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Background: Deep venous thrombosis (DVT) is much less common in the upper than in the lower extremity. Furthermore, there is limited information on risk factors for and the prognosis of upper extremity (UE)DVT in the general population., Aims: To estimate incidence, risk factors, and prognosis in UEDVT., Material and Methods: Among a total of 1203 patients with venous thromboembolism (VTE) diagnosed during 1998-2006 in the prospective population-based Malmö thrombophilia study, 63 (5%, 33 men [52%, age 54+/-17years], and 30 women [48%, age 55+/-22years]) had UEDVT and were evaluated concerning risk factors, treatment, recurrent VTE, and mortality., Results: At diagnosis, 19(30%) patients had known malignancy and 6(10%) had VTE heredity. Among female UEDVT patients 4(13%) used hormone therapy, 1(3%) was pregnant, while none was in the postpartum period. Of all 63 UEDVT patients, 12(19%) were heterozygous, and 3(5%) homozygous for the Factor V Leiden (FVL)-mutation. Two (3%) patients were heterozygous for the prothrombin mutation, and 1 patient (1.6%) showed both heterozygous FVL-mutation and lupus anticoagulant antibodies. Phlebography had been used for diagnosis in 48(76%), ultrasonography in 16(25%), and computer tomography (CT) in 9(14%) patients. Twenty-two patients (35%) were treated in hospital, and the remaining 41(65%) as out-patients. Sixty-two (98%) was treated with low molecular weight heparin (LMH), 60(95%) with oral anticoagulants (OAC), 3(5%) with unfractionated heparin, and 3(5%) with thrombolysis. VTE recurrence rate during median 62 (range 31-117) month of follow-up was 8/63(13%). Fifteen (24%) UEDVT patients died during follow-up; 9(47%) of the 19 patients with known malignancy at diagnosis and 6(14%) of the other patients. Yearly incidence of UEDVT was 3.6/100.000 (95% confidence interval [CI], 3.3 - 4.03)., Conclusion: Malignancies and the FVL mutation were common among patients with UEDVT. Mortality during follow-up vas high., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Despite venous thromboembolism (VTE) being a major cause of morbidity and mortality, there is still limited information on its prevalence and incidence in the general population., Objective: To evaluate risk factors, distribution and epidemiology of VTE in the Malmö area with 280,000 inhabitants., Methods: Patients diagnosed with VTE at Malmö University Hospital in 1998-2006 were invited to a prospective population-based study. Blood sampling and a questionnaire study could be performed in 70% of patients. Remaining 30% were excluded due to language problems, dementia, other severe disease, or unwillingness to participate., Results: During 1998-2006 1140 VTE patients (559 men [49%, age 62+/-16 years] and 581 women [51%, age 61+/-20 years]) were included. Deep venous thrombosis (DVT) occurred in 882 (77%), pulmonary embolism (PE) in 330 (29%), and both DVT and PE in 72 (6%). The most common acquired risk factors among VTE patients were hormone therapy (24% of female DVT patients and 19% of female PE patients), immobilisation (17% of DVT patients and 18% of PE patients), previous surgery (13% of DVT patients and 19% of PE patients), and concomitant malignant disease (12% of DVT patients and 11% of PE patients). A positive family history for VTE was obtained from 25% of DVT patients and 22% of PE patients. Yearly incidences of VTE, DVT and PE in Malmö were 66, 51, and 19/100.000, respectively., Conclusion: Hormone therapy, immobilisation, previous surgery and concomitant malignancy were the most common acquired risk factors among VTE patients in this population-based study. The VTE-incidence was lower than in earlier epidemiological studies.

Heparin, a negatively charged sulphated glycosaminoglycan, is clinically the most important antithrombotic drug. Heparin augments the inhibitory activity of antithrombin (AT) towards thrombin, factor Xa (FXa) and other activated clotting enzymes. Tissue factor pathway inhibitor (TFPI) is an endogenous heparin releasable three domain Kunitz-type coagulation inhibitor which inhibits the crucial tissue factor-factor VIIa (TF-FVIIa) dependent coagulation pathway in the presence of FXa. The importance of the TF-FVIIa pathway and TFPI has recently been reviewed (1). TFPI is located to different vascular pools, the largest being the vascular endothelium from where TFPI can be released dose-dependently to the blood by heparins (2). TFPI is speculated to contribute to the anticoagulant properties of heparins, but to which degree is not yet fully understood. In recent years low molecular weight heparins (LMWH) have proven to be effective and safe both for prophylactic (3) and therapeutic treatment (4) of deep vein thrombosis (DVT). Protamine is the least toxic and clinically most commonly used antidote to heparin. However, in vitro and in vivo LMW heparinized blood is not fully neutralized by protamine, as substantial anti-Xa activity remains following neutralization (5). This post-protamine effect has been shown to be partly TFPI dependent when measured in a dilute TF-dependent assay (6,7). We undertook this in vivo study on healthy volunteers in order to investigate whether TFPI released by UH or LMWH (intravenous (iv) or subcutaneous (sc)) remains in the circulation following neutralization of the heparin activity with protamine sulphate (PS). We measured TFPI by three different methods-chromogenic activity, anticlotting activity and a new antigen assay specific for full-length and three-domain TFPI.

Tissue Factor Pathway Inhibitor (TFPI) is a naturally occurring inhibitor of the TF-FVIIa induced coagulation in the presence of FXa. Recombinant two domain TFPI, where Asn 117 on the FXa-inhibitory domain was exchanged to a Gln yielding non-glycosylated TFPI (117QTFPI1-161), was evaluated regarding pharmacokinetics and delayed antithrombotic potential in the rabbit. Pharmacokinetic study; 117QTFPI1-161 vs glycosylated TFPI1-161. Three rabbits/group were used and received 1,0 mg/kg a bolus iv injection. Plasma-TFPI was measured for three hours. The alpha-phase half-life was similar, the beta-phase half-life was close to four times longer for 117QTFPI1-161 (37 vs 10 min). Clearance of 117QTFPI1-161 was nearly two times lower (45 vs 21 ml/kg/min). Delayed anti-thrombotic study; 10 rabbits/group were used. 5 Groups; placebo + placebo, placebo + LMWH60 anti-Xa IU/kg, placebo + 117QTFPI1-161 0,25 mg/kg, 117QTFPI1-161 1,0 and 4,0 mg/kg + placebo. First injection 60 min prior to the second one, which coincided with the thrombus induction. The experimental thrombosis used combines a chemical destruction of the endothelium with a partial restriction of the bloodflow in the jugular veins. The thrombusweight was significantly reduced in LMWH and 117QTFPI1-161 1,0 and 4,0 mg/kg groups (0,6-2,6 vs 11,8 mg). Frequency of occlusive thrombosis was significantly reduced in the LMWH and 117QTFPI1-161 4,0 mg groups. All groups significantly effected the aXa-assay, the LMWH-group the most (0,85 IU/ml). LMWH was the only substance to prolong the dilute-PT-assay at the different timepoints. Absence of glycosylation increases the beta-phase half-life and decreases clearance of two domain TFPI. 117QTFPI1-161 (1,0 and 4,0 mg) has an antithrombotic effect indistinguishable from LMWH even though given 60 min before the thrombusinduction but with a considerable less effect on anti-Xa, APTT and no effect on dilute-PT. Glycosylation of TFPI influences the pharmacokinetics but not the antithrombotic capacity in this experimental setting.

An in vivo experimental venous thrombosis model based on endothelial damage and flow reduction was used to investigate the effect of low molecular weight heparin (LMWH) alone and in combination with dextran and the effect of surgical and endothelial trauma on thrombus formation, formation of occlusive thrombi and thrombus weights. Five groups with 15 rabbits in each were studied. Two groups received dalteparin (50 anti-Xa IU/kg i.v.) before surgical trauma or after, during the endothelial trauma and two groups received dalteparin (50 anti-Xa IU/kg i.v.) with dextran 70 (1 g/kg i.v.) before surgical trauma or after, during the endothelial trauma. Compared to a control group (saline) all treatment regimes reduced significantly the frequency of thrombosis and occlusive thrombi as well as thrombus weights. No significant difference was observed between the identical treatment groups when the substances were introduced before respective after surgical trauma. It is concluded, from the present study that thromboprophylaxis with LMWH in this particular in vivo model, given before or after surgical trauma is equally effective. Dextran has a certain augmenting thromboprophylactic effect when added to LMWH in this model.

The aim of the study was to determine whether an impairment of the haemostasis could be observed experimentally when thromboprophylactic substances, which act differently on the haemostatic mechanism, were given single or in combination in prophylactic doses. In 36 rabbits we measured the primary haemostatic plug formation time (PHT), rebleedings and total haemostatic plug formation time (THT) after transection of venules and arterioles using an intravital microscope. We combined unfractionated heparin (UH) and low molecular weight heparin (LMWH) in low dose with either dextran 70 or polygeline (placebo volume expander) in a randomized double-dummy set up. In the placebo group (NaCl and polygeline) the median PHT was 55 and 101 seconds for arterioles and venules respectively, which are well-comparable to earlier results from our group. Most prolonged PHT and THT for arterioles were seen for dextran+NaCl, actually less prolongation was seen for UH+dextran. We did not observe any differences, except for a prolongation of THT for venules in rabbits given dextran+NaCl (p less than 0.05). Thus, in thromboprophylactic doses used, there does not seem to be an impaired or additive effect between heparins and dextran 70 in primary haemostasis in rabbits.

Hemodynamic and hematologic effects of protamine reversal of low molecular weight heparin (LMWH) anticoagulation with and without protamine pretreatment, as well as reversal of anticoagulation with unfractionated standard heparin (SH), were studied in canine subjects. Protamine reversal caused less severe thrombocytopenia in the two LMWH groups compared to SH animals, while neutropenia occurred equally in all groups. Cl-esterase inhibitor levels were minimally increased, whereas C3 levels and leucotriene levels were unaltered. TxB2 and 6-keto-PGF1 alpha increased during protamine reversal of LMWH anticoagulation. TCT and APTT were affected less with LMWH than SH anticoagulation. Anti-Xa levels increased with anticoagulation in all animals, but protamine did not reverse the elevated anti-Xa levels in LMWH anticoagulated dogs to the same degree as occurred with SH anticoagulation. TCT, APTT and bleeding times were normalized by protamine in all animals. Protamine reversal of LMWH anticoagulation with or without protamine pretreatment did not reveal any clear differences in eicosanoids or complement factors compared to SH anticoagulation, although differences in anti-Xa activity clearly separated these two heparins.

The effect of dihydroergotamine (DHE) on platelets, coagulation and fibrinolysis was studied in healthy volunteers ex vivo before and after intravenous administration (0.5 mg). In addition, the effect of DHE in different concentrations on platelet aggregation was evaluated in vitro. Haematocrit was found to increase, as did factor VIII:C and antithrombin III - though the latter increases were not significant when correction was made for the altered haematocrit. Though platelet function ex vivo was unchanged, inhibition of adrenaline induced platelet aggregation was noted in vitro when the plasma concentrations of added DHE were higher than those obtained with clinically relevant doses. No effect on fibrinolysis was noted.

Ketanserin is a new selective 5-HT2 receptor blocker. It has been used to indirectly study the influence of serotonin on hemostatic function in vitro. Coagulation and fibrinolysis in vitro were not affected. In high doses adrenalin induced platelet aggregation was inhibited but no influence was seen on collagen or ADP induced aggregation. It can be concluded that it is not very likely that serotonin plays an important role in initial hemostasis. However, the findings ought to be confirmed in vivo.