Antonio Girolami

Accuracy of clinical assessment of deep-vein thrombosis

The clinical diagnosis of deep-vein thrombosis is generally thought to be unreliable. From experience, we hypothesised that this widely held view might be incorrect. We developed a clinical model and prospectively tested its ability in three tertiary care centres to stratify symptomatic outpatients with suspected deep-vein thrombosis into groups with high, moderate, or low probability groups of deep-vein thrombosis. We evaluated our clinical model in combination with venous ultrasonography to determine the potential for an improved and simplified diagnostic approach in patients with suspected deep-vein thrombosis. All patients were clinically assessed to determine the probability for deep-vein thrombosis before they had ultrasonography and venography. All tests were performed and interpreted by independent observers. In 529 patients, the clinical model predicted prevalence of deep-vein thrombosis in the three categories: 85% in the high pretest probability category, 33% in the moderate, and 5% in the low category. There was no statistical difference in the performance of the model in the three centres. The model demonstrated excellent interobserver reliability (Kappa = 0.85). There were important differences with ultrasonography between the high and low pretest probability groups for both positive predictive values (100% (95% CI, 94-100%) vs (63% [35-85%], respectively). Thus, use of the clinical model combined with ultrasonography would decrease the number of false positive and negative diagnosis if venography were done when the ultrasound result and pretest probability were discordant. The diagnostic process could be simplified by excluding those patients with low pretest probability and normal ultrasound results from serial testing.

The Risk of Recurrent Venous Thromboembolism in Patients with an Arg506→Gln Mutation in the Gene for Factor V (Factor V Leiden)

BACKGROUND A recently discovered mutation in coagulation factor V (Arg506-->Gln, referred to as factor V Leiden), which results in resistance to activated protein C, is found in approximately one fifth of patients with venous thromboembolism. However, the risk of recurrent thromboembolism in heterozygous carriers of this genetic abnormality is unknown. METHODS We searched for factor V Leiden in 251 unselected patients with a first episode of symptomatic deep-vein thrombosis diagnosed by venography. The patients were followed prospectively for a mean of 3.9 years to determine the frequency of recurrent venous thrombosis and pulmonary embolism. RESULTS Factor V Leiden was found in 41 of the patients (16.3 percent; 95 percent confidence interval, 11.8 to 20.9 percent). The cumulative incidence of recurrent venous thromboembolism after follow-up of up to eight years was 39.7 percent (95 percent confidence interval, 22.8 to 56.5 percent) among carriers of the mutation, as compared with 18.3 percent (95 percent confidence interval, 12.3 to 24.3 percent) among patients without the mutation (hazard ratio, 2.4; 95 percent confidence interval, 1.3 to 4.5; P<0.01). CONCLUSIONS The risk of recurrent thromboembolic events is significantly higher in carriers of factor V Leiden than in patients without this abnormality. Large trials assessing the risk-benefit ratio of long-term anticoagulation in carriers of the mutation who have had a first episode of venous thromboembolism are indicated.

A simple ultrasound approach for detection of recurrent proximal-vein thrombosis.

BackgroundThe objective of this study was to develop a simple ultrasound method for measuring thrombus regression in patients with proximal deep-vein thrombosis (DVT) and to test its utility for the detection of DVT recurrence.Methods and Resuls. The study comprised a cross-sectional survey and a prospective investigation (149 and 145 patients, respectively). In both phases, the normalization rate of a previously abnormal ultrasound test, applying the criterion of full compressibility of the common femoral and popliteal veins (C-US method), was assessed. In the prospective study, the vein diameter under maximum compression (thrombus thickness) was measured in the abnormal venous segments at scheduled times (1, 3, 6, and 12 months). In patients presenting with suspected DVT recurrence, the procedure was repeated and results were compared with those available from the previous examination. Noncompressibility of a previously normal(ized) venous segment and enlargement of thrombus thickness (.

Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial

2 mm) were considered diagnostic of proximal DVT recurrence. The diagnostic accuracy of the C-US method alone, as well as of the combined ultrasound methods (C-US + thrombus thickness), was assessed against contrast phlebography. C-US test normalization occurred in only 301% of patients within 1 year. A significant reduction of the thrombus mass (P<.0001) was recorded throughout the entire study period. However, a major decrease in thrombus mass (>50%o) was recorded within the first 3 months. Of 29 patients who developed a suspected recurrent DVT, phlebography confirmed diagnosis in 11. The C-US method alone showed an excellent accuracy (100%) but was applicable in only 6 patients (21%). Both the sensitivity and the specificity for proximal DVT recurrence of the combined ultrasound methods were 100%o (95% confidence interval, 69% to 100% and 81% to 100%, respectively) and were applicable in all patients. ConclusionsThe serial ultrasound measurement of thrombus mass after an acute episode of DVT may allow the correct identification of patients who develop a recurrent proximal-vein thrombosis.

D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study

Summary.  Patients with symptomatic idiopathic venous thromboembolism and apparently cancer‐free have an approximate 10% incidence of subsequent cancer. Apparently cancer‐free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2‐year follow‐up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow‐up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3–36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer‐related mortality during the 2 years follow‐up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI, −5.5–10.9)]. Although early detection of occult cancers may be associated with improved treatment possibilities, it is uncertain whether this improves the prognosis.

Frequency of Pregnancy-Related Venous Thromboembolism in Anticoagulant Factor-Deficient Women: Implications for Prophylaxis

Abstract Objective To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. Design D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. Main outcome measure Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. Setting University research and affiliated centres. Subjects 946 patients with clinically suspected deep vein thrombosis. Results Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% confidence interval 0% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. Conclusions Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.

Recurrence of Venous Thromboembolism in Patients With Familial Thrombophilia

Deep venous thrombosis is an important, although relatively infrequent, problem during pregnancy and the postpartum period. Pulmonary embolism, a much-dreaded complication of deep venous thrombosis of the leg, is one of the most frequent causes of maternal illness and death [1, 2]. Among women in the general population between 20 and 40 years of age, the annual frequency of deep venous thrombosis is 1.8% [3]. In other observational studies [4-7], the frequency of venous thromboembolism has varied from 1.3% to 7% during pregnancy and from 6.1% to 23% during the postpartum period. These findings indicate that the risk for venous thromboembolism might be increased only moderately during pregnancy but that it is clearly enhanced during the postpartum period. However, the absolute frequencies during both of these periods remain low. In contrast, in women who have an inherited deficiency of a naturally occurring anticoagulant-antithrombin, protein C, or protein S-it has been reported that pregnancy and the postpartum period are associated with a greatly increased risk for venous thromboembolism [8-11]. During pregnancy, the observed frequency of venous thromboembolism per woman per pregnancy varied from 12% to 48% in antithrombin-deficient women and from 2% to 8% in protein C-deficient women; no thrombosis was seen in protein S-deficient women [8-11]. During the postpartum period, the following frequencies were seen: 28% to 47% in antithrombin-deficient women, 11% to 20% in protein C-deficient women, and 14% in protein S-deficient women [8-11]. However, the usefulness of these data for clinical decision making is limited because the studies that produced the data lacked appropriate control groups and included many patients who were identified because they presented with venous thrombosis, either associated with or unrelated to pregnancy. In addition, most of the identified thrombotic events were diagnosed on the basis of clinical findings only, which are known to be nonspecific, particularly during pregnancy [12]. Hence, the frequencies reported previously are likely to be overestimates. As a result, the best approach to anticoagulative prophylaxis for venous thromboembolism in anticoagulant factor-deficient women during pregnancy and the postpartum period is actively debated. Advocated regimens range from surveillance combined with noninvasive tests for deep venous thrombosis only to prophylaxis with therapeutic doses of heparin and oral anticoagulants throughout pregnancy and the postpartum period [13, 14] combined with intravenous administration of the lacking proteins. Also debated are the maternal and fetal adverse effects associated with the use of heparin and oral anticoagulants during pregnancy. The administration of coumarins during pregnancy may cause embryopathy [15], and the use of heparin has been associated with osteoporosis, which may result in bone fractures [16, 17]. Both of these drugs may also induce hemorrhagic complications, especially during delivery [15, 18]. Because the lack of accurate clinical data on the frequency of venous thromboembolism contributes to a wide variation in clinical practice regarding this event, physicians obviously need better information about the frequency of venous thromboembolism in anticoagulant factor-deficient women. We therefore sought to determine the frequency of venous thromboembolism during pregnancy and the postpartum period among otherwise asymptomatic women with a deficiency of antithrombin, protein C, or protein S. We investigated all female family members of probands known to have a deficiency of one of these factors and assessed the frequency of pregnancy-related venous thromboembolism in this group. The deficiency status of the female family members was determined only after a careful, structured history was obtained. The female family members found to be nondeficient were used as a representative control group. Methods Patients Female members of 69 families that had a documented deficiency of antithrombin, protein C, or protein S were investigated. The study participants were identified through the family trees of unselected patients who had an objective diagnosis of venous thromboembolism and were referred to the participating study centers (Academic Medical Center, Amsterdam, the Netherlands; Institute of Medical Semeiotics, Padua, Italy). These probands were excluded from further study. All of the women were interviewed by an investigator blinded to anticoagulant factor-deficiency status. A medical history, with attention to episodes of venous thromboembolism and to events in the obstetric history (such as pregnancy, childbirth, and postpartum periods), was obtained from each participant. An episode of venous thromboembolism was considered to have occurred only if it had been documented by objective tests (ultrasonography, impedance plethysmography, or venography for deep venous thrombosis; ventilation-perfusion lung scanning or pulmonary angiography for pulmonary embolism) or if it had been clinically diagnosed and the patient had been treated with anticoagulative drugs for at least 3 months. If a patient reported having had a venous thromboembolic event, further medical information was sought and reviewed by one of the investigators to establish the methods that had been used to diagnose the event. A venous thromboembolic event was considered to be pregnancy related if it occurred during pregnancy or within 3 months after childbirth. Episodes of pregnancy-related venous thromboembolism were classified according to the period in which they occurred: first trimester of pregnancy, second trimester of pregnancy, third trimester of pregnancy, puerperium ( 7 days after delivery), and the remaining postpartum period. If a patient had an episode of venous thromboembolism, all subsequent pregnancies were excluded from the analysis to avoid risk enhancement and because anticoagulative prophylaxis is often given after such an episode. After the history was recorded, blood samples were collected for the determination of anticoagulant factor status. Blood samples (20 mL) were collected by venipuncture with 21-gauge butterfly infusion sets into a plastic syringe containing 3.8% sodium citrate; the ratio of the volume of anticoagulant to the volume of blood was 0.1:0.9. Plateletpoor plasma was obtained by using centrifugation at 2000 g for 20 minutes and was stored at 80C until it was analyzed. Antithrombin antigen concentrations were measured using the Asseraplate Antithrombin III Kit (Boehringer Mannheim, Mannheim, Germany); antithrombin activity was measured using Berichrom ATIII (Behringwerke, Marburg, Germany). Protein C antigen concentrations were measured with enzyme-linked immunosorbent assay (ELISA) using rabbit anti-protein C polyclonal antibody (DAKO, Glostrup, Denmark) as catching antibody. Rabbit anti-protein C polyclonal horseradish peroxidase conjugated antibody (DAKO) was used as the second antibody according to the manufacturers instructions. Protein C activity was measured using the Protein C Reagent Kit (Behringwerke). Concentrations of total and free protein S were measured by ELISA using rabbit anti-protein S polyclonal antibody (DAKO). The 15C4 anti-protein S monoclonal antibody (Serbio, Gennevilliers, France) was used as catching antibody, and the rabbit anti-protein S polyclonal horseradish peroxidase conjugated antibody (DAKO), diluted 1:1000, was used as the second antibody. The 15C4 anti-protein S monoclonal antibody recognized only free protein S antigen. Protein S activity was measured using the Protein S IL-Kit (Instrumentation Laboratories, Milan, Italy). A participant was considered to be deficient if repeated tests done 1 month apart showed values that were subnormal for the protein deficiency in that participants family. The following reference values were used: antithrombin antigen concentration, 0.80 to 1.20 U/mL; antithrombin activity, 0.80 to 1.20 U/mL; protein C antigen concentration, 0.70 to 1.30 U/mL; protein C activity, 0.70 to 1.30 U/mL; total protein S concentration, 0.70 to 1.20 U/mL; and free protein S concentration, 0.26 to 1.08 U/mL. The criteria used to classify antithrombin, protein C, and protein S deficiencies accord with those reported in the current literature [19]. Activated partial thromboplastin time and prothrombin time were determined in an effort to exclude vitamin K deficiency. Activated partial thromboplastin time was measured by using ActinFS (Dade, Miami, Florida) (normal range, 25 to 36 seconds); prothrombin time was measured by using Thromboplastin IS (Dade) (normal range, 11 to 14 seconds). During the time of the laboratory investigation, none of the study participants were pregnant or in the postpartum period [20-23]. The participants were categorized according to deficiency status into a nondeficient group and a deficient group. The deficient group was further subdivided according to specific deficiency. Statistical Analysis In each group, the frequency of venous thromboembolism was calculated by dividing the number of pregnancy-related venous thromboembolic episodes by the total number of recorded pregnancies and by the total number of women. The percentages of deficient and nondeficient women who had thromboembolic episodes were compared using the Fisher exact test. Using a Cox model, we calculated the hazard ratio (and its mid-p corrected 95% CI) for pregnancy-related venous thromboembolism in deficient women compared with nondeficient women (SAS, Inc., version 6.11, Cary, North Carolina). The P values were calculated by using the exact log-rank test. For this purpose, a pregnancy was regarded as the unit of time and women who had not had a venous thromboembolic event by the end of their last pregnancy were considered to be censored. Results Of the female members of the 69 families, 282 women were potentially eligible for the study. Of these, 52 could not be contacted because they lived

A ‘New’ Congenital Haemorrhagic Condition due to the Presence of an Abnormal Factor X (Factor X Friuli): Study of a Large Kindred

BACKGROUND Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.

Vein abnormalities and the post-thrombotic syndrome.

Summary Three related patients are presented who show a congenital coagulation disorder with laboratory features intermediate between classical factor‐VII and factor‐X deficiencies. A woman and two men had suffered from bleeding since early childhood, with epistaxis, bleeding from the gums, post‐traumatic haemarthroses, bleeding after tooth extractions and other surgical procedures. Investigation demonstrated a prolonged prothrombin time, prolonged partial thromboplastin time, abnormal prothrombin consumption and abnormal thromboplastin generation corrected by normal serum. Platelet and vascular tests were normal and no hyperfibrinolysis was found. Factors I, II, V, VII, IX, XI and XII were within normal limits in all three patients. Mutual correction was demonstrated with a known factor‐VII‐deficient plasma but not with Stuart (X‐deficient) plasma. Factor‐X assay yielded low (4–9%) levels using tissue whole thromboplastin or tissue partial thromboplastin; but the results were normal with a Stypven‐cephalin mixture. In agreement with these results, the Stypven‐cephalin clotting time, the Stypven clotting time and the factor II + factor X level using a Stypven‐cephalin mixture were normal, ‘correction’ being attributable to the Russells Viper venom. These results were thought to indicate an abnormal factor X rather than a real deficiency.

Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature.

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