR and non-LR cFFP. However, some individual units of LR cFFP had coagulation factor activity < 60% (factor V, 1 unit with 34% activity; factor VII, 3 units with 57%, 57%, and 59% activity; and factor X, 4 units with 31%, 51%, 54%, and 56% activity), and some individual units of non-LR cFFP had coagulation factor activity < 60% (factor VII, 1 unit with 38% activity; factor VIII, 1 unit with 32% activity). When 70% of the activity of a pooled plasma standard was used as a lower limit for coagulation factor VIII, only 1 unit of LR cFFP (with 69% activity) and 1 unit of non-LR cFFP (with 62% activity) were below this lower limit. Median activity of coagulation factor VIII was 215% (range, 69% to 383%) and 111% (range, 32% to 418%) in LR and non-LR cFFP, respectively. Median activity of coagulation factor XI was 134% (range, 80% to 170%) and 94% (range, 74% to 154%) in LR and non-LR cFFP, respectively.

Table 1—

Results of linear mixed model analyses to identify potential differences in results for coagulation variables evaluated in units of non-LR versus LR cFFP prepared from whole blood collected from 8 healthy research dogs.

Non-LR cFFPLR cFFP 
VariablesMean ± SD95% CIMean ± SD95% CIP value
Factor V (%)*79 ± 1171 to 8774 ± 2135 to 1130.523
Factor VII (%)*78 ± 2162 to 9482 ± 329 to 1550.620
Factor VIII (%)*162 ± 13363 to 260196 ± 109−92 to 4840.559
Factor X (%)*85 ± 10.177 to 9263 ± 22−3 to 1280.108
Factor XI (%)*105 ± 2784 to 125124 ± 3120 to 2280.243
PT (s)13.1 ± 0.512.7 to 13.513.6 ± 1.112.3 to 14.80.347
aPTT (s)14.5 ± 1.813.1 to 15.817.3 ± 3.314.8 to 19.70.182
Fibrinogen (mg/dL)277.7 ± 69.3226.3 to 329.1248.4 ± 49.9173.7 to 323.20.480
Antithrombin (%)*97 ± 990 to 10490 ± 1052 to 1280.289
Protein C (%)*121 ± 15110 to 132111 ± 1836 to 1850.126

Reported as a comparative percentage of activity of the same variable in a canine pooled plasma standard.

CI = Confidence interval.

The mean ± SD activities of antithrombin and protein C in LR and non-LR cFFP, reported as percentages of those activities determined in a pooled plasma standard, were calculated (Table 1; Supplementary Figure S1, available at http://avmajournals.avma.org/doi/suppl/10.2460/ajvr.80.9.846). In addition, the means ± SD of fibrinogen concentration, PT, and aPTT were calculated (Supplementary Figures S2 and S3, available at http://avmajournals.avma.org/doi/suppl/10.2460/ajvr.80.9.846).

On the basis of histogram assessment, all outcomes were considered normally distributed. There were no significant (P > 0.05 for all) differences detected between results for units of LR versus non-LR cFFP.

Figure 1—
Figure 1—

Box-and-whisker plots of coagulation factors V, VII, VIII, X, and XI activity (reported as a comparative percentage of the corresponding factor's activity determined in a canine pooled plasma standard) in units of non-LR (white boxes) and LR (gray boxes) cFFP prepared from whole blood collected from 8 healthy research dogs. For each plot, the lower and upper boundaries of the box represent the 25th and 75th percentiles, respectively; the horizontal line in the box represents the median; and the whiskers represent the range.

Citation: American Journal of Veterinary Research 80, 9; 10.2460/ajvr.80.9.846

Discussion

In veterinary medicine, the use of WBC- and platelet-depleted blood products to reduce the risk of transfusion reactions is becoming more common8,20; therefore, it is important to determine whether the leukoreduction process adversely affects the quality of plasma. Although leukoreduction has been shown to reduce the concentration and function of coagulation factors in hFFP,12–15 the results of the present study suggested that most canine coagulation factors were not markedly depleted by leukoreduction.

On the basis of human transfusion recommendations, the minimum coagulation factor activity needed to support surgical hemostasis is > 60%.21,22 In the present study, the mean coagulation activity across all measured coagulation factors was > 60% in all units of LR cFFP; however, some individual units of LR cFFP had coagulation factor activity < 60% (factor V, 1 unit with 34% activity; factor VII, 3 units with 57% to 59% activity; and factor X, 4 units with 31% to 56% activity). At the time of the present study, there were no established minimal standards for residual coagulation factor content and activity for hFFP or cFFP12,17; however, in some European countries, thawed plasma must contain 70% of the original amount of coagulation factor VIII and exceed 70 U/100 mL.12,17 In our study, only 1 unit of LR cFFP was below this amount, with 69% activity; therefore, our findings suggested that LR cFFP most likely has similar therapeutic benefits to non-LR cFFP, with the caveat that individual units may have coagulation factor VIII activity below the 70% minimum coagulation factor activity benchmark.

In units of human blood products, a reduction in coagulation factor VIII has been the most common change reported following leukoreduction, but decreases in factors V, IX, XI, and XII have also been identified.12–15 Williamson et al23 detected a significant decrease in coagulation factor VIII following leukoreduction, but the postfiltration values remained within the minimum requirements. In contrast, Heiden et al24 and Runkel et al25 did not identify a significant change in any coagulation factor measured following leukoreduction. The differences could potentially be attributed to the type of filter and the length and temperature of storage before leukoreduction.12

There are several proposed mechanisms that could explain a reduction in coagulation factor content following leukoreduction. The coagulation factors could bind to the filter, preventing their passing into the plasma. Differences in the surface coatings of filters could explain inconsistent adherence of coagulation factors to filters, resulting in variation of coagulation factor losses in different studies.12 In addition, the contact system of coagulation could have become activated. As blood passed through the filter, the contact system, particularly of coagulation factor XII, could become activated and subsequently consumed during coagulation.15 Activation of factor XII, prekallikrein, and high-molecular-weight kininogen results in production of kallikrein and bradykinin, which in turn mediate inflammatory pathways and vascular permeability.15,26 We did not measure prekallikrein or high-molecular-weight kininogen, and additional studies would be needed to determine whether the contact system becomes activated during leukoreduction of canine blood.

One unit of non-LR cFFP had hemolysis, which could have contributed to the high activity of coagulation factor VIII (1,000%). The presence of hemolysis or cell-free hemoglobin can variably activate coagulation, resulting in the ex vivo formation of thrombin and potentially increasing or depleting activities of coagulation factors.27,28 Additionally, 1 unit of LR cFFP contained fibrin clot fragments and had high activity for coagulation factor VIII (663%), indicating the action of thrombin on plasma fibrinogen. A problem during collection was considered the likely cause of hemolysis and clot fragments because 1 unit of cFFP from each protocol was involved, and these potential problems could have included traumatic venipuncture, turbulent blood flow, and inadequate mixing of blood with the anticoagulant.27,28 Therefore, the 2 affected units of cFFP were excluded from statistical analysis.

In our study, canine whole blood was LR within 30 minutes after collection and was not cooled before filtration. Although a previous study29 of dogs suggests that cooling blood before leukoreduction with a filter made of surface-modified nonwoven polyester fibers may improve WBC removal, the present study used a different type of filter, a neutrally charged polyurethane filter, which the manufacturer's guidelines specified acceptable for use without prior cooling of the blood product. Our study demonstrated that the polyurethane leukoreduction filters used were effective at removing WBCs despite a lack of prior cooling of the blood. Although results suggested that the polyurethane filters used in the present study were less effective at removing platelets from blood than were the filters used in the previous study,29 cooling of the blood in that study did not appear to improve platelet removal. The time needed for leukoreduction of cooled (4°C) blood is longer than that for blood at room temperature when a polyester fiber filter is used, suggesting that cells in cooled blood would be exposed to less shear forces when passing through the filter.29 Although less shear forces might be beneficial, the prolonged contact time in the filter might also alter components of coagulation. The effects on coagulation factors by leukoreduction of cooled blood are unknown.

A major limitation of the study was a small sample size. Our a priori sample size calculation was based on findings for coagulation factor VII in humans,12 and results suggested that a sample size of 8 dogs would provide ample power for the present study. However, there were limited data available pertaining to study power for the other coagulation factors, and thus our calculation did not incorporate sample size variables for all coagulation factors measured, some of which might have required a different, potentially larger number of samples. In addition, given the variability of results noted among dogs for some of the coagulation factors evaluated in the present study, a larger sample size would have been required to demonstrate the presence or absence of a significant difference in results for some coagulation factors. Therefore, conclusions on how leukoreduction affected the hemostatic proteins and indices evaluated were limited. However, before the present study, coagulation factor activities in LR cFFP were unknown, and as a preliminary assessment of the quality of cFFP, a relatively low power (0.65) was used in the sample size calculation. Results of the present study indicated high variability among dogs, especially for coagulation factors VIII and XI, and an increase in sample size could help identify differences in coagulation factor activities in LR versus non-LR cFFP. Nonetheless, results indicated that median activity of coagulation factors VIII and XI was > 100% in LR and non-LR cFFP, suggesting that statistically significant differences in coagulation factor activities between LR and non-LR cFFP may not be biologically relevant. Coagulation factors in dogs can have a broad range of values,21 and a larger sample size would be required to fully assess the effects of leukoreduction on coagulation factors. Thus, it was possible that a type II error could have occurred in the present study. Additional research with a larger sample size and different breeds is indicated.

Additional limitations to the study were that PT and aPTT are best suited to detect severe depletion of fibrinogen or coagulation factors, and methods such as thrombin generation assays and viscoelastometry could have provided more global qualitative assessments of the enzymatic potential of coagulation pathways and the tensile properties of a nascent fibrin clot, respectively. We used only 1 type of leukoreduction filter, a polyurethane filter, whereas different types of leukoreduction filters have different effects on coagulation factors in humans.15 Additional studies that evaluate multiple types of leukoreduction filters would be necessary to determine whether all leukoreduction filters would yield results for cFFP similar to those in the present study. Further, the WBC counts in our study were determined by a hematology analyzer, and manual counts were not performed. Because of the limit of detection for the analyzer (0 to 99.9 × 103 ± 0.4 × 103 WBCs/μL), it was possible that the WBC counts were actually higher than reported. Performing a manual cell count could have provided a more accurate assessment of the number of residual WBCs following filtration.30

Although there was variation among residual activities of coagulation factors in LR and non-LR cFFP, the variations and differences were considered unlikely to impact the efficacy of LR cFFP transfused for coagulation factor replacement in dogs. Future treatment trials are worthwhile to develop treatment guidelines for the use of LR cFFP in dogs with congenital and acquired coagulopathies.

Acknowledgments

Sample collection was performed at the College of Veterinary Medicine, Mississippi State University, and coagulation assays were performed at the Comparative Coagulation Laboratory, Cornell University.

Funded by the Morris Animal Foundation and the Mississippi State University College of Veterinary Medicine Office of Research and Graduate Studies. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.

The authors declare that there were no conflicts of interest.

Presented in abstract form at the 2015 American College of Veterinary Internal Medicine Forum, Indianapolis, June 2015.

The authors thank Matthew Raby and Cyndi Dunaway for technical assistance with the collection of blood.

ABBREVIATIONS

aPTT

Activated partial thromboplastin time

cFFP

Canine fresh-frozen plasma

hFFP

Human fresh-frozen plasma

LR

Leukoreduced

Non-LR

Nonleukoreduced

PT

Prothrombin time

Footnotes

a.

Teruflex Optisol Triple Collection Blood Bag, Terumo BCT Inc, Tokyo, Japan.

b.

Imuflex-WB-RP Blood Bag with integral whole blood leukocyte reduction filter, Terumo BCT Inc, Tokyo, Japan.

c.

Abbott Cell-Dyn 3700, Abbott Laboratories, Abbott Park, Ill.

d.

Dade Actin, Siemens Health Diagnostics Inc, Marburg, Germany.

e.

Thromoplastin LI, Helena Laboratories, Beaumont, Tex.

f.

STA-Stachrom ATIII, Diagnostica Stago Inc, Parsippany, NJ.

g.

STA-Stachrom Protein C, Diagnostica Stago Inc, Parsippany, NJ.

h.

SAS for Windows, version 9.4, SAS Institute Inc, Cary, NC.

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