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PubMed1989

Comparison of laboratory tests used for identification of the lupus anticoagulant.

A comparison of the sensitivities of the ten most commonly used tests for the identification of the lupus anticoagulant (LA) and the lupus cofactor phenomenon was undertaken on 18 patients. All investigations, except the cardiolipin-antibody ELISA assay, were carried out using patient's plasma alone followed by a 1:1 mix with control plasma. Dilution studies (1:3, 1:6, 1:9--patient:control) were also carried out. The kaolin clotting time (KCT) was the only test positive in all patients at all dilutions, while the dilute activated partial thromboplastin time with kaolin (Dil-APTT) registered 17 of 18 positive at all dilutions. Both the dilute Russell viper venom time (Dil-RVVT) and the tissue thromboplastin inhibition time (TTI) (1/500 thromboplastin) identified the LA in 17 of 18 patients on initial testing but were less sensitive in the dilution studies. The KCT is not a suitable test for routine laboratory use, as it requires an individual filtration step. Therefore a combination of either the Dil-APTT or Dil-RVVT together with the TTI (1/500 dilution thromboplastin) is recommended for routine LA screening, as all patients with LA in this study were identified using these easily automated tests. The lupus cofactor phenomenon was most frequently demonstrated using the Dil-APTT.

Antibodies↗

PubMed1994

Monitoring of anticoagulation in aprotinin-treated patients during heart operation.

Since aprotinin has become extensively used during cardiopulmonary bypass the maintenance of safe anticoagulation is a concern. Aprotinin affects anticoagulation measurement by the activated clotting time. Therefore, a reliable new measurement is needed to monitor anticoagulation during cardiopulmonary bypass. In the present study, we tested the efficacy of two alternative measurements in which whole blood clotting was stimulated by high-dose thromboplastin or by high-dose thrombin. During cardiopulmonary bypass under standardized heparinization, the activated clotting time was twofold longer in the aprotinin group than in control group (p < 0.05), whereas high-dose thromboplastin and high-dose thrombin groups were not significantly affected by aprotinin. In laboratory tests using blood from healthy volunteers, all methods showed linear correlation with heparin concentration in the absence of aprotinin (p < 0.05). However, the activated clotting time measurement was prolonged more by heparin when aprotinin was present (p < 0.05), whereas high-dose thromboplastin and high-dose thrombin measurements were not. Moreover, these measurements were faster and more dependable than the activated clotting time. Therefore, high-dose thromboplastin time and high-dose thrombin time seem to be reliable for monitoring anticoagulation when aprotinin is used during cardiopulmonary bypass.

Aged↗

PubMed1992

Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA).

BACKGROUND AND OBJECTIVES: The conjunctive use of intravenous heparin may influence the efficacy of alteplase for coronary thrombolysis in patients with acute myocardial infarction. In this study we examined the relation between the level of intravenous anticoagulation with heparin and sustained coronary artery patency in a subgroup of patients of the European Cooperative Study Group (ECSG) trial. METHODS: In the ECSG trial, patients treated with alteplase and aspirin were randomized to concomitant fixed doses of intravenous heparin (a bolus dose of 5,000 U followed by a continuous infusion of 1,000 U/h or placebo). The current study group comprised 149 of 324 ECSG patients allocated to heparin therapy and 132 of 320 ECSG patients allocated to placebo administration who had both an interpretable coronary angiogram obtained within 6 days of treatment and sufficient plasma samples to assess the level of anticoagulation. Activated partial thromboplastin times, fibrinogen and D-dimer levels were determined on plasma samples at baseline and at 45 min and 3, 12, 24 and 36 h after the start of alteplase administration. RESULTS: The coronary artery patency rate was higher in patients allocated to heparin therapy than in those allocated to placebo (80% and 71%, respectively, p = 0.05). Patients allocated to heparin were classified into three subgroups: 48 patients (32%) with all activated partial thromboplastin times at least twice their own baseline value (optimal anticoagulation), 40 patients (27%) with the lowest activated partial thromboplastin time at 3, 12, 24 or 36 h between 130% and 200% of the baseline value (suboptimal anticoagulation) and 61 patients with at least one activated partial thromboplastin time less than 130% of baseline (inadequate anticoagulation). In the heparin group, coronary artery patency correlated with the level of anticoagulation: 90%, 80% and 72%, respectively, in patients with optimal, suboptimal and inadequate anticoagulation (p = 0.02, optimal vs. inadequate anticoagulation). Heparin administration was associated with a smaller reduction in fibrinogen and a smaller increase in D-dimer level during and after alteplase administration. No correlation was found between fibrinogen or D-dimer levels and coronary artery patency. No intracerebral hemorrhage occurred in these patients; however, bleeding was more frequent in the subgroup with optimal anticoagulation (p = 0.05). CONCLUSIONS: Intense anticoagulation with intravenous heparin enhances coronary artery patency after alteplase treatment of acute myocardial infarction.

Adult↗

PubMed1994

Procoagulant activity of PPD-stimulated human lymphocytes after cryopreservation.

OBJECTIVE: Human mononuclear cells from a previously sensitized donor generate procoagulant activity (PCA) following stimulation with purified protein derivative (PPD). Lymphocytes of tuberculous pleural effusions are also highly responsive to PPD stimulation. We examined the influence of cryopreservation on lymphocytes following stimulation with PPD. DESIGN: Peripheral blood lymphocytes of 5 healthy PPD skin test positive subjects were incubated with either PPD, thromboplastin, or concanavalin A (Con A) at concentrations of 0, 1, and 10 micrograms/ml. PCA was determined by measuring the recalcification time. Tests were repeated following cryopreservation for 4 weeks. RESULTS: Incubation of fresh lymphocytes led to a dose dependent shortening of recalcification time: PPD (0-1-10 micrograms/ml: 100-84-65%), thromboplastin (0-1-10 micrograms/ml: 100-85-62%), and Con A (0-1-10 micrograms/ml: 100-85-42%). These results were highly reproducible when tests were repeated 6 weeks later. Cryopreservation did not significantly affect the expression of PCA following incubation with PPD and with thromboplastin. In contrast, cryopreservation significantly diminished the degree of Con A generated PCA. CONCLUSION: Cryopreservation and storage of human lymphocytes is possible without alteration of PCA expression following their incubation with PPD or thromboplastin.

Blood Coagulation Factors↗

PubMed1985

Effect of hydatidiform molar vesicular fluid on blood coagulation.

The effect of fluids from both complete and partial hydatidiform moles on blood coagulation was determined. Coagulation was evaluated with use of the one-stage prothrombin time and the activated partial thromboplastin time. These studies demonstrated that the fluids shortened the activated partial thromboplastin time but not the prothrombin time. The use of plasmas deficient in factors V, VIII, IX, and X as substrate showed that the fluids shortened the activated partial thromboplastin time in the presence of plasmas deficient in factors VIII and IX but had no effect on the activated partial thromboplastin time in the presence of plasmas deficient in factors V and X. These data suggest that hydatidiform mole fluids possess procoagulant activity and that the activation of blood coagulation takes place at the level of factor X. These findings may have relevance to the placental and decidual focal necrosis seen in molar pregnancies, especially those of the complete variety.

Amniotic Fluid↗

PubMed1997

Reliability of delayed INR determination: implications for decentralized anticoagulant care with off-site blood sampling.

In order to develop decentralized anticoagulant care by off-site blood sampling and transport of samples to a centralized laboratory for International Normalized Ratio (INR) determination we have performed a direct comparative study of INR stability. Analysis was performed daily for 5 d using nine thromboplastins. The overall mean difference of INR after 3d was only 0.05 INR units for samples with a therapeutic INR. After 5 d there was a mean difference of 0.11 INR units with 'non-Manchester' reagents and 0.44 INR units with 'Manchester' reagents. With over-anticoagulated samples mean differences of 0.55-0.72 INR units were observed after 3 d and 1.16-2.46 INR units after 5 d. Although there was some variation in stability of results with different thromboplastins, the difference over time with each thromboplastin was much less than the difference between thromboplastins. In conclusion, there is no clinically significant change in INR when analysis is delayed for up to 3 d. Off-site blood sampling can accommodate a large increase in patient workload without a major revenue increase in primary care and with continued total quality management and central expert advice.

Blood Coagulation Disorders↗

PubMed1996

Prothrombin time in liver failure: time, ratio, activity percentage, or international normalized ratio?

Prothrombin time (PT) is a universal indicator of liver disease severity. However, variability in thromboplastin reagents leads to large interlaboratory differences in PT results. The aim of this study was to determine whether the use of the international normalized ratio (INR) or other modes of expression might achieve PT standardization in patients with liver failure. PT was measured with seven thromboplastin reagents with different sensitivities in plasmas from 27 patients with miscellaneous chronic and acute liver failure and, as a control population, 29 patients on oral anticoagulation therapy. PT was expressed in seconds, ratio, activity percentage, and INR. In patients with liver failure, only activity percentage expression eliminated variability in PT results obtained with the seven thromboplastins while INR, seconds, and ratio values remained significantly different (P < .01). In patients on oral anticoagulant therapy, only INR normalized PT results. We conclude that, in patients with liver failure, INR fails to yield a PT expression independent of the thromboplastin used and only activity percentage expression may provide a common international scale of PT reporting.

Analysis of Variance↗

PubMed2001

[An uncommon cause of severe soft tissue bleeding during phenprocoumon treatment].

HISTORY AND ADMISSION FINDINGS: A 66-year-old patient presented to our clinic with extensive left arm and left flank haematomas, anaemia, a prolonged activated partial thromboplastin time (aPTT), and reduced factor IX activity 6 weeks after prosthetic mechanical aortic valve implantation. INVESTIGATION: Treatment with both vitamin K and a single injection of factor IX concentrate led to normalization of the activated partial thromboplastin time and factor IX activity, which remained constant for several days. No acquired factor IX inhibitor was detectable. Analysis of exon 2 of the factor IX gene revealed a C-->T mutation in codon 10 of the propeptide region, resulting in the substitution of alanine by valine. Echocardiography revealed a significant paravalvular leak. TREATMENT AND COURSE: The substitution of valine for alanine in the factor IX propeptide leads to an impaired affinity of factor IX to the vitamin K-carboxylase complex. In this situation, treatment with coumarin derivatives can profoundly reduce factor IX activity and result in severe bleeding episodes. This patient was re-exposed to warfarin under close hematological monitoring. After 4 days factor IX activity had decreased to 15%, which was associated with an increase of the aPTT and a mild decrease of the prothrombin time. Due to rapid progression of the paravalvular leak and almost impossible long-term orale anticoagulation with coumarin derivatives, we recommended replacement of the prosthetic mechanical valve with a biological device. CONCLUSION: The development of severe bleeding in the context of initiating warfarin therapy raises the suspicion of a factor IX propeptide mutation. The initial screening test is the activated partial thromboplastin time, which is elevated in the presence of the mutation. If concomitantly diminished factor IX activity is found the factor IX propeptide mutation should be excluded. Use of lifelong coumarin derivatives is contraindicated in patients with this mutation. However, a general screening of the activated partial thromboplastin time after coumarin initiation is not justified by cost/benefit analysis.

Aged↗

PubMed1985

Obstetric complications associated with the lupus anticoagulant.

We identified eight patients with the lupus anticoagulant (an autoantibody acquired by some patients with systemic lupus erythematosus), by observation of an increased activated partial thromboplastin time and abnormal results on a tissue thromboplastin-inhibition test. The patients had experienced a total of 30 spontaneous abortions and fetal deaths in 31 previous pregnancies (96.8 per cent). During their next pregnancy, the patients were treated with 40 to 50 mg of prednisone per day and 81 mg of aspirin per day. The therapy shortened their activated partial thromboplastin times, produced normal values for tissue thromboplastin inhibition, and reduced the rate of pregnancy loss to 37.5 per cent. However, preeclampsia developed in the five patients who gave birth to live infants, and fetal growth retardation occurred in three cases. The corticosteroid and low-dose aspirin regimen appears to improve perinatal outcome in cases in which the mother has the lupus anticoagulant, but such practices as careful fetal surveillance and preterm delivery when appropriate are also important to successful obstetric management of such cases.

Abortion, Spontaneous↗

PubMed1991

Intravenous recombinant soluble human thrombomodulin prevents venous thrombosis in a rat model.

Thrombomodulin is an endothelial surface thrombin receptor. Thrombin bound to thrombomodulin loses all procoagulant activity and instead activates the protein C anticoagulant pathway. We developed a recombinant thrombomodulin analog and compared the effects of recombinant thrombomodulin (100 micrograms/ea), saline (controls), recombinant hirudin (1.0 mg/kg), and heparin (100 units/kg) on thrombus formation, activated partial thromboplastin time, and tail transection bleeding time in a rat model of stasis-induced venous thrombosis. Results showed that thrombus was detected in the vena cava in six of the six rats treated with saline solution, in zero of the six rats treated with recombinant thrombomodulin (p less than 0.05), in one of six rats treated with recombinant hirudin (p less than 0.05), and in zero of six rats treated with heparin (p less than 0.05). The activated partial thromboplastin time in rats receiving recombinant thrombomodulin was slightly longer than controls (22 +/- 8 vs 37 +/- 6, p less than 0.05). The bleeding times in rats receiving recombinant thrombomodulin were approximately twice as long as controls (215 +/- 68 vs 545 +/- 173, p = 0.037). In all rats treated with recombinant hirudin or heparin, activated partial thromboplastin times were greater than 120 seconds and bleeding times were greater than 1200 seconds. We conclude that recombinant thrombomodulin inhibits venous thrombosis in a rat model with less prolongation of activated partial thromboplastin time and bleeding time than heparin or hirudin.

Animals↗

PubMed1984

Trials of commercial reagents in anion-exchange coagulation procedures: ortho diagnostics.

The suitability of Ortho Diagnostics one-stage prothrombin time (PT) reagent (Ortho Brain Thromboplastin) and activated partial thromboplastin (aPTT) reagent (Activated Thrombofax) has been evaluated for use in conjunction with the anion-exchange heparin removal maneuver. The PT/HR and aPTT/HR are tests used to follow the anticoagulant influence of coumarins when heparin also is being administered. After establishing a coumarin therapeutic range for Activated Thrombofax, a parallel trial was conducted with Ortho Brain Thromboplastin on coumarin-treated patient plasmas. Determinations also were made after heparin (0.2 mu/mL) was added and then removed by ECTEOLA microchromatography columns. Ortho Brain Thromboplastin was found to induce a shortening bias associated with a spurious improvement in the precision of tests run on anion-exchange treated plasmas that potentially could result in coumarin overdosage. The systematic error did not appear to result either from protracted incubation or the activation of prekallikrein, high molecular weight kininogen, Factor XI or XII. This reagent was found to perform appropriately with plasma not exposed to ECTEOLA. Activated Thrombofax gave reliable and reproducible results before and after heparin removal. This aPTT reagent could be used in the aPTT/HR anticoagulant surveillance scheme.

Blood Coagulation Tests↗

PubMed1992

Imprecision of prothrombin time monitoring of oral anticoagulation. A survey of hospital laboratories.

Prothrombin time monitoring of oral anticoagulation is highly dependent on the tissue thromboplastin used. In the United States, patients have received a higher level of anticoagulation because of the use of a less sensitive thromboplastin. Many advocate the use of an International Normalized Ratio to rectify this problem. Laboratory supervisors from all acute care hospitals in Massachusetts were surveyed to determine the disparity in thromboplastin use and reporting practices for prothrombin time testing. Eighty-eight of 103 (86%) hospitals responded. Fifty-eight lots from six manufacturers of thromboplastin were in use. The International Sensitivity Index of these lots ranged from 1.89 to 2.74. Ninety-nine percent of hospitals reported prothrombin times in raw seconds. Only 5% reported an International Normalized Ratio. Sixteen different coagulation instruments were in use. Close to 70% of laboratory supervisors had little or no understanding of the significance of an International Sensitivity Index or an International Normalized Ratio. The management of oral anticoagulation appears far less precise than had been believed. Prothrombin times in the same individual from different laboratories may have poor correlation. Based on the level of understanding of laboratory supervisors, extensive education will be necessary to change practices and improve accuracy and comparability of prothrombin time testing.

Administration, Oral↗

PubMed1992

Effect of hypothermia on the coagulation cascade.

BACKGROUND AND METHODS: The development of a multifactorial coagulopathy after massive transfusion is a well-recognized clinical problem that is almost always accompanied by hypothermia. The purpose of this study was to investigate the isolated effect of alterations of temperature on the integrity of the coagulation cascade. Prothrombin times and partial thromboplastin times were each performed 15 times on samples of pooled normal plasma at the temperatures of 37 degrees C, 34 degrees C, 31 degrees C, and 28 degrees C, as well as 39 degrees C and 41 degrees C. RESULTS: Mean prothrombin time results increased from 11.8 +/- 0.3 (SD) secs at 37 degrees C to 12.9 +/- 0.5, 14.2 +/- 0.5, and 16.6 +/- 0.2 secs at 34 degrees C, 31 degrees C, and 28 degrees C, respectively (p < or = .001 for each). Partial thromboplastin time determinations increased from 36.0 +/- 0.7 (SD) secs at 37 degrees C to 39.4 +/- 1.0, 46.1 +/- 1.1, and 57.2 +/- 0.6 secs at 34 degrees C, 31 degrees C, and 28 degrees C, respectively (p < or = .001 for each). Both prothrombin time and partial thromboplastin time determinations were only minimally shortened at hyperthermic temperatures. CONCLUSIONS: The series of enzymatic reactions of the coagulation cascade are strongly inhibited by hypothermia, as demonstrated by the dramatic prolongation of prothrombin time and partial thromboplastin time tests at hypothermic deviations from normal temperature in a situation where factor levels were all known to be normal. Clinicians who deal with critically ill massively transfused hypothermic patients all recognize the inevitable appearance of a coagulopathy that has a multifactorial origin. Unless specifically considered, the contribution of hypothermia to the hemorrhagic diathesis may be overlooked since coagulation testing is performed at 37 degrees C, rather than at the patient's actual in vivo temperature.

Blood Coagulation Disorders↗

PubMed2000

Contact activation in shock caused by invasive group A Streptococcus pyogenes.

OBJECTIVES: The aim of this study was to characterize abnormalities of coagulation in mice with experimental, invasive group A, streptococcal shock, in an attempt to explain the prolongation of the activated partial thromboplastin time identified in patients with streptococcal toxic shock syndrome. DESIGN: A longitudinal descriptive animal model study of coagulation times and single coagulation factors in mice infected with Streptococcus pyogenes. This was followed by an experimental study to determine whether streptococci or streptococcal products could activate the human contact system in vitro. SETTING: University infectious diseases and hemostasis molecular biology laboratories. SUBJECTS: CD1 outbred mice. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Coagulation times, single factor assays, and bradykinin assays were conducted on murine plasma at different times after streptococcal infection and compared with uninfected mice. In experiments in which streptococcal products were co-incubated with human plasma, we compared coagulation times, single factor assays, and activities against a range of chromogenic substrates with control plasma. In a murine model of streptococcal necrotizing fasciitis, the activated partial thromboplastin times were significantly prolonged in infected mice compared with controls, whereas prothrombin times were normal, suggesting an isolated abnormality of the intrinsic pathway. Bleeding was not seen. Prolongation of activated partial thromboplastin time was associated with reduced factor XII and prekallikrein, whereas levels of factors VIII, IX, XI, and high molecular weight kininogen were elevated. In vitro studies suggested that streptococcal supernatants can activate prekallikrein, in addition to causing plasminogen activation through the action of streptokinase. CONCLUSIONS: Prolongation of activated partial thromboplastin time in streptococcal toxic shock syndrome is associated with activation of the contact system, possibly contributing to the profound shock associated with streptococcal toxic shock syndrome.

Animals↗

PubMed2002

Frequent development of lupus anticoagulants in critically ill patients treated under intensive care conditions.

OBJECTIVE: To investigate how often a prolongation of the activated partial thromboplastin time in critically ill patients is caused by lupus anticoagulants and to identify possible triggering events. DESIGN: Prospective study. SETTING: Internal medicine intensive care unit (University Hospital of Vienna, Vienna, Austria). PATIENTS: Fifty-one critically ill patients without severe coagulopathy, hepatopathy, or anticoagulant treatment (35 male, 16 female, median age 60 yrs, range: 22-85 yrs). INTERVENTIONS: All patients were screened daily for lupus anticoagulants with the activated partial thromboplastin time STA assay. MEASUREMENTS AND MAIN RESULTS: Diluted Russell's viper venom time, plasma mixing studies, and confirmation assays were used to identify lupus anticoagulants at the time of an unexplained prolongation of the activated partial thromboplastin time. The influence of heparin was excluded by determination of thrombin clotting time and anti-Xa activity. In 27 of 51 patients (52.9 %) lupus anticoagulants were found after a median stay of 13 days. None of the patients had concomitant immune thrombocytopenia, hypoprothrombinemia, bleeding, or thromboembolic complications. Sepsis (p =.006) and/or catecholamine treatment (p =.002) were significantly associated with the development of lupus anticoagulants. Extracorporeal circulation, transfusion of blood products, or surgery did not increase this risk. Lupus anticoagulants resolved spontaneously in 63% of the patients after a median stay of 17 days. CONCLUSIONS: Lupus anticoagulants are frequent in critically ill patients and associated with sepsis syndrome and/or catecholamine treatment. The prolonged activated partial thromboplastin time does not warrant the administration of coagulation factors or the cessation of anticoagulant therapy or prophylaxis, inasmuch as this phenomenon is not associated with bleeding or thromboembolic complications.

Adult↗

PubMed1997

Influence of contrast media on blood coagulation.

RATIONALE AND OBJECTIVES: Contrast agents have been reported to influence the blood clotting system to an extent depending mainly on whether the compounds are ionic or nonionic. The objective of the current series of studies was to determine interspecies differences; the effect of variable incubation times; and the effect on thromboplastin times (TPT) of adding heparin to a number of x-ray and magnetic resonance imaging (MRI) contrast agents. In addition, the stability of clots formed in the presence of iopromide was studied. In a final experiment, the effect of the contrast agents on the bleeding time was studied in rats. METHODS: Nine x-ray and three MRI contrast agents were used in the study. Thromboplastin times was determined in platelet-poor plasma of humans, rats, rabbits, or dogs using calcium (Ca) thromboplastin from human placenta or rabbit brain and lung tissue and incubation times as long as 4 hours. Bleeding times were determined in rats 5 minutes, 4 hours, 24 hours, and 48 hours after intravenous injection of the contrast agents by making a small incision into the tail of the animal, immersing the tail in saline, and measuring the time period during which small blood streaks were visible. RESULTS: Nonionic contrast agents (x-ray and MRI) increased the TPT by a factor of 1.5 to 2, whereas ionic compounds prolonged TPT by a factor of > 3. Thromboplastin times increased in the order of dog < rabbit < rat < human 2- to 4-fold. However, the ranking of different contrast agents remained unchanged. Prolongation of bleeding time lasted as long as 24 hours for some contrast agents. Clots formed in the presence of iopromide were unstable and did not absorb the contrast agent. CONCLUSIONS: The animal models used in the current series of studies seem to be valid for predicting the effect of contrast agents on the blood clotting system in humans.

Animals↗

PubMed1982

Relation of simple clotting tests to clotting factor levels in liver disease.

The prothrombin time with Manchester and ox thromboplastins, the 'P & P' test of Owren and Aas, the partial thromboplastin time, the thrombin time and assays for factors II, V, VII, VIII:C, IX and X were performed by one observer in 18 patients with liver disease and 27 normal subjects; the prothrombin time and partial thromboplastin time were also carried out on another 28 similar patients by various observers. Routine liver function tests were measured in all patients. The prothrombin time with Manchester thromboplastin was well correlated with other clotting tests, and performing the other tests did not add to the information. Discriminant function analysis confirmed that clotting tests did not distinguish between different types of liver disease. Correlations between clotting tests and liver function tests reflected liver cell damage but were also influenced by acute phase reactions.

Adolescent↗

PubMed1990

Superficial migratory thrombophlebitis and the lupus anticoagulant.

The lupus anticoagulant is an antiphospholipid antibody found in association with systemic lupus erythematosus and in a variety of other diseases, as well as in healthy individuals. In the laboratory, the antibody interferes with the conversion of prothrombin to thrombin and prolongs the partial thromboplastin time. In vivo, it exerts a procoagulant effect resulting in thrombosis, mainly of the larger veins and arteries. The case of a young woman who developed superficial migratory thrombophlebitis in association with a high titer lupus anticoagulant is presented. Her diagnosis was initially missed because the partial thromboplastin time was not elevated. This appears to have resulted from the use of a specific thromboplastin relatively insensitive to the presence of the antibody. Retesting with a more sensitive reagent showed a markedly prolonged partial thromboplastin time.

Adult↗