Patients admitted to the hospital for acute exacerbation of COPD are generally regarded as being at high risk of venous thromboembolism (VTE) (prevalence 5%-29%), possibly due to the frequent coexistence of other risk factors, such as immobility, history of smoking, and venous stasis.1 The exact mechanism(s) behind this association remains poorly understood, however.
Among patients with moderate-very severe COPD (GOLD criteria stage II-IV), high BMI, low exercise tolerance, history of pneumothorax, congestive heart failure, and peripheral vascular disease have also been associated with VTE.1
Systemic inflammation has also been implicated in increasing the risk of VTE in patients with COPD. Although the pathophysiology of COPD is largely defined by the local inflammatory response to airway injury, evidence suggests that there is also a systemic inflammatory response in COPD.2,3 This systemic inflammation could in turn contribute to the increased risk of vascular disease, including VTE, coronary artery disease, and cerebrovascular disease.4
Bonus pearl: Did you know that VTE may be 3x more prevalent among patients with COPD exacerbation without known cause (vs those with identifiable cause) and is associated with a 1-year mortality of 61.9%! 5
- Kim V, Goel N, Gangar J, et al. Risk factors for venous thromboembolism in chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis 2014;1: 239-249. https://www.ncbi.nlm.nih.gov/pubmed/25844397
- Lankeit M, Held M. Incidence of venous thromboembolism in COPD: linking inflammation and thrombosis? Eur Respir J 2016;47(2):369-73. https://www.ncbi.nlm.nih.gov/pubmed/26828045
- Sinden NJ1, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010;65:930-6. https://www.ncbi.nlm.nih.gov/pubmed/20627907
- King PT. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clinical and Translational Medicine 2015;4:26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518022/
- Gunen H, Gulbas G, In E, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;36:1243-8. https://www.ncbi.nlm.nih.gov/pubmed/19926740
Contributed by Camilo Campo, Medical Student, Harvard Medical School, Boston, MA.
The mechanism behind digital clubbing has yet to be fully elucidated, with hypotheses ranging from a circulating vasodilator, tissue hypoxia, a neurocirculatory reflex, and genetic factors. 1 Although hypoxemia is often cited as a cause of clubbing, it is often absent in the presence of clubbing and many patients with hypoxemia do not have clubbing.
A potentially unifying pathophysiologic mechanism of clubbing revolves around platelet clustering and associated growth factor release. 2.3 Platelet clumps/megakaryocytes—either because of circumvention of the lung capillary network (eg, in intracardiac shunts or lung cancer) or increased production (eg, in left-sided endocarditis or chronic inflammatory conditions)—may wedge in the fine vasculature of distal fingertips or toes and cause release of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).
Together, PDGF and VEGF promote neovascularization, increase vessel dilation and permeability, and modify connective tissue to create the distinct club-like appearance. Local hypoxic condition from reduced capillary perfusion is thought to further stimulate the release of these growth factors.
Potential causes of clubbing in our patient include lung cancer, interstitial lung disease, bronchiectasis, core pulmonale and secondary polycythemia, among many others. 1
Fun Fact: Did you know that clubbing, also known as “Hippocratic finger”, was first described by Hippocrates in a patient with chronic empyema (don’t ask how chronic empyema was diagnosed in 400 BC!)?1
- McPhee SJ. Clubbing. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths;1990. Chapter 44. Available from https://www.ncbi.nlm.nih.gov/books/NBK366/
- Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987;2:1434-4. https://www.ncbi.nlm.nih.gov/pubmed/2891996/
- Atkinson S, Fox SB. Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol 2004;203:721-8. https://www.ncbi.nlm.nih.gov/pubmed/15141388
Contributed by George Bugarinovic, Medical Student, Harvard Medical School
Any respiratory rate (RR) greater than 20/min in an adult patient may be cause for concern, particularly in the setting of potentially serious disease and absence of an obvious cause such as pain or fever.
Our patient’s RR is outside the commonly cited normal range of 12-20/min. It indicates increased alveolar ventilation which may in turn be caused by hypoxia, hypercapnea, or metabolic acidosis, all portending possibly poor outcome, if left untreated.1 It’s no surprise that an abnormal RR is often the ﬁrst sign of clinical deterioration.2 RR is also the least likely of the vital signs to be affected by polypharmacy (eg, NSAIDs affecting temperature, beta-blockers affecting heart rate and blood pressure).
Another reason for not dismissing an RR of 22 in our patient is the common practice of guessing rather than measuring the RR by healthcare providers in part likely due to the more “labor-intensive” nature of measuring RRs compared to other vital signs and lack of appreciation for its importance in assessing severity of disease. 1 Of note, in an experimental study of doctors viewing videos of mock patients, over 50% failed to detect abnormal RR when using the “spot” technique of estimating without a timer.3 Even when presented with a RR of 30/min, over 20% of doctors reported it as normal (12-20/min)!
Final tidbit: Do you want to know what a RR of 20/min really feels like? Take a breath every 3 seconds. If you are like most, it doesn’t feel “normal”!
1. Cretikos MA, Bellomo R, Hillman K. Respiratory rate: the neglected vital sign. MJA 2008;188:657-59. https://www.ncbi.nlm.nih.gov/pubmed/18513176
2. Flenady T, Dwer T, Applegarth J. Accurate respiratory rates count: So should you! Australas Emerg Nurs J 2017; 20:45-47. https://www.ncbi.nlm.nih.gov/pubmed/28073649
3. Philip KEJ, Pack E, Cambiano V et al. The accuracy of respiratory rate assessment by doctors in a London teaching hospital: a cross-sectional study. J Clin Monit Comput2015;29:455-60. https://www.ncbi.nlm.nih.gov/pubmed/25273624
Evidence supporting the efficacy of direct oral anticoagulants (DOACs) in obesity is limited. A major concern is the possibility of subtherapeutic anticoagulation in obese patients when standard doses of DOACs are used.
The International Society on Thrombosis and Haemostasis recommends1:
- Standard fixed dosing of DOACs for patients with BMI ≤ 40 kg/m2 or weight ≤ 120 kg.
- Avoiding DOACs in patients with BMI > 40 kg/m2 or weight > 120 kg. However, if a DOAC is needed, laboratory confirmation of therapeutic drug concentrations (eg, by checking anti-factor Xa depending on the agent) should be performed, and if subtherapeutic, a vitamin K antagonist (eg, warfarin) is recommended instead.
Based on the individual comparison of DOACs with warfarin in patients with “high” body weight (cut-off of 90 kg or 100 kg, depending on the study) and limited data, apixaban may be more effective in preventing recurrent venous thromboembolism or its related deaths. However, other DOACs, such as rivaroxaban, dabigatran, and edoxaban have also been used in patients with high body weight2.
To add to the controversy, the efficacy of fixed dose dabigatran in obese patients has been questioned3 and some have recommended avoiding DOACs altogether in patients with BMI ≥ 35 kg/m2 or weight > 120 kg, until more data become available4.
As in many situations in medicine, a case-by-case decision based on clinical judgment and patient preferences may be the best way to go!
- Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 1308–13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936273
- Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med 2015; 47: 61-8. https://www.ncbi.nlm.nih.gov/pubmed/25665582
- Breuer L, Ringwald J, Schwab S, et al. Ischemic Stroke in an Obese Patient Receiving Dabigatran. N Engl J Med 2013; 368: 2440–2. http://www.nejm.org/doi/pdf/10.1056/NEJMc1215900
- Burnett AE, Mahan CE, Vasquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE Treatment. J Thromb Thrombolysis 2016; 41: 206-32. https://www.ncbi.nlm.nih.gov/pubmed/26780747
Contributed by Mahesh Vidula, MD, Mass General Hospital, Boston, MA.
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
- 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?
- 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
- 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
- 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
- Haptoglobin blood test. https://medlineplus.gov/ency/article/003634.htm. Accessed August 6, 2017.
- 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
There is no firm evidence either for or against the use of systemic anticoagulants (ACs) in patients with asymptomatic pulmonary embolism (PE) following hemodialysis vascular access declotting (HVAD).
However, despite the common occurrence of asymptomatic PE following HVAD procedures (~40%), symptomatic PE—at times fatal—has also been reported in these patients1,2.
In the absence of hard data and any contraindications, anticoagulation can be justified in our patient for the following reasons:
- Asymptomatic segmental PE is commonly treated as symptomatic PE irrespective of setting2,3
- Hemodialysis patients are often considered hypercoagulable due to a variety of factors eg, platelet activation due to extracorporeal circulation, anti-cardiolipin antibody, lupus anticoagulant, decreased protein C or S activity, and/or reduced anti-thrombin III activity4-7
- Overall, chronic dialysis patients have higher incidence of PE compared to the general population8
- There is no evidence that asymptomatic PE following HVAD has a more benign course compared to that in other settings
- Untreated PE may be associated with repeated latent thrombosis or progression of thrombosis in the pulmonary artery5
- Calderon K, Jhaveri KD, Mossey R. Pulmonary embolism following thrombolysis of dialysis access: Is anticoagulation really necessary? Semin Dial 2010:23:522-25. https://www.ncbi.nlm.nih.gov/pubmed/21039878
- Sadjadi SA, Sharif-Hassanabadi M. Fatal pulmonary embolism after hemodialysis vascular access declotting. Am J Case Rep 2014;15:172-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004792/pdf/amjcaserep-15-172.pdf
- Chiu V, O’Connell C. Management of the incidental pulmonary embolism. AJR 2017;208:485-88. http://www.ajronline.org/doi/pdf/10.2214/AJR.16.17201
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. CHEST 2016;149:315-52. http://journal.chestnet.org/article/S0012-3692(15)00335-9/fulltext
- Yamasaki K, Haruyama N, Taniguchi M, et al. Subacute pulmonary embolism in a hemodialysis patient, successfully treated with surgical thrombectomy. CEN Case Rep 2016;5:74-77 https://link.springer.com/article/10.1007/s13730-015-0195-9
- Nampoory MR, Das KC, Johny KV, et al. Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 2003;42:797-805. https://www.ncbi.nlm.nih.gov/pubmed/14520631
- O’Shea SI, Lawson JH, Reddan D, et al. Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg 2003;38: 541-48. http://www.jvascsurg.org/article/S0741-5214(03)00321-5/pdf
- Tveit DP, Hypolite IO, Hshieh P, et al. Chronic dialysis patients have high risk for pulmonary embolism. Am J Kidney Dis 2002;39:1011-17. https://www.ncbi.nlm.nih.gov/pubmed/11979344
Not extremely well! Although a recent multicenter prospective study in adult hospitalized patients reported that the median procalcitonin (PCT) concentration was significantly lower for community-acquired pneumonia (CAP) caused by viral pathogens ( 0.09 u/ml vs atypical bacteria [0.2 ug/ml] and typical bacteria [2.5 ug/ml]), PCT was <0.1 ug/ml and <0.25 ug/ml in 12.4% and 23.1% of typical bacterial cases, respectively1.
This means that we could potentially miss about a quarter of CAP cases due to typical bacterial causes if we use the <0.25 ug/ml threshold (<0.20 is ug/ml has been used to exclude sepsis2). For these reasons and based on the results from another study3, no threshold for PCT can reliably distinguish bacterial from viral etiologies of CAP4. Clinical context is essential in interpreting PCT levels! Also go to a related pearl on this site5.
Can PCT distinguish Legionella from other atypical bacterial causes of CAP (eg, caused by Mycoplasma or Chlamydophila)? The answer is “maybe”! Legionella was associated with higher PCT levels compared to Mycoplasma and Chlamydophila in one study1, but not in another3.
- Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2017;65:183-90. https://www.ncbi.nlm.nih.gov/pubmed/28407054
- Meisner M. Update on procalcitonin measurements. Ann Lab Med 2014;34:263-73.
- Krüger S, Ewig S, Papassotiriou J, et al. Inflammatory parameters predict etiologic patterns but do not allow for individual prediction of etiology in patients with CAP-Results from the German competence network CAPNETZ. Resp Res 2009;10:65. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714042/pdf/1465-9921-10-65.pdf
- Bergin SP, Tsalik EL. Procalcitonin: the right answer but to which question? Clin Infect Dis 2017; 65:191-93. https://academic.oup.com/cid/article-abstract/65/2/191/3605416/Procalcitonin-The-Right-Answer-but-to-Which?redirectedFrom=fulltext