case study 11 1 prothrombin test collection

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Phlebotomy best practices : a case study approach

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PT (Prothrombin Time) and INR

• « Find Another Test

Photo-optical clot detection using recombinant thromboplastin.

The PT is sensitive to a factor VII deficiency and it is moderately sensitive to deficiencies of factors II, V, X and fibrinogen. The PT assay can also be used to determine, Warfarin (Coumadin) therapy, vitamin K deficiencies, liver disease, and intravascular coagulation syndrome (DIC).

9.4 - 12.2 seconds. Critical value: INR >5.0. Recommended therapeutic ranges for oral anticoagulant therapy: INR 1.2 - 1.5 Prevention of catheter-related venous thrombosis; INR 2.0 - 3.0 Treatment of venous or pulmonary embolism, prevention of systemic embolism, tissue heart valves, atrial fibrillation, valvular heart disease; INR 2.5 - 3.5 Mechanical prosthetic valves; INR >2.0 - 3.0 Certain patients with thrombosis and the antiphospholipid syndrome.

* Reference ranges may change over time. Please refer to the original patient report when evaluating results.

A large number of drugs can interfere with the action of warfarin in vivo, either potentiating or inhibiting its effect on the coagulation factors II, VII, IX, and X. The Prothrombin Time is insensitive to unfractionated heparin up to approximately 2.0 units per mL. Inhibitors such as the lupus anticoagulant may interfere with Prothrombin Times. Direct thrombin inhibitors (Argatroban, Bivalarudin, etc) in therapeutic doses will result in prolonged Prothrombin Times.Patients with abnormally elevated hematocrits may show falsely prolonged PT.

STAT 1 hour, Routine 4 hours

• International Normalized Ratio (INR)
• Prothrombin Time
• Protime-INR
• PT7 NO CHARGE

STAT requests for this test will be performed on a STAT basis (supervisory staff approval is not required).

Collect specimen in a blue top (citrate 3.2%) tube. Mix by inversion. Specimen should arrive at lab within 23 hours of collection; transport at room temperature. Alternatively, centrifuge, aliquot plasma into a plastic tube, and freeze the specimen within 4 hours of collection. Transport frozen specimen on dry ice. Collection of the blood through lines that have been previously flushed with heparin should be avoided. If the blood must be drawn through a VAD (vascular access device), the line should be flushed with 5 mL of saline and the first 5 mL of blood or six dead space volumes of the VAD discarded.

The Prothrombin time in seconds is reported along with the corresponding International Normalized Ratio (INR).

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Open Access

Peer-reviewed

Research Article

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

* E-mail: [email protected]

Affiliations Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, United States of America, MMF Systems, Inc., New York, New York, United States of America

Affiliation Department of Anesthesia, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America

Affiliation MMF Systems, Inc., New York, New York, United States of America

Affiliation Department of Anesthesia, Englewood Hospital and Medical Center, Englewood, New Jersey, United States of America

Affiliation Ludwig-Maximilian University of Munich, Munich, Germany

Affiliation Westchester Medical Center/New York Medical College, Valhalla, New York, United States of America

Affiliation Hospital for Special Surgery, New York, New York, United States of America

Affiliation Department of Surgery, North Shore University Hospital, Manhasset, New York, United States of America

Affiliation Department of Anesthesia, Washington Hospital Center, Washington, DC, United States of America

Affiliation Atlantic Health System, Morristown, New Jersey, United States of America

•  [ ... ],

Affiliation Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, United States of America

• [ view all ]
• [ view less ]
• Manu N. Capoor, 
• Jerry L. Stonemetz, 
• John C. Baird, 
• Fahad S. Ahmed, 
• Ahsan Awan, 
• Christof Birkenmaier, 
• Mario A. Inchiosa Jr., 
• Steven K. Magid, 
• Kathryn McGoldrick, 

• Published: August 11, 2015
• https://doi.org/10.1371/journal.pone.0133317
• Reader Comments

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.

Citation: Capoor MN, Stonemetz JL, Baird JC, Ahmed FS, Awan A, Birkenmaier C, et al. (2015) Prothrombin Time and Activated Partial Thromboplastin Time Testing: A Comparative Effectiveness Study in a Million-Patient Sample. PLoS ONE 10(8): e0133317. https://doi.org/10.1371/journal.pone.0133317

Editor: Sinuhe Hahn, University Hospital Basel, SWITZERLAND

Received: March 20, 2015; Accepted: June 25, 2015; Published: August 11, 2015

Copyright: © 2015 Capoor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data Availability: Data in support of the paper are provided in the Supporting Information. The ultimate data owners of the underlying dataset are the participating hospitals who allowed MMF Systems to deidentify and aggregate relevant patient information. As system access does not prevent access to personal health information, further access can be arranged by contacting the corresponding author.

Funding: Support was provided by Rockefeller University Center for Clinical and Translational Science (grant # UL1 TR000043 from NCATS, NIH, CTSA Program) and application development resources were contributed by MMF Systems, Inc. MMF Systems, of which FA, JCB, MNC, and RGS are employees or consultants, provided access to its proprietary data on de-identified hospital patients.

Competing interests: Manu N. Capoor, John C. Baird, and Fahad S. Ahmed are paid employees of MMF Systems, Inc. and also have stock ownership in MMF Systems, Inc. In addition Manu N. Capoor is on the Board of MMF Systems, Inc. and R. Grant Steen is a paid consultant of MMF Systems Inc. There are no other financial or non-financial competing interests. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Introduction

Estimates suggest that 20% to 30% of total American healthcare expenditures may be unnecessary. [ 1 – 4 ] Over-diagnosis of disease has been described as a modern epidemic in high-income countries.[ 5 ] A comprehensive review of 146 medical practices found that 40% of those practices recommended when new were reversed upon more rigorous evaluation; some practices were unhelpful, and some were found to substantially increase patient costs without improving outcomes.[ 6 ]

Recently, there has been a focus on using objective evidence to combat over-diagnosis and over-treatment of disease.[ 7 ] This strategy is motivated by the need to contain medical costs as mandated by the Affordable Care Act; but, also derives from a sense that there are human as well as economic costs to consider when allocating treatment.[ 8 ]

Factors that potentially could contribute to higher medical costs include practices that have persisted in medicine and surgery without objective validation of their efficacy. One such practice may be ordering a panel of pre-operative tests that include a prothrombin time (PT) test and/or an activated partial thromboplastin time (aPTT) test prior to surgery to determine whether bleeding is a potential surgical risk.[ 9 – 11 ]

We hypothesize that if PT and aPTT tests are used correctly as diagnostic tests (rather than as screening tests), then there should be specific findings on the patient’s history and physical (H&P) chart to justify such tests. Further, these indications should be consistent with current guidelines as to when PT and aPTT tests should be ordered. Conversely, if PT and aPTT tests are used for screening, then specific findings in a patient’s H&P will not necessarily be present.[ 12 – 14 ] Therefore, we compared each patient’s PT and/or aPTT results with findings on that patient’s H&P to determine whether the tests had been used as diagnostic tests or as screening tests.

Materials and Methods

We utilized a web-based patient information warehouse and designed a tool for our comparative-effectiveness research. The warehouse is used by hospitals to manage information required for scheduled surgeries that originates with their affiliated surgeons. Our research tool provided us access to de-identified and aggregated patient information through appropriate de-identification provisions (e.g., via hospital service agreements). [ 15 , 16 ] This research was reviewed and approved by the Rockefeller University Institutional Review Board (MCA-0669) on June 10, 2014.

De-identified pre-surgical patient data (H&Ps and lab reports), generated at 19 hospitals and 8 associated ambulatory surgery centers ( Table 1 ) were aggregated. The time period covered was 48 months (from 2008 through 2012), with the exception of facilities 6, 16, 22, and 27 (data aggregated for 36 months) and facilities 9 and 24 (data aggregated for 46 months).

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

https://doi.org/10.1371/journal.pone.0133317.t001

The research tool accessed scheduling systems for elective surgery at each hospital. In-patient and emergency room patients who underwent surgeries were not included; such patient information resides on in-house hospital systems, not accessible to the tool. This approach yielded patient information on a consecutive sample of 1,053,472 patients, representing every patient admitted for elective surgery between 2009 and 2012 at all 27 settings, provided that these patients were scheduled, confirmed, and actually underwent surgery (Table A in S1 File ).

Joint Commission requirements mandate that all hospitals have a recent H&P in place for every patient scheduled for surgery. Therefore, each hospital has an H&P for each patient either in the data warehouse (from its surgeons) or on their own EHR system[ 17 ] Lab tests are not required for surgery and may not be available on the research tool.

Patient H&P records were evaluated to determine whether there was justification for PT and aPTT testing. Unnecessary tests were defined as PT tests done on patients without a history of: 1) abnormal bleeding, 2) warfarin therapy, 3) vitamin K-dependent clotting factor deficiency, or 4) liver disease; or aPTT tests done on patients without a history of: 1) heparin use, 2) hemophilia, 3) antiphospholipid antibodies (lupus anticoagulant), or 4) von Willebrand disease ( Fig 1 ).

https://doi.org/10.1371/journal.pone.0133317.g001

Our research tool included 682,049 H&Ps from the 1,053,472 patient records in surgeon EHRs. Thus 65% of patients had H&Ps in our data set ( Table 1 ). The remaining 371,423 H&Ps were in-hospital EHRs and therefore not available for analysis.

Among the 682,049 H&Ps, we found 411,998 associated with PT and aPTT tests (60.4%) ( Fig 2 ). Some of the remaining 270,051 surgeries may have had associated labs on hospital lab systems that were not accessible to us; therefore, this analysis under-represents the actual ratio of labs to H&Ps. Roughly 39.1% of all potential records (411,998/1,053,472) were evaluated in this study. We cannot assess how many patients received PT and aPTT testing whose records are not available to us.

https://doi.org/10.1371/journal.pone.0133317.g002

Roughly 26.2% of all pre-surgical patients accessible in the database received PT tests, of which 94.3% of tests were deemed unnecessary, given the absence of findings on the H&P ( Table 2 ); this means that at least 158,378 unnecessary PT tests were done. Similarly, 23.3% of all pre-surgical patients received aPTT tests, of which 99.9% were deemed unnecessary given an absence of H&P findings ( Table 2 ); this is equivalent to at least 149,484 unnecessary aPTT tests. In most cases, PT and aPTT tests were ordered together ( Fig 3 ). The PT test was ordered 178,898 times, and the aPTT test was ordered 159,132 times. The tests were ordered together in 157,770 instances. This represents 88.2% of all PT tests ordered, and 99.1% of all aPTT tests ordered. The aPTT test was ordered on its own in only 1362 cases.

https://doi.org/10.1371/journal.pone.0133317.g003

https://doi.org/10.1371/journal.pone.0133317.t002

There is a wide range between facilities in the frequency with which PT and aPTT tests are ordered. For example, facilities 18 and 19 are both eye and ear specialty hospitals; hospital 18 ordered PT tests for 63.8% of patients, while hospital 19 ordered the same tests for 9.4% of patients.

Across all hospitals and centers, the proportion of unnecessary PT tests ranged from 82.1% to 97.4% and the proportion of unnecessary aPTT tests ranged from 99% to 100% ( Table 2 ). Extrapolating the lowest of these proportions to all patients, some of whom had no H&P records available, enables us to calculate that 90.0% of all patients may have received unnecessary PT tests, and 99.6% of all patients may have received unnecessary aPTT tests ( Table 2 ).

The number and proportion of unnecessary PT and aPTT tests that nevertheless produced abnormal findings is shown ( Fig 4 ). The rate of abnormal test results was significantly higher in patients with relevant findings on their H&P than in patients with no relevant findings. There were a substantial number of patients for whom unnecessary tests were positive (6.6% and 7.1%). We lack sufficient information to tell whether these results are unanticipated true positives or false positives.

https://doi.org/10.1371/journal.pone.0133317.g004

The rate of abnormal test results declined with patient age ( Table 3 ). Abnormal PT and aPTT tests were nearly 3-fold more prevalent in patients younger than 30 years than in patients older than 50 years.

https://doi.org/10.1371/journal.pone.0133317.t003

Statistical Analysis

We tested a hypothesis that the percentage of abnormal results on both the PT and aPTT tests is the same ( Fig 5 ). This hypothesis was rejected, the p-value being practically 0. The 95% confidence intervals (PT: 6.48–6.72) and (aPTT: 6.97–7.23) were non-overlapping, indicating that the proportion of false positives on PT and aPTT tests are independent of one another. This suggests that patients who get a false positive on one test are not more likely to get an abnormal result on the other test.

https://doi.org/10.1371/journal.pone.0133317.g005

Similarly, a χ 2 test was used to test the hypothesis that the PT and aPTT tests were used independently. The fourfold contingency table (see Table 4 and Fig 2 ) for the two tests shows that this hypothesis can be rejected (again the p-value being practically 0), suggesting that physicians tend to order both tests together. This is also evident from the large number of patients who were given both tests or neither test ( Table 4 ).

https://doi.org/10.1371/journal.pone.0133317.t004

We have demonstrated that 94.3% of all PT tests and 99.9% of all aPTT tests in our data set were ordered without documented justification in patient H&Ps. Our results clearly show that both PT and aPTT tests are routinely used as screening tests ( Table 2 ), although no rationale exists to conclude that these tests are anything other than diagnostic.

Unnecessary PT tests may actually comprise 97.6% rather than 94.3% ( Fig 4 ) if the data is adjusted to eliminate patients on warfarin whose tests were ordered too early (typically patients should be off warfarin therapy five days prior to surgery allowing PT levels to normalize and tested within 24–48 h of surgery to confirm the patient has stopped warfarin therapy). [ 18 ]

Though it is well known that these tests are often ordered with no clinical justification, we have shown that this practice of ordering these tests is widespread, at least in the surgical environment.[ 19 ] If extrapolated on a national and international level, the scope of unnecessary testing could be significant as well as the direct and indirect healthcare costs and burdens. For instance, the CDC estimates that in the US, there are over 50 million surgical patients operated on annually. [ 20 , 21 ]

Given the extent to which surgeons order PT and aPTT tests, they must believe that results are important in predicting bleeding complications. The following two questions provide a better perspective regarding these tests.

• How useful are the tests in predicting bleeding complications?
• Does an abnormal test result represent a false positives or a true positive?

How useful are the tests in predicting bleeding complications?[ 22 ] The PT test was introduced in 1935 for the management of warfarin therapy[ 23 ], while the aPTT test was introduced in 1953 and became the test of choice for the management of heparin therapy.[ 24 ] Both tests are useful when employed for their intended purposes. However, under most circumstances, even if there is an H&P finding that suggests a need for testing, it is still unlikely that the patient will have a prolonged PT or aPTT as well as a meaningful bleeding complication, since most of the findings on an H&P (disseminated intravascular coagulation, liver disease[ 25 ], vitamin K deficiency, congenital factor VII deficiency[ 26 ], dysfibrinogenemia[ 27 ], factors XII, XI, IX, and VII, lupus anticoagulant, and von Willebrand disease[ 28 – 30 ]) must be quite advanced, and these patients would already have been identified. Accordingly, in contrast with the eight H&P findings commonly used by physicians, the literature only supports the use of these tests where the patient is utilizing warfarin or heparin. Further, near-unanimous results from peer reviewed publications have demonstrated that abnormalities on coagulation tests are not predictive of bleeding events.[ 31 – 39 ]

• Inadequate determination of reference standards (reagents and instrumentation)[ 42 ];
• High patient hematocrit resulting in an artifactual prolongation of the clotting time[ 43 ];
• Variations in citrate anticoagulant (3.2% or 3.8%), which is known to affect results[ 44 ];
• Fasting state of the patient (plasma turbidity can interfere with optical systems in non-fasting lipemic, hemolyzed, or icteric specimens)[ 45 ];
• PT tests should be done within 24 h of collection, and aPTT should be determined within 4 h, especially if the sample is heparinized.[ 46 ]

Some weaknesses of the present study may limit the scope of our conclusions. First, our study tool could not access all H&P and lab information from the various sites. Patient information was received from some hospital surgeons who did not utilize the hospital’s in-house EMR and/or lab systems; these patients may constitute a different patient population than other patients in the hospitals studied here. Second, the Joint Commission mandates that an H&P exist for each surgery undertaken. Therefore, the study tool should have had access to an H&P for each of the 1,053,472 surgeries. In contrast, we had access to only 65% of these H&Ps, because all other H&Ps were on hospital systems that were not accessible to our tool. The research tool also had access to only some labs, which underrepresents the actual ratio of H&Ps to labs ( Fig 1 ). Third, on a geographic basis, our sample reflects surgeon ordering practices compiled from data from seven states and the District of Columbia, which may or may not be representative of surgeon ordering practices in the unevaluated portion of the United States. Fourth, the study did not include pregnancy morbidity as an indicator, which is relevant to diagnosing antiphospholipid syndrome (APS) and a potential factor prompting PT and aPTT testing and unexplained thrombosis.

Since a meaningful percentage of surgeons use these tests as screening tests ( 88 . 2% of PT tests and 99 . 1% of aPTT tests ) it would appear these tests are being ordered by surgeons as part of their routine pre-surgical process. Accordingly, given the previously mentioned cost burdens, consideration by the relevant industry constituencies could be given to exploring the use of change agents to evolve these apparent pre-surgical processes to conform with evidence-based practices. Some hospitals appear to be proactive in reducing unnecessary testing ( e.g., Table 2 : facility 19 vs. facility 18, both specialty eye and ear hospitals ). Our data reflect substantially lower levels of unnecessary testing at some hospitals. For example, one hospital performed roughly 15% as many tests as a comparable hospital with similar surgery cases. The burdens and costs of unnecessary testing may not only refer to the test per se, but also extend to the follow-on professional obligations placed on health-care professionals.

We report what we believe to be the largest prospective sample of surgical patients ever assembled. Our sample includes 1,053,472 consecutive patients from 27 medical facilities enrolled from 2009 to 2012, and we were able to gather complete data for a subset of 65% of those patients (N = 682,049). Our results show that both PT and aPTT are used as screening tests, though no rationale exists to conclude that these tests are anything other than diagnostic. Overall, 26.2% of patients received PT testing, and 94.3% of those tests were not necessary, given the absence of findings on the patient H&P. Similarly, 23.3% of preoperative patients received aPTT testing, of which 99.9% of tests were unnecessary. For patients with no H&P findings suggestive of bleeding risk, 6.6% of PT tests and 7.1% of aPTT tests were positive, indicating either a false positive or an unanticipated true positive finding. Given that bleeding conditions are likely to be diagnosed symptomatically prior to surgery, most positive findings are likely to be false positives.

We therefore document routine pre-surgical practices for which there is no clinical justification and which can put patients at risk of false-positive findings. Useless tests are clinically inappropriate because they consume resources, yet bring no benefit to patients or clinicians. Empty testing is also ethically wrong, because it puts patients at risk to no purpose. If our study set is representative of national practices in the United States, then modification of current testing practices could substantially reduce the number of unnecessary PT and aPTT tests, thereby saving hospitals, the Centers for Medicare and Medicaid Services, and insurance companies the costs of unnecessary testing. Our tool offers an unprecedented window into unnecessary testing in the United States.

Supporting Information

S1 file. aggregate data for h&p and lab data..

https://doi.org/10.1371/journal.pone.0133317.s001

Acknowledgments

We would like to acknowledge the advice and sharing of expertise from: Donna Brassil, Barry Coller M.D., Emil Gotschlich, M.D. of Rockefeller University; Jayant Deshpande, Ph.D., Department of Statistics, Michigan State University; Walter H. Dzik, MD, of Massachusetts General Hospital; Malgorzata B. Trela and Ashwini Valimbe of MMF Systems who contributed significantly to the data collection process; and the encouragement of Paul Verkuil, J.S.D. of the Administrative Council of the United States.

Author Contributions

Conceived and designed the experiments: MC FA JS. Performed the experiments: MC FA JS. Analyzed the data: MC VF JS JB RGS JW AA AS SN SKM MU EM CB MI PS KM SMP FA. Contributed reagents/materials/analysis tools: MC VF JS JB RGS JW AA AS SN SKM MU EM CB MI PS KM SMP FA. Wrote the paper: MC VF JS JB RGS JW AA AS SN SKM MU EM CB MI PS KM SMP FA.

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• 13. Dugdale, DC. Partial thromboplastin time (PTT), Medline Plus. US National Library of Medicine, National Institutes of Health. 2013. Available: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm .
• 16. Hirsch R, Deixler H. HIPAA Business Associates and Health-Care Big Data: Big Promise, Little Guidance. Bureau of National Affairs. 17 February 2014. Available: http://www.bna.com/hipaa-business-associates-and-health-care-big-data-big-promise-little-guidance/ . Accessed 15 August 2014.
• 17. Joint Commission on Accreditation of Healthcare Organizations. 2015 Hospital Accreditation Standards. Oakbrook Terrace: Joint Commission on Accreditation of Healthcare Organizations; 2014.
• 22. Newman MF, Fleisher LA, Fink MP. Perioperative medicine: managing for outcome. Philadelphia: Saunders Elsevier; 2008. xix, 723 p. p.

MICHAEL BALLAS, MD, AND ERIC H. KRAUT, MD

Am Fam Physician. 2008;77(8):1117-1124

A more recent article on bleeding and bruising is available .

Author disclosure: Nothing to disclose.

Primary care physicians are often asked about easy bruising, excessive bleeding, or risk of bleeding before surgery. A thorough history, including a family history, will guide the appropriate work-up, and a physical examination may provide clues to diagnosis. A standardized bleeding score system can help physicians to organize the patient's bleeding history and to avoid overlooking the most common inherited bleeding disorder, von Willebrand's disease. In cases of suspected bleeding disorders, initial laboratory evaluations should include a complete blood count with platelet count, peripheral blood smear, prothrombin time, and partial thromboplastin time. More specialized yet relatively simple tests, such as the Platelet Function Analyzer-100, mixing studies, and inhibitor assays, may also be helpful. These tests can help diagnose platelet function disorders, quantitative platelet disorders, factor deficiencies, and factor inhibitors.

Numerous disorders can cause abnormal bleeding and bruising, including platelet function disorders, quantitative platelet disorders, factor deficiencies, and factor inhibitors. Additionally, there are diseases that affect the connective tissue and integrity of the blood vessel, making the skin bruise more easily and vessels more prone to bleed. Table 1 lists the differential diagnosis of bleeding and bruising disorders. Table 2 1 , 2 shows the diagnostic work-up, which begins with a focused history.

Illustrated Case Studies

A 52-year-old man gave a lifelong history of easy bruising and excessive bleeding following tooth extractions. After taking aspirin, he developed severe nosebleeds. Family history was remarkable for heavy vaginal bleeding in his mother and sister.

A 35-year-old woman presents with bruising of the upper thighs. She denies menorrhagia or other bleeding symptoms. She reports two vaginal deliveries, an appendectomy, and a tubal ligation, all without excessive bleeding. Her family history does not suggest a bleeding disorder and, except for the simple bruising, her physical examination is unremarkable.

A 43-year-old woman was admitted to the hospital with a large hematoma in the right thigh. She had no history of trauma or spontaneous bleeding and had tolerated minor surgical procedures in the past without bleeding. Her family history was negative and she had not been on any medications associated with increased bleeding risk.

History and Physical Examination

Taking a personal history starts with a list of screening questions based on a bleeding score system ( Table 3 ) . 3 This bleeding score system is a clinical decision rule to screen for von Willebrand's disease, the most common inherited bleeding disorder. This disease results from a quantitative or qualitative defect in von Willebrand's factor, which is required for platelet aggregation. Although the bleeding score system is intended for the diagnosis of von Willebrand's disease, it lists criteria necessary to diagnose other bleeding disorders as well. 4 – 9 A history of bleeding that requires surgical intervention, blood transfusion, or replacement therapy is a significant red flag for a bleeding disorder and, therefore, receives a high number of points. More information on the bleeding score can be found at http://www.euvwd.group.shef.ac.uk/bleed_score.htm . Table 4 3 indicates the probability of von Willebrand's disease based on the bleeding score.

A positive family history increases the risk of a bleeding disorder and is reason to initiate a work-up, 10 , 11 especially in women with menorrhagia. 12 Many bleeding disorders have an inheritance pattern, including the X-linked recessive hemophilias. Family history is especially important in children because they may not have had the opportunity to experience a hemostatic challenge (e.g., surgery, delivery, tooth extraction). In a study of children referred to a tertiary care center with either a personal or family history of bleeding, a positive family history was significantly associated with a diagnosis of a bleeding disorder. 10

The patient in case study one who had a history of bruising and bleeding after tooth extraction would have a bleeding score of at least 4 (epistaxis: 1; bruising: 1; and tooth extraction: 2). This score, coupled with his family history of menorrhagia in the mother and sister, creates a high index of suspicion for a bleeding disorder, even before any laboratory testing is obtained.

The bleeding score system assigns a negative number if there is no significant bleeding after a hemostatic challenge. The importance of the “negative history” is illustrated by the woman in case study two who had bruising on her upper thigh (score: 1); an appendectomy and tubal ligation without a significant bleed (score: −1); two vaginal deliveries without a significant bleed (score: −1); and no other bleeding symptoms (score: 0). This gives her a total bleeding score of −1.

As illustrated in case study three, a patient may have a low bleeding score and a negative family history, but still present with physical examination findings suggestive of a bleeding disorder. Pertinent physical examination findings of bleeding and bruising disorders are listed in the second column of Table 1 .

Table 5 4 – 6 lists medications that cause bleeding or bruising. The physician should not rule out a bleeding disorder just because a patient is receiving one of these medications, especially if the patient has a high bleeding score. Medications may cause the disease to manifest itself with bleeding symptoms, as illustrated in case study one.

Initial Laboratory Evaluation

Understanding of the complexity of hemostasis has greatly increased since it was originally described in 1964. 13 , 14 Interactions of basic “ingredients” are required for a clot to form, and a qualitative or quantitative defect of any “ingredient” can result in a bleeding or bruising disorder. Knowledge of basic clot formation can help the physician to understand these disorders and their initial laboratory work-up, which includes complete blood count with platelet count, peripheral blood smear, prothrombin time (PT), and partial thromboplastin time (PTT).

COMPLETE BLOOD COUNT AND PERIPHERAL BLOOD SMEAR

A shortage of platelets (thrombocytopenia) can be detected on complete blood count. A peripheral blood smear can help to rule out pseudothrombocytopenia and to look for abnormally shaped platelets.

The PT measures the factors of the extrinsic and common pathways. Deficiencies of these factors (most notably factor VII) will prolong the PT. Vitamin K is required for the synthesis of the critical factors of these pathways; therefore, patients with vitamin K deficient conditions may have a prolonged PT. 15

The PTT measures the factors of the intrinsic and common pathways. Deficiencies of these factors, including factor VIII (hemophilia A) and factor IX (hemophilia B), will prolong the PTT. Factor VIII levels may be low in patients with von Willebrand's disease; therefore, these patients could present with a prolonged PTT. 1

Inhibitors, autoantibodies that attach to a factor and render it useless for clot formation, can also prolong the PTT. The most common inhibitors are the factor VIII inhibitors and the lupus anticoagulant (“lupus anticoagulant” is incorrectly named and typically presents more often as thrombosis than as bleeding). A factor VIII inhibitor should be suspected in anyone who has no history of bleeding, but develops significant bleeding (such as the woman with the large spontaneous hematoma in case study three) and has a prolonged PTT. 16

Specialized Laboratory Tests

Platelet function activity.

Traditionally, the test of choice for evaluation of platelet function was bleeding time; however, the use of bleeding time to predict surgical bleeding has been questioned 17 , 18 and its use has been discouraged or eliminated at some institutions. 1 , 19 The Platelet Function Analyzer (PFA)-100 has been shown to be superior to bleeding time in detecting von Willebrand's disease. 20 – 22

The PFA-100 simulates the formation of the platelet plug in vivo by passing the patient's blood through an aperture coated with collagen/epinephrine and collagen/adenosine diphosphate. In patients with von Willebrand's disease and other platelet function disorders, the amount of time required for the platelets to aggregate from both collagen/epinephrine and collagen/adenosine diphosphate is prolonged. A prolonged time to clot to just collagen/epinephrine usually indicates a drug effect, such as from aspirin.

The reported sensitivity of the PFA-100 for diagnosing von Willebrand's disease and other platelet function disorders is 88 to 90 percent with a specificity of 86 to 94 percent. 23 , 24 Studies have concluded that the PFA-100 is a useful screening test, 23 , 24 but this conclusion is still being debated. 24 – 28 Although the PFA-100 is more sensitive than bleeding time, a negative result should not preclude further testing for von Willebrand's disease or other platelet function disorders. If the PFA-100 is negative, the physician should review the initial history to determine if further testing should be performed.

MIXING STUDIES AND INHIBITOR AND FACTOR ASSAYS

A mixing study determines if the patient has a clotting factor deficiency or an inhibitor to a factor. When one part of the patient's blood is mixed with one part of normal blood, the inhibitor in the patient's blood disables the factor in the normal blood. The PTT stays prolonged and does not “correct.” Inhibitor assays are then performed to identify which inhibitor is present. When the blood from a patient with a factor VIII deficiency is mixed with normal blood, the PTT should normalize or correct. Factor assays are then performed to identify which factor is deficient.

The sensitivity of the mixing study to detect a lupus anticoagulant is 95 percent with a specificity of 60 percent. 29 In a study of 42 laboratories asked to analyze known samples, 30 97.5 percent correctly identified the sample with a lupus anticoagulant and 90.2 percent correctly reported the negative serum sample as negative. However, 53.6 percent did not correctly identify the factor VIII inhibitor and many did poorly with contaminated specimens. Therefore, knowledge of a laboratory's limitations, especially when trying to identify an inhibitor that is not a lupus anticoagulant, is helpful when interpreting the results.

If the laboratory work-up does not diagnose a bleeding disorder, but there is still high suspicion based on personal and family history, the patient should be referred to a hematologist. If von Willebrand's disease, a factor VIII inhibitor, or factor deficiencies are discovered, referral is based on the diagnosis and severity, as well as the comfort level of the physician. If the history, physical examination, or the routine laboratory studies are abnormal in the preoperative assessment, surgery should be delayed until a cause can be determined with a work-up or by referral.

RESOLUTION OF CASE STUDIES

Case One . Laboratory testing included a normal blood count and platelet count. A PFA-100 test was abnormal to collagen/epinephrine and collagen/adenosine diphosphate. Further testing was diagnostic for von Willebrand's disease.

Case Two . A complete blood count, PT, PTT, and PFA-100 were normal. The patient was reassured that with a low bleeding score, a negative family history, and an unremarkable physical examination, she most likely has purpura simplex (easy bruising). She was told to follow up if her symptoms got worse or if she had any new symptoms.

Case Three . Laboratory evaluation included a hemoglobin count of 7 g per dL (70 g per L), a platelet count of 400 × 10 3 per μL (400 × 10 9 per L), a PT of 12 seconds, and a PTT of 100 seconds. A mixing study did not return the PTT to normal. Measurement of factor VIII showed a level of 1 percent, and an assay for the presence of a factor VIII inhibitor showed a high-titer inhibitor.

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