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Background Antibodies against the "self" protein, platelet factor 4 (PF4), bound to heparin—the cause of immune heparin-induced thrombocytopenia—are believed invariably to be triggered by preceding heparin therapy. We describe a novel syndrome, spontaneous heparin-induced thrombocytopenia , in which clinical and serologic features characteristic of this adverse drug reaction develop in patients despite the absence of preceding heparin therapy. Methods Three patients met the study criteria (clinical and serologic features of heparin-induced thrombocytopenia without preceding heparin exposure), of whom 2 patients were identified among 225 patients (0.89%, 95% confidence interval, 0.11%-3.17%) with serologically confirmed heparin-induced thrombocytopenia recognized during an 18-year period at 1 hospital. The platelet serotonin-release assay was used to detect heparin-dependent immunoglobulin G-induced platelet activation, and 2 enzyme immunoassays were used to detect antibodies against PF4/heparin. Results Two patients presented with thrombocytopenia and multiple arterial thrombosis, and 1 patient presented with anaphylactoid reactions after 2 subcutaneous injections of low-molecular-weight heparin. All 3 patients had high levels of platelet-activating anti-PF4/heparin antibodies of immunoglobulin G class at presentation despite the absence of previous heparin exposure. However, each patient did have a preceding infectious or inflammatory event; 1 patient had concomitant antiphospholipid antibodies. Conclusion Circumstances other than heparin use can trigger a spontaneous disorder that closely mimics heparin-induced thrombocytopenia, further supporting the autoimmune nature of this adverse drug reaction.

Recent advances in our understanding of the mechanisms of physiological hemostasis and the limitations of existing antithrombotic drugs (ASA, Unfractionated Heparin and Oral Vitamin K antagonists) have led to the development and expanding clinical use of a number of new antithrombotic agents designed to target specific steps in the platelet and coagulation hemostatic pathways. Although these new agents hold the promise of increased efficacy, safety, and clinical utility for many patients on antithrombotic therapy, they also pose potential drawbacks and new challenges when those patients undergo neuroaxial blockade. A clear understanding of the mechanisms of action, pharmacokinetics, and duration of action and strategies to reverse the anticoagulant effect of both old and new antithrombotic agents are essential for the safe delivery of regional anesthesia/analgesia.

Background Low-molecular-weight heparin is known to be safe and effective for the initial Treatment of patients with proximal deep-vein thrombosis. However, its application to patients with pulmonary embolism or previous episodes of thromboembolism has not been studied.Methods We randomly assigned 1021 patients with symptomatic venous thromboembolism to fixed-dose, subcutaneous low-molecular-weight heparin (reviparin sodium) or adjusted-dose, intravenous unfractionated heparin. Oral anticoagulant therapy with a coumarin derivative was started concomitantly and continued for 12 weeks, Approximately one third of the patients had associated pulmonary embolism, The outcome events studied over the 12 weeks were symptomatic recurrent venous thromboembolism, major bleeding, and death. We sought to determine whether low-molecular-weight heparin is at least equivalent to unfractionated heparin in patients with venous thromboembolism.Results Twenty-seven of the 510 patients assigned to low-molecular-weight heparin (5.3 percent) had recurrent thromboembolic events, as compared with 25 of the 511 patients assigned to unfractionated heparin (4.9 percent). The difference of 0.4 percentage point indicates that the two therapies have equivalent value according to our predetermined definition of equivalence. Sixteen patients assigned to low-molecular-weight heparin (3.1 percent) and 12 patients assigned to unfractionated heparin (2.3 percent) had episodes of major bleeding (P=0.63), and the mortality rates in the two groups were 7.1 percent and 7.6 percent, respectively (P=0.89).Conclusions Fixed-dose, subcutaneous low-molecular-weight heparin is as effective and safe as adjusted-dose, intravenous unfractionated heparin for the initial management of venous thromboembolism, regardless of whether the patient has pulmonary embolism or a history of venous thromboembolism. (C) 1997, Massachusetts Medical Society.

Background. Flatfoot deformities are common in children and are treated using many conservative and surgical approaches. Subtalar extra-articular arthroereisis, in particular, limits talar motion, spares the subtalar joint, and prevents excessive subtalar joint pronation. Addressing the underlying equinus deformity with gastrocnemius recession is an important factor in optimizing outcomes in patients with flatfoot deformity. Methods. This study included 20 children, 4 to 17 years old. The patients presented 34 cases of functional flexible flatfoot, and each was treated with gastrocnemius recession and a subtalar implant insertion of either a resorbable arthroereisis plug constructed of poly-L lactic acid or a threaded titanium alloy plug. Clinical evaluation was based on the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale as well as subjective assessments of pain, function, shoe wear, and overall preoperative and postoperative satisfaction. Results. The average AOFAS Ankle-Hindfoot Scale reading improved by 21.3 points (standard deviation = 8.1; 95% confidence interval = 17.5-25.1), from an average preoperative reading of 67.7 points to an average postoperative reading of 89 points (P < .0001). Subjectively, patients experienced reduced pain and improved function, cosmesis, and shoe wear. Conclusions. Treating equinus deformity with gastrocnemius recession significantly improved patient outcomes when treating flatfoot deformity. Reconstructive flatfoot surgery that combined subtalar arthroereisis with a resorbable arthroereisis plug and gastrocnemius recession resulted in favorable clinical outcomes and patient satisfaction. Symptom improvement and preservation of the subtalar joint were seen with these procedures, which are reasonable and useful options in treating children with symptomatic flexible flatfoot. Levels of Evidence: Therapeutic, Level IV, Retrospective case series

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition that can develop after exposure to unfractionated or low-molecular-weight heparins. Treatment options appear to be limited in patients on concurrent intermittent hemodialysis. We report the case of an 88-year-old man newly initiated on high-flux hemodialysis who developed HIT and extracorporeal circuit thrombosis after 3 weeks of exposure to unfractionated heparin. Our patient was successfully treated with fondaparinux 2.5 mg subcutaneously three times per week and citrate during dialysis sessions. Antifactor Xa levels were measured on several occasions while receiving fondaparinux.

Although deep-vein thrombosis and pulmonary embolism are considered common complications after major trauma, their frequency and the associated risk factors have not been carefully quantified.We performed serial impedance plethysmography and lower-extremity contrast venography to detect deep-vein thrombosis in a cohort of 716 patients admitted to a regional trauma unit. Prophylaxis against thromboembolism was not used.Deep-vein thrombosis in the lower extremities was found in 201 of the 349 patients (58 percent) with adequate venographic studies, and proximal-vein thrombosis was found in 63 (18 percent). Three patients died of massive pulmonary embolism before venography could be performed. Before venography, only three of the patients with deep-vein thrombosis had clinical features suggestive of the condition. Deep-vein thrombosis was found in 65 of the 129 patients with major injuries involving the face, chest, or abdomen (50 percent); in 49 of the 91 patients with major head injuries (53.8 percent); in 41 of the 66 with spinal injuries (62 percent); and in 126 of the 182 with lower-extremity orthopedic injuries (69 percent). Thrombi were detected in 61 of the 100 patients with pelvic fractures (61 percent), in 59 of the 74 with femoral fractures (80 percent), and in 66 of the 86 with tibial fractures (77 percent). A multivariate analysis identified five independent risk factors for deep-vein thrombosis: older age (odds ratio, 1.05 per year of age; 95 percent confidence interval, 1.03 to 1.06), blood transfusion (odds ratio, 1.74; 95 percent confidence interval, 1.03 to 2.93), surgery (odds ratio, 2.30; 95 percent confidence interval, 1.08 to 4.89), fracture of the femur or tibia (odds ratio, 4.82; 95 percent confidence interval, 2.79 to 8.33), and spinal cord injury (odds ratio, 8.59; 95 percent confidence interval, 2.92 to 25.28).Venous thromboembolism is a common complication in patients with major trauma, and effective, safe prophylactic regimens are needed.

We performed a randomized trial comparing two dosing regimens of recombinant tissue plasminogen activator (rt-PA) plus heparin vs heparin alone in the treatment of acute proximal deep vein thrombosis in 83 patients. Of 12 patients who received 0.5 mg/kg rt-PA plus heparin over 4 h, seven (58 percent) had greater than 50 percent lysis of the thrombus, compared with none of 12 who received placebo plus heparin (p=0.002). Of 28 patients who received 0.5 mg/kg rt-PA over 8 h, repeated in 24 h, six (21 percent) had greater than 50 percent lysis, compared with two (7 percent) of 30 patients who received placebo plus heparin (p=0.11). The 4-h infusion of rt-PA produced a 40 percent reduction and the 8-h infusion an 11 percent reduction in plasma fibrinogen concentration. At long-term follow-up, three (25 percent) of 12 patients in whom greater than 50 percent lysis was achieved had symptoms of the postphlebitic syndrome, compared with 19 (56 percent) of 34 patients in whom lysis was less than 50 percent (p=0.07).

Two randomized, double-blind, placebo-controlled studies assessed the analgesic efficacy of valdecoxib in patients with moderate-to-severe pain after bunionectomy. Study 1 (N = 374) assessed the efficacy of two regimens of valdecoxib on the day after surgery (valdecoxib, 40 mg, with a 20-mg redose [n = 127]; valdecoxib, 40 mg, with a placebo redose [n = 122]; and placebo/placebo [n = 125]), and study 2 (N = 478) examined the efficacy of two different multiple-dose regimens on postoperative days 2 through 5 (valdecoxib, 20 mg, twice daily [n = 160]; valdecoxib, 20 mg, once daily [n = 159]; and placebo [n = 159]). Valdecoxib provided significant pain relief and reduced the use of opioid rescue medication. This efficacy was accompanied by improved global scores, decreased pain interference with function, and increased patient satisfaction. (J Am Podiatr Med Assoc 96(5): 393–407, 2006)

After resection of bone or amputation, postoperative stump breakdown occurs frequently. Furthermore, the altered mechanics with ambulation are difficult to control with bracing and orthoses alone. During the past 10 years, the peroneus brevis tendon has been transferred to various locations in the foot after resection of the fifth metatarsal base in an effort to provide continued balance between the supinatory and pronatory forces needed for a steady gait. In patients who have had a peroneus brevis tendon transfer, the rate of postoperative ulceration and the need for further bony resection is minimal. Analysis of the biomechanical influences and effects of different anatomical placements of the transferred tendon reveals the importance of transfer of the peroneus brevis tendon. (J Am Podiatr Med Assoc 94(6): 594–603, 2004)

Patients who have had major trauma are at very high risk for venous thromboembolism if they do not receive thromboprophylaxis. We compared low-dose heparin and a low-molecular-weight heparin with regard to efficacy and safety in a randomized clinical trial in patients with trauma.Consecutive adult patients admitted to a trauma center who had Injury Severity Scores of at least 9 and no intracranial bleeding were randomly assigned to heparin (5000 units) or enoxaprin (30 mg), each given subcutaneously every 12 hours in a double-blind manner, beginning within 36 hours after the injury. The primary outcome was deep-vein thrombosis as assessed by contrast venography performed on or before day 14 after randomization.Among 344 randomized patients, 136 who received low-dose heparin and 129 who received enoxaparin had venograms adequate for analysis. Sixty patients given heparin (44 percent) and 40 patients given enoxaparin (31 percent) had deep-vein thrombosis (P=0.014). The rates of proximal-vein thrombosis were 15 percent and 6 percent, respectively (P=0.012). The reductions in risk with enoxaparin as compared with heparin were 30 percent (95 percent confidence interval, 4 to 50 percent) for all deep-vein thrombosis and 58 percent (95 percent confidence interval, 12 to 87 percent) for proximal-vein thrombosis. Only six patients (1.7 percent) had major bleeding (one in the heparin group and five in the enoxaparin group, P=0.12).Low-molecular-weight heparin was more effective than low-dose heparin in preventing venous thromboembolism after major trauma. Both interventions were safe.

Background The study objective was to determine the relative efficacy and safety of a low-molecular-weight heparinoid (Orgaran) compared with aspirin for the prevention of postoperative venous thromboembolism in patients undergoing surgery for fractured hips. A double-blind, randomized, controlled trial was used to study 251 consecutive eligible and consenting patients undergoing surgery for hip fracture in seven participating hospitals. Methods and Results Patients received either fixed-dose Orgaran by subcutaneous injection every 12 hours in a dose of 750 anti–Factor Xa units or aspirin 100 mg orally twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge, if sooner. All patients had postoperative 125 I-fibrinogen leg scanning and impedance plethysmography. If the results of one or both tests were positive, then venography was performed. Otherwise, venography was done at day 14, or sooner if the patient was ready for discharge. Pulmonary embolism in symptomatic patients was diagnosed on the basis of a high probability perfusion/ventilation lung scan, a positive angiogram, or a clinically significant embolism detected at autopsy. Evaluable venograms were obtained in 90 of the 125 patients randomly assigned to receive Orgaran and in 87 of the 126 patients assigned to receive aspirin. Venous thromboembolism was detected in 25 (27.8%) patients in the Orgaran group and in 39 (44.3%) patients in the aspirin group. Thus, there was a relative risk reduction of 37% with Orgaran ( P =.028; 95% confidence interval, 3.7% to 59.7%). Six (6.8%) of 88 patients in the Orgaran group and 12 (14.3%) of 84 patients in the aspirin group developed proximal deep vein thrombosis or pulmonary embolism, a relative risk reduction of 52% with Orgaran ( P =.137; 95% confidence interval, −30.7% to 84.6%). Hemorrhagic complications occurred in 2 (1.6%) patients given Orgaran and 8 (6.4%) patients given aspirin ( P =.10). There was one major bleed in the Orgaran group compared with four in the aspirin group. Conclusions This study demonstrates that Orgaran is significantly more efficacious than aspirin in preventing postoperative venous thromboembolism in patients undergoing surgery for fractured hips, with no evidence of any increase in hemorrhagic complications.

In a study of 50 children, the Dynamic Stabilizing Innersole System (DSIS) was found to decrease the mean resting calcaneal stance position (RCSP) by an average of 6 degrees. A comparison between the neutral calcaneal stance position and the RCSP with the DSIS showed no statistically significant difference between the means for the right or left foot, indicating that the DSIS is capable of returning severe flat foot deformities to their neutral calcaneal stance position. The RCSP with and without the DSIS differed significantly, indicating that the DSIS provides a considerable and statistically significant amount of correction in the RCSP in our study population. Furthermore, the results of linear regression showed that the DSIS appears to be sensitive to the severity of the deformity, preventing overcorrection of less severe flatfoot deformities and providing a long awaited alternative to traditional pediatric corrective flatfoot devices.

Objective To compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. Design Double-blind randomized trial. Setting Seven Canadian university-affiliated hospitals. Participants Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis. Intervention Patients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner. Measurements Deep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically. Results Venous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups. Conclusion Low-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder with autoimmune features: its target antigen is a “self” protein, platelet factor 4 (PF4), that is conformationally modified in the presence of heparin or certain other polyanions. A central dogma in HIT is that the antibodies are invariably triggered by treatment with heparin. We report four patients who developed an acute illness strongly resembling immune HIT despite the absence of any preceding heparin administration [Table 1]. Various inflammatory or invasive events were documented during the two-week period prior to each patient’s acute illness, suggesting that factors other than heparin can trigger an immune response against PF4/polyanion complexes. Following onset of their HIT-like illness, three of the patients received unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to treat proven or suspected thrombosis, which precipitated abrupt platelet count falls in all. Serum from all four patients contained antibodies serologically indistinguishable from those causing HIT, namely platelet-activating immunoglobulin G (IgG) recognizing PF4 bound to heparin or polyvinyl sulfonate [Table 2]. Two patients died from thrombosis; in the two survivors, antibodies became undetectable during follow-up, consistent with the transient nature of the anti-PF4/heparin immune response reported in HIT. Conclusion: These four patient cases suggest that on rare occasions a transient prothrombotic autoimmune disorder strongly resembling immune HIT can occur, “spontaneous HIT”. Table 1. Clinical features: 4 patients with “spontaneous HIT” Case Age M/F Platelet count nadir (× 10^9^/L) Sequelae Event(s) in preceding two weeks * UFH or LMWH were only given for proven or suspected thrombosis after “spontaneous HIT” disorder was established; DIC = disseminated intravascular coagulation 1 69 M 17 (no heparin given) Limb artery thromboses (amputations); pulmonary embolism; DIC; fatal myocardial infarction Ampicillin (sore tooth); corticosteroid injection into wrist 2 40 F 175 (pre-UFH*); 59 (post-UFH*) Stroke; limb artery thrombosis (amputation) Incision & draining procedures (recurrent groin cyst) 3 69 F 33 (pre-UFH*); 11 (post-UFH*) Bilateral adrenal infarction; digital infarcts; deep-vein thrombosis; DIC Knee replacement surgery 4 24 F 301 (pre-LMWH*); 62 (post-LMWH*) Acute systemic reaction after LMWH Pneumonia Table 2. Serologic features: 4 patients with “spontaneous HIT” Case Maximum serotonin release (0.1-0.3 U/mL UFH) (N80% inhibition in presence of 100 U/mL UFH was seen with all 4 blood samples and in both ELISAs (not shown) 1 99% 1% 0% 2.028 2.722 2 95% 0% 0% 2.909 2.284 3 100% 0% 0% 1.888 2.950 4 80% 0% 0% 1.866 2.622

The authors discuss an unusual disorder of myelin metabolism. Initial presentation was due to an unstable gait pattern. Characteristics of the disease and a representative case are evaluated.

Objective To determine the relative efficacy and safety of low molecular weight (LMW) heparin (Enoxaparin) compared with standard calcium heparin for the prevention of postoperative deep vein thrombosis in patients undergoing elective hip surgery. Design A double-blind, randomized, controlled trial. Patients Six hundred sixty-five consecutive patients undergoing hip replacement at five participating hospitals. Interventions Patients received either fixed-dose LMW heparin, 30 mg subcutaneously twice daily, or fixed-dose standard calcium heparin, 7500 units subcutaneously twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge if sooner. Measurements All patients had postoperative I-125-fibrinogen leg scanning and impedance plethysmography. If results of one or both tests were positive, then venography was done. Otherwise, venography was done between day 10 and day 14, or sooner if the patient was ready for discharge. Results Evaluable venograms were obtained in 258 of the 333 patients randomly assigned to receive LMW heparin and in 263 of the 332 patients assigned to receive calcium heparin. For patients with evaluable venograms, thrombosis was detected in 50 patients (19.4%) who received LMW heparin compared with 61 patients (23.2%) who received standard heparin (difference, -3.8%; 95% CI, -11.1% to 3.6%) (P greater than 0.2). Proximal deep vein thrombosis was detected in 5.4% of the patients receiving LMW heparin and in 6.5% of the patients receiving standard heparin (difference, -1.1%; CI, - 5.2% to 3.3%) (P greater than 0.2). For the entire group of 665 patients, venous thrombosis occurred in 17.1% given LMW heparin and in 19.0% given standard heparin. Hemorrhagic complications occurred in 31 patients (9.3%) given standard heparin and in 17 patients (5.1%) given LMW heparin (difference, 4.2%; CI, 0.3% to 8.2%) (P = 0.035). The relative risk reduction was 45%. The rate of major bleeding in the standard heparin group was 5.7% compared with 3.3% in the LMW heparin group (difference, 2.4%; CI, -1.0% to 5.4%) (P = 0.13). The relative risk reduction was 42%. Conclusion Low molecular weight heparin is significantly less hemorrhagic than standard unfractionated heparin; the difference in the rate of deep vein thrombosis, although not statistically significant (P greater than 0.2), favors the use of LMW heparin.

Differing opinions about the value of ventilation-perfusion lung scanning have created controversy concerning the correct approach to the diagnosis of pulmonary embolism. In a prospective study of 305 consecutive patients with clinically suspected pulmonary embolism and abnormal perfusion lung scans, we evaluated the role of ventilation-perfusion lung scanning, pulmonary angiography, and objective testing for venous thrombosis in the diagnostic process. Segmental or greater perfusion defects with ventilation mismatch have a high probability (86 percent) of pulmonary embolism. Contrary to current clinical practice, however, the approach of ruling against pulmonary embolism by a "low probability" scan pattern is incorrect, even with an improved technique for ventilation imaging; the frequency of pulmonary embolism in these patients ranged from 25 to 40 percent. Objective testing for venous thrombosis provides a practical alternative to performing pulmonary angiography in the diagnostic work-up; by providing an endpoint for commencing anticoagulant therapy, a positive result obviates the need for further testing in 20 to 30 percent of patients.

Recurrent venous thrombosis presents a diagnostic challenge. Venography, impedance plethysmography and fibrinogen leg scanning all have potential limitations, and their role in this context has not been evaluated. We performed a prospective cohort study evaluating impedance plethysmography and leg scanning, plus venography, using outcome on long-term follow-up as the end point in 270 patients with clinically suspected recurrent deep-vein thrombosis. Anticoagulant treatment was withheld in the 181 patients negative by noninvasive testing and was given in patients positive by impedance plethysmography if leg scanning was positive or if intraluminal filling defects were detected by venography. The validity of this approach was tested by long-term follow-up. Three of 181 patients (1.7%) negative by noninvasive testing had a recurrence, compared with 18 of 89 (20%) with positive findings (p less than 0.001). Our objective diagnostic approach has high clinical utility; an objective rationale for withholding or giving treatment was established in 95% of patients.

SummaryVenous thromboembolism is a common post-operative complication in patients following hip surgery. 125I-fibrinogen leg scanning and impedance plethysmography (IPG), are often used in the detection of venous thrombi in such patients. Information on the sensitivity and specificity of these non-invasive tests for the diagnosis of venous thrombosis following hip surgery is relevant for both patient management and for choosing the appropriate outcome measure for clinical trials evaluating new prophylactic regimens.We determined the sensitivity and specificity of the IPG alone, the 125I-fibrinogen leg scan alone, as well as the combined use of the two tests from a retrospective analysis of 685 hip surgery patients who participated in clinical trials of anti-thrombotic prophylaxis. These patients were followed prospectively with non-invasive tests. Bilateral venography was attempted either when one or both screening tests became positive or on day 10-14 post-operatively if both screening tests remained negative. Adequate venography was obtained in 1,010 (73.7%) legs and thrombi were identified in 198 (19.6%) legs.The sensitivities of the IPG and leg scanning were 12.9% and 44.6% respectively; the corresponding specificities were 98.1% and 95.0%. The sensitivity of a positive result on one or both screening tests was 49.6% with a specificity of 93.9%.Therefore, leg scanning and IPG, even in combination, are not sufficiently accurate to be recommended as the only strategy for the diagnosis of venous thrombosis following hip surgery. Venography should be considered in all patients undergoing surveillance testing either when one or both of the screening tests become positive or on day 10-14 if the screening tests remain negative.

We have previously reported that long-term therapy with warfarin is effective for preventing recurrent venous thromboembolism in patients with proximal-vein thrombosis but that there is an appreciable risk of hemorrhage. To determine whether that risk could be reduced without a loss of effectiveness, we randomly allocated 96 patients with proximal-vein thrombosis to a group receiving less intense anticoagulant therapy, with a mean prothrombin time of 26.9 seconds using the Manchester comparative reagent (corresponding Simplastin time, 15 seconds), or a group given more intense therapy, with a mean Simplastin time of 19.4 seconds (corresponding prothrombin time 41 seconds with the Manchester comparative reagent) (P less than 0.001). Two of 47 patients (4 per cent) in the less intensely treated group had hemorrhagic complications, as compared with 11 of 49 patients (22 per cent) in the more intensely anticoagulated group (P = 0.015 by the two-tailed test). This difference was due to minor bleeding episodes. The frequency of recurrent venous thromboembolism was low in both groups (2 per cent). Our findings indicate that less intense anticoagulant therapy is associated with a low frequency of recurrent venous thromboembolism (2 per cent) and a reduced risk of hemorrhage.

The prothrombin time (PT) is frequently performed to monitor anticoagulant therapy. Although relatively simple to perform, it requires venipuncture and laboratory resources for sample handling and analysis. A recently developed capillary whole blood device that uses fingerstick samples was evaluated. Paired capillary whole blood and reference plasma PTs were performed in 858 samples from 732 subjects. The PT for normal volunteers (n = 193) was 11.8 +/- 0.9 seconds with the use of the new instrument and 12.1 +/- 0.5 seconds with the use of the reference method. In samples from 539 patients receiving anticoagulants, the correlation coefficient between the two methods was 0.96. Venous whole blood without anticoagulant and capillary whole blood gave equivalent results, which suggests that the fingersticks do not effect the quality of the specimen. Variation in hematocrit between 23.4% (0.34) and 53.8% (0.538) did not alter the performance of the instrument. The new instrument is easy to use and may allow testing by nonlaboratory personnel and patients. It obviates the need for venipuncture, provides immediate results, and appears to be comparable in accuracy to current reference methods.

The clinical diagnosis of venous thrombosis is highly non-specific. The reason for this is that none of the symptoms or signs of venous thrombosis is unique to this condition--that is, each can be caused by nonthrombotic disorders. Objective testing to confirm or exclude the diagnosis of venous thrombosis, then, is mandatory in patients with clinically suspected deep vein thrombosis.

The optimal method of venous thrombosis prophylaxis in patients with stroke is uncertain. ORG 10172 is a low molecular weight heparinoid consisting principally of heparan and dermatan sulphates. In animal studies, ORG 10172 is as effective as unfractionated heparin in preventing venous thrombosis but produces less bleeding. There have been a limited number of descriptive studies on its use in humans, but to date randomized efficacy trials of ORG 10172 in the prevention of venous thrombosis have not been reported. A double blind randomized trial was carried out to compare ORG 10172 with placebo in the prevention of deep vein thrombosis in patients with thrombotic stroke. Seventy-five patients were randomized to receive ORG 10172 (50 patients) in a loading dose of 1,000 anti-Xa units intravenously followed by 750 anti-Xa units subcutaneously 12 hourly or placebo (25 patients). Prophylaxis was commenced within 7 days of stroke onset, continued for 14 days or until discharge from hospital, if earlier. Venous thrombosis surveillance was carried out with 125-1 fibrinogen leg scanning and impedance plethysmography. Venous thrombosis was confirmed by venography which occurred in 2 of 50 (4%) in the ORG 10172 group and 7 of 25 (28%) in the placebo group (p=0.005). The corresponding rates for proximal vein thrombosis were 0% and 16%, respectively (p=0.01). There was one major haemorrhage in the treated group and one minor haemorrhage in the placebo group. The anti-factor Xa levels (units/ml; mean ± SE) gradually rose from 0.18 ± 0.001 and 0.06 ± 0.01 six and 12 hours after injection on the first day to 0.24 ± 0.02 and 0.12 ± 0.01 after 11 days treatment. The results of this study indicate that ORG 10172 heparinoid is effective prophylaxis against deep vein thrombosis in patients with acute thrombotic stroke.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

• A randomized trial was carried out with 194 patients to compare the effectiveness of sodium warfarin or aspirin with that of placebo in the prevention of venous thromboembolism after surgery for fractured hip. Prophylaxis was commenced postoperatively and continued for 21 days or until patient discharge, whichever was earlier. All patients underwent surveillance with iodine 125–fibrinogen leg scanning and impedance plethysmography, with subsequent venography. Venous thromboembolism occurred in 13 patients (20.0%) in the warfarin group, 27 patients (40.9%) in the aspirin group, and 29 patients (46.0%) in the placebo group. Proximal vein thrombosis or pulmonary embolism occurred in 6 patients (9.2%) in the warfarin group, 7 patients (10.6%) in the aspirin group, and 19 patients (30.2%) in the placebo group. The results of this study show that sodium warfarin therapy is safe and effective in preventing thromboembolic complications in patients undergoing surgery for fractured hip, and that aspirin therapy is an equally safe and effective method for preventing proximal vein thrombosis or pulmonary embolism. (Arch Intern Med. 1989;149:771-774)

Inherent contradictions in current diagnostic recommendations for pulmonary embolism have created considerable confusion and controversy. To resolve these contradictions, we did a prospective study of ventilation-perfusion scanning, pulmonary angiography, and venography in consecutive patients with clinically suspected pulmonary embolism and abnormal perfusion scans. Ventilation scanning increased the probability of pulmonary embolism in patients with large perfusion defects and ventilation mismatch, but a ventilation-perfusion match was not helpful in ruling out pulmonary embolism. Small perfusion defects with mismatch had neither sufficiently high nor low probability to be of diagnostic value. The observed frequency of proximal vein thrombosis (19% to 51%) and its association with the range of ventilation-perfusion defects have important implications for management of pulmonary embolism. Pulmonary angiography is required in combination with venography in most patients with perfusion abnormalities because the probability of pulmonary embolism is neither sufficiently high nor low to confirm or exclude pulmonary embolism.

Impedance plethysmography is an accurate noninvasive method to test for proximal vein thrombosis, but it is insensitive to calf-vein thrombi. We randomly assigned patients on referral with clinically suspected deep-vein thrombosis and normal impedance plethysmographic findings to either serial impedance plethysmography alone or combined impedance plethysmography and leg scanning (which has been shown to be essentially as sensitive as venography) and compared the long-term outcomes. During the initial surveillance, deep-vein thrombosis was detected in 6 of 311 patients (1.9%) tested by serial impedance plethysmography alone and in 30 of 323 patients (9.3%) (most with calf-vein thrombi) tested by the combined approach (p less than 0.001). During long-term follow-up, no patient died from pulmonary embolism; but 6 patients (1.9%; 95% confidence limits, 0.7% to 4.2%) tested by serial impedance plethysmography developed deep-vein thrombosis compared with 7 patients (2.2%; 95% confidence limits, 0.9% to 4.4%) tested by the combined approach. Serial impedance plethysmography used alone is an effective strategy to evaluate such symptomatic patients.

Considerable progress has been made over the last 15 years in our understanding of the natural history, diagnosis, and treatment of deep vein thrombosis.1The nonspecificity of clinical diagnosis has been confirmed by several studies,2-5and the reliability of objective tests such as fibrinogen I 125 leg scanning,6venography,7and impedance plethysmography (IPG) has been established for patients who present with their first episode of clinically suspected venous thrombosis.8,9In contrast, relatively few studies have been performed to clarify the diagnostic process in patients with a history of venous thrombosis who have recurrent symptoms of leg pain and swelling.10,11 Until recently, most of these symptomatic patients were considered to have acute recurrent deep vein thrombosis (which is potentially life-threatening) on the basis of their clinical presentation alone. They then received long-term anticoagulant therapy or, in some cases, caval interruption procedures. Some patients experienced the inconvenience of multiple hospital admissions or