The use of tourniquet in primary total knee arthroplasty does not increase the risk of venous thromboembolism within 90 days of surgery: a Danish nationwide cohort study of 19,804 patients.

PURPOSE: Existing evidence estimates a twofold risk of venous thromboembolisms (VTEs) if tourniquet is applied during total knee arthroplasties (TKAs). However, this estimate relies on multiple trials with a low number of patients analyzing VTEs as a secondary outcome. We hypothesized that tourniquet-use increases the risk of symptomatic VTE within 90 days of contemporary primary TKA and aimed to use the extensive Danish healthcare registries to quantify this risk. METHODS: Prospectively collected registry data from Danish patients receiving primary TKAs between 2014 and 2018 were included in the study. Patients were divided by tourniquet-use during surgery. By merging information from four nationwide registries, the study included 44 baseline characteristics with the potential to confound the association between tourniquet-use and VTE. Incidence rate and odds ratios were used to compare the risk of VTE within 90 days of surgery. RESULTS: 19,804 patients of whom 10,111 (51%) were operated with tourniquet and 9693 (49%) without were included. The mean age (SD) was 70 (9) in both groups and 62% were females in the tourniquet group compared with 61% in the no tourniquet group. The groups were similarly comparable across all other baseline characteristics except type of post-operative thromboprophylaxis, type of anaesthesia, implant fixation, and year of surgery. The 90-days incidence of VTE was 0.77% (95% CI 0.60-0.94) in the tourniquet group compared with 1.10% (95% CI 0.90-1.31) in the no tourniquet group. Following adjustment for the unbalanced confounders, the odds ratio for VTE was 0.77 (95% CI 0.54-1.10) associated with tourniquet-use. CONCLUSION: In contemporary TKAs the rate of VTE within 90 days is low and not significant altered by tourniquet-use. Thus, tourniquet can safely be applied during primary TKA-surgery without jeopardizing the risk of postoperative VTE. LEVEL OF EVIDENCE: II-prospective cohort study.

Cancer risk in persons with new-onset anaemia: a population-based cohort study in Denmark.

BACKGROUND: The time interval from first symptom and sign until a cancer diagnosis significantly affects the prognosis. Therefore, recognising and acting on signs of cancer, such as anaemia, is essential. Evidence is sparse on the overall risk of cancer and the risk of specific cancer types in persons with new-onset anaemia detected in an unselected general practice population. We aimed to assess the risk of cancer in persons with new-onset anaemia detected in general practice, both overall and for selected cancer types. METHODS: This observational population-based cohort study used individually linked electronic data from laboratory information systems and nationwide healthcare registries in Denmark. We included persons aged 40-90 years without a prior history of cancer and with new-onset anaemia (no anaemia during the previous 15 months) detected in general practice in 2014-2018. We measured the incidence proportion and standardised incidence ratios of a new cancer diagnosis (all cancers except for non-melanoma skin cancers) during 12 months follow-up. RESULTS: A total of 48,925 persons (median [interquartile interval] age, 69 [55-78] years; 55.5% men) were included in the study. In total, 7.9% (95% confidence interval (CI): 7.6 to 8.2) of men and 5.2% (CI: 4.9 to 5.5) of women were diagnosed with cancer during 12 months. Across selected anaemia types, the highest cancer incidence proportion was seen in women with 'anaemia of inflammation' (15.3%, CI: 13.1 to 17.5) (ferritin > 100 ng/mL and increased C-reactive protein (CRP)) and in men with 'combined inflammatory iron deficiency anaemia' (19.3%, CI: 14.5 to 24.1) (ferritin < 100 ng/mL and increased CRP). For these two anaemia types, the cancer incidence across cancer types was 10- to 30-fold higher compared to the general population. CONCLUSIONS: Persons with new-onset anaemia detected in general practice have a high cancer risk; and markedly high for 'combined inflammatory iron deficiency anaemia' and 'anaemia of inflammation'. Anaemia is a sign of cancer that calls for increased awareness and action. There is a need for research on how to improve the initial pathway for new-onset anaemia in general practice.

A low level of naturally occurring antibodies associates with functional antibody deficiency.

Functional antibody deficiency is clinically assessed from antibody responses to vaccination. However, diagnostic vaccination is complex and may fail in practice. We hypothesized that the levels of naturally occurring antibodies against galactose-α-1,3-galactose (αGal) may represent alternative markers of functional antibody capacity. We included data from 229 patients with suspected primary immunodeficiency in a retrospective study. Antibody levels against αGal and twelve pneumococcal serotypes were determined with solid-phase immunoassays. Pneumococcal vaccinations and treatment with normal human immunoglobulin were assessed from medical records. Anti-αGal antibody levels correlated positively with anti-pneumococcal antibody levels measured before and after pneumococcal vaccination. Contrary to the anti-pneumococcal antibody levels, the anti-αGal antibody level showed potential for predicting subsequent immunoglobulin treatment - a marker of disease severity. Naturally occurring antibodies may reflect the functional capacity tested by diagnostic vaccination but add more useful clinical data. The clinical utility of this easy test should be evaluated in prospective studies.

Diagnostic Vaccination in Clinical Practice.

Testing the antibody response to vaccination (diagnostic vaccination) is crucial in the clinical evaluation of primary immunodeficiency diseases. Guidelines from the American Academy of Allergy, Asthma & Immunology (AAAAI) provide detailed recommendations for diagnostic vaccination with pure pneumococcal polysaccharide vaccines (PPV). However, the degree of compliance with these guidelines and the utility of the guidelines in actual practice are undescribed. To address this, we systematically evaluated diagnostic vaccination in adult patients with suspected primary immunodeficiency diseases in a single tertiary center from 2011 to 2016 (n = 229). We found that full compliance with the AAAAI guidelines was achieved for only 39 patients (17%), suggesting that the guidelines are not easy to follow. Worse, interpretation according to the guidelines was heavily influenced by which serotype-specific antibodies that were used for the evaluation. We found that the arbitrary choices of serotype-specific antibodies could change the fraction of patients deemed to have 'adequate immunity' by a factor of four, exposing an inherent flaw in the guidelines. The flaw relates to dichotomous principles for data interpretation under the AAAAI guidelines. We therefore propose a revised protocol for diagnostic vaccination limited to PPV vaccination, subsequent antibody measurements, and data interpretation using Z-scores. The Z-score compiles multiple individual antibody levels, adjusted for different weighting, into one single continuous variable for each patient. In contrast to interpretation according to the AAAAI guidelines, the Z-scores were robust to variations in the choice of serotype-specific antibodies used for interpretation. Moreover, Z-scores revealed reduced immunity after vaccination in the patients with recurrent pneumonia (a typical symptom of antibody deficiency) compared with control patients. Assessment according to the AAAAI guidelines failed to detect this difference. We conclude that our simplified protocol and interpretation with Z-scores provides more robust clinical results and may enhance the value of diagnostic vaccination.

Diagnostic workup of cancer in patients with new-onset anaemia: a Danish cohort study in general practice.

BACKGROUND: Anaemia is associated with adverse outcomes, including increased morbidity and all-cause mortality. Diagnostic workup of patients with anaemia is essential to detect underlying disease, especially undiagnosed malignancy. OBJECTIVE: To describe the cancer-relevant diagnostic workup in patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and the diagnostic workup. DESIGN: Observational population-based cohort study using electronic laboratory and register data. SETTING: Danish general practice. SUBJECTS: Patients aged 40-90 years with new-onset anaemia (no anaemia in the preceding 15 months) detected in general practice. Patients were identified in Danish laboratory information systems and nationwide registries in 2014-2018. MAIN OUTCOME MEASURES: We measured the proportion of patients receiving predefined diagnostic investigations, that is, cancer patient pathway, colonoscopy, gastroscopy, computerised tomography (CT) scan, faecal test for haemoglobin, and bone marrow examination within three months of the anaemia index date. RESULTS: We included 59,993 patients, and around half of the patients with 'iron deficiency anaemia', 'anaemia of inflammation', or 'combined inflammatory iron deficiency anaemia' had no cancer-relevant diagnostic investigations performed. Patients aged 60-79 years and patients with severe anaemia were more likely to have investigations performed, while patients with comorbidity were less likely to have investigations performed. CONCLUSION: Around half of the patients with anaemia subtypes that may indicate underlying cancer had no cancer-relevant diagnostic investigations performed. This may represent missed diagnostic opportunities. Future interventions are needed to improve the diagnostic workup of cancer in patients with anaemia, for example, laboratory alert systems and clinical decision support.KEY POINTSThe general practitioners are often the first to detect anaemia and its underlying disease (e.g. undiagnosed malignancy).Large-scale studies are needed on the diagnostic workup of patients with anaemia in general practice in relation to an underlying malignancy.This study shows that the majority of patients with anaemia had no cancer-relevant diagnostic investigations performed, which may cause diagnostic delay.Interventions seems needed to improve the diagnostic workup of cancer in these patients to ensure timely diagnosis.

Insufficient classification of anaemia in general practice: a Danish register-based observational study.

BACKGROUND: Anaemia can be a pointer of underlying severe disease, including undiagnosed malignancy. Subsequent blood tests are essential to classify the anaemia into subtypes and to facilitate targeted diagnostic investigation to ensure timely diagnosis of underlying disease. OBJECTIVE: We aimed to describe and classify anaemia based on laboratory tests from patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and unclassified anaemia (not classifiable according to an algorithm). DESIGN: Population-based cross-sectional study. SETTING: Danish general practice. SUBJECTS: A total of 62,731 patients (age: 40-90 years) with new-onset anaemia were identified in Danish laboratory information systems and nationwide registries, and data were obtained for 2014-2018. MAIN OUTCOME MEASURES: We measured the proportion of patients classified into subtypes of anaemia based on blood tests requested by general practitioners within 31 days of the anaemia index date. RESULTS: Of the 62,731 patients with new-onset anaemia, we identified unclassified anaemia in 78.9% (95% confidence interval (CI): 77.3-80.5) of men and 65.1% (CI: 63.4-66.9) of women. The likelihood of unclassified anaemia increased with age, increasing comorbidity and decreasing severity of anaemia. CONCLUSION: The majority of patients with new-onset anaemia could not be classified through a simple algorithm due to missing blood tests, which highlights a potential missed opportunity for diagnosis. Standardised laboratory testing of patients with anaemia is warranted to ensure adequate follow-up and early detection of underlying severe disease.KEY POINTSAnaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders.The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests.Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia.Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis.

Comparison of Patients with Hospital-Recorded Nephrotic Syndrome and Patients with Nephrotic Proteinuria and Hypoalbuminemia: A Nationwide Study in Denmark.

Background: Registry-based studies of nephrotic syndrome (NS) may only include a subset of patients with biochemical features of NS. To address this, we compared patients with laboratory-recorded nephrotic proteinuria and hypoalbuminemia to patients with hospital-recorded NS. Methods: We identified adult patients with first-time hospital-recorded NS (inpatients, outpatients, or emergency-room visitors) in the Danish National Patient Registry and compared them with adults with first-time recorded nephrotic proteinuria and hypoalbuminemia in Danish laboratory databases during 2004-2018, defining the date of admission or laboratory findings as the index date. We characterized these cohorts by demographics, comorbidity, medication use, and laboratory and histopathologic findings. Results: We identified 1139 patients with hospital-recorded NS and 5268 patients with nephrotic proteinuria and hypoalbuminemia; of these, 760 patients were identified in both cohorts. Within 1 year of the first record of nephrotic proteinuria and hypoalbuminemia, 18% had recorded hospital diagnoses indicating the presence of NS, and 87% had diagnoses reflecting any kind of nephropathy. Among patients identified with nephrotic proteinuria and hypoalbuminemia, their most recent eGFR was substantially lower (median of 35 versus 61 ml/min per 1.73 m2), fewer underwent kidney biopsies around the index date (34% versus 61%), and the prevalence of thromboembolic disease (25% versus 17%) and diabetes (39% versus 18%) was higher when compared with patients with hospital-recorded NS. Conclusions: Patients with nephrotic proteinuria and hypoalbuminemia are five-fold more common than patients with hospital-recorded NS, and they have a lower eGFR and more comorbidities. Selective and incomplete recording of NS may be an important issue when designing and interpreting studies of risks and prognosis of NS.

[Venous thromboembolism in patients with COVID-19].

The importance of venous thromboembolism (VTE) as a major complication in patients with severe corona virus disease 2019 (COVID-19) is becoming increasingly evident. In this review, we describe the proposed pathophysiology of the prothrombotic coagulation changes observed in patients with COVID-19. Further, based on a review of the currently available evidence on VTE prevalence in patients with COVID-19, we present and discuss the recommendations from the Danish Society of Thrombosis and Haemostasis on the use of thromboprophylaxis in patients with COVID-19.

Existing Data Sources in Clinical Epidemiology: Laboratory Information System Databases in Denmark.

Routine biomarker results from hospital laboratory information systems, covering hospitals and general practitioners, in Denmark are available to researchers through access to the regional Clinical Laboratory Information System Research Database at Aarhus University and the nationwide Register of Laboratory Results for Research. This review describes these two data sources. The laboratory databases have different geographical and temporal coverage. They both include individual-level biomarker results that are electronically transferred from laboratory information systems. The biomarker results can be linked to all other Danish registries at the individual level, using the unique identifier, the CPR number. The databases include variables such as the CPR number, date and time (hour and minute) of sampling, NPU code, and name of the biomarker, identification code for the laboratory and the requisitioner, the test result with the corresponding unit, and the lower and upper reference limits. Access to the two databases differs since they are hosted by two different institutions. Data cannot be transferred outside Denmark, and direct access is provided only to Danish institutions. It is concluded that access to data on routine biomarkers expands the detailed biological and clinical information available on patients in the Danish healthcare system. The full potential is enabled through linkage to other Danish healthcare registries.

Lectin pathway proteins of the complement system in normotensive pregnancy and pre-eclampsia.

PROBLEM: The lectin pathway of the complement system may be involved in the pathogenesis of pre-eclampsia. We aimed to investigate changes in serum concentrations of a broad range of lectin pathway proteins during normal pregnancy and their association with pre-eclampsia, placental infarctions and intrauterine growth restriction (IUGR). METHOD OF STUDY: We included 51 women with normotensive pregnancies and 54 women with pregnancies complicated by pre-eclampsia. Blood samples were obtained at gestational weeks 16, 33, 37, and after delivery for the normotensive pregnant women and before and after delivery for women with pre-eclampsia. Mannose-binding lectin (MBL), H- and M-ficolin, collectin liver-1 (CL-L1), MBL-associated serine protease (MASP)-1, MASP-2 and MASP-3 and MBL-associated proteins of 19 (MAp19) and 44 (MAp44) kDa were analysed. Clinical information was obtained from medical records. The placentae were examined by two experienced perinatal pathologists. RESULTS: Lectin pathway protein concentrations generally increased during normal pregnancy and decreased after delivery in both normotensive pregnant women and women with pre-eclampsia. Exceptions were MASP-3 which increased after delivery in both groups (P < 0.0001) and H-ficolin which increased after delivery in pre-eclampsia (P < 0.0001). H-ficolin (P < 0.0001), M-ficolin (P = 0.005) and MASP-3 (P = 0.03) concentrations were lower in women with pre-eclampsia than in normotensive pregnant women. Low MASP-3 concentrations were associated with placental infarction (P = 0.03) and IUGR (P = 0.04). Low H-ficolin concentrations were associated with IUGR (P < 0.01). CONCLUSION: In general, lectin pathway protein serum concentrations increased during normal pregnancy. H-ficolin and MASP-3 may be involved in the pathophysiology of pre-eclampsia and IUGR and could be potential future pre-eclampsia biomarkers.

Retinal vein thrombosis and risk of occult cancer: A nationwide cohort study.

BACKGROUND: Retinal vein thrombosis has in case reports been reported a clinical sign of cancer, especially hematological cancer. However, it is unclear whether retinal vein thrombosis is a marker of underlying cancer, as is the case for deep venous thrombosis and pulmonary embolism. We investigated the risk of occult cancer in patients with retinal vein thrombosis. METHODS: A nationwide population-based cohort study in Denmark on all patients diagnosed with a retinal vein thrombosis during 1994 and 2013. The main outcome measures were any cancer and site-specific cancers <6 months, 6-12 months, and 5 years following a retinal vein thrombosis diagnosis, as registered in the Danish Cancer Registry and the National Pathology Registry. We calculated the absolute cancer risk and computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for cancer within <6 months, 6-12 months, and 5 years following a retinal vein thrombosis diagnosis. RESULTS: Among 9589 patients with retinal vein thrombosis, we observed 1514 cancer cases. The risk of any cancer was 1.2% <6 months and 28.8% after 5 years. The <6 months SIR was 1.20 (95% CI 0.99-1.44), 6-12 months SIR was 1.15 (95% CI 0.94-1.39), and the 5 years' SIR was 1.08 (95% CI 1.03-1.14). Stratification by age, gender, calendar year, and Charlson Comorbidity Index score did not change overall cancer risk estimates. CONCLUSION: Retinal vein thrombosis was not an important clinical marker for occult cancer. An extensive diagnostic cancer workup does not appear warranted for retinal vein thrombosis patients.

Tinzaparin for the treatment of foetal growth retardation: An open-labelled randomized clinical trial.

OBJECTIVE: Foetal growth retardation (FGR) is a leading cause of perinatal death and long-term harms at survivors. Placental infarction plays a role in FGR, yet, no trials have evaluated whether low molecular weight heparins increase birth weight in ongoing FGR pregnancies. METHODS: An open-labelled randomized trial in Denmark during 2011-2016, including singleton pregnant women with FGR (estimated foetal weight < 2.3 percentile) diagnosed before gestational weeks 32. Participants were randomly assigned using sealed, blinded envelopes 1:1 to tinzaparin (4500 IU daily until 37 gestational weeks) or no tinzaparin. The primary outcomes were the observed birthweight relative to the expected for gestational age and gender, and foetal growth rates in the two trial groups evaluated by an intention to treat analysis. RESULTS: We enrolled 53 women. The mean gestational age was 261 days in the tinzaparin group and 246 days in the no treatment group. The mean birth weight was 2229 g in the tinzaparin group compared to 1968 g in the no treatment group. However, the birth weight relative to the expected from gestational age and gender was only 2.5 percentage points higher in the tinzaparin group [-5.1 to 10.0] (p = 0.51). The foetal growth rate during follow-up was 124 g/week in the tinzaparin group and 119 g/week in the no treatment group, a difference of 5 g/week [-19 to 29] (p = 0.67). Two perinatal deaths both occurred in the no treatment group. CONCLUSION: We found no evidence of a tinzaparin effect on the foetal growth rate or the birth weight after adjustment for gestational age.

The genetic component of preeclampsia: A whole-exome sequencing study.

Preeclampsia is a major cause of maternal and perinatal deaths. The aetiology of preeclampsia is largely unknown but a polygenetic component is assumed. To explore this hypothesis, we performed an in-depth whole-exome sequencing study in women with (cases, N = 50) and without (controls, N = 50) preeclampsia. The women were identified in an unselected cohort of 2,545 pregnant women based on data from the Danish National Patient Registry and the Medical Birth Registry. Matching DNA was obtained from a biobank containing excess blood from routine antenatal care visits. Novogene performed the whole-exome sequencing blinded to preeclampsia status. Variants for comparison between cases and controls were filtered in the Ingenuity Variant Analysis software. We applied two different strategies; a disease association panel approach, which included variants in single genes associated with established clinical risk factors for preeclampsia, and a gene panel approach, which included biological pathways harbouring genes previously reported to be associated with preeclampsia. Variant variability was compared in cases and controls at the level of biological processes, signalling pathways, and in single genes. Regardless of the applied strategy and the level of variability examined, we consistently found positive correlations between variant numbers in cases and controls (all R2s>0.88). Contrary to what was expected, cases carried fewer variants in biological processes and signalling pathways than controls (all p-values ≤0.02). In conclusion, our findings challenge the hypothesis of a polygenetic aetiology for preeclampsia with a common network of susceptibility genes. The greater genetic diversity among controls may suggest a protective role of genetic diversity against the development of preeclampsia.

Delayed sample arrival at the laboratory does not lead to more false negatives in the Danish population screening for colorectal cancer.

In Denmark, biennial population screening for colorectal cancer was introduced in 2014 for all aged 50-74 years. Five laboratories representative for the regional division of Denmark perform the immunochemical testing of faecal occult blood in the screening samples (iFOBT, OC-Sensor (Eiken Chemical, cut-off 100 µg/L)). In July 2016, a new agreement on the public post-delivery entailed an increased lag time (five days) from the screening participant drops the screening sample into a mail-box until sample arrival at the laboratories. Previous work had reported that a lag time above five days led to more false negative iFOBT tests. We investigated if this was true also under Danish conditions. We performed two stability tests; one with sample storage at 30 °C for 14 days (N = 60), and another with sample storage at room temperature for 13 days (N = 10). We extracted data from our laboratory information system (LABKA) on all iFOBT tests performed in the entire Central Denmark Region (N = 104,328 patients) during the last six months for each calendar year 2014-16. For each year, we computed the distribution of iFOBT tests below and above cut-off. Our stability tests showed no positive samples switching to false negative after storage; however, some negative samples turned false positive, especially at 30 °C. The data showed no change in the distribution of iFOBT tests below and above cut-off after July 2016. We found no evidence that an enhanced lag time increased the number of false negative iFOBT tests in the Danish screening program for colorectal cancer.

Pregnancy-related venous thromboembolism and risk of occult cancer.

The cancer risk during the first year after a pregnancy-related venous thromboembolism episode is higher than expected.An aggressive search for cancer in women with pregnancy-related venous thromboembolism is probably not warranted, due to low absolute risk.

Thrombophilia testing in young patients with ischemic stroke.

INTRODUCTION: The possible significance of thrombophilia in ischemic stroke remains controversial. We aimed to study inherited and acquired thrombophilias as risk factors for ischemic stroke, transient ischemic attack (TIA) and amaurosis fugax in young patients. MATERIALS AND METHODS: We included patients aged 18 to 50 years with ischemic stroke, TIA or amaurosis fugax referred to thrombophilia investigation at Aarhus University Hospital, Denmark from 1 January 2004 to 31 December 2012 (N=685). Clinical information was obtained from the Danish Stroke Registry and medical records. Thrombophilia investigation results were obtained from the laboratory information system. Absolute thrombophilia prevalences and associated odds ratios (OR) with 95% confidence intervals (95% CI) were reported for ischemic stroke (N=377) and TIA or amaurosis fugax (N=308). Thrombophilia prevalences for the general population were obtained from published data. RESULTS: No strong associations were found between thrombophilia and ischemic stroke, but patients with persistent presence of lupus anticoagulant (3%) had an OR at 2.66 (95% CI 0.84-9.15) for ischemic stroke. A significantly higher risk of TIA/amaurosis fugax was found for factor V Leiden heterozygote (12%) (OR: 1.99 (95% CI 1.14-3.28)). No other inherited or acquired thrombophilia was associated with ischemic stroke, TIA or amaurosis fugax. CONCLUSIONS: In young patients, thrombophilia did not infer an increased risk of ischemic stroke. Only factor V Leiden heterozygote patients had an increased risk of TIA/amaurosis fugax, and persistent presence of lupus anticoagulant was likely associated with ischemic stroke. We suggest the testing restricted to investigation of persistent presence of lupus anticoagulant.

Changes in fibrin D-dimer, fibrinogen, and protein S during pregnancy.

BACKGROUND: Pregnancy is a hypercoagulable state with a 5- to 10- fold higher risk of venous thromboembolism. Existing reference intervals for fibrin D-dimer (D-dimer), functional fibrinogen (fibrinogen) and protein S, free antigen (protein S) are based on non-pregnant patients and reference intervals for pregnant patients are warranted. Objectives. The aim of the present study was to contribute to the establishment of reference intervals for D-dimer, fibrinogen and protein S during pregnancy and to discuss the use of the analyses during pregnancy. METHODS: We included 55 healthy pregnant women in gestational week 11-17, with normal current pregnancy. Blood samples were collected in gestational weeks 11-17, 21-27 and 34-37. The three plasma parameters D-dimer, fibrinogen and protein S were analysed by STA-R Evolution®. RESULTS: A significant rise in D-dimer was found from first to second trimester (p < 0.0001) and from second to third trimester (p < 0.0001). The level of fibrinogen rose significantly from second to third trimester (p < 0.0001). Protein S showed a statistically significant fall in the level from first to second trimester (p < 0.0001) and remained stable thereafter. CONCLUSION: Changes during pregnancy in plasma D-dimer, protein S and fibrinogen were confirmed. Further clinical studies are needed to clarify a clinical useful cut-off point for D-dimer in pregnancy. We suggest careful attention to a low peripartum fibrinogen, since it indicates an increased bleeding risk. We confirmed an earlier suggested lower cut-off point for protein S, during pregnancy.