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Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography.

BACKGROUND/AIMS: Patients with primary biliary cirrhosis and primary sclerosing cholangitis survive variceal bleeding better than patients with alcoholic cirrhosis and have less bleeding at liver transplantation. Recently, patients with primary biliary cirrhosis have been found to have a higher incidence of thrombosis in the portal venous tree. We hypothesized that primary biliary cirrhosis and primary sclerosing cholangitis patients may be hypercoagulable. METHODS: We used thrombelastography, which is a simple technique for evaluating whole blood clotting and fibrinolysis, to establish if hypercoagulability was present, defined by thrombelastography values greater than 2SD over controls: r<19 mm (this reflects plasma clotting factors), maximum amplitude (ma) >60 mm, and alpha angle >43 degrees (these reflect platelets and fibrinogen levels). We evaluated 47 primary biliary cirrhosis and 21 primary sclerosing cholangitis patients, 40 with non-cholestatic cirrhosis and 40 healthy subjects as control groups with thrombelastography, full blood count, prothrombin time, partial thromboplastin time and, fibrinogen concentrations. In those with hypercoagulability we evaluated protein S, C, anti-thrombin III levels and activated protein C phenotype. RESULTS: All three thrombelastography abnormalities present together defined hypercoagulability: these were found in 13 of 47 (28%) primary biliary cirrhosis and in nine of 21 (43%) primary sclerosing cholangitis patients independent of cirrhosis, and bilirubin concentration, but in only 2 of 40 (5%) patients with noncholestatic cirrhosis and in none of the healthy controls (p<0.03 and p<0.0002, respectively). There was no correlation between the fibrinogen concentration (which was normal in all patients) or platelet count and the thrombelastography parameters. Only six of the 22 hypercoagulable patients had lower than normal values of protein S, C or antithrombin III. Activated protein C phenotype was normal in all. CONCLUSIONS: This diffference between biliary and parenchymal liver disease may have clinical implications, which need to be defined.

Adolescent↗

Coagulation status during aortic aneurysm surgery: comparison of thrombelastography with standard tests.

A prospective comparison of thrombelastography to standard coagulation tests was undertaken in ten patients undergoing routine, uncomplicated abdominal aortic aneurysm surgery in order to explore potential clinical utility and establish normal patterns of change. Thrombelastograph k values increased (7.1 vs 5.4 min baseline, P < or = .01), and alpha angle (43 vs 52 degrees baseline, P < or = .001) and ma (39 vs 52 mm baseline, P < or = .01) values decreased following graft placement, while r values remained unaffected (6.4 vs 7.5 min baseline, P > .05). Weak correlations were observed between alpha angle and fibrinogen, prothrombin time, and partial thromboplastin time (aPTT), as well as between k and aPTT (0.70 < r < 0.79 for all). Systemic fibrinolysis was suggested by thrombelastography in 25% of samples, although euglobulin lysis times were abnormal in only 5% (chi 2 = 4.80, P < or = .05). Fibrin degradation product detection increased through the fifth postoperative day in all patients. Variations in thrombelastographic parameters and their correlation to standard coagulation tests in patients undergoing uncomplicated abdominal aortic aneurysm repair were documented. In such a setting, no clear advantages to thrombelastography were defined. Further observations will be necessary to establish the role for thrombelastography in the management of patients experiencing clinically significant perioperative coagulation disorders.

Aged↗

Effects of progressive blood loss on coagulation as measured by thrombelastography.

The effects of progressive blood loss on coagulation were studied in 87 adults (age 23-66 yr) undergoing a variety of operations under general anesthesia. None had preoperative alterations in coagulation or liver function and none were receiving anticoagulant or antiplatelet medication. Whole blood coagulation status was quantitated using thrombelastography (TEG). Blood samples for TEG were obtained 5 min before and 15 min after induction of anesthesia, after each increment of blood loss (EBL) equalling 5% of estimated blood volume (EBV), at the end of surgery, and 2 hr post-operatively. Patients with EBL exceeding 0.15 EBV were given packed red cells and crystalloid solution. Patients with EBL less than 0.15 EBV received only crystalloid. Thrombelastography analysis showed a trend toward increased coagulability with progressive blood loss. Two of four patients with 80% loss of EBV maintained normal to enhanced coagulation status, although the other two developed clinical and thrombelastographic evidence of coagulopathy. Thrombelastography allowed rapid intraoperative diagnosis and specific treatment of loss of platelet activity in the latter two patients. We conclude that during moderate to massive blood loss, use of supplemental fresh frozen plasma and/or platelets should be reserved for patients with documented defects in coagulation. Thrombelastography is useful for the detection and management of coagulation defects associated with intraoperative blood loss.

Adult↗

Influence of blood coagulation factor XIII and FXIII Val34Leu on plasma clot formation measured by thrombelastography.

Blood coagulation factor XIII (FXIII) plays an important role in the final stage of the blood coagulation process. Thrombelastography (TEG) enables global assessment of the hemostatic function. The present study tested for the first time the specificity and sensitivity of the rotation thrombelastography (ROTEG: rotation thrombelastography) method for the influence of FXIII and the FXIIIVal34Leu polymorphism on thrombelastograms measured in citrated plasma. Three thrombelastographic parameters were determined in (a) citrated pool plasma, (b) FXIII-deficient plasma, (c) different mixtures of both, and (d) in 60 plasma samples genotyped for FXIIIVal34Leu. Thrombelastograms from FXIII-deficient plasma were significantly smaller than those from pool plasma (8 mm vs. 20.9 mm). Increasing amounts of pool plasma added to FXIII-deficient plasma led to an increase in maximum clot firmness (MCF). FXIIIVal34Leu showed an influence on clot formation time (CFT) values, which decreased with increasing number of Leu alleles. The difference between the wild type and the homozygote mutant genotype was statistically significant (median 185.3 vs. 86.0 s, P=.031). ROTEG is a simple but effective method for the investigation of FXIII function in plasma. The ROTEG method has shown to be not only specific for the FXIII influence, as effects exclusively dependent on FXIII could be observed, but also sensitive, as already smallest amounts of FXIII could be detected. Additionally, the impact of a common genetic polymorphism on ROTEG could be shown for the first time.

Amino Acid Substitution↗

Use of abciximab-modified thrombelastography in patients undergoing cardiac surgery.

UNLABELLED: Thrombelastography (TEG) is a reliable coagulation monitoring system that can guide blood product transfusion in cardiac surgery. The maximum amplitude (MA) of TEG measures clot strength, which is dependent on both fibrinogen level and platelet function. Inhibition of platelet function with abciximab-fab is suggested to permit quantitative assessment of the contribution of fibrinogen to clot strength. We hypothesized that abciximab-modified TEG permits prediction of plasma fibrinogen levels and that the difference of standard MA and abciximab-modified MA (deltaMA) is a correlate for platelet function. We correlated abciximab-modified MA with plasma fibrinogen levels and deltaMA with platelet count in patients undergoing coronary revascularization. Correlation between plasma fibrinogen levels and abciximab-modified MA was significant (adjusted r2: 0.8; P < 0.0001). Correlation of deltaMA with platelet count was not significant when calculated in millimeters (adjusted r2: 0.04; P = 0.73). However, when deltaMA was calculated in dynes per square centimeter (deltaGMA), it correlated significantly with platelet count (adjusted r2: 0.51; P < 0.0001). We conclude that abciximab-modified TEG may therefore help to discriminate between hypofibrinogenemia and platelet dysfunction as a cause of decreased MA. IMPLICATIONS: We examined the use of abciximab-modified thrombelastography in patients undergoing cardiac surgery. Modification of thrombelastography with abciximab-fab allows prediction of fibrinogen levels, despite coagulation altered by cardiac surgery. The difference of standard maximum amplitude and abciximab-modified maximum amplitude correlates with platelet function when expressed in dynes per square centimeter.

Abciximab↗

Thrombelastography of blood from subjects with chronic renal failure.

Blood samples from 23 subjects with chronic renal failure and 19 controls were tested using thrombelastography and other hematologic tests. The uremic subjects were divided into two groups, those who had not yet begun maintenance hemodialysis treatments (12 subjects) and those who had (11 subjects). Compared to those from control subjects, the thrombelastograms from the uremic subjects consistently indicate normal clotting times but significantly elevated amplitudes. The increased amplitudes correlate positively in the dialyzed uremic group with both platelet count and fibrinogen concentration and correlate negatively in both uremic groups with hematocrit. Thrombelastography demonstrates a hypercoagulability in these samples in vitro, despite the prolonged bleeding time that commonly occurs in uremic subjects.

Fibrinogen↗

Functional maturity of the coagulation system in children: an evaluation using thrombelastography.

There are quantitative deficiencies in the coagulation system for at least the first 6 mo of life. Clinical experience, however, does not indicate an increased risk of excessive bleeding during surgical procedures. Thrombelastography, a test providing a functional evaluation of coagulation, was used to assess the hemostatic system of pediatric patients under 2 yr of age. Thrombelastographic data were obtained from 237 healthy pediatric patients less than 2 yr of age undergoing elective noncardiac surgery. Five groups were distinguished: under 30 days, 1-3 mo, 3-6 mo, 6-12 mo, and 12-24 mo. Thrombelastography revealed no defects in coagulation when these groups were compared to each other or to adults, indicating a functionally intact hemostatic process even in neonates. Indeed, children less than 12 mo of age were found to initiate and develop clot faster than adults, with the coagulation process slowing to adult rates after 1 yr of age. In addition to defining functional integrity, our data represents a set of pediatric control thrombelastographic values that have not been previously reported and that may become important in understanding coagulation changes that accompany disease states and surgery in pediatric patients.

Age Factors↗

Hemodilution with albumin, but not Hextend, results in hypercoagulability as assessed by Thrombelastography in rabbits: role of heparin-dependent serpins and factor VIII complex.

UNLABELLED: Isovolemic hemodilution (IVHD) has been advocated as an effective method of reducing the need for transfusion but has been associated with hypercoagulability. We tested the hypothesis that IVHD enhances hemostatic function by decreasing circulating antithrombin activity in rabbits. Furthermore, it was determined whether different replacement solutions would affect hemostasis. Sedated rabbits were randomly assigned to groups that underwent IVHD (40% blood volume removed) with 5% human albumin (n = 10) or a 6% hetastarch solution (Hextend). Antithrombin and Factor VIII complex (VIII:C) activities were determined, and thrombelastography(R) was performed with or without platelet inhibition. IVHD resulted in a significant (P < 0.05) decrease in antithrombin (32%-39%) without fluid-specific differences observed. VIII:C did not change in the albumin group, whereas the hetastarch group had a significant (P < 0.05) decrease (43%) in VIII:C that was also significantly (P < 0.05) less than the albumin group. The time to clot initiation was decreased, and the rate of clot formation increased significantly via thrombelastography(R) in albumin animals. No significant change in clot kinetics was observed in hetastarch animals. In rabbits, the primary determinant of hemostasis after IVHD was the interaction of changes in antithrombin activity and VIII:C. These data serve as a rational basis to determine whether IVHD-mediated hypercoagulability encountered clinically may be attenuated or exacerbated by the choice of colloid administered. IMPLICATIONS: Isovolemic hemodilution (IVHD) is associated with hypercoagulability. Rabbits hemodiluted with albumin, but not Hextend, became hypercoagulable secondary to a loss of antithrombin activity with simultaneous maintenance of Factor VIII complex activity (VIII:C). Hextend-treated animals had proportionate decreases in both antithrombin activity and VIII:C. IVHD-mediated hypercoagulability encountered clinically may be attenuated or exacerbated by the choice of colloid administered.

Animals↗

The detection of changes in heparin activity in the rabbit: a comparison of anti-xa activity, thrombelastography, activated partial thromboplastin time, and activated coagulation time.

UNLABELLED: Thrombelastography (TEG) has been used to detect both exogenous and endogenous circulating heparin activity in clinical and laboratory settings. Thus, in this study I sought to compare the sensitivity of TEG, activated partial thromboplastin time (aPTT), and activated coagulation time (ACT) values with changes in anti-Xa activity after small-dose heparin administration in rabbits. Conscious rabbits (n = 11) had blood obtained from ear arteries for hematological analyses after the administration of 0, 10, 20, and 30 U/kg of IV heparin. Anti-Xa activities after the administration of 0, 10, 20, and 30 U/kg of heparin were, respectively, 38 +/- 9 mU/mL, 74 +/- 15 mU/mL, 105 +/- 14 mU/mL, and 134 +/- 17 mU/mL; all values were significantly different from each other. TEG variables (R and alpha) significantly (P < 0.05) changed between 0, 10, and 20 U/kg heparin doses, but a difference between 20 and 30 U/kg could not be discerned secondary to loss of a detectable clot. The aPTT was significantly (P < 0.05) different between 0, 20, and 30 U/kg doses. ACT values were significantly different between the 0 U/kg heparin dose and all other doses; however, there were no significant differences between the 10, 20, and 30 U/kg heparin doses. Changes in anti-Xa activity were significantly linearly related to R (r = 0.81, P < 0.0001), alpha (r = -0.85, P < 0.0001), aPTT (r = 0.74, P < 0.0001), and ACT (r = 0.41, P = 0.005). In this model of small-dose heparin administration, TEG variables were more sensitive to changes in heparin activity than aPTT and ACT. IMPLICATIONS: Changes in thrombelastography (TEG) variables more sensitively reflect changes in circulating heparin activity than activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) after small-dose heparin administration in rabbits. Thus, TEG may be more helpful than aPTT and ACT in the detection of heparin in both laboratory and clinical settings wherein heparin may play a role in coagulopathy.

Animals↗

Postoperative fibrinolysis diagnosed by thrombelastography.

Thrombelastography is a useful method for the monitoring of bedside coagulation, especially for fibrinolysis. We report a case where thrombelastography facilitated early detection of fibrinolysis with significant clinical bleeding in a patient immediately following hip replacement surgery. The early diagnosis enabled institution of antifibrinolytic therapy and monitoring of the patient's response. It is likely to have led to less blood product transfusion and may possibly have prevented unnecessary surgical re-exploration.

Aged↗

Patterns of coagulopathy during liver transplantation: experience with the first 75 cases using thrombelastography.

Using both conventional laboratory clotting profile and thrombelastography, coagulation status was monitored intraoperatively during liver transplantation in the first 75 cases performed at the Austin Hospital between June 1988 and October 1992. Superimposed on a baseline coagulopathy due to liver disease is a specific pattern of coagulation disturbance which occurs during a liver transplant. Fibrinolysis occurs in the anhepatic stage, worsens with early reperfusion and then spontaneously resolves. In addition reperfusion is associated with a transient clotting defect. If blood loss is excessive, coagulopathy due to massive transfusion may compound the situation. Thrombelastography is a measurement technique allowing rapid on-site assessment of functional clotting status. It is particularly useful in liver transplant surgery. In combination with clinical bleeding assessment it facilitates selective use of component therapy (fresh frozen plasma, platelets and cryoprecipitate) and specific drug treatment only when it is appropriate. It also acts as a liver function test, being especially useful in assessing the graft after reperfusion.

Blood Coagulation↗

The effect of low-dose bupivacaine on postoperative epidural fentanyl analgesia and thrombelastography.

We performed a prospective, randomized, double-blind study to determine the effect of bupivacaine on postoperative epidural fentanyl analgesia and thrombelastography in 120 patients who underwent extensive gastrointestinal or genitourinary surgery. The patients were randomized into four groups, 30 patients per group: Group I = epidural fentanyl (EF), 10 micrograms/mL in saline; Group II = EF with 0.1% bupivacaine; Group III = EF with 0.15% bupivacaine; and Group IV = EF with 0.2% bupivacaine. Pain relief was evaluated by a visual analog scale (VAS), both at rest and during coughing, and by a visual rating scale (VRS). The VAS, VRS, degree of sedation, and side effects (nausea, vomiting, and pruritus) were evaluated every 2 h from 8:00 AM to 6:00 PM, for 24 h after surgery. Forced vital capacities (FVCs) were determined before surgery and at 24 h after surgery. Blood was withdrawn for thrombelastography (TEG) measurements preoperatively, in the recovery room (PARR), and 24 h postoperatively. The VAS, VRS, sedation scores, changes in postoperative FVCs, and the incidence of side effects were not statistically different among the four groups. The 24-h total volumes of infusion in the four groups (146 +/- 40 mL, 140 +/- 38 mL, 142 +/- 40 mL, 124 +/- 21 mL, respectively) were not statistically different from each other. There were no significant differences in the TEG values [reaction time (R), coagulation time (K), angle (alpha), and maximum amplitude (mA)] among the four groups at anytime nor was there any difference between the baseline, PARR, and 24-h TEG values within any group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Comparison of thrombelastography with common coagulation tests in preeclamptic and healthy parturients.

BACKGROUND AND OBJECTIVES: Epidural analgesia/anesthesia is often beneficial in the management and treatment of preeclampsia. However, some preeclamptic patients have a coagulopathy that is a contraindication to regional anesthesia. A routine coagulation battery (RCB) consisting of prothrombin time, partial thromboplastin time, platelet count, and bleeding time, is commonly performed to assess coagulation status. Thrombelastography (TEG) is a measure of clotting that allows evaluation of overall coagulation activity. The goal of this study was to examine whether TEG can predict normal and abnormal coagulation as diagnosed by RCB in healthy and preeclamptic parturients. METHODS: Forty-seven parturients participated in this prospective study, performed early in the first stage of labor. Twenty healthy parturients (group I), 19 mild (group II), and 8 severe preeclamptic/eclamptic parturients (group III) had RCB and TEG performed. RESULTS: Five patients (1, group I; 3, group II; 1, group III) had a normal RCB, but a mildly abnormal TEG (prolonged K, small alpha) (specificity = 0.88). Five of 27 preeclamptic parturients (1, group II; 4, group III) had abnormal RCBs. Three of these 5 patients had thrombocytopenia with normal bleeding times and TEGs. Two patients had thrombocytopenia and prolonged bleeding times and abnormal TEGs (sensitivity = 0.40). CONCLUSION: Thrombelastography is not an effective means of predicting abnormal coagulation, as diagnosed by RCB, in preeclamptic parturients, using currently defined normal TEG values for nonpregnant patients. However, an abnormal TEG maximum amplitude value always correlated with a prolonged bleeding time. Therefore, TEG may be useful in assessing platelet function in the presence of thrombocytopenia. Further studies are warranted.

Adult↗

Infection and hemostasis in decompensated cirrhosis: a prospective study using thrombelastography.

Bacterial infections are common complications in decompensated cirrhosis, but their relationship with hemostasis has not been studied. We prospectively assessed whether infection affects hemostasis in cirrhosis using routine hemostasis tests and thrombelastography (TEG), a global test of hemostatic function. Eighty-four cirrhotic patients (Child-Pugh B: 26; C: 58) without overt bleeding or blood-product transfusion were prospectively evaluated with routine hemostasis tests and TEG on admission and/or the first day with signs of infection and 5 days later. There were 30 patients with infection; 15 had infection on admission, and 15 developed infection in hospital. In the patients who developed infection in hospital, there was a significant deterioration in all routine hemostasis tests except platelet count (PLT) and in all TEG parameters, on the first day of infection compared with 7 +/- 3 days previously. The same parameters significantly improved from the first day of infection to day 5 and after (P <.02) only in the 22 patients whose infection resolved, while the r, k, and alpha TEG parameters significantly worsened in the 8 patients with persistent infection. In those who developed infection in hospital and were cured (n = 11), the 5-day parameters did not differ from their preinfection values. In conclusion, bacterial infections frequently impair hemostasis in decompensated cirrhotic patients. Successful treatment of infection usually restores hemostasis parameters to preinfection levels in 5 days. Thus, infection may have a role in the bleeding diathesis of cirrhosis.

Adult↗

Effect of delay and storage on whole-blood clotting analysis as determined by thrombelastography.

The thrombelastogram (TEG) measures the viscoelastic properties of clotting blood, displaying a visual trace of all phases of coagulation and fibrinolysis. Thrombelastography can be performed on whole blood (WBTEG) or on citrated blood or plasma, citrated samples facilitating delayed analysis but requiring recalcification of the sample. The aim of this study was to investigate the effect of delay and storage method on WBTEG measurement. Thrombelastographic analysis of coagulation in whole blood was investigated after delays of 3 and 6 minutes in polystyrene syringes (PS3 and PS6) and 3 minutes in silicone-coated glass tubes (SG3). Thrombelastograms of the delayed samples were compared with those measured immediately. Silicone-coated glass tubes activated coagulation, as seen by shorter r times (p < 0.01), shorter r + k times (p < 0.01), and larger maximum amplitude (ma) values (p < 0.01) compared with TEG values determined immediately after sampling. In the SG3 group, 20% of samples had clotted by 3 minutes, and the use of SG tubes for this purpose cannot be recommended. A delay of 6 minutes in PS had less effect on the activation of clotting in the earlier stages in that the r time was prolonged (p < 0.01). However, there appeared to be some activation later in that k time was shorter (p < 0.01) and ma was wider (p < 0.05). Overall, a 3-minute delay in PS produced the best values.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗

Monitoring of coagulation status using thrombelastography during paediatric open heart surgery.

Thrombelastography (TEG) has proved useful in identifying coagulopathies (via assessment of clot elasticity properties) during hepatic surgery, but its role in cardiac surgery has as yet not been defined. Twenty-two children [11M, 11F, mean age (range) 4.9 (0.1-16) years] undergoing open heart surgery were investigated [1] preoperatively, [2] 15 min post protamine, [3] 2 h and [4] 24 h postoperatively using TEG. Comparisons were made between pre- and postoperative measurements and haematological indices. The values obtained from the TEG were: R phase (indicative of thrombokinase and thrombin formation disorders), K phase (indicative of fibrinogenesis) and MA phase (providing information on clot stability and platelet function). The patients were divided into two groups based upon 24 h blood loss; Group 1 - blood loss less than 0.7 ml/kg/h and Group 2 - blood loss greater than 0.7 ml/kg/h. In Group 2 there was a highly significant correlation between post-protamine MA phase and platelet number (r = 0.93, p less than 0.001) but there was no correlation in Group 1 (p greater than 0.1). Furthermore, in Group 2 elevated postoperative blood loss was associated with a prolonged K phase (mean [SD] 12.0 [6.0] versus 6.3 [2.1] min, p less than 0.05) and diminished MA phase (37 [12.5] versus 56 [4.9] mm, p less than 0.01) relative to preoperative values. In Group 1, K and MA phase did not alter significantly (p greater than 0.5 and p greater than 0.2, respectively). TEG predicted with 100% (8/8) accuracy increased post-operative bleeding. The specificity of TEG prediction of future bleeding was 73% [8/11]. Alterations in TEG parameters merit further evaluation as markers of postoperative haemorrhage.

Blood Coagulation↗

Material thrombelastography: an assessment of phosphorylcholine compounds as models for biomaterials.

The use of phosphorylcholine (PC) containing compounds as possible biomaterials has been evaluated by material thrombelastography (MTEG). The detailed analysis of the MTEG technique is discussed. A remarkable reduction of thrombogenicity by compounds containing the PC group is demonstrated. The results observed with a polymerised PC-lipid indicate potential use of such substances as biomaterials with minimal thrombogenicity.

1,2-Dipalmitoylphosphatidylcholine↗

New haemocompatible polymers assessed by thrombelastography.

Mimicry of the nonthrombogenic surface of the erythrocyte has been advocated as the starting point for the development of nonthrombogenic biomaterials. Phosphorylcholine forms 88% of the outer surface of the erythrocyte, and so materials containing it should be nonthrombogenic. We have evaluated the thrombogenicity of such materials and compared them with Dacron and PTFE. Three materials containing phosphorylcholine were used: a naturally occurring phospholipid (dipalmitoylphosphatidylcholine, DPPC), a polymerized phospholipid (diacetylenic phosphatidylcholine, DAPC) and a polyester polyurethane (Polyester G). The thrombogenic potential of these materials was assessed by material thrombelastography (MTEG). This technique uses human whole blood at 37 degrees C, without an air interface, and records the elasticity of the blood clot produced. Since each material is evaluated with a control surface, extraneous differences due to factors other than the test material are eliminated. Analysis, and examples of the MTEG traces are shown and discussed. The phosphorylcholine containing materials were found to have a reduced amount of clotting factor activation, but only DPPC was better than Dacron and PTFE. MTEG demonstrated the known thrombogenicity of Dacron towards platelets. A striking reduction in platelet activation was shown for the three phosphorylcholine containing materials. These three materials show only 25% of the platelet activation of PTFE. These materials warrant further investigation as potentially very useful biomaterials.

Biocompatible Materials↗