[Show abstract][Hide abstract] ABSTRACT: Post-thrombotic syndrome is a common complication after acute proximal deep vein thrombosis (DVT) and is associated with reduced quality of life and a substantial cost burden. In the 2-year results of the CaVenT study, additional catheter-directed thrombolysis reduced the risk of post-thrombotic syndrome by 14% compared with conventional therapy, but did not affect quality of life. In this study we report results at the 5-year follow-up, aiming to assess whether findings for post-thrombotic syndrome and quality of life have persisted.
[Show abstract][Hide abstract] ABSTRACT: Background:
Allogeneic stem cell transplantation (ASCT) has been a treatment option for patients with serious diseases of the blood and haematopoietic organs in Norway since 1985. Such treatment is potentially curative for selected patients who have a relatively short predicted survival with other treatment modalities. This article summarises the experience and results from ASCT at Oslo University Hospital Rikshospitalet.
Material and method:
The study included all of the 734 adult patients who had undergone allogeneic stem cell transplantation at the Department of Haematology, Rikshospitalet, later Oslo University Hospital Rikshospitalet, from November 1985 to October 2012.
At the time of analysis, altogether 384 patients were alive, and the five and ten-year survival rates were 54% and 48% respectively. The median follow-up time was six years. A total of 339 patients (46%) had developed acute graft-versus-host disease (GvHD), and 250 (73%) of these had GvHD ≥ grade II. Altogether 280 out of 602 patients who lived ≥ 100 days after the transplantation (46.5%) developed chronic GvHD. The most frequent causes of death included recurrence of the initial disease in 116 patients (33.1 %), multi organ failure after transplantation in 88 patients (25.4%), infections in 54 patients (16%) and GvHD in 33 patients (9.4%).
ASCT is a treatment option with a curative potential for patients with serious haematological diseases when other forms of treatment provide few prospects for recovery. The total survival rate in our study is in accordance with international results for the same time period, and the indications have consistently been in line with what is accepted internationally.
Full-text · Article · Sep 2014 · Tidsskrift for den Norske laegeforening
[Show abstract][Hide abstract] ABSTRACT: Stormorken syndrome is a rare autosomal dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca2+ depletion in the endoplasmic reticulum (ER) lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca2+ release-activated Ca2+ (CRAC) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the CC1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a pre-activated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca2+ levels were elevated in platelets from the patients compared to controls, and store-operated Ca2+ entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome. This article is protected by copyright. All rights reserved
[Show abstract][Hide abstract] ABSTRACT: Surgery in persons with hemophilia and high-titer inhibitors is a clinical challenge. At present, bypassing agents, such as activated prothrombin complex concentrate (aPCC) and activated recombinant factor VII (rFVIIa) are the only coagulation factor concentrates available for surgery in inhibitor patients if the inhibitor titer is above 5 Bethesda units (BU). Clinical experience during the last two decades has shown that surgery with bypassing agents is safe and efficacious in maintaining hemostatic control and the risk of major bleeding complications during and following surgery is minimized. Consequently, no patients with inhibitors should be denied surgical intervention. However, it requires thorough planning and proper management since no product can guarantee sustained hemostasis. Present data indicate that both products are effective in most patients, but in some patients one or the other seems to be superior.
[Show abstract][Hide abstract] ABSTRACT: Arthropathy of the knee is a frequent complication in patients with severe bleeding disorders leading to considerable pain and disability. Total knee arthroplasty (TKA) provides marked pain relief. However, a modest functional outcome and a high number of complications due to prosthetic infection and loosening are reported. Data on long-term outcomes are scarce, and most case series include few patients. We have studied clinical outcomes and complications of TKAs with special emphasis on prosthetic survival and periprosthetic infection.
A consecutive series of 107 TKAs in 74 patients with haemophilic arthropathy were retrospectively reviewed. Follow-up was mean 11.2years (range 0.8-33.1years).
Five- and 10-year survival rates, with component removal for any reason as the end point, were 92% and 88%, respectively. Twenty-eight TKAs were removed after median 10years (range 0.8-28years). The most common cause of failure was aseptic loosening (14 knees) and periprosthetic infection (seven knees). The overall infection rate was 6.5%. The mean postoperative drop in haemoglobin levels was 4.3g/dL (range 0.5-9.4) with a significant difference between haemophilia A patients with and without inhibitor (6.3g/dL (range 3.6-9.4) versus 3.7g/dL (range 0.5-8.1) (p<0.001). A painless knee was reported in 93% of the TKAs at the latest follow-up.
The medium and long-term results of primary TKA in a large haemophilic population show good prosthetic survival at five and 10years with an excellent relief of pain. Periprosthetic infection is still a major concern compared to the non-haemophilic population.
[Show abstract][Hide abstract] ABSTRACT: Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study.
Ten factor VII deficient patients were treated with either recombinant activated (20μg/kg) or plasma-derived (25IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points.
Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236ml/kg; 175ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206ml/kg; 64ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII.
Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products.
Full-text · Article · Jul 2013 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20μg/kg rFVIIa or 25IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy.
No preview · Article · May 2013 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: Conventional anticoagulant treatment for acute deep vein thrombosis (DVT) effectively prevents thrombus extension and recurrence, but does not dissolve the clot, and many patients develop post-thrombotic syndrome (PTS). We aimed to examine whether additional treatment with catheter-directed thrombolysis (CDT) using alteplase reduced development of PTS.
Participants in this open-label, randomised controlled trial were recruited from 20 hospitals in the Norwegian southeastern health region. Patients aged 18-75 years with a first-time iliofemoral DVT were included within 21 days from symptom onset. Patients were randomly assigned (1:1) by picking lowest number of sealed envelopes to conventional treatment alone or additional CDT. Randomisation was stratified for involvement of the pelvic veins with blocks of six. We assessed two co-primary outcomes: frequency of PTS as assessed by Villalta score at 24 months, and iliofemoral patency after 6 months. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00251771.
209 patients were randomly assigned to treatment groups (108 control, 101 CDT). At completion of 24 months' follow-up, data for clinical status were available for 189 patients (90%; 99 control, 90 CDT). At 24 months, 37 (41·1%, 95% CI 31·5-51·4) patients allocated additional CDT presented with PTS compared with 55 (55·6%, 95% CI 45·7-65·0) in the control group (p=0·047). The difference in PTS corresponds to an absolute risk reduction of 14·4% (95% CI 0·2-27·9), and the number needed to treat was 7 (95% CI 4-502). Iliofemoral patency after 6 months was reported in 58 patients (65·9%, 95% CI 55·5-75·0) on CDT versus 45 (47·4%, 37·6-57·3) on control (p=0·012). 20 bleeding complications related to CDT included three major and five clinically relevant bleeds.
Additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding.
South-Eastern Norway Regional Health Authority; Research Council of Norway; University of Oslo; Oslo University Hospital.
[Show abstract][Hide abstract] ABSTRACT: Recovery and survival of transfused platelets (PLTs) are usually assessed by radioisotope labeling methods for evaluation of transfusion efficacy and new progress in the processing of PLT concentrates. Alternative, nonradioactive methods are warranted.
A multicolor flow cytometry method was developed for simultaneous studies of recovery, survival, and function of transfused PLTs. Eight consecutive patients undergoing allogeneic stem cell transplantation (TX) were transfused with apheresis PLTs of nonself human leukocyte antigen (HLA) Class I types, and HLA Class I discrepancy between donor and recipient was used to identify transfused PLTs. Hematologic status and HLA Class I surface expression were analyzed immediately before transfusion, 1 and 6 hours after transfusion, and daily during the subsequent week. PLT activation was assessed by surface expression of CD63, CD62P, or CD42a, before and after stimulation with thrombin receptor agonist peptide.
PLT recovery was 43, 41, and 31% for fresh (5-72 hr old) and 30, 27, and 17% for stored (73-148 hr old) PLTs, after 1, 6, and 15 to 28 hours, respectively. Survival of fresh versus stored PLTs were 160 and 105 hours, respectively. Spontaneous PLT activation and residual activation potential were almost equal for fresh and stored PLTs. PLT engraftment was detected between Day 7 and Day 9, which was significantly earlier than first sign of neutrophil engraftment (Days 11-19; p=0.01).
Flow cytometry is an attractive alternative to radiolabeling of PLTs for simultaneous studies of survival, recovery, and function of transfused PLTs and early detection of PLT engraftment after allogeneic stem cell TX.
[Show abstract][Hide abstract] ABSTRACT: 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).
Full-text · Article · Jul 2011 · Seminars in Thrombosis and Hemostasis
[Show abstract][Hide abstract] ABSTRACT: Immune thrombocytopenia (ITP) is caused by immune-mediated platelet destruction and reduced platelet production. The aim of this review article is to provide an updated overview of pathophysiology and new therapeutic modalities in ITP.
The article is based on literature identified through a non-systematic search in PubMed and our own clinical experience.
ITP is diagnosed in patients with platelet count < 100 × 10(9)/l after excluding other causes of thrombocytopenia. Anti-platelet autoantibodies are important in the platelet destruction mechanism, but other important mechanisms have been identified in recent years. Patients with very low platelet count < 30 × 10(9)/l are particularly susceptible to bleeding complications. The goal of treatment so far has been to increase the platelet count to a level that reduces the risk of serious bleeding. Thrombopoietin receptor agonists are new therapeutic agents that target the thrombopoietin receptor to increase platelet production. These drugs are shown to be effective in treatment of ITP.
New knowledge about pathophysiological mechanisms, such as sub-optimal platelet production in ITP, has led to the development of new therapeutic options which focus on stimulation of platelet production.
Preview · Article · Nov 2010 · Tidsskrift for den Norske laegeforening
[Show abstract][Hide abstract] ABSTRACT: Acquired hemophilia is a rare, but often severe, bleeding disorder caused by autoantibodies against a coagulation factor, usually factor VIII (FVIII). The most common clinical presentations are diffuse bruising, soft tissue bleeds, and hematuria. As acquired hemophilia is associated with severe bleeding complications with high mortality, early diagnosis and intervention are crucial. The bypassing agents, recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), have been shown to be effective as first-line treatment for bleeds, and treatment should be switched to the other product if the first choice fails. Starting immune therapy to eradicate the autoantibodies should not be postponed. The combination of oral corticosteroids and cyclophosphamide is effective in eradicating the neutralizing autoantibodies, and should probably be the choice for first-line treatment. Rituximab is a promising drug in acquired hemophilia, but should perhaps be limited to second-line treatment.This paper reviews the current literature in management of bleeds and immune therapy to eradicate autoantibodies in patients with acquired hemophilia.
[Show abstract][Hide abstract] ABSTRACT: Traditional anticoagulant treatment of deep venous thrombosis (DVT) in the upper extremities (UEDVT) is associated with a relatively high incidence of postthrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) for UEDVT would provide efficient thrombolysis with less subsequent PTS than during traditional anticoagulation. Primary efficacy, complications, and long-term results after CDT are reported in a retrospective cohort (2002-2007) of patients (n = 30) with DVT in the upper extremities. PTS was assessed by a modified Villalta scale. UEDVT was unprovoked in 11 (37%) cases and effort related in 9 (30%) cases. The median duration of symptoms prior to CDT was 7.0 days (range, 1-30); median duration of thrombolysis treatment, 70 h (range, 24-264 h); and the median amount of rt-PA infused during CDT, 52 mg (range, 19-225 mg). Major bleeding was registered in three (9%) patients, and CDT was stopped prematurely in three patients due to local hematoma. No intracerebral bleeding, clinical pulmonary embolism, or deaths occurred during treatment. Grade II (>50%) or III (>90%) lysis was present in 29 patients (97%) at the end of CDT. Bleeding complications increased by each day of delay from the debut of symptoms to the start of treatment (OR, 1.20; 95% CI, 1.01-1.42). At follow-up (n = 29; median, 21 months; range, 5-58 months), 11 (38%) patients had occluded veins, whereas 18 (62%) had patent veins. However, stenosis of varying severity was present in eight of those with a patent vein. No patients had severe PTS, whereas six (21%) experienced mild PTS. In conclusion, our retrospective cohort study of patients with UEDVT showed that treatment restored venous drainage, with a subsequent low frequency of mild PTS at follow-up. Early intervention with CDT prevented bleeding complications.
No preview · Article · Jul 2009 · CardioVascular and Interventional Radiology
[Show abstract][Hide abstract] ABSTRACT: The success rate for chemotherapy of adults with acute lymphoblastic leukaemia in Norway compares favourably with that in international reports, but improvements are still needed. Allogeneic stem cell transplantation is an option for patients up to 60 years and may contribute to improving the outcome for these patients.
Allogen stem cell transplantation was performed in 61 high-risk patients (38 men and 23 women) with acute lymphoblastic leukaemia at Rikshospitalet between 1985 and 2005. 19 patients were transplanted in first remission and 42 at a later stage of the disease.
At the end of 2006, 26 patients (43%) were alive; 21 (35%) in complete remission and 5 with relapse. Median survival time was 1.5 years. Relapse was the most important cause of treatment failure (38%), but transplantation-related mortality (25%) was also a substantial problem. Estimated 5-year actuarial leukemia-free survival was 35 %.
Our results are in line with international reports on the results of allogen stem cell transplantation in high-risk acute lymphoblastic leukaemia. This treatment offers cure for patients with an otherwise dismal prognosis. A larger number of patients should be offered such treatment during the first remission than what was the case in the 20-year period this study took place.
No preview · Article · Dec 2008 · Tidsskrift for den Norske laegeforening