Ins and outs of inferior vena cava filters in patients with venous thromboembolism: the experience at Monash Medical Centre and review of the published reports.

BACKGROUND: Inferior vena cava (IVC) filters are an alternative management strategy to anticoagulation in patients with venous thromboembolism (VTE). However, an IVC filter has its own inherent risks and complications and may not be the best management strategy. The aims of this study were to evaluate our institution's practice of permanent Vena Tech (B. Braun Medical S.A., Boulogne, France) and retrievable Gunther Tulip (William Cook Europe, Bjaeverskov) IVC filters and to review the available published reports. METHODS: Retrospective single centre audit from the medical record. RESULTS: Eighty-three and 42 patients had a VT and GT filter inserted, respectively. Median age was 57 years for VT and 63 years for GT. The majority (75% for VT and 83% for GT) was inserted for acute VTE and contraindication to anticoagulation. Both filters were efficacious at preventing pulmonary embolism (PE) and there was a low rate of recurrent deep venous thrombosis in both groups. Insertion-related complications were low in both groups. Of the GT filters (n = 42), 16 were deemed an ongoing requirement, and thus, removal was not planned. In a further six patients, there was insufficient documentation as to why removal was not planned. Removal was attempted in 19 patients and was successful in 11. Failure of removal was as a result of clot in the filter (n = 7) or inability to snare it (n = 1). CONCLUSIONS: Both the permanent and retrievable filters are efficacious at preventing PE and are associated with a low complication rate. Planned removal of the GT filter may not be possible in a significant proportion of cases.

Heparin-induced thrombocytopenia and the use of r-hirudin during cardiopulmonary bypass.

We report the successful use of r-hirudin (lepirudin) for cardiopulmonary bypass in a 67-year-old man who developed heparin-induced thrombocytopenia type II during heparin treatment of an extensive deep venous thrombosis. Lepirudin was monitored by the modified ecarin clotting time in a "mobile laboratory" set up next to the cardiac theatre, aiming for lepirudin levels of 3.5 to 4.5 microg/ml during bypass.

Effects of balloon mitral valvuloplasty on systemic and regional left atrial levels of prothrombin fragment 1+2 in mitral stenosis.

A proportion of mitral stenosis patients with left atrial spontaneous echo contrast but without thrombus exhibit a regional hypercoagulable state, characterized by increased left atrial levels, but normal venous levels, of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. Valve dilatation by balloon mitral valvuloplasty has beneficial effects on left atrial spontaneous echo contrast, but its effect on left atrial thrombin generation is unknown. We examined the effects of balloon mitral valvuloplasty on venous and left atrial levels of F1+2 in 37 patients with mitral stenosis, divided into those with normal (group 1; n=22) and those with increased (group 2; n=15) regional left atrial thrombin generation, as described previously. The mitral valve area increased by a similar degree after the valvuloplasty procedure in the two groups. In group 1, the venous (P<0.005) and left atrial (P<0.0005) levels of F1+2 increased similarly after valvuloplasty, and as a result the left-atrial-venous F1+2 difference was unchanged. The venous F1+2 level also increased after valvuloplasty in group 2 (P<0.005); however, in contrast with group 1, the left atrial level decreased (P<0.03) and as a result the left-atrial-venous difference fell (P<0.05). These results show that balloon mitral valvuloplasty results in an immediate increase in thrombin generation, but a decrease in the left-atrial-venous F1+2 difference, in patients with increased left atrial thrombin generation. The divergent changes in venous and left atrial levels of F1+2 further highlight the limitations of assessing regional changes in coagulation activity by measuring venous levels of coagulation markers.

Increased left atrial thrombin generation in mitral stenosis is not reflected in arterial prothrombin fragment 1+2 levels.

A proportion of patients with mitral stenosis have increased left atrial thrombin generation, with elevated left atrial but normal peripheral venous levels of prothrombin fragment 1+2 (F1+2). Whether this pattern of left atrial and venous F1+2 levels is related to limited spillover of F1+2 from the left atrium into the systemic circulation, or to washout of increased left atrial F1+2 production into the arterial circulation with subsequent systemic clearance, is unclear. We examined the relationship between arterial and venous F1+2 levels in mitral stenosis patients without left atrial thrombus. The study group comprised 36 patients with either a normal (n=29) or prolonged (n=7) international normalized ratio (INR; a measure of clotting time) who were undergoing percutaneous balloon mitral valvuloplasty. Baseline arterial and venous blood samples were collected at the beginning of the valvuloplasty procedure, and left atrial and venous samples were collected after trans-septal puncture. The left atrial F1+2 level exceeded the corresponding venous level in patients with a normal INR (P<0.03); however, baseline arterial and venous F1+2 levels were similar. Arterial and venous F1+2 levels were also similar in the subgroup of patients with evidence of a regional increase in left atrial thrombin generation, and were not different from arterial and venous F1+2 levels in patients without such an increase. Baseline arterial and venous F1+2 levels were both lower in the presence of a prolonged INR. Thus the pattern of increased left atrial but normal venous F1+2 levels in mitral stenosis is due to limited spillover from the left atrium into the systemic circulation.

Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives.

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

PIP: This article reports the findings of a study that determined whether use of oral contraceptive (OC) is associated with significant changes in plasma tissue factor pathway inhibitor (TFPI), which may contribute to thrombotic risk. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1 and 2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in 40 women aged 16-45 taking OCs and 40 age-matched women not taking OCs. Results revealed that the plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OCs had a 25% reduction in plasma TFPI antigen (median, 51.0 ng/ml; 95% confidence interval (CI), 37.5-85.5; controls, 68.0 ng/ml; CI, 61.0-95.0) and a 29% reduction in TFPI activity (78.5 U/ml; CI, 57.5-107.5; controls, 111.0 U/ml; CI, 79.5-171.0) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1 and 2 were also significantly increased in women using OCs, indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progesterone in OCs result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulation inhibitor. In conclusion, reduced plasma TFPI levels may underlie the thrombotic effects of OCs.

Dalteparin for deep venous thrombosis: a hospital-in-the-home program.

OBJECTIVE: To assess the efficacy, safety and cost savings of home treatment of lower-limb deep venous thrombosis (DVT). SETTING: A hospital-in-the-home treatment program. PATIENTS: One hundred patients with acute lower limb DVT (53 proximal, 47 distal), and no contraindication to home treatment, were entered into the program from March 1995 to February 1997. INTERVENTION: All patients received dalteparin, 200 units/kg subcutaneously, once daily for a minimum of five days, with commencement of oral anticoagulation (warfarin) on Day 2. Patients with proximal DVT had lung ventilation-perfusion scans performed and were admitted to hospital for at least 24 hours. Patients with distal DVT were discharged directly to home treatment. MAIN OUTCOME MEASURES: Clinical responses and the results of sequential duplex ultrasonography at one week, one month, three months and six months. RESULTS: There were no major, but six minor, bleeding complications, two of which led to dalteparin being withdrawn. Sixteen patients had lung ventilation-perfusion scans showing a high probability of pulmonary embolism. All were asymptomatic, and follow-up for at least three months showed no symptomatic thromboembolic events. Duplex ultrasonography showed progression of thrombosis in the first week of therapy in 13.2% of distal and 2.7% of proximal thromboses. Thereafter, distal DVT improved at a much greater rate than proximal DVT; after six months complete resolution was seen in 60.7% of distal and 18.5% of proximal thromboses, respectively. Cost saving was $197 per bed-day equivalent compared with inpatient care. At 15 months' follow-up, swelling and/or pain was reported by 49% of patients with distal DVT and 66% of those with proximal DVT. CONCLUSIONS: Once-daily dalteparin therapy for DVT in a hospital-in-the-home setting was safe, efficacious and cost effective. However, DVT resolution is a slow process, with significant long term morbidity.

Effect of warfarin on regional left atrial coagulation activity in mitral stenosis.

Increased regional left atrial (LA) coagulation activity has recently been implicated in the pathophysiology of LA thrombus and systemic embolism in mitral stenosis (MS). Anticoagulation with warfarin reduces the risk of such thromboembolism, but the effect of warfarin on LA coagulation activity is unknown. We have addressed this question in MS patients with normal or prolonged clotting times. Peripheral venous and LA coagulation activities were measured in MS patients on long-term oral anticoagulation, who were predisposed to increased LA coagulation activity because of the presence of LA spontaneous echo contrast. Patients ceased warfarin 4 days before percutaneous balloon mitral valvuloplasty, and had either a normal (n = 15) or prolonged (n = 8) International Normalized Ratio (INR) at valvuloplasty. Coagulation activity was assessed during the valvuloplasty procedure, but before valve dilation, by measuring levels of prothrombin fragment 1 + 2 (F1 + 2), a marker of thrombin generation. The LA F1 + 2 level exceeded the peripheral venous level in patients with a normal INR (p <0.001), but these levels were similar in patients with a prolonged INR (p = 0.16). Moreover, the LA (p <0.005) and peripheral venous (p <0.03) F1 + 2 levels, as well as the LA-peripheral venous F1 + 2 difference (p <0.03) were lower in patients with a prolonged INR. These results suggest that anticoagulation with warfarin in MS not only reduces systemic coagulation activity but is associated with a greater reduction in LA coagulation activity. The latter may contribute to the reduced risk of LA thrombus formation that accompanies warfarin therapy in MS.

Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.

BACKGROUND: Recent evidence suggests that regional left atrial coagulation activity may be increased in mitral stenosis and perhaps contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown, and the relation between left atrial and systemic coagulation activities is unresolved. METHODS AND RESULTS: Left atrial and peripheral venous levels of the coagulation marker prothrombin fragment 1 + 2 (F1 + 2) were measured in 32 patients with mitral stenosis with normal clotting times and no left atrial thrombus who were undergoing percutaneous balloon mitral valvuloplasty. Baseline peripheral venous F1 + 2 levels, measured at the beginning of the valvuloplasty procedure, did not differ from those of 30 age-matched control patients. Prevalvuloplasty left atrial F1 + 2 levels, obtained immediately after transseptal puncture, were similar to femoral venous levels in patients without left atrial spontaneous echo contrast (LASEC) (0.81 +/- 0.32 versus 0.81 +/- 0.27 nmol/L, n = 7) but greater than femoral venous levels in patients with LASEC and either sinus rhythm (1.57 +/- 0.86 versus 0.99 +/- 0.38 nmol/L, n = 16, P < .001) or atrial fibrillation (1.52 +/- 0.69 versus 0.85 +/- 0.33 nmol/L, n = 9, P < .003). Furthermore, LASEC emerged as the only significant predictor of increased regional left atrial coagulation activity (P = .005) on stepwise multivariate logistic regression analysis. CONCLUSIONS: Increased regional left atrial coagulation activity in mitral stenosis occurs in the presence of LASEC, is evident in either sinus rhythm or atrial fibrillation, and is associated with normal systemic coagulation activity.

Genetic expression of adenosine deaminase in human lymphoid malignancies.

Adenosine deaminase (ADA) is an enzyme in the purine catabolic pathway that has been used as an enzymatic marker of T cell lymphoblastic malignancies due to its high specific activity in thymocytes and immature T cells. We have investigated whether the level of ADA activity in lymphoid leukemic cells correlates with the amount of ADA-specific RNA and/or immunoreactive protein in these cells as an initial step toward characterizing the nature of the genetic regulation of ADA expression during differentiation. We have found a good correlation between the steady state levels of ADA-specific RNA and ADA-immunoreactive protein in T lymphoblastic leukemic cell lines, mature T cell lines, a B lymphoblast cell line, and leukemic cells directly isolated from four patients with acute lymphoblastic leukemia and three patients with chronic lymphocytic leukemia. Southern blot analysis of DNA from these cells shows no evidence for differences in ADA gene copy number or gene rearrangement to account for the variability in ADA expression. We conclude that levels of ADA in lymphoid leukemic cells are directly related to the amount of ADA-specific mRNA present. These findings imply that ADA expression in leukemic cells reflects either the transcriptional activity of the ADA gene or the stability of ADA mRNA in these cells.

Pyrimidine and purine activities in non-Hodgkin's lymphoma. Correlation with histological status and survival.

The levels of the purine catabolic enzymes, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), together with the pyrimidine activities, thymidine phosphorylase (TP) and thymidine kinase isozymes (TK) have been determined for cells obtained from solid lymphoid tissue of 38 patients with non-Hodgkin's lymphoma (NHL) and 14 individuals exhibiting benign reactive lymphoid hyperplasia. Within each NHL histological group subtyped according to the Rappaport classification, and in the reactive hyperplasia group, there was considerable variation in these activities. However, higher levels of TK and TP activities occurred in cells of the histologically unfavourable prognostic NHL groups compared with those of favourable histology or reactive hyperplasia. There was an inverse relationship between survival and elevated TK isozyme 1 and TP levels, which was independent of histological classification and clinical staging. These results indicate that, in addition to morphology, estimations of TK and TP of involved lymphoma cells in NHL is of clinical relevance.

Human thymidine kinase. Purification and properties of the cytosolic enzyme of placenta.

Cytosolic thymidine kinase (EC 2.7.1.21) has been purified 5200-fold to apparent homogeneity from normal human placenta. The purification includes sequential affinity chromatography on blue-Sepharose and a thymidine column. The molecular weight of the enzyme determined by gel filtration and sucrose density ultracentrifugation is 92,000. The subunit molecular weight is 44,000, suggesting that the enzyme is a dimer in its native state. With isoelectric focusing, placental thymidine kinase demonstrated a single form with an isoelectric point of 9.1. The final purified enzyme preparation exhibits no immunological cross-reactivity with human mitochondrial thymidine kinase.

Leg oedema due to bladder overdistension.

Peripheral oedema due to pelvic vein compression is a rare complication of bladder overdistension. Case reports in the literature are few and all have concerned bladder overdistension in men. We report what we believe to be the first case of peripheral oedema due to an overdistended bladder in an adult woman. Pari passu with the relief of bladder obstruction there was resolution of pelvic vein compression and peripheral oedema.

Fetal thymidine kinase (TK1) in hairy cell leukaemia.

The thymidine kinase isoenzyme profile was determined in peripheral blood mononuclear cells and splenic tissue from 4 patients with hairy cell leukaemia, in order to assess the proliferative state of the hairy cell. The predominance of TK1 activity in all 4 spleens and in 2 out of 3 peripheral blood mononuclear cells examined, indicates that the hairy cell has significant proliferative capacity when compared to the neoplastic cell in other chronic lymphoproliferative disorders. It is suggested, in view of the heterogeneity in peripheral blood mononuclear TK isoenzyme types, that more extensive studies are warranted to examine the relationship between peripheral blood mononuclear TK1 activity and the occurrence of progressive disease in post-splenectomy patients.

Diagnostic information derived from immunotyping 1000 patients with leukemia and lymphoma.

Immunotyping analysis has been performed on cells from 1000 patients with leukemia or lymphoma using 14 markers of cell lineage or differentiation stage over a 4 yr period. Results showed considerable heterogeneity of cell type among these groups of malignant diseases not readily apparent by morphology and histochemistry. Immunotyping contributed additional diagnostic information in 30% of patients and should be a routine procedure in 8 disease categories. These are: acute leukemia, cell type not determined; acute lymphoblastic leukemia; lymphocytosis of undetermined origin; chronic myeloid leukemia-terminal blast crisis; chronic lymphocytic leukemia; malignant lymphoma-leukemic phase; Sézary syndrome, mycosis fungoides and chronic T cell leukemia; malignant lymphoma and lymphadenopathy- ? lymphoma. Immunotyping provided information on cell lineage and differentiation stage of major leukemic cell populations. Abnormal monoclonal proliferations of B lymphocytes and the presence of primitive cells amongst normally mature tissue cells were identified. Disturbances in normal lymphoid and monocytic cell populations in blood, marrow or tissues could also be demonstrated. Many of the reagents used in this period are now replaced by monoclonal antibody reagents to human lineage and differentiation antigens. These are expected to increase diagnostic usefulness of these techniques.