Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?

There is virtually no utility to obtaining heritable thrombophilia testing in acute hospital setting. In fact, there are potential harms due to false-positive and false-negative results which in turn may lead to increasing anxiety in the patient and added cost due to repeat testing.

As many tests obtained as part of this workup are functional assays—eg, the protein S, C, or antithrombin activity, and activated protein C resistance (often used to screen for factor V Leiden)— they are easily impacted by the physiologic effects of acute thrombosis as well as all anticoagulants.1

More importantly, testing for inherited thrombophilia will not impact management in the acute setting, as decisions regarding duration of anticoagulation are often made later in the outpatient setting. The proper time to evaluate the patient for inherited thrombophilias (if indicated) is at least one week following discontinuation of anticoagulation (minimum 3 months from the time of the index event). 2 

Testing for antiphospholipid syndrome (APS) may be considered in this setting though it should be noted that the lupus anticoagulant assay is impacted by nearly every anticoagulant, resulting in frequent false-positive results1, and therefore should be performed before initiation of these agents (or delayed until later if anticoagulation has already begun). A false-positive result has downstream implications as many patients with acute, uncomplicated venous thromboembolism (VTE) are discharged on a direct oral anticoagulant (DOAC), and antiphospholipid syndrome is currently considered a relative contraindication to the use of DOACs in VTE.

References
1. Moll, S. “Thrombophilia: Clinical-practical aspects.” J Thromb Thrombolysis 2015;39:367-78. https://www.ncbi.nlm.nih.gov/pubmed/25724822
2. Connors JM. “Thrombophilia Testing and Venous Thrombosis.” N Engl J Med 2017; 377:1177-1187. http://www.nejm.org/doi/full/10.1056/NEJMra1700365 

Contributed by Hanny Al-Samkari, MD, Mass General Hospital, Boston, MA

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Continue reading “Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?”

Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?

Are two sets of blood cultures adequate for evaluation of bacteremia in my febrile patient?

For great majority of patients, more than 2 sets of blood cultures is not likely to significantly improve the yield of detecting bacteremia. 

Although a 2004 report suggested that 2 sets of blood cultures over 24 h period had a sensitivity of only 80% for bacteremia, several other studies have found much higher sensitivities, ranging from ~90%- 99% 2-3. When broken down by organism, sensitivity of 2 sets of blood cultures may be highest for Staphylococcus aureus (97%), followed by E. coli (91%), and Klebsiella pneumoniae (90%) 2.  The Clinical and Laboratory Standards Institute guidelines recommend paired blood culture sets (each set with 2 bottles, 10 ml of blood in each) to detect about 90-95% of patients with documented bacteremia, and 3 sets for 95-99% detection rate 4.

It seems prudent to strike a balance between drawing more than 2 sets of blood cultures—with its attendant risk of picking up contaminants— and what may be a definite but small incremental increase in the rate of detection of true bacteremia.

Whatever you do,  please don’t order only 1 set of blood cultures! Aside from its generally low yield, when positive it may be difficult to distinguish contaminants from true invaders.

 

References

  1. Cockerill FR, Reed GS, Hughes JG, et al. Clinical comparison of BACTEC 9240 Plus Aerobic/F resin bottles and the Isolator aerobic cultures. Clin Infect Dis 2004;38:1724-30. https://www.ncbi.nlm.nih.gov/pubmed/9163464
  2. Lee A, Mirrett S, Reller LB, et al. Detection of bloodstream infections in adults: how many cultures are needed? J Clin Microbiol 2007; 45:3546-48. http://jcm.asm.org/content/45/11/3546
  3. Towns ML, Jarvis WR, Hsueh PR. Guidelines on blood cultures. J Microbiol Immunol Infect 2010;43:347-49. https://www.ncbi.nlm.nih.gov/pubmed/20688297
  4. Weinstein MP, Reller LB, Murphy JR, et al. The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and eipidemiologic observations. Rev Infect Dis 1982;5:35-53. https://www.ncbi.nlm.nih.gov/pubmed/6828811
Are two sets of blood cultures adequate for evaluation of bacteremia in my febrile patient?

What is the utility of urine dipstick for blood in diagnosing rhabdomyolysis?

Although the dipstick method of detecting blood in the urine is convenient, it cannot differentiate between hemoglobin, myoglobin, or red blood cells. 1

Several reviews suggest that urine myoglobin is unstable with subpar performance in rhabdomyolysis1, often defined as creatine kinase (CK) elevation 5 times the upper limit of normal in the proper context (eg, crush injury, hypoxic/ischemic or drug injury). A sensitivity of 71% and a specificity of 54% for urine hemoglobin by dipstick, and a sensitivity of 25% and specificity of 75%  for urine myoglobin  has been reported in patients with serum CK >10,000 U/L. 3  

So while a positive dipstick for blood with few or no RBCs in the urine may make us think about rhabdomyolysis, its absence should not be used to exclude it in a susceptible host.

Final fun pearl: Did you know that consumption of quail has been associated with rhabdomyolysis, possibly due to their feeding on poisonous plants such as hemlock?

References

  1. Rodriguez-Capote Karina, Balion CM, Hill SA, et al. Utility of urine myoglobin for the prediction of acute renal failure in patients with suspected rhabdomyolysis: A systematic review. Clin Chem 2009;55:2190-97. https://www.ncbi.nlm.nih.gov/pubmed/19797717
  2. Nance JR, Mammen AL. Diagnostic evaluation of rhabdomyolysis. Muscle Nerve 2015;51:793-810. https://www.ncbi.nlm.nih.gov/pubmed/25678154
  3. Grover DS, Atta MG, Eustace JA, et al. Lack of clinical utility of urine myoglobin detection by microconcentrator ultrafiltration in the diagnosis of rhabdomyolysis. Nephrol Dial Transplant 2004;19:2634-38. https://www.ncbi.nlm.nih.gov/pubmed/15280520
What is the utility of urine dipstick for blood in diagnosing rhabdomyolysis?

Is measurement of amylase and lipase useful in patients with renal insufficiency suspected of pancreatitis?

Depends on how high the serum levels are! Although the clearance of both amylase and lipase appears to be impaired in patients with significant renal insufficiency (eg,  creatinine clearance <50ml/min), serum levels greater than 2-4 times the upper limits of normal for these enzymes are still considered suggestive of pancreatitis in these patients1-3.

Interestingly, in hemodialysis patients, elevation of lipase may also be due to the lipolytic effect of heparin during this procedure.  That’s why obtaining serum lipase levels before, not after,  hemodialysis has been recommended4

Also fascinating is that most of the elevation of serum amylase in patients with significant renal insufficiency appears to be related to the elevation of salivary, not pancreatic, isoenzyme of amylase4.

Final fun fact: Did you know that at one time the diagnosis of pancreatitis was based on the activity of serum on starch (for amylase) and olive oil (for lipase)? 5

References

  1. Levitt MD, Rapoport M, Cooperband SR. The renal clearance of amylase in renal insufficiency, acute pancreatitis, and macroamylasemia. Ann Intern Med 1969;71:920-25. http://annals.org/aim/article/683643/renal-clearance-amylase-renal-insufficiency-acute-pancreatitis-macroamylasemia
  2. Collen MJ, Ansher AF, Chapman AB, et al. Serum amylase in patients with renal insufficiency and renal failure. Am J Gastroenterol 1990;85:1377-80. https://www.ncbi.nlm.nih.gov/pubmed/1699413
  3. Royce VL, Jensen DM, Corwin HL. Pancreatic enzymes in chronic renal failure. Arch Intern Med 1987;147:537-39. https://www.ncbi.nlm.nih.gov/pubmed/2435254
  4. Vaziri ND, Change D, Malekpour A, et al. Pancreatic enzymes in patients with end-stage renal disease maintained on hemodialysis. Am J Gastroenterol 1988;83:410-12. https://www.ncbi.nlm.nih.gov/pubmed/2450453
  5. Editorial. Pancreatic enzymes. N Engl J Med 1963;268:901-2. http://www.nejm.org/doi/pdf/10.1056/NEJM196304182681613
Is measurement of amylase and lipase useful in patients with renal insufficiency suspected of pancreatitis?

What could be causing low serum haptoglobin in my patient with no evidence of hemolysis?

 

There are many causes of low serum haptoglobin besides hemolysis, including1-4:

  • Cirrhosis of the liver
  • Disseminated ovarian carcinomatosis
  • Pulmonary sarcoidosis
  • Elevated estrogen states
  • Repetitive physical exercise
  • Hemodilution
  • Blood transfusions
  • Drugs (eg, oral contraceptives, chlorpromazine, indomethacin, isoniazid, nitrofurantoin, quinidine, and streptomycin)
  • Iron deficiency anemia
  • Megaloblastic anemia (by destruction of megaloblastic RBC precursors in the bone marrow)
  • Congenital causes

Less well-known is that congenital haptoglobin deficiency (“anhaptoglobinemia”) may not be so rare in the general population at a prevalence of 1% among whites and 4% among African-Americans (>30% in blacks of West African origin)3. Measurement of serum hemopexin, another plasma protein that binds heme, may help distinguish between this condition and acquired hypohaptoglobinemia— in the absence of hemolysis, hemopexin levels should remain unchanged3,5.

Final Fun Fact: Did you know that serum haptoglobin is often low during the first 6 months of life?

References

  1. Shih AWY, McFarane A, Verhovsek M. Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol 2014;89: 443-47. https://www.ncbi.nlm.nih.gov/pubmed/24809098
  2. Sritharan V, Bharadwaj VP, Venkatesan K, et al. Dapsone induced hypohaptoglobinemia in lepromatous leprosy patients. Internat J Leprosy 1981;307-310. https://www.ncbi.nlm.nih.gov/pubmed/7198620
  3. Delanghe J, Langlois M, De Buyzere M, et al. Congenital anhaptoglobinemia versus acquired hypohaptoglobinemia. Blood 1998;9: 3524. http://www.bloodjournal.org/content/bloodjournal/91/9/3524.full.pdf
  4. Haptoglobin blood test. https://medlineplus.gov/ency/article/003634.htm. Accessed August 6, 2017.
  5. Smith A, McCulloh RJ. Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders. Front. Physiol 2015;6:187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485156/pdf/fphys-06-00187.pdf

 

In collaboration with Kris Olson, MD, MPH, Mass General Hospital, Boston, MA

What could be causing low serum haptoglobin in my patient with no evidence of hemolysis?

Does oral iron cause false-positive stool guaiac test?

The general agreement in the literature is that oral iron supplementation does not cause a false-positive guaiac-based fecal occult blood test (GFOBT).

GFOBT is based on rapid oxidization of α-guaiaconic acid to “guaiacum blue”, with hemoglobin serving as a catalyst through a non-enzymatic or “pseudoperoxidase” action. Although in vitro Fe3+ may serve as an oxidizing agent, this reaction is possible only under acidic conditions not found in the stool (pH ≥ 6-7)1.  Also, in the absence of a catalyst, Fe3+ alone would not be expected to cause rapid (within 30 seconds) conversion of α-guaiaconic acid to guaiacum blue1

Although a number of earlier clinical studies reported false-positive GBFOBT because of oral iron supplementation, subsequent investigations have uniformly failed to confirm these findings2. Potential reasons for earlier false-positive GBFOBT results include false interpretation of the color change—eg, green instead of blue— particularly when the discoloration is weakly positive, and non-standardized method of stool collection with the possibility of stool sample contamination by toilet water.

Other fascinating facts: Did you know that guaiac plant extract was used for centuries for treatment of syphilis and that the earliest application of guaiac testing was in forensic medicine in 1800s?

References

  1. McDonnell WM, Ryan JA, Seeger DM, Elta GH. Effect of iron on the guaiac reaction. Gastroenterology. 1989 Jan;96(1):74-8. https://www.ncbi.nlm.nih.gov/pubmed/2909440
  2. Anderson GD, Yellig TR, Krone RE. An investigation into the effects of oral iron supplementation on in vivo hemoccult stool testing. Am J Gastroenterol 1990;85:558-561. https://www.ncbi.nlm.nih.gov/pubmed/218661

Contributed by Brian Li, Medical Student, Harvard Medical School

Does oral iron cause false-positive stool guaiac test?

Should male patients with suspected urinary tract infection routinely undergo a prostate exam?

Yes! That’s because any urinary tract infection (UTI) in men has the potential for prostatic involvement1 —-as high as 83% by one report2.  

To make the matters more confusing, patients with acute bacterial prostatitis (ABP) often present with symptoms just like those of UTI such as urinary frequency, dysuria, malaise, fever, and myalgias3.  In the elderly, atypical presentation is not uncommon (eg, confusion, incontinence, fall)4.  Under these circumstances, bacteriuria and pyuria may also be related to ABP and the prostate exam should be an important part of your evaluation.

Although the sensitivity of prostate tenderness on digital rectal exam varies widely for ABP (9%-100%), a painful exam should raise suspicion for ABP, and by itself may be an independent predictor for clinical and bacteriologic failure of therapy1. Along with tenderness, fluctuance of prostate, particularly in the setting of voiding difficulties and longer duration of symptoms, may also suggest the presence of prostatic abscess5,6

But be gentle when performing a prostate exam and don’t massage it because you could potentially cause bacteremia and worsening of sepsis!1,7

References

  1. Etienne M, Chavanet P, Sibert L, et al. Acute bacterial prostatitis: heterogeneity in diagnostic criteria and management. Retrospective multicentric analysis of 371 patients diagnosed with acute prostatitis. BMC Infectious Diseases 2008;8:12. https://bmcinfectdis.biomedcentral.com/track/pdf/10.1186/1471-2334-8-12?site=bmcinfectdis.biomedcentral.com
  2. Ulleryd P, Zackrisson B, Aus G, et al. Prostatic involvement in men with febrile urinary tract infection as measured by serum prostate-specific antigen and transrectal ultrasonography. BJU Int 1999;84:470-4. http://onlinelibrary.wiley.com/doi/10.1046/j.1464-410x.1999.00164.x/pdf
  3. Krieger JN, Nyberg L, Nickel JC. NIH consensus definition and classification. JAMA 1999;282:236-37. http://jamanetwork.com/journals/jama/article-abstract/1030245
  4. Harper M, Fowlis. Management of urinary tract infections in men. Trends in Urology Gynaecology & Sexual Health. January/February 2007. http://onlinelibrary.wiley.com/doi/10.1002/tre.8/pdf
  5. Lee DS, Choe HS, Kim HY, et al. Acute bacterial prostatitis and abscess formation. BMC Urology 2016;16:38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936164/
  6. Oliveira P, Andrade JA, Porto HC, et al. Diagnosis and treatment of prostatic abscess. International Braz J Urol 2003;29: 30-34. http://www.scielo.br/pdf/ibju/v29n1/v29n1a06.pdf
  7. Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clin Infect Dis 2010; 50:1641-52. https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/cid/50/12/10.1086/652861/2/50-12-1641.pdf?Expires=1501276981&Signature=X5SLG2Pq5IpbsjDigES70~Nk6g5onrPwhrFClIAFIvdFiEyCsc1~2aWN9LpR~56DlGqxjmZuIX33JtOn-tURGG0puEwnulZDEDXFjFt6fXucSgtKMDOmGXSKoMvgtPZe86nduJMNDuaifEZXITpDXjSLXAJXVamJ-bbSUMEqSysnCCMxZx~5MaAb6WEikqG5Vi~Xnp58fXABG7BJS~ZFRn2~BTlVEEvmIIDDaY5cJjgUcN7SNOhs0rOS71WzlNtlXSqnXffZEdFSJ~iDcbyRL-wh-9OZqZ2fwojdk8Be89DsKJg8rIh8dlLc5O7v92yL~cZ6iieiP8xTGOU-21tVeA__&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q
Should male patients with suspected urinary tract infection routinely undergo a prostate exam?