Prothrombin Time and Activated Partial Thromboplastin Time Testing: A Comparative Effectiveness Study in a Million-Patient Sample

Background

A substantial fraction of all American healthcare expenditures are potentially wasted, and practices that are not evidence-based could contribute to such waste. We sought to characterize whether Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) tests of preoperative patients are used in a way unsupported by evidence and potentially wasteful.

Methods and Findings

We evaluated prospectively-collected patient data from 19 major teaching hospitals and 8 hospital-affiliated surgical centers in 7 states (Delaware, Florida, Maryland, Massachusetts, New Jersey, New York, Pennsylvania) and the District of Columbia. A total of 1,053,472 consecutive patients represented every patient admitted for elective surgery from 2009 to 2012 at all 27 settings. A subset of 682,049 patients (64.7%) had one or both tests done and history and physical (H&P) records available for analysis. Unnecessary tests for bleeding risk were defined as: PT tests done on patients with no history of abnormal bleeding, warfarin therapy, vitamin K-dependent clotting factor deficiency, or liver disease; or aPTT tests done on patients with no history of heparin treatment, hemophilia, lupus anticoagulant antibodies, or von Willebrand disease. We assessed the proportion of patients who received PT or aPTT tests who lacked evidence-based reasons for testing.

Conclusions

This study sought to bring the availability of big data together with applied comparative effectiveness research. Among preoperative patients, 26.2% received PT tests, and 94.3% of tests were unnecessary, given the absence of findings on H&P. Similarly, 23.3% of preoperative patients received aPTT tests, of which 99.9% were unnecessary. Among patients with no H&P findings suggestive of bleeding risk, 6.6% of PT tests and 7.1% of aPTT tests were either a false positive or a true positive (i.e. indicative of a previously-undiagnosed potential bleeding risk). Both PT and aPTT, designed as diagnostic tests, are apparently used as screening tests. Use of unnecessary screening tests raises concerns for the costs of such testing and the consequences of false positive results.     

临床标本采集量对凝血系统检测结果的影响

目的：探讨临床标本采血量的准确性对凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）测定的影响。方法：用BE-RockRotor全自动血凝仪和配套试剂分别对15例临床患者不同抽血量标本进行检测,观察不同的采血量对PT、APTT检测结果的影响,并将所得检测结果采用统计方法处理。结果：与标准采血量为1．8mL相比,采血量大于或小于1．8mL时测得的PTT、APTT结果有显著性差异。结论：临床标本采集量对凝血系统检测结果的准确性有直接影响;必须严格按照标准采血量规定采集标本,才能确保凝血系统检测结果的准确,为病人疾病的诊断提供可靠的实验室依据。     

Control of Heparin Therapy

Heparin therapy in 114 patients was controlled by daily blood tests—the whole blood coagulation time, kaolin-activated partial thromboplastin time of plasma, and plasma heparin assay. Bleeding episodes occurred in 7 out of 92 patients (7·6%) who had normal haemostatic mechanisms before therapy and in 11 out of 22 patients (50%) with defective haemostasis, mostly due to intravascular coagulation or renal failure. The dose of heparin ranged from 20,000 to 60,000 units in each 24-hour period. In some patients bleeding was related to overdosage, but in others the laboratory tests indicated satisfactory or suboptimal dosage at the time of bleeding. Though there were positive correlations between the results of the three tests, these were not close, and no one test was preferable. Hence laboratory control of heparin therapy is unsatisfactory and patients may bleed despite careful control of the dose by all three methods.     

Myeloperoxidase Exocytosis from Activated Neutrophils in the Presence of Heparin

Exocytosis of myeloperoxidase (MPO) from activated neutrophils has been investigated in the presence of the anionic polysaccharide heparin. The optimal concentration of heparin (0.1 U/mL), which did not cause additional activation of cells (lack of augmentation of lysozyme exocytosis from specific and azurophilic granules), was determined. After preincubation of cells with heparin (0.1 U/mL) MPO exocytosis from neutrophils was stimulated by various activators (fMLP, PMA, plant lectins CABA and PHA-L) and was higher as compared to the effects of the activators alone. Experiments performed using MPO isolated from leukocytes have shown that heparin in the range of concentrations 0.1–50 U/mL had no effect on MPO peroxidase activity. Thus, the use of heparin at a concentration of 0.1 U/mL avoids the artifact caused by the “loss” of MPO due to its binding to neutrophils and increases the accuracy of the method of registration of degranulation of neutrophil azurophilic granules based on determination of the MPO concentration or its peroxidase activity in cell supernatants.     

Initial Heparin Therapy in Acute Myocardial Infarction

The administration of heparin during the first 48 hours following acute myocardial infarction is widely practised. Heparin treatment is also recommended for acute coronary insufficiency on the grounds that it may prevent development of an impending myocardial infarction. These measures had been accepted without support of a controlled clinical trial. By random selection, 101 patients hospitalized with a provisional diagnosis of acute myocardial infarction received heparin (100 mg. intravenously every eight hours for 48 hours) and 105 patients were assigned to a control group. Both groups of patients received bishydroxycoumarin (Dicumarol). The mortality in the heparin series was 30% and in the control group, 28%. A significantly large number of the heparin-treated patients developed clinical and laboratory proof of recent myocardial infarction. It is concluded that early intermittent intravenous heparin treatment does not lower the mortality in patients with acute myocardial infarction nor does it prevent impending myocardial infarction in patients with acute coronary insufficiency.     

Vascular Complications in Nephrotic Syndrome: Relationship to Steroid Therapy and Accelerated Thromboplastin Generation

Arterial thrombosis and renal vein thrombosis occurred in two men and one woman, respectively, treated with steroids for the nephrotic syndrome. Raised serum cholesterol occurred in one patient only. Though bleeding, clotting, and prothrombin times, as well as the platelet counts, were normal, the rate of thromboplastin generation was increased in all three patients. Adding heparin to the plasma of one patient slowed the rate, and suggested that the raised rate could be due to removal or suppression of such normal circulating coagulation inhibitors. The thromboplastin generation test seems to be useful in diagnosing and managing such hypercoagulable states, and may help in further investigations of their causes.     

T-wave Oversensing with Inappropriate Therapy in Remote Monitoring

T-wave oversensing can cause inappropriate implantable cardioverter-defibrillator (ICD) therapies that are difficult to correct. Remote monitoring allows follow-up of ICD patients without visiting the hospital and can help in early detection of any malfunctions. We describe the case of a patient who experienced inappropriate antitachycardia pacing therapy due to T-wave oversensing; the problem was promptly detected by remote monitoring and corrected by device reprogramming.     

Horizons of Heparin Therapy in COVID-19 and Pandemic-Related Diseases

Journal of Evolutionary Biochemistry and Physiology - The disease caused by the coronavirus SARS-CoV-2, named COVID-19, has been spread around the world at a high transmission rate. It was...     

Heparin as a Therapy for Atherosclerosis: Preliminary Observations on the Intrapulmonary Administration of Low-Dose Heparin in the Morning Versus Evening Gauged by Its Effect on Blood Variables

Reports on clinical trials with subcutaneous and intrapulmonary administration of low-dose heparin suggest that it may be an attractive therapeutic modality for the treatment of coronary artery disease because of unprecedented reduction in mortality of treated subjects. As a preliminary to a clinical trial with low-dose intrapulmonary heparin, a pilot study was conducted on three subjects. It compares overall circadian responses of 37 blood variables following intrapulmonary administration of heparin (10,500-18,800 U) in the morning (0800 h) and in the evening (2000 h). After each of these times, blood samples, mostly at 3 h intervals for the ensuing 27 h, were analyzed for heparin, APTT, TT, functional fibrinogen, CBC, enzymes, lipids, electrolytes, and hormones. Each time series was analyzed for circadian rhythm by the least-squares fit of a 24 h cosine and circadian mesors were compared by the Bingham test of rhythm parameters. Following heparin in the evening, but not in the morning, a statistically significant increase in circulating heparin levels, as well as directional increases in APTT and TT and decreases in fibrinogen, were observed in all three subjects. Same direction changes in several other variables were also observed. It is concluded that inhalation of heparin in low-dose levels results in variable circadian effects on blood parameters measured, ranging from no changes in their levels to minimal within normal range changes, and that these effects are dependent upon the timing of dose administration. It is suggested that the timed self-administration of low-dose heparin by inhalation be seriously considered for long-term clinical trials in the treatment and prevention of atherosclerosis.     

Heparin as a Therapy for Atherosclerosis: Preliminary Observations on the Intrapulmonary Administration of Low-Dose Heparin in the Morning Versus Evening Gauged by Its Effect on Blood Variables

Reports on clinical trials with subcutaneous and intrapulmonary administration of low-dose heparin suggest that it may be an attractive therapeutic modality for the treatment of coronary artery disease because of unprecedented reduction in mortality of treated subjects. As a preliminary to a clinical trial with low-dose intrapulmonary heparin, a pilot study was conducted on three subjects. It compares overall circadian responses of 37 blood variables following intrapulmonary administration of heparin (10,500-18,800 U) in the morning (0800 h) and in the evening (2000 h). After each of these times, blood samples, mostly at 3 h intervals for the ensuing 27 h, were analyzed for heparin, APTT, TT, functional fibrinogen, CBC, enzymes, lipids, electrolytes, and hormones. Each time series was analyzed for circadian rhythm by the least-squares fit of a 24 h cosine and circadian mesors were compared by the Bingham test of rhythm parameters. Following heparin in the evening, but not in the morning, a statistically significant increase in circulating heparin levels, as well as directional increases in APTT and TT and decreases in fibrinogen, were observed in all three subjects. Same direction changes in several other variables were also observed. It is concluded that inhalation of heparin in low-dose levels results in variable circadian effects on blood parameters measured, ranging from no changes in their levels to minimal within normal range changes, and that these effects are dependent upon the timing of dose administration. It is suggested that the timed self-administration of low-dose heparin by inhalation be seriously considered for long-term clinical trials in the treatment and prevention of atherosclerosis.     

Time Delay and Partial Coherence Analyses to Identify Cortical Connectivities

Recently it has been demonstrated by Albo that partial coherence analysis is sensitive to signal to noise ratio (SNR) and that it will always identify the signal with the highest SNR among the three signals as the main (driving) influence. We propose to use time delay analysis in parallel to partial coherence analysis to identify the connectivities between the multivariate time series. Both are applied to a theoretical model (used by Albo) to analyse the connections introduced in the model. Time delay analysis identifies the connections correctly. We also apply these analyses to the electroencephalogram (EEG) and electromyogram of essential tremor patients and EEG of normal subjects while bimanually tapping their index fingers. Biologically plausible cortico-muscular and cortico-cortical connections are identified by these methods.