Elevated FVIII levels in hereditary hemorrhagic telangiectasia: Implications for clinical management.

Objectives: The objective of this study was twofold: to determine the prevalence of arterial and venous thromboembolic events in the Norwegian Hereditary Hemorrhagic Telangiectasia (HHT) population, and to explore potential factors linked to such events, with particular emphasis on FVIII. Methods: Patients with an HHT diagnosis attending the Otorhinolaryngology Department at Oslo University Hospital-Rikshospitalet were included consecutively between April 2021 and November 2022. We recorded the participants' medical history with an emphasis on thromboembolic events. Measurements of blood constituents, including FVIII, FIX, vWF, hemoglobin, iron, ferritin, and CRP were performed. Results: One hundred and thirty-four patients were included in the study. The total prevalence of thromboembolic events among the participants was 23.1%. FVIII levels were high (>150 IU/dL) in the majority of HHT patients (n = 84) (68.3%) and were significantly associated with thromboembolic events (p < .001), as was age. Of the patients with high FVIII levels, 28 (33%) had experienced a thromboembolic event. Furthermore, FVIII levels were measured consecutively in 51 patients and were found to fluctuate above or below 150 IU/dL in 25% of these cases. Conclusion: Thromboembolic events are highly prevalent in the Norwegian HHT population and are significantly associated with FVIII levels. FVIII levels can fluctuate, and measurements should be repeated in HHT patients to assess the risk of thromboembolic events. Level of Evidence: 4.

Report on 4 cases with decreased recovery due to neutralizing antibodies specific for PEGylated recombinant factor VIII.

BACKGROUND: The immunogenicity, safety, and efficacy of recombinant factor VIII (rFVIII) have gained increasing interest after the introduction of extended half-life products with various modifications of the rFVIII molecule, such as covalent attachment of polyethylene glycol (PEG). Anti-PEG antibodies may be associated with a temporary reduction of FVIII recovery, but according to previous studies, they usually disappear after continuous dosing. Anti-PEG antibodies with an inhibitory capacity have never been demonstrated in patients treated with PEGylated rFVIII products. OBJECTIVES: To routinely switch from standard half-life to PEGylated extended half-life rFVIII products in patients with hemophilia A. METHODS: From December 2022 until May 2023, 83 adults with hemophilia A attending Oslo Haemophilia Comprehensive Care Centre received a test dose with a PEGylated rFVIII product to switch treatment. Four patients presented with decreased recovery without the presence of an FVIII inhibitor. Accordingly, we performed a variant inhibitor test utilizing different rFVIII concentrates as a source of FVIII and enzyme-linked immunosorbent assay to search for anti-PEG antibodies. RESULTS: We found inhibitory anti-PEG/anti-PEGylated rFVIII antibodies in 4 patients (5%), both persistent and transient, explaining the impaired recovery. The patients had neutralizing anti-PEG antibodies prior to the first dosing of PEGylated rFVIII. We demonstrated neutralizing antibodies (mainly immunoglobuline G) specific for PEG and all 3 commercially available PEGylated rFVIII products. CONCLUSION: The number of patients with inhibitory anti-PEG antibodies was significant, and the presence of inhibitors against PEGylated rFVIII emphasizes the importance of individual monitoring when switching FVIII concentrates to ensure safety and efficacy of the treatment.

An international study on activated partial thromboplastin time prolongation. Part 2: Interpretative commenting.

BACKGROUND: Providing evidence-based interpretative comments (IC) is an integral task of clinical laboratory professionals. It may be of special relevance for coagulation testing, where pathological first-line tests could trigger more specialized tests. Our aim was to evaluate the quality of ICs provided to the physician in two samples with activated partial thromboplastin time (APTT) prolongation. MATERIAL AND METHODS: Two lyophilized plasma samples and their respective fictional clinical cases (case 1: heparin contamination and case 2: factor VIII deficiency) were sent to European laboratories for APTT and APTT mixing test measurement, and elaboration of ICs based on their results. The quality of ICs was evaluated in terms of analytical classification, laboratory interpretation, advice to physician, clarity, length and whether the clinical question was answered. RESULTS: A total of 214 laboratories were included. Classification of the analytical result was stated in 57 % of comments. Laboratory interpretation was found in 91 % of comments for case 1 and 83.3 % for case 2, among which 9.3 % and 6.5 % were considered wrong, respectively. Advice for the requesting physician was provided in 65.8 % of comments for case 1 and 61.2 % for case 2, among which 36 % and 4.7 % were considered wrong, respectively. More than 70 % of comments for both cases were evaluated as clear and of an adequate length. CONCLUSION: A significant number of laboratories provide clear interpretations and helpful advice for the management of altered coagulation results. Nevertheless, the finding of several confusing and misleading comments highlights the need for recommendations on elaboration of interpretative comments.

Rapid Detection of Apixaban by a ROTEM-Based Approach and Reversibility with Andexanet Alfa or DOAC-Stop.

Background A rapid test to detect apixaban treatment would be useful in acute situations such as major bleeding, urgent surgery, or in acute thrombosis. Objective This article aims to study if the viscoelastic test rotational thromboelastometry (ROTEM) can rapidly detect apixaban in whole blood using modified triggers based on factor Xa (FXa) or Russell viper venom (RVV). Method ROTEM clotting time (CT) was measured in samples from 40 patients on apixaban treatment, and in vitro in samples spiked with apixaban (20-500 ng/mL). Commercially available trigger Ex-tem was compared with modified triggers based on FXa or RVV. Reversibility of apixaban in the samples was studied; CT was measured with and without addition of DOAC-Stop or andexanet alfa, respectively, and the difference in CT was calculated (CT diff ). Results Using FXa as trigger, we detected apixaban concentrations at 20 ng/mL and above with 100% sensitivity and 100% specificity in patient samples and in vitro. Corresponding data for Ex-tem were 92% sensitivity and 100% specificity in patients, and 94% sensitivity and 100% specificity in vitro, and for RVV 97% sensitivity and 94% specificity in patients, and 97% sensitivity and 100% specificity in vitro, respectively. CT diff data were similar. Patient sample data were obtained within 20 minutes from sampling. Conclusion Apixaban at low therapeutic concentrations was detected within 20 minutes, and with high sensitivity and specificity. A trigger based on FXa outperformed the commercial trigger Ex-tem and a trigger based on RVV. ROTEM with a FXa-based trigger is a promising method to detect apixaban bedside in acute settings.

An international study on activated partial thromboplastin time prolongation. Part 1: Analytical results.

BACKGROUND: Unexpected prolongation of first-line coagulation tests, including activated partial thromboplastin time (APTT), should trigger further work-up by performing mixing tests to elucidate the underlying cause, direct further specific testing and clarify their possible clinical impact. The aim of our study was to assess whether methodological diversity has any impact on the APTT mixing test results and their interpretation. MATERIAL AND METHODS: Two lyophilized plasma samples (case 1: heparin contamination [0.5 IU/mL]; case 2: factor VIII deficiency [0.13 IU/mL]) and their respective fictional clinical cases were sent to European laboratories for APTT measurement and performance of mixing tests. Participants were surveyed about the methodology (reagents, analytical platform, reference ranges), APTT results, mixing test conditions, their classification (normal, equivocal, prolonged) and categorization of the sample (factor deficiency, presence of inhibitor, anticoagulant, unknown). RESULTS: A total of 269 responses were included. For case 1, all participants reported a prolonged APTT, and 91% obtained no correction in the mixing test, without differences among reagents or analytical platforms. Only 15% of them selected the presence of an anticoagulant as the single cause for the prolongation. For case 2, 99% of participants reported a prolonged APTT, while some heterogeneity in the mixing test results was found. Eighty-six percent of participants selected factor deficiency as the cause for APTT prolongation. CONCLUSIONS: Most European laboratories obtained valid results for APTT and the subsequent mixing tests, despite using different methodologies. However, their classification could be improved. Therefore, more training and periodic evaluations are recommended to harmonize protocols and ensure proper result classification and categorization.

[Routine screening with APTT is not indicated before surgery]. / Rutinmässig screening med APTT är inte indicerad före operation.

Activated partial thromboplastin time (APTT) is widely practiced in preoperative screening. The value of using this test to predict the risk of perioperative bleeding is not well documented in Sweden. In this article, a literature review is performed to determine whether unselected APTT testing can predict abnormal perioperative bleeding. The current literature does not support coagulation screening with APTT in routine perioperative bleeding assessment, as preoperative screening with APTT has a low sensitivity for detection of clinically significant bleeding disorder. While a comprehensive bleeding history is crucial, the APTT test should only be performed on patients with a history of increased bleeding tendency. The conclusion of this literature review is that patients with a negative bleeding history do not require routine screening with APTT prior to surgery, which, if implemented, would lead to a more cost-effective perioperative routine.

Associations between hemostatic markers and mortality in COVID-19 - Compounding effects of D-dimer, antithrombin and PAP complex.

In this single-center cohort study, we applied a panel of laboratory markers to characterize hemostatic function in 217 consecutive patients that underwent testing for COVID-19 as they were admitted to Linköping University Hospital between April and June 2020. In the 96 patients that tested positive for SARS-CoV-2 (COVID-19+), the cumulative incidences of death and venous thromboembolism were 24.0% and 19.8% as compared to 12.4% (p = 0.031) and 11.6% (p = 0.13) in the 121 patients that tested negative (COVID-19-). In COVID-19+ patients, we found pronounced increases in plasma levels of von Willebrand factor (vWF) and fibrinogen. Excess mortality was observed in COVID-19+ patients with the following aberrations in hemostatic markers: high D-dimer, low antithrombin or low plasmin-antiplasmin complex (PAP) formation, with Odds Ratios (OR) for death of 4.7 (95% confidence interval (CI95) 1.7-12.9; p = 0.003) for D-dimer >0.5 mg/L, 5.9 (CI95 1.8-19.7; p = 0.004) for antithrombin (AT) ˂0.85 kIU/l and 4.9 (CI95 1.3-18.3; p = 0.019) for PAP < 1000 µg/L. Compounding increases in mortality was observed in COVID-19+ patients with combined defects in markers of fibrinolysis and coagulation, with ORs for death of 15.7 (CI95 4.3-57; p < 0.001) for patients with PAP <1000 µg/L and D-dimer >0.5 mg/L and 15.5 (CI95 2.8-87, p = 0.002) for patients with PAP <1000 µg/L and AT ˂0.85 kIU/L. We observed an elevated fraction of incompletely degraded D-dimer fragments in COVID-19+ patients with low PAP, indicating impaired fibrinolytic breakdown of cross-linked fibrin.

Haemoglobin and red blood cell reference intervals during infancy.

OBJECTIVES: There is a need for updated haematological reference data in infancy. This study aimed to define intervals for haemoglobin and red blood cell biomarkers based on data from a large cohort of longitudinally followed Swedish infants. DESIGN: Longitudinal cohort study. SETTING: Two Swedish study centres. PARTICIPANTS: Three community-based populations including 442 presumably healthy infants born at term and with umbilical cord clamping delayed to 30 s or more after birth. METHODS: Blood samples were collected from umbilical cord blood (a), at 48-118 hours (b), at 4 months (c) and at 12 months (d). Reference intervals as the 2.5th and 97.5th percentiles were calculated in coherence with Clinical and Laboratory Standards Institute guidelines. RESULTS: Reference intervals for haemoglobin (g/L) were: (a) 116-189, (b) 147-218, (c) 99-130, (d) 104-134, and for mean cell volume (fL): (a) 97-118, (b) 91-107, (c) 71-85, (d) 70-83. Reference intervals for erythrocyte counts, reticulocyte counts, reticulocyte haemoglobin, mean cell haemoglobin and mean cell haemoglobin concentration were also estimated. According to the WHO definition of anaemia, a haemoglobin value less than 110 g/L, 16% of this presumably healthy cohort could be classified as anaemic at 12 months. CONCLUSION: We found mainly narrower reference intervals compared with previously published studies. The reference intervals for each parameter varied according to the infants' age, demonstrating the necessity of age definitions when presenting infant reference intervals. The discrepancy with the WHO classification for anaemia at 12 months, despite favourable conditions in infancy, needs future investigation.

Serum amyloid P component: a new biomarker for low sperm concentration?

Serum amyloid P component (SAP) is present in seminal plasma, on spermatozoa, and in different tissues of the male reproductive tract, but its function is not known. The aims of this study were to determine if the concentration of SAP in seminal plasma is associated with commonly assessed semen parameters and to investigate if SAP could be a new, indirect biomarker for these parameters. In a cross-sectional study of 203 young volunteers, the concentration of SAP in seminal plasma was measured with a in-house developed enzyme-linked immunosorbent assay. Scatter plots, Pearson's correlation coefficients (r), and linear regression models were produced, and SAP showed a statistically significant correlation with sperm concentration (r = 0.75), sperm number (r = 0.68), semen volume (r = -0.19), progressive sperm motility (r = 0.24), and sperm immotility (r = -0.20). When the study group was dichotomized, SAP could be used to discriminate samples with a sperm concentration < or ≥5 × 106 ml-1, 15 × 106 ml-1, or 40 × 106 ml-1, and in receiver operating characteristic curves, the corresponding areas under the curves were 0.97, 0.93, and 0.82, respectively, with P < 0.001 for all three cutoff values studied. The concentration of SAP in seminal plasma showed a strong, positive correlation with the concentration of spermatozoa in semen. SAP may be used as a new indirect potential biomarker for sperm concentration in fresh and in frozen, stored samples. In addition, it is envisaged that the assay could be developed into a home fertility test to differentiate between a low and a normal sperm concentration.

Presentation and formatting of laboratory results: a narrative review on behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group "postanalytical phase" (WG-POST).

In laboratory medicine, much effort has been put into analytical quality in the past decades, making this medical profession one of the most standardized with the lowest rates of error. However, even the best analytical quality cannot compensate for errors or low quality in the pre or postanalytical phase of the total testing process. Guidelines for data reporting focus solely on defined data elements, which have to be provided alongside the analytical test results. No guidelines on how to format laboratory reports exist. The habit of reporting as much diagnostic data as possible, including supplemental information, may lead to an information overload. Considering the multiple tasks physicians have to do simultaneously, unfiltered data presentation may contribute to patient risk, as important information may be overlooked, or juxtaposition errors may occur. As laboratories should aim to answer clinical questions, rather than providing sole analytical results, optimizing formatting options may help improve the effectiveness and efficiency of medical decision-making. In this narrative review, we focus on the underappreciated topic of laboratory result reporting. We present published literature, focusing on the impact of laboratory result report formatting on medical decisions as well as approaches, potential benefits, and limitations for alternative report formats. We discuss influencing variables such as, for example, the type of patient (e.g. acute versus chronic), the medical specialty of the recipient of the report, the display of reference intervals, the medium or platform on which the laboratory report is presented (printed paper, within electronic health record systems, on handheld devices, etc.), the context in which the report is viewed in, and difficulties in formatting single versus cumulative reports. Evidence on this topic, especially experimental studies, is scarce. When considering the medical impact, it is of utmost importance that laboratories focus not only on the analytical aspects but on the total testing process. The achievement of high analytical quality may be of minor value if essential results get lost in overload or scattering of information by using a non-formatted tabular design. More experimental studies to define guidelines and to standardize effective and efficient reporting are most definitely needed.

Soluble Transferrin Receptor during infancy and reference intervals for the Roche Cobas platform.

INTRODUCTION: Infant iron status assessments may be difficult to interpret due to infections. The soluble transferrin receptor (sTfR) has been suggested as a biomarker mainly unaffected by the acute phase response. Reference intervals reflecting dynamics of infant growth first year in life are not well established. METHODS: The sTfR and CRP concentrations were measured in samples from 451 term infants with the Roche Cobas platform in umbilical cord, at 48-96 hours, 4 and 12 months. Reference values were constructed as the 2.5th and 97.5th percentiles. The relationship between CRP concentrations >1 mg/L and sTfR was tested by Kendall correlation. RESULTS: Reference intervals for girls and boys were 2.4-9.5 mg/L at birth, 2.9-8.4 mg/L at 48-96 hours, 2.6-5.7 mg/L at 4 months and 3.0-6.3 mg/L at 12 months. No differences between sexes were observed except for at 4 months. sTfR did not covariate with CRP concentrations >1 mg/L except in 48-96 hours samples. CONCLUSION: This study reports reference intervals for sTfR from birth to 12 months of age in a large group of infants in a low-risk area for iron deficiency. sTfR might add value to infant iron status diagnostics since no covariation with CRP was found at birth, at 4 months or at 12 months.

Unveiling the complex effects of direct oral anticoagulants on dilute Russell's viper venom time assays.

INTRODUCTION: Dilute Russell viper venom time (dRVVT) assays can be affected by direct oral anticoagulants (DOACs), which may cause false-positive results. However, there are conflicting results indicating significant differences between different reagents and DOACs. OBJECTIVES: To evaluate the effect of DOACs on dRVVT assays. MATERIAL AND METHODS: Samples were prepared by adding DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) to pooled normal plasma in the concentration range 0 to 800 µg/L. Six integrated dRVVT reagents were used, all composed of a screen assay (low phospholipid content) and a confirm assay (high phospholipid content). The screen/confirm dRVVT results were expressed as normalized ratios. To further evaluate the observed differences between tests and DOACs, addition of synthetic phospholipids was used. RESULTS: The dRVVT ratios increased dose dependently for all DOACs, with four of the six tests and the DOAC rivaroxaban having the greatest effect. With one test, the ratios were almost unaffected with increasing DOAC concentration, whereas another test revealed a negative dose dependency for all DOACs. Variable DOAC effects can be explained by different effects on dRVVT screen and confirm clotting time. Adding synthetic phospholipids to samples containing rivaroxaban resulted in greatly reduced screen clotting times and thereby lower calculated dRVVT ratios. CONCLUSIONS: There is a great variability in the dRVVT test result with different DOACs. The dRVVT ratios are unaffected for some reagents and this can be explained by an equal dose-dependent effect on both screen and confirm assays. The phospholipid type and content of the different reagents may contribute to the observed differences.

When age really matters; ferritin reference intervals during infancy revisited.

Infants are at risk for iron deficiency. Despite research advances, assessing iron stores during infancy remains a challenge to the clinician. Ferritin is the first-choice laboratory marker for measuring iron stores but it is today still unclear how to evaluate reference intervals among infants. We have studied Swedish infants (n = 456), born at term after normal pregnancies. Ferritin was measured at birth (umbilical cord sample), 48-72 h, 4 months and 12 months. Lower and upper reference interval limits were constructed as the 2.5th and 97.5th percentiles. By a large study population, we were able to use more stringent measures to avoid interference from the acute phase response than previous reports on ferritin reference intervals. When we used mathematical transformation we furthermore avoided potential information loss in precision and confirmed earlier reports of sex differences. At the lower reference interval limits there were small differences between sexes. For the higher limits, the differences were more pronounced in the older infant. At 0-3 d of age we observed a difference between the sexes of only 5% at the upper limits. The differences peaked at 12 months, where the boys' upper 97.5th percentile was 56% compared to girls.

Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays.

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0-742 µg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539-758 µg/L for the APTT and between 329 and 2505 µg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell's viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 µg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.

Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD - A longitudinal study.

BACKGROUND: Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. PATIENTS AND METHODS: This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. RESULTS: Overall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64-0.82, p<0.001) and between PC and AT (r = 0.62-0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation. CONCLUSION: The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.

Concurrent acquired inhibitors to factor VIII and IX, a laboratory artifact: a case report.

Acquired inhibitors to coagulation factors other than factor VIII are extremely rare. We describe a case of a 59-year-old woman with abnormal bleeding, diagnosed with concurrent inhibitor antibodies to factor VIII and IX by Bethesda testing. We demonstrate that anti-FVIII antibodies of a very high titre are capable of disturbing the aPTT-based Bethesda assay, resulting in falsely-positive antibodies to factor IX. The case also illustrates the usefulness of the immunological assay (ELISA) in complementing the inhibitor diagnosis.

Intraoperative Hydroxyethyl Starch and its Effects on Different Fibrinogen Measurements.

BACKGROUND: Intravenous fluids with synthetic colloids such as hydroxyethyl starch (HES) are known to interfere with plasma fibrinogen concentration measurements. The aim of this study was to evaluate the effects of an HES solution on fibrinogen measurements in a clinical setting. METHODS: The study was performed in patients who received at least 1 L of HES during intracranial tumor resection surgery. Blood samples were drawn before the start of surgery (baseline), after infusion of 1 L of HES, and at later time points. The fibrinogen concentration was measured using 3 different methods: (a) enzyme-linked immunosorbent assay (ELISA), (b) Clauss method with a photometric readout, and (c) Clauss method with an electromechanical readout. In addition, the fibrin-based clot quality was evaluated with the thromboelastometric FIBTEM test. RESULTS: Forty patients were enrolled, and 25 patients were included in the analysis. The fibrinogen concentrations at baseline were 2.2, 2.3, and 2.6 g/L and after 1 L of HES 1.6, 1.7, and 1.9 g/L as measured by ELISA, the photometric test, and the electromechanical test, respectively. The electromechanical Clauss test measured significantly higher concentrations at these time points. The relative decrease, however, was comparable between methods (31%, 29%, and 25%, respectively) but significantly lower than the 44% relative decrease with FIBTEM maximum clot firmness. CONCLUSION: Despite providing different fibrinogen concentration values at baseline, the relative decrease in fibrinogen concentration after HES infusion was comparable among the 3 tests. In contrast, fibrin-based clot quality was more affected than fibrinogen concentration tests by HES infusion.

Factor H Autoantibodies in Patients with Antiphospholipid Syndrome and Thrombosis.

OBJECTIVE: Autoantibodies to complement factor H (FH) are associated with atypical hemolytic uremic syndrome, but can also be detected in patients with rheumatoid arthritis and in patients positive for lupus anticoagulants and thus potentially antiphospholipid syndrome (APS). To our knowledge, no data are available on the association between the presence of FH autoantibodies in APS and clinical manifestations. METHODS: We determined FH autoantibody levels using ELISA in 2 cohorts of patients with primary (PAPS) and secondary APS (SAPS) from Serbia and Italy, and an additional cohort including patients with venous thromboembolism (VTE) from Sweden. RESULTS: FH autoantibodies were detected in 13.7% of patients (n = 73) with PAPS and 30.3% of patients (n = 33) with SAPS in the Serbian cohort. FH autoantibody frequency in the Italian cohort was 33.3% (n = 15) and 36% (n = 25) in PAPS and SAPS, respectively. Both FH autoantibody levels and frequencies observed in both APS cohorts were significantly higher than in matched healthy controls (5%). Further, patients with PAPS with venous thrombosis in the Serbian cohort had significantly higher levels of FH autoantibodies. Therefore, we analyzed a dedicated Swedish thrombosis cohort and found that patients with FH autoantibody positivity had higher risk of VTE recurrence (HR 2.0, 95% CI 1.2-3.3, p = 0.011) compared with the reference group of FH autoantibody-negative patients. CONCLUSION: Overall, the data indicate that in patients with APS and recurrent venous thrombosis, there are increased levels of FH autoantibodies, a finding associated with poor clinical outcome.

Perioperative changes in PIVKA-II.

BACKGROUND AND AIMS: Proteins induced by vitamin K absence for factor II (PIVKA-II) is an enzyme-linked immunosorbent assay that monitors uncarboxylated prothrombin and responds to vitamin K deficits prior to changes in the prothrombin test. The aim of this project was to study perioperative PIVKA-II changes during various types of surgery in a prospective observational study. METHODS: Patients undergoing abdominal or orthopaedic surgery were included. Blood was sampled on the day of surgery (preoperatively) and up to 5 days after surgery. The activated partial thromboplastin time, Quick and Owren prothrombin times were analyzed, together with PIVKA-II. RESULTS: Thirty-nine patients were included, 27 +male and 12 +female. All but 7 +patients had elevated PIVKA-II levels preoperatively. PIVKA-II levels had already increased significantly (p < 0.017) on day 1 after surgery as compared to presurgery plasma levels. The median PIVKA-II was highest on day 5. Routine tests were mostly normal. No significant difference in PIVKA-II was seen when comparing patients undergoing abdominal versus orthopaedic surgeries. There was no significant correlation between PIVKA-II and routine coagulation tests. Patients with anterior resection, emergency laparotomy and emergency hip fractures had higher postoperative increases, which could be linked to increased gastrointestinal recovery times, paralytic ileus, peritonitis and comorbidities. CONCLUSIONS: PIVKA-II levels increase during the perioperative period, despite mostly normal routine coagulation tests. Pre- and perioperative vitamin K supplementation in patients with elevated PIVKA-II levels should be studied, and its clinical significance be defined in future studies.