Maja Jørgensen

Haemostatic reference intervals in pregnancy.

Haemostatic reference intervals are generally based on samples from non-pregnant women. Thus, they may not be relevant to pregnant women, a problem that may hinder accurate diagnosis and treatment of haemostatic disorders during pregnancy. In this study, we establish gestational age-specific reference intervals for coagulation tests during normal pregnancy. Eight hundred one women with expected normal pregnancies were included in the study. Of these women, 391 had no complications during pregnancy, vaginal delivery, or postpartum period. Plasma samples were obtained at gestational weeks 13-20, 21-28, 29-34, 35-42, at active labor, and on postpartum days 1 and 2. Reference intervals for each gestational period using only the uncomplicated pregnancies were calculated in all 391 women for activated partial thromboplastin time (aPTT), fibrinogen, fibrin D-dimer, antithrombin, free protein S, and protein C and in a subgroup of 186 women in addition for prothrombin time (PT), Owren and Quick PT, protein S activity, and total protein S and coagulation factors II, V, VII, VIII, IX, X, XI, and XII. The level of coagulation factors II, V, X, XI, XII and antithrombin, protein C, aPTT, PT remained largely unchanged during pregnancy, delivery, and postpartum and were within non-pregnant reference intervals. However, levels of fibrinogen, D-dimer, and coagulation factors VII, VIII, and IX increased markedly. Protein S activity decreased substantially, while free protein S decreased slightly and total protein S was stable. Gestational age-specific reference values are essential for the accurate interpretation of a subset of haemostatic tests during pregnancy, delivery, and puerperium.

Long-Term Results using Catheter-directed Thrombolysis in 103 Lower Limbs with Acute Iliofemoral Venous Thrombosis

OBJECTIVES The long-term outcome of catheter-directed thrombolysis (CDT) in patients with acute iliofemoral venous thrombosis (IFVT) is evaluated in this study. MATERIAL AND METHODS Patients presenting for treatment with IFVT between June 1999 and May 2007 were considered for treatment using CDT. The following inclusion criteria were used: first episode of IFVT, age below 60 years, age of thrombus <14 days and open distal popliteal vein. Ultrasonography (US) was used to verify the diagnosis. The popliteal vein was punctured under local anaesthesia using US guidance, and a multi-side-hole catheter with tip occlusion was placed in the thrombus. A solution of r-TPA was infused either continuously or using the pulse spray technique together with heparin. Any occlusion or residual stenosis in the iliac vein system was treated by stenting. Compression stockings and anticoagulation treatment were given for at least 12 months. Patients with severe thrombophilias were treated for longer periods. The patients were assessed by colour-duplex US for assessment of patency and valve function after 6 weeks, 3, 6 and 12 months and afterwards on a yearly basis. RESULTS A total of 101 patients with 103 extremities affected by iliofemoral venous thrombosis were included (median age; 29 years, 78 women, and 79 had left-sided thrombosis). A stent was inserted in 57 limbs. The median follow-up time was 50 months (range 3 days-108 months). At 6 years, 82% of the limbs had patent veins with competent valves and without any skin changes or venous claudication. CONCLUSION Treatment with CDT for IFVT achieves good patency and vein function after 6 years of follow-up in this highly selected group of patients. We suggest that results from future studies should be presented as Kaplan-Meier plots using venous patency without reflux as the main outcome, since it is an early indicator of the clinical outcome.

Laboratory reference intervals during pregnancy, delivery and the early postpartum period

Abstract Background: Physiological changes during pregnancy may affect laboratory parameters. Reference values based on samples from non-pregnant women are not necessarily useful for clinical decisions during pregnancy. There is a need to establish reference values during pregnancy in order to recognize pathological conditions. Methods: Eight hundred and one women with expected normal pregnancies were included in the study. Of these, 391 had no complications during pregnancy, delivery, or the early postpartum period. Blood samples were obtained at gestational weeks 13–20, 21–28, 29–34, 35–42, at labor, and 1 and 2 days postpartum. Reference intervals were calculated for 36 tests as recommended by the International Federation of Clinical Chemistry and Laboratory Medicine. Results: Many tests showed such large variations indicating that gestational age-specific reference intervals were necessary. Other tests had different but stable values when compared to non-pregnant women. A minor decrease in albumin levels was observed. This was not only due to pregnancy-associated hemodilution, since other components with the same or a larger molecular diameter did not show a similar decrease. Many tests exhibited a broad distribution around vaginal delivery and in the early postpartum period. Conclusions: Only a few parameters were unaffected during uncomplicated pregnancy, delivery, and the early postpartum period suggesting that implementation of gestational age-specific reference intervals is necessary. Clin Chem Lab Med 2010;48:237–48.

Postthrombotic syndrome and quality of life in patients with iliofemoral venous thrombosis treated with catheter-directed thrombolysis

BACKGROUND Postthrombotic syndrome (PTS) is a common complication after iliofemoral venous thrombosis, often resulting in poor quality of life (QOL) among the affected patients. This study assessed development of PTS and its effect on QOL among patients treated for iliofemoral venous thrombosis by catheter-directed thrombolysis. METHODS Patients admitted with an iliofemoral venous thrombosis and treated with catheter-directed thrombolysis at Gentofte University Hospital from 1999 to 2008 were invited to participate. Duplex ultrasound imaging was used to assess venous patency and valve function. Each patient completed the generic Short-Form 36-item (SF-36) health survey assessment, producing physical component (PCS) and mental component summary (MCS) scores, and the disease-specific Venous Insufficiency Epidemiological and Economic Study (VEINES)-Quality of Life (QOL)/Symptoms (Sym), questionnaires to assess QOL. PTS was assessed using the Villalta scale. RESULTS The study included 109 patients. Median follow-up was 71 months. PTS developed in 18 patients (16.5%) and of those, initial thrombolysis was successful in 13. Patients with PTS had significantly worse mean ± standard deviation scores than patients without PTS on VEINES-QOL (34.2 ± 9.6 vs 53.1 ± 6.6; P < .0001), VEINES-Sym (34.0 ± 8.8 vs 53.2 ± 6.6; P < .0001), SF-36 MCS (44.2 ± 15.5 vs 52.3 ± 11.0; P = .005), and SF-36 PCS (42.3 ± 9.1 vs 53.5 ± 7.8; P < .0001) subscales. Patients with reflux or chronic occlusions, or both, had significantly lower mean ± SD scores than patients with patent veins without reflux on VEINES-QOL (43.5 ± 14.3 vs 51.0 ± 8.8; P = .044) and SF-36 PCS (47.2 ± 10.9 vs 52.4 ± 8.5; P = .049) scales. CONCLUSION PTS was associated with worse QOL, although only a few patients developed PTS after catheter-directed thrombolysis of iliofemoral venous thrombosis. Patients with patent veins and sufficient valves have higher QOL scores than patients with reflux and occluded veins.

Acute Iliofemoral Venous Thrombosis in Patients with Atresia of the Inferior Vena Cava Can Be Treated Successfully with Catheter-directed Thrombolysis

PURPOSE To assess the effectiveness and clinical outcomes of catheter-directed thrombolysis in patients with atresia of the inferior vena cava (IVC) and acute iliofemoral deep vein thrombosis (DVT). MATERIALS AND METHODS From 2001 to 2009, 11 patients (median age, 32 y) with atresia of the IVC and acute iliofemoral DVT in 13 limbs were admitted for catheter-directed thrombolysis. Through a multiple-side hole catheter inserted in the popliteal vein, continuous pulse-spray infusion of tissue plasminogen activator and heparin was performed. Thrombolysis was terminated when all thrombus was resolved and venous outflow through the paravertebral collateral vessels was achieved. After thrombolysis, all patients received lifelong anticoagulation and compression stockings and were followed up at regular intervals. RESULTS Ultrasound or computed tomography revealed absence of the suprarenal segment of the IVC in two patients, and nine were diagnosed with absence of the infrarenal segment of the IVC. Median treatment time was 58 hours (range, 42-95 h). No deaths or serious complications occurred. Overall, complications were observed in four patients, one of whom required blood transfusion. Three patients were diagnosed with thrombophilia. Median follow-up was 37 months (range, 51 d to 96 mo). All patients had patent deep veins and one developed reflux in the popliteal fossa after 4 years. No thromboembolic recurrences were observed during follow-up. CONCLUSIONS Catheter-directed thrombolysis of patients with acute iliofemoral DVT and atresia of the IVC is a viable treatment option, as reasonable clinical outcomes can be obtained.

Pregnancy after catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis

Objective: To assess the safety and efficacy of low-molecular-weight heparin (LMWH) in pregnancy and puerperium in women with previous acute iliofemoral deep venous thrombosis (DVT) treated with catheter-directed thrombolysis (CDT). Materials and methods: Consecutive patients treated for acute iliofemoral DVT using CDT between June 1999 and June 2009 were followed yearly by colour duplex ultrasound scanning. A subgroup of these patients who became pregnant during the follow-up period, three months to 10 years after CDT, was included in the present study. During pregnancy, thromboprophylaxis using LMWH was prescribed according to individual risk assessment, and the women were regularly assessed for adverse events. Women on warfarin had this treatment discontinued before the sixth week of pregnancy in order to prevent potential teratogenic adverse effects. Administration of LMWH was started at international normalized ratio ≤<2.0, and continued during pregnancy, delivery and puerperium. Postnatal, the anticoagulation treatment was converted back to warfarin and LMWH discontinued after a bridging period. Women, who, prior to pregnancy, had discontinued anticoagulation treatment after CDT, were prescribed anticoagulation treatment using LMWH as early in pregnancy as practical. LMWH was continued during pregnancy, delivery and for six weeks postpartum. All women were prescribed graduated compression stockings. Results: A total of 33 women completed 45 pregnancies, 44 singletons and 1 gemelli. In 24 (53%) of the cases, the mother had been treated with adjunctive stenting immediately following the CDT. In nine (21%) of the pregnancies, the mother had been on long-time anticoagulation treatment using warfarin prior to conception due to permanent severe risk factors. Thrombophilia was demonstrated in 31 (69%) of the pregnancies, and in 29 (64%) of the patients, the previous DVT was oestrogen-related. Thromboprophylaxis using tinzaparin was given in 41 (91%) and using dalteparin in four (9%) of the pregnancies. Doses of LMWH during pregnancy were adjusted according to risk assessment. One pregnancy was terminated by induced delivery at week 22 due to fetal malformations, and two of the pregnancies (4%) were complicated by intrauterine fetal death, one in week 39 due to severe fetal infection and one in week 23 due to intrauterine fetal growth restriction caused by severe antiphospholipid syndrome. All but one of the pregnancies was carried out without recurrence of DVT or maternal pulmonary embolism and the mother remained having patent deep veins postnatal. The mother with the antiphospholipid syndrome had a recurrent DVT complicated by iliac stent occlusion. This mother was prior to pregnancy on long-time treatment using warfarin. During pregnancy, she was erroneously treated with LMWH in standard prophylaxis doses instead of therapeutic doses and without adding aspirin. Conclusions: After CDT for acute iliofemoral DVT including adjunctive stenting, pregnancy can be carried out almost uneventful even in women at high risk of thromboembolism. Thromboprophylaxis during pregnancy using LMWH in a dosage adjusted to individual risk assessment, is essential.

Successful treatment of massive deep vein thrombosis using catheter‐directed thrombolysis and inferior vena cava filter in a puerperal woman

Sir, Venous thromboembolism is one of major the causes of maternal mortality and morbidity in the western world and has in Denmark been estimated at around 1.3 per 100 000 live births (1). Systemically and locally administered thrombolytic agents have been used with success in extreme situations in pregnant and in puerperal women (2). It is important to emphasize the favorable outcome of these methods in the event of extreme life-threatening situations. We therefore wish to call attention to a woman with puerperal bilateral massive deep venous thrombosis, treated with catheter-directed thrombolysis and a temporary inferior vena cava filter. A 32-year-old woman presented with a history of lumbar pain and a painful and swollen right leg. Two weeks earlier, she had delivered vaginally at term without complications. She had several risk factors for thromboembolism, such as smoking, a pre-pregnancy body mass index of 39kg/m2, gestational diabetes mellitus and a current urinary tract infection. Duplex ultrasound and CT scan with contrast demonstrated iliofemoral deep venous thrombosis of her left leg, as well as massive thrombosis of her right leg (Figure 1). The patient was initially treated with low-molecular-weight heparin in therapeutic doses. A temporary inferior vena cava filter was inserted through her right jugular vein. Catheter-directed thrombolysis of her left iliofemoral deep venous thrombosis was initiated with recombinant tissue plasminogen activator and heparin. After 117hours, all thrombus was resolved. An underlying stenosis of her left common iliac vein was treated with stenting. Although the patient did not fulfil the inclusion criteria for catheter-directed thrombolysis of her right leg (3), this was attempted and completed after 66hours, with all thrombus material having resolved. The inferior vena cava filter was removed and anticoagulation initiated. The patient was discharged after 14days. One year later, duplex ultrasound demonstrated patent deep veins in the left lower limb, and some residual thrombus in the right common femoral vein. No signs of post-thrombotic syndrome were present. She was found to carry Factor V Leiden and prothrombin mutations, both in heterozygous form, and anticoagulation therapy was recommended indefinitely. Treatment of venous thromboembolism during pregnancy and in the puerperal period is challenging. The indication for thrombolysis must be considered as a risk–benefit evaluation and is usually only chosen on vital indications. The advantages of catheterdirected thrombolysis include a high local concentration of thrombolytic agents, resulting in rapid lysis and decreased risk of systemic bleeding complications (4). Major bleeding complications have only rarely been described. The use of an inferior vena cava filter in pregnant or puerperal women has likewise only been described in a few cases. The main risks of such filters are migration, perforation and thrombosis, but the latter two risks can be reduced with a retrievable filter. In a retrospective audit of prospectively collected data, including 560 inserted filters in 507 non-pregnant patients, major complications were seen in two cases (0.4%) (5). It is important to be aware of the different treatment modalities mentioned above, but the choice of modality must be individualized, based on risk factors, clinical presentation, diagnostic findings, local resources and experiences.

Should catheter-directed thrombolysis be monitored?

Catheter-directed thrombolysis for deep venous thrombosis is considered the basic treatment modality for intrathrombus removal. This method is preferably used in patients with iliofemoral deep venous thrombosis due to poor spontaneous recanalization in this segment, especially on the left side. The method was published almost 25 years ago and has gained ground in the treatment because of poor results from systemic thrombolysis and because of the possibility of stenting any underlying iliac obstruction during the procedure. However, the publications of catheter-directed thrombolysis reveal a great heterogeneity concerning catheter-directed thrombolysis technique and the lack of high quality evidence about monitoring as a tool to minimize the risk of bleeding and pulmonary embolism. Strict inclusion and exclusion criteria, correct composition and infusion of thrombolysis agent, imaging thrombus clearance during catheter-directed thrombolysis, ensuring flow enhancement during the bedridden situation, careful evaluation of indication for stenting based on imaging, and sufficient conversion to anticoagulation treatment following catheter-directed thrombolysis are essential. The aim of this paper is to discuss different treatment aspects of catheter-directed thrombolysis for iliofemoral thrombosis and to suggest a monitoring model for future treatment.

O481 Gestational age-specific reference intervals for 32 chemical, 13 hematological, 10 coagulation and 3 thyroid laboratory tests during 391 uncomplicated pregnancy, vaginal delivery and early postpartum period

Objective: To design a method by which any laboratory information system (LIS) can present gestational age-specific reference values known to differ from reference values in non-pregnant individuals. Methods: In LIS the usual test name is given a period suffix and defined as a separate test with the correct gestational age-specific reference values. The test with its period suffix appears on the ordering screen or sheet as a new test, although the analysis performed is exactly the same as usual. In this way “D-dimer” may in addition appear as “D-dimer gestation week 35–42” etc. Also packages with a period suffix may be defined, for instance “Preeclampsia gestation week 35–42” containing a number of tests all with the same period suffix ordered simultaneously by only one click or tick on the name of the package with its suffix. Results: Test results will appear on the final lab report with relevant gestational age-specific reference values. If the LIS allows a special typography for results outside reference values, this will also be the case for test results in the pregnant woman, but only if they are outside the gestational age-specific reference interval. In our hospital, with 2000 deliveries yearly, such gestational age-specific ordering has been established for 30 different commonly used chemical tests each with a period suffix for relevant gestation weeks and for day-1-postpartum. Conclusion: The lab report now shows test results and appropriate reference values not only for non pregnant but also for pregnant women. The traditional need of pocket folders for reference values during pregnancy has been eliminated.