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.

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.

One-stage vs. chromogenic assays in haemophilia A.

Haemophilia A severity is closely correlated to the factor VIII (FVIII) activity, which can be measured in different ways. The original one-stage clotting assay is still the most widely used. The two-stage coagulation assay eliminated many of the drawbacks of the one-stage assay and was further developed into the chromogenic assay, a two-staged test with purified coagulation factors in the first stage, and a FXa-specific chromogenic substrate in the second stage. In many patients with mild or moderate haemophilia A, there is a discrepancy between the one-stage and the two-stage assays. If only the one-stage assay is used, some patients will have normal FVIII levels and not be diagnosed as having haemophilia or be considered to have a milder bleeding risk than is the case. Other patients who have normal FVIII activity will be diagnosed as haemophilia A. All haemophilia treatment centre laboratories should have access to both one-stage and chromogenic FVIII:C assays. Appropriate standards should be employed to enable accurate FVIII:C measurement. Different assays to measure inhibitor activity to infused FVIII have been developed since 1959. Inhibitor results based on the one-stage or chromogenic FVIII:C assays are well correlated, but the one-stage assay may be influenced by nonspecific inhibition.

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.

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.

Long-term anti-FVIII antibody response in Bethesda-negative haemophilia A patients receiving continuous replacement therapy.

It has previously been shown that patients with haemophilia A may develop non-neutralizing anti-factor VIII (FVIII) antibodies (NNA) that escape detection by the Bethesda assay, but are detected using immune-based assays. We and others found NNAs to be directed not only towards non-functional parts of the protein, but towards all regions of the FVIII protein. We also showed a heterogeneous antibody response towards different FVIII products. However, the clinical relevance and the natural history of NNA remain unclear. Therefore, we followed a cohort of unrelated subjects with haemophilia A for 4 years with the goal of exploring the long-term development of NNA using an enzyme-linked immunosorbent assay (ELISA). Ten of 78 subjects (12·8%) exhibited an immune response that was transient and heterogeneous, and none of the subjects developed an FVIII inhibitor. The result of the ELISA was examined in relation to clinical variables and no significant associations between a positive ELISA and age, F8 mutation, port-à-cath implantation and HCV infection were shown. Interestingly, patients with NNA had significantly fewer bleeding episodes (P = 0·048) compared with NNA-negative subjects. The results indicate that the immune response to FVIII products within an individual may vary over time. However, the clinical impact of NNA remains unclear.

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.

Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy.

BACKGROUND: Hemostatic disorders are common in obstetric complications. Thromboelastography (TEG®) simultaneously measures coagulation and fibrinolysis within 10 to 20 minutes. Our primary aim in this prospective longitudinal study was to obtain knowledge about physiological changes in TEG® variables during normal pregnancy and 8 weeks postpartum. The secondary aims were to compare TEG® variables during pregnancy with TEG® variables 8 weeks postpartum and gestational weeks 10 to 15 and to correlate TEG® variables to standard laboratory analyses. METHODS: Blood samples were collected from 45 healthy pregnant women at gestational weeks 10 to 15, 20 to 22, 28 to 30, and 38 to 40, and at 8 weeks postpartum. The following TEG® analyses were performed: time until start of clotting (TEG®-R), time until 20-mm clot firmness (TEG®-K), angle of clotting (TEG®-Angle), maximum amplitude (TEG®-MA), and lysis after 30 minutes (TEG®-LY30). Activated partial thromboplastin time, prothrombin time, soluble fibrin, antithrombin, D-dimer, and platelet count were analyzed. RESULTS: Compared to 8 weeks postpartum TEG®-R was at least 0.9 minutes shorter (upper limit 99% confidence intervals) until gestational weeks 28 to 30 and the mean reduction varied between 23%-26%. TEG®-K was at least 0.1 minutes shorter throughout pregnancy and the mean reduction varied between 18%-35%. TEG®-Angle was at least 2.5 degrees greater during pregnancy and the mean increase varied between 12%-20%. TEG®-MA was also at least 0.4 mm greater during pregnancy and the mean increase varied between 6%-8%. TEG®-LY30 was at least 0.03% lower during gestational weeks 28 to 30 and 38 to 40 and the mean reduction varied between 67%-73%. The routine coagulation laboratory values were within normal pregnant limits. There were no or weak correlations between TEG® and the laboratory variables. CONCLUSIONS: TEG® demonstrates increased coagulability and decreased fibrinolysis during pregnancy. There was a faster initiation of hemostasis, with a minor increase in clot strength. Fibrinolysis decreased during late pregnancy. Alternative cutoff limits for TEG® variables may be required during pregnancy. Standard hemostatic laboratory tests were as expected during pregnancy. Future studies are needed to ascertain whether viscoelastic methods are preferable to standard hemostatic tests for the diagnosis of coagulopathy during obstetric hemorrhage.

Lupus anticoagulants in two children--bleeding due to nonphospholipid-dependent antiprothrombin antibodies.

UNLABELLED: We describe two children with significant bleeding: one with multiple ecchymoses and the other with scrotal bleeding. In both patients, the activated partial thromboplastin time (APTT) was prolonged, with positivity for lupus anticoagulants (LA). However, the Owren prothrombin time (PT), usually insensitive for LA, was also prolonged. The presence of LA is associated with diverse clinical manifestations, with most patients being asymptomatic while others present venous or arterial thrombosis. Bleeding in conjunction with LA is rare and it is unusual to see prolongation of the Owren PT assay due to LA. An extended laboratory investigation of one of the patient's plasma revealed not only LA but also a specific nonphospholipid-dependent antiprothrombin antibody causing an acquired hypoprothrombinemia. CONCLUSION: It is likely that the low prothrombin activity and not the LA caused the bleeding. The bleeding signs and symptoms in both patients subsided when the PT was normalized, although the prolonged APTT and the LA remained.

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.

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.

[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.

Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagnostic procedure is complicated because VWD is highly heterogeneous, and differential diagnosis from platelet disorders may be challenging. Moreover, these defects may even coexist, impacting the bleeding phenotype. Mild and moderate VWD can be difficult to distinguish from the normal population, and VWD subtyping may also be problematic. This article summarizes the guidelines of the Nordic Haemophilia Council (NHC), which are intended to serve as a practical tool and provide the standards for diagnosing and treating VWD patients. The complete Nordic Guidelines on VWD are available at the NHC Web site (http://nordhemophilia.org).

Practical viewpoints on the diagnosis and management of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT, type II) is an immune-mediated disorder due to antibodies formed against heparin-platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of o Ther causes (the 4T's). Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. Even in the absence of HIT-associated thrombosis, an active policy for prolonged thromboprophylaxis is demanded. Rapid and reliable assays should be developed for diagnosis and anticoagulation monitoring to secure safe management with nonheparins. Semiquantitative testing for on-call hours should be available and later confirmed as clinically needed. Alternative therapeutic options are available, but because their use is infrequent, experienced coagulation treatment centers should provide guidance in the treatment and in laboratory monitoring. Most of the evidence in HIT is grade IC, and thus the best evidence is provided by clinical experience. New anticoagulants and platelet inhibitors may offer future alternatives in the management of HIT, but the current treatment options provide the best experience and benefit. The joint clinical and laboratory guidelines provided in this article along with two practical case scenarios were prepared by a Nordic expert panel. They will be valuable for hematologists and colleagues who do not routinely encounter HIT.

Determination of serum amyloid P component in seminal plasma and correlations with serum hormone levels in young, healthy men.

Serum amyloid P component (SAP) belongs to the pentraxin family of proteins. SAP is evolutionary conserved, and involved in amyloidosis, innate immunity, inflammation, and apoptosis. We have previously described SAP in the male reproductive tract, where it occurs in seminal fluid, on spermatozoa, and in epididymal, seminal vesicle, and prostate tissue. In the present investigation, our aim was to characterize SAP in male reproduction. In short, we developed and evaluated an immunoassay, analysed the concentration of SAP in seminal plasma and serum in samples from healthy men (N = 203), and studied hormonal regulation. SAP in seminal plasma showed a positively skewed distribution and a median concentration of 1.01 mg/L (inter quartile range [IQR] 0.56-1.65 mg/L). SAP in serum had a Gaussian distribution and a median concentration of 40.5 mg/L (IQR 34.2-49.2 mg/L). Furthermore, SAP concentrations in seminal plasma were not correlated with serum concentrations of SAP, testosterone, sex hormone-binding globulin (SHBG), the testosterone/SHBG ratio, inhibin B, or estradiol. Only a weak negative correlation was found between seminal plasma SAP and serum levels of follicle-stimulating hormone (FSH) (Spearman's rho -0.159; p = 0.023) and luteinizing hormone (LH) (Spearman's rho -0.162; p = 0.021). In conclusion, all men investigated had measurable SAP levels in seminal plasma and in serum. SAP concentrations were 40 times lower in seminal fluid than in serum, and there was no correlation between those two variables. It seems that hormonal regulation is not the major pathway regulating seminal plasma SAP, and seminal plasma SAP and serum SAP are not co-regulated.

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.