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Patients who are receiving warfarin therapy require frequent blood testing to monitor the intensity of anticoagulation. Although previous studies suggest that capillary blood monitoring of the international normalize ratio (INR) is rapid and reliable, patient preferences for the method of blood drawing have not been investigated.We performed a randomized controlled trial of patients attending an anticoagulation clinic in which patients were randomly allocated to undergo capillary or venous INR monitoring. Patient satisfaction with the outpatient visit, pain associated with blood drawing, and time spent in the clinic were assessed for each patient.Sixty patients were studied. Using a 10-point visual analogue scale to quantify patient satisfaction (0-very satisfied; 10-very dissatisfied), patients expressed a strong preference for capillary INR monitoring over venous INR monitoring (1.64 vs. 4.45; P0.001). Using a 10-point visual analogue scale to quantify pain with blood sampling (0-no pain; 10-very painful), patients who underwent capillary INR testing had less pain than venous INR testing (0.83 vs. 2.23; Por = 0.004). Patients spent, on average, 33 fewer minutes in the clinic with capillary INR testing than venous INR testing (P0.001).Our findings support the routine use of capillary blood testing, using a portable monitor, for the management of patients in outpatient anticoagulation clinics.

To determine the adequacy of initial anticoagulation by intravenous heparin for patients who have deep venous thrombosis (DVT), and the factors that influence delayed anticoagulation, independent, duplicate chart review of 63 consecutive patients who had venography-proven DVT was conducted. Adequate heparinization (AH) was defined as an activated partial thromboplastin time (PTT) of more than 1.5 times the normal laboratory control. The proportions of patients achieving AH within 24 hours and 48 hours of initial heparin bolus were 46% and 62%, respectively. Patients who weighed more were less likely to achieve AH (p

SummaryThe optimal duration of oral anticoagulant therapy for patients with acute proximal deep vein thrombosis (DVT) is uncertain. Based on the hypothesis that a normal impedance plethysmogram (IPG) following DVT defines a group of patients at low risk of recurrent venous thromboembolism (VTE), a trial was conducted to evaluate the efficacy of only four weeks of warfarin. Patients with venographically confirmed acute proximal DVT who had received four weeks of warfarin after initial heparin and whose four week IPG was normal were allocated to either continue warfarin (targeted International Normalized Ratio 2.0 to 3.0) for a further eight weeks or receive placebo. Patients with an abnormal four week IPG received warfarin for a further eight weeks. Based on clinical characteristics at the time of the qualifying thrombosis, all patients were classified as having either continuing or transient risk factors for recurrent VTE. During the eight weeks following randomization, nine (8.6%) of the 105 placebo patients developed recurrent VTE compared to one (0.9%) of the 109 warfarin patients, P = 0.009. Over the entire 11 months of follow-up, 12 placebo patients developed recurrence compared to seven warfarin patients, P = 0.3. Nineteen of the 192 patients with an abnormal four week IPG experienced recurrence during the nine months after discontinuing warfarin.In the 301 patients who received three months of warfarin in the randomized trial or in the cohort study, all 26 recurrent events were in the 212 patients with continuing risk factors.In conclusion, an IPG four weeks after proximal DVT is not a useful predictor for recurrent VTE; whereas the presence of continuing risk factors is a very strong predictor. Four weeks of oral anticoagulants may be all that is required in patients without continuing risk factors. Patients with continuing risk factors may require more than three months of oral anticoagulants.

Patients with acute proximal deep-vein thrombosis are usually treated first in the hospital with intravenous standard (unfractionated) heparin. However, the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins make them attractive for possible home use. We compared these two approaches.Patients with acute proximal deep-vein thrombosis were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or low-molecular-weight heparin (1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home (247 patients). The study design allowed outpatients taking low-molecular-weight heparin to go home immediately and hospitalized patients taking low-molecular-weight heparin to be discharged early. All the patients received warfarin starting on the second day.Thirteen of the 247 patients receiving low-molecular-weight heparin (5.3 percent) had recurrent thromboembolism, as compared with 17 of the 253 patients receiving standard heparin (6.7 percent; P=0.57; absolute difference, 1.4 percentage points; 95 percent confidence interval, -3.0 to 5.7). Five patients receiving low-molecular-weight heparin had major bleeding, as compared with three patients receiving standard heparin. After randomization, the patients who received low-molecular-weight heparin spent a mean of 1.1 days in the hospital, as compared with 6.5 days for the standard-heparin group; 120 patients in the low-molecular-weight- heparin group did not need to be hospitalized at all.Low-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

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.

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.

Background: Deep vein thrombosis is common in patients undergoing major knee surgery. Static graduated compression stockings effectively prevent venous thrombosis in general surgery. Because of the demonstrated prophylactic efficacy of pneumatic compression in knee surgery, the similar efficacy of static graduated compression and pneumatic compression in neurosurgery, and the easier use of static graduated compression in knee surgery, graduated static compression stockings were used as the control arm in our clinical trial. Although low-molecularweight heparin had been shown to be effective in general surgery and hip replacement, its efficacy was unproved in knee surgery. Methods: A double-blind, randomized trial compared the combination of low-molecular-weight heparin and graduated compression stockings with graduated compression stockings alone in patients undergoing major knee surgery. Patients received either ardeparin (Normiflo) (lowmolecular-weight heparin), 0.005 mL/kg (50 anti-Xa U/kg), or placebo. Both were administered subcutaneously twice daily commencing 12 to 24 hours after surgery and continued for 14 days or until discharge, if sooner. Both study groups wore graduated compression stockings. Bilateral venography was performed on day 14, or sooner if the patient was ready for discharge. Results: One hundred twenty-two patients were allocated to receive ardeparin and 124 received placebo. Ninety-six patients in the ardeparin group and 103 in the placebo group had evaluable venograms. Deep vein thrombosis was detected in 28 patients in the ardeparin group and in 60 in the placebo group. Proximal deep vein thrombosis was detected in two patients who received ardeparin and 16 who received placebo. One patient in each group, both of whom did not have venography, experienced pulmonary embolism. Thus, deep vein thrombosis or pulmonary embolism was detected in 29 (29.9%) of the 97 patients in the ardeparin group and in 61 (58.7%) of the 104 patients in the placebo group, a relative risk reduction of 49% (P Conclusion: Ardeparin administered postoperatively twice daily is effective and safe for the prevention of venous thrombosis in patients undergoing major knee surgery. Whereas graduated compression stockings have been shown to be effective prophylactic agents in general surgery and neurosurgery, they have little effect in knee surgery. (Arch Intern Med. 1996;156:851-856)

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.

The management of the pregnant patient with immune thrombocytopenia is complicated by the unavailability of the fetal platelet count. Since the transplacental passage of antiplatelet antibodies mediates infant thrombocytopenia, measurement of maternal platelet-associated IgG might predict infant outcome. We related the maternal platelet count and platelet-associated IgG level to the infant's platelet count in 41 pregnancies in 38 patients who were clinically diagnosed as having immune thrombocytopenia. Fifteen of 39 live-born infants were thrombocytopenic at delivery. Maternal platelet-associated IgG was predictive of infant platelet count but maternal platelet count was not; only one of the 20 infants delivered of the 18 thrombocytopenic mothers with normal platelet-associated IgG was affected, whereas 11 of 12 thrombocytopenic mothers with elevated platelet-associated IgG had thrombocytopenic infants. Five infants died in utero between 18 and 28 weeks' gestation, but otherwise there was no significant morbidity in the live births. Measurement of platelet associated IgG in mothers with immune thrombocytopenia during pregnancy can be used to predict infant thrombocytopenia, although it does not predict the severity of the thrombocytopenia.

Although it is generally accepted that negative venography excludes deep vein thrombosis (DVT) in patients in whom it is clinically suspected, there is no evidence to support this conclusion. To test the correctness of withholding anticoagulant therapy in these patients, we followed 160 consecutive patients who had clinically suspected DVT and negative venograms to determine the frequency of postvenographic DVT. Anticoagulant therapy was withheld in all patients. No patient died or developed pulmonary embolism during 3 months of follow-up. Two of the 160 patients (1.3%) attended the clinic on an emergency basis during follow-up with new symptoms of DVT and in both patients, DVT was confirmed by objective testing. These events developed within 5 days of venography, which suggests that they were induced by venography. Nevertheless, the findings indicate it is safe to withhold treatment in patients with clinically suspected DVT and negative venograms.

A number of methods have been developed to measure platelet-associated IgG (PAIgG). The antiglobulin consumption assay directly quantitates IgG on the platelet and is sensitive and specific. A fluorescent anti- IgG assay has recently been described and has the advantage of simplicity. We compared the results of these two PAIgG assays in immune and nonimmune thrombocytopenia and nonthrombocytopenic controls. The antiglobulin consumption assay was negative in 61 of 62 and the fluorescent negative in 54 of 62 assays in nonthrombocytopenic controls, and they were negative in 11 of 13 and 8 of 13 assays, respectively, in nonimmune thrombocytopenic patients. The antiglobulin consumption assay was positive in 54 of 58 and the fluorescent positive in 24 of 58 assays of patients with immune thrombocytopenia (ITP and SLE). The overall sensitivity and specificity of the antiglobulin consumption assay was 94% and 95% and of the fluorescent assay was 44% and 82%.

We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.

Thrombocytopenia is a common serious adverse effect of drug treatment. A variety of in vitro diagnostic techniques to confirm the diagnosis are available, but the majority lack sufficient sensitivity to detect all cases of drug-induced thrombocytopenia. We studied 19 patients with suspected drug-induced thrombocytopenia and demonstrated that platelet- associated IgG (PAIgG) was elevated in all at the time of thrombocytopenia, and PAIgG returned to normal levels as the thrombocytopenia resolved. In the majority of patients, the platelet count rapidly returned to normal after the drug was discontinued; however, in six patients, the thrombocytopenia persisted well beyond the period of time that the offending drug would be expected to be cleared from the blood. In 13 patients, serum obtained after recovery was used to identify the drug responsible for the thrombocytopenia in an in vitro assay. In all cases, the addition of the drug historically associated with the thrombocytopenic episode was associated with an increased binding of IgG to control platelets. For uncertain reasons, the concentration of drug required to increase the in vitro binding of IgG to test platelets was often more than the concentration usually achieved in vivo. Wider application of these techniques may provide better understanding of the clinical characteristics and mechanisms responsible for drug-induce thrombocytopenia.

Venography remains the standard method for the diagnosis of deep venous thrombosis but it is invasive and frequently causes discomfort. A randomised double-blind study was performed to determine the efficacy of lidocaine in reducing pain and discomfort associated with venography. Sixty patients undergoing ascending venography received 40 mg of lidocaine (2 ml of 2% lidocaine mixed with 50 ml of contrast medium) in one leg and saline in the other. Assessment of pain was by a standard questionnaire administered by an investigator unaware of the sequence of administration of lidocaine or saline placebo. Twenty-four patients reported no difference in pain or discomfort between the two limbs. Of the 36 patients experiencing an overall difference in pain between the two legs, 12 reported more pain in the leg receiving lidocaine and 24 reported more pain in the leg receiving saline (p = 0.023). There were no significant side effects attributable to lidocaine. These results indicate that lidocaine is beneficial in reducing pain and discomfort associated with venography.

The measurement of platelet-associated IgG (PAIgG) is a potentially useful diagnostic test for idiopathic thrombocytopenia purpura (ITP). However, the restricted application of PAIgG measurements to thrombocytopenic populations primarily comprised of ITP patients will artificially enhance its diagnosis specificity. For this reason, we performed a prospective study in which the results of a sensitive technique for quantitating PAIgG were related to the cause of the thrombocytopenia. Over a 1-yr period, clinicians were invited to submit patient blood samples encompassing as wide a spectrum of thrombocytopenic disorders as possible for PAIgG measurements. The physician was then contacted and requested to indicate the likeliest cause for the thrombocytopenia. The PAIgG was elevated in only 24 of 254 samples obtained from nonthrombocytopenic patients. In contrast, 134 (79%) of the 169 thrombocytopenic patients had elevated PAIgG results, and the increased levels were apparent in all diagnostic categories. The sensitivity of the PAIgG test for clinically diagnosed idiopathic thrombocytopenic purpura was 91% and the specificity was 27%. The positive predictive value for a raised PAIgG as a diagnostic test for ITP in a thrombocytopenic patient was only 46%, while the negative predictive value was 82%. This study indicates that the presence of increased PAIgG provides little additional information in the diagnosis of ITP. This study also suggests that immune mechanisms may mediate many more thrombocytopenic disorders than have been previously thought likely.

The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St JosePh′s Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 week's gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high- molecular weight kininogen. Factor XIII subunits A and S, von Willebrand factor, and the inhibitors antithrombin III, alpha 2- antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C, and protein S were measured immunologically. Plasminogen, prekallikrein, and heparin cofactor II were measured by using chromogenic substrates. The large number of infants studied at each time point allowed us to determine the following: the range of normal for each test at five time points in the postnatal period; that coagulation tests vary with the postnatal age of the infant; that different coagulation factors show different postnatal patterns of maturation; and that near-adult values are achieved for most components by 6 months of life. In summary, this large cohort of infants studied consecutively in the postnatal period allowed us to determine the normal development of the human coagulation system in the full-term infant.

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.

We investigated the hypothesis that the diagnostic accuracy of impedance plethysmography (IPG) for thrombosis of the popliteal or more proximal veins increases with enhanced venous filling. Venous filling was increased by prolonging cuff occlusion and by sequential testing. IPG and vengography were performed on 169 legs with and 317 legs without proximal vein thrombosis. The sensitivity and specificity of IPG rose significantly with increased venous filling. Changes in venous filling were associated with corresponding changes in emptying in normal legs, but not those with proximal vein thrombosis, so that the regression lines relating venous filling and emptying in normal and abnormal legs diverged significantly (P less than 0.001). If the IPG sequence had been terminated after only a single 45 second occlusion time test, sensitivity would have deteriorated by 10% and specificity by 20%. These observations indicate that the accuracy of IPG can be significantly enhanced if optimal venous filling is obtained.

A number of investigators have recently reported that human female platelets have increased reactivity in vitro compared to platelets from age-matched males. A possible explanation for these observations is that the lower hematocrit in females results in a larger volume of distribution of the anticoagulant, with resultant higher ionized calcium concentrations. To examine this possibility, we performed adenosine diphosphate (ADP) and collagen aggregations on platelets obtained from 11 male and 11 female healthy subjects. When aggregations were performed on blood samples using the standard amount of 3.8% sodium citrate as an anticoagulant (9:1, v:v, blood:anticoagulant), the female platelets were significantly more reactive than the male platelets over a wide range of ADP and collagen concentrations (p

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.

This study was designed to determine the postnatal development of the human coagulation system in the healthy premature infant. Consecutive mothers of healthy premature infants born at either St Joseph's Hospital or McMaster University Medical Centre in Hamilton were asked for consent. One hundred thirty-seven premature infants (30 to 36 weeks of gestational age) entered the study. The premature infants did not have any major health problems and did not require ventilation or supplemental oxygen. Demographic information and a 20-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 96 premature infants were studied on each day for each of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, plasminogen; 13 factor assays [fibrinogen, II, V, VII, VIII, IX, X, XI, XII, XIII, high-mol-wt kininogen (HMWK), prekallikrein (PK), von Willebrand factor (vWF)] and eight inhibitors [antithrombin III (AT-III), heparin cofactor II, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C (PC), and protein S (PS)]. A combination of biologic and immunologic assays were used. Between 30 to 36 weeks there was a minimal effect of gestational age for levels of AT-III, PC, and factors II and X only; therefore, the entire data set was used to generate reference ranges for these components of the coagulation system for premature infants. Next, the results for the premature infants were compared with those of a previously published study in 118 fullterm infants and with those for adults. An effect of gestational age was shown for plasminogen, fibrinogen, factors II, V, VIII, IX, XI, XII, HMWK, and all eight inhibitors. In general, the postnatal maturation towards adult levels was accelerated in premature infants as compared with the fullterm infants. By 6 months of age, most components of the coagulation system in premature infants had achieved near adult values.

PASSIVE immune neonatal thrombocytopenia is caused by the transplacental passage of platelet antibodies, either from a mother with autoimmune thrombocytopenia or from one who is alloimmunized by he...

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.

Two variations of a method for the determination of sulphinpyrazone in plasma by gas chromatography and by gas chromatography/mass spectrometry are described. Both are based upon methylation of sulphinpyrazone by phase transfer catalysis with methyl iodide as the alkylating agent. The range of plasma concentrations in patients with transient cerebral ischemia being treated with sulphinpyrazone as well as hemodialysis patients being treated for arteriovenous shunt thrombosis are described. Accumulation of sulphinpyrazone did not occur in hemodialysis patients, indicating that in these patients the drug is effectively cleared by a non-renal mechanism.

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.

We describe a prospective study comparing four different assays for PAIgG. Platelets from patients with a variety of thrombocytopenic disorders were collected into ACD, washed, and the PAIgG then measured using three assays for surface PAIgG. These included: (a) a direct binding assay using 125I-monoclonal anti-IgG (MoAb); (b) a direct binding assay using 125I-staphylococcal protein A (SPA); and (c) a two-stage assay. PAIgG also was measured using an assay for 'total' PAIgG following platelet lysis. The mean +/- SD number of molecules of IgG per platelet on washed platelets from 29 healthy, non-thrombocytopenic controls was: 86 +/- 80 (125I-MoAb); 94 +/- 96 (125I-SPA); 3520 +/- 1890 (two-stage surface assay); and 10,850 +/- 3720 (total PAIgG). A total of 62 different patients with idiopathic thrombocytopenic purpura or thrombocytopenia complicating systematic lupus erythematosus, and 73 different patients with 'non-immune' thrombocytopenia, were tested using each of the four assays. These 'non-immune' thrombocytopenic patients included patients with carcinoma, septicaemia, pre-eclampsia, chronic leukaemia, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, acute leukaemia and myelodysplasia. All four assays gave similar results for both the immune and non-immune thrombocytopenic patients. The sensitivity of the assays for the most severely thrombocytopenic patients with immune thrombocytopenia was: MoAb 60%; SPA 88%; two-stage 82%; and 'total' PAIgG 88%. The specificity of the four assays in the non-immune thrombocytopenic patients was 57% 'total' PAIgG; 63% two-stage surface; 25% SPA; 38% MoAb.(ABSTRACT TRUNCATED AT 250 WORDS)

Impedance plethysmography (IPG) combined with leg scanning is highly sensitive and specific for deep vein thrombosis (DVT) in patients with their first episode of clinically suspected DVT. This approach has not been evaluated in patients with suspected recurrent DVT. In this group of patients venography alone is of limited value in excluding acute DVT in the presence of previous DVT but is useful if constant intraluminal filling defects (ILFD) suggesting acute DVT are present. We have evaluated the clinical utility of IPG plus leg scanning and venography in 132 patients with clinically suspected acute recurrent DVT. If the IPG on referral was negative the patient was leg scanned daily for 72 hours and if both were negative, anticoagulant therapy was witheld. The validity and safety of this approach was tested by 3 months follow-up. If IPG was positive, venography was performed to distinguish ILFD’s from chronic DVT. If ILFD’s were detected, anticoagulant therapy was commenced. If no ILFD’s were detected the patient was leg scanned for 72 hours and if negative treatment was witheld. The clinical utility of this non-invasive approach is demonstrated by the results of this study. Of 132 patients, 82 (62%) were negative by both non-invasive tests and none died, developed pulmonary embolism or recurrent DVT during follow-up. The remaining 50 patients were positive by noninvasive testing; in 31 patients ILFD’s were detected and in 16 venography was indeterminate showing collaterals, absent segments, recanalization or inadequate visualization. The leg scan was positive in 10 of the latter 16 patients. Thus the diagnosis of recurrent acute DVT was established by the presence of ILFD’s or a positive leg scan. In 6 patients with a positive IPG, negative leg scan and indeterminate venogram the diagnosis remained uncertain. In conclusion this combined non-invasive and invasive approach provided definitive management in 126 of 132 patients (95%).

The clinical value of adding impedance plethysmography (IPG) to 125 I-fibrinogen leg scanning was evaluated and compared in 630 patients who had general surgical procedures and 385 patients who had hip surgery. Patients were screened by both tests and venography was performed if either test was positive to determine a) the frequency with which proximal VT, confirmed by venography, was detected by IPG but not by leg scanning, and b) the positive predictive value of these tests used either alone or in combination. Either the IPG or leg scan result was abnormal in 67 of 630 general surgical patients (11%) and in 158 of 385 hip surgery patients (41%). The positive predictive values of the tests in general surgical and hip surgery patients was 79% and 86% respectively for the leg scan alone, 33% and 90% for IPG alone and 87% and 95% when both the leg scan and IPG were positive. The addition of IPG to leg scanning in general surgical patients identified only 1 addition patient with proximal vein thrombosis (0.2%) whereas in hip surgery patients the addition of IPG identified 25 additional patients with proximal vein thrombosis (6%). It is concluded that the addition of IPG to leg scanning is not useful among general surgical patients but is of substantial clinical value in hip surgery patients.

Venography is the standard method for the diagnosis of venous thrombosis but is invasive and may cause discomfort. We evaluated the combination of impedance plethysmography and 125I-fibrinogen leg scanning as an alternative to venography in 200 symptomatic patients. One or both of these less invasive tests was positive in 81 of 86 patients with positive venograms (sensitivity of 94 per cent) and both were negative in 104 of 114 patients with negative venograms (specificity of 91 per cent). These two tests detected all 60 patients with popliteal or more proximal venous thrombosis and 21 of 26 patients with calf-vein thrombosis. In addition, this approach detected 21 of 22 patients with calf-vein thrombosis with symptoms for eight days or less. These results suggest that the combination of these two less invasive tests can be used as an alternative to venography in selected patients with clinically suspected venous thrombosis. (N Engl J Med 296:1497–1500, 1977)

A cohort study was performed to determine the postnatal development of the coagulation system in the “healthy” premature infant. Mothers were approached for consent and a total of 132 premature infants were entered into the study. The group consisted of 64 infants with gestational ages of 34-36 weeks (prem 1) and 68 infants whose gestational age was 33 weeks or less (prem 2). Demographic information and a 2 ml blood sample were obtained on days 1, 5, 30, 90, and 180. Plasma was fractionated and stored at −70°C for batch assaying of the following tests: screening tests, PT, APTT; factor assays (biologic (B)); fibrinogen, II, V, VII, VIII:C, IX, X, XI, XII, prekallikrein, high molecular weight kininogen, XIII (immunologic (I)); inhibitors (I), antithrombin III, aα2-antiplasmin, α2-macroglobulin, α-anti-trypsin, Cl esterase inhibitor, protein C, protein S, and the fibrinolytic system (B); plasminogen. We have previously reported an identical study for 118 full term infants. The large number of premature and full term infants studied at varying time points allowed us to determine the following: 1) coagulation tests vary with the gestational age and postnatal age of the infant; 2) each factor has a unique postnatal pattern of maturation; 3) near adult values are achieved by 6 months of age; 4) premature infants have a more rapid postnatal development of the coagulation system compared to the full term infant; and 5) the range of reference values for two age groups of premature infants has been established for each of the assays. These reference values will provide a basis for future investigation of specific hemorrhagic and thrombotic problems in the newborn infant.

Platelet-associated IgG (PAIgG) can be measured on intact platelets or following platelet lysis. Measurement of PAIgG following platelet lysis may provide different or additional information compared to PAIgG measured on intact platelets. The PAIgG of lysed platelets represents “total” PAIgG, ie, IgG on the surface of platelets plus any IgG that was inside the platelet. To investigate the clinical relevance of the two types of PAIgG assay we performed a prospective study on washed platelets collected from 47 patients with idiopathic thrombocytopenic purpura (ITP). The PAIgG was measured on intact and lysed platelets using an immunoradiometric assay. Platelet-associated IgG was 2–3 times higher when measured on lysed platelets from healthy controls or patients with ITP compared to PAIgG measured on the same intact platelets. The higher level of PAIgG observed following platelet lysis was not due to the reactions not achieving equilibrium. Using lysed platelets, PAIgG was elevated on 29 of 47 samples from different ITP patients and elevated in 31 samples when measured on intact platelets. The PAIgG is invariably higher when measured following platelet lysis compared measurements made on intact platelets. Neither technique offers a diagnostic advantage over the other.

Noninvasive diagnostic testing is gaining acceptance in the evaluation of patients with clinically suspected venous thrombosis. Although clinically useful, all these tests have limitations, and the safety of basing therapeutic decisions on their outcome has not been assessed. We have done a prospective study of 322 symptomatic patients to ascertain the safety of replacing venography with impedance plethysmography and leg scanning. To provide a diagnostic reference, we did venography in all patients but withheld anticoagulants if the noninvasive tests were negative irrespective of the results of venography. None of the 163 patients with negative noninvasive tests died or developed clinical pulmonary embolism during 3 months' follow-up, confirming the safety of this approach. In two, clinically evident postvenographic venous thrombosis developed, confirmed by repetition of these objective tests. Also, the positive predictive values indicate that therapeutic decisions can be based on a positive noninvasive outcome in patients without clinical disorders known to produce false-positive results.

• 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)

In a prospective study to determine the frequency of thrombocytopenia in patients treated with intravenous heparin sodium of porcine gut origin, only four of 120 patients with suspected venous thromboembolism showed a depression of the platelet count to below 150×10 9 /L. In two of these patients, heparin was not considered to be the cause of thrombocytopenia because the platelet count, which fell transiently, rose again while heparin therapy was continued. These results indicate that thrombocytopenia is an uncommon complication of anticoagulant therapy with heparin derived from porcine gut mucosa. ( JAMA 241:2396-2397, 1979)

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.