What is the significance of teardrop cells (dacrocytes) on the peripheral smear of my patient with newly-discovered pancytopenia?

The presence of teardrop cells (dacrocytes) (Figure below) in the peripheral blood, named for their tear drop shape, is a prominent feature of myelophthisic (marrow infiltrative) conditions, including myelofibrosis, hematologic malignancies, cancer metastatic to the bone marrow, and granulomatous diseases. Teardrop cells may also be seen in beta-thalassemia, autoimmune and microangiopathic hemolytic anemia and severe iron deficiency (1-4).

 
When evaluating patients with leucoerythroblastic smears (defined by the presence of early myeloid and erythroid forms), the presence of teardrop cells can be helpful in distinguishing often malignant marrow infiltrative conditions from a benign reactive process.  Conditions where teardrop cells are seen with high frequency may also have extramedullary hematopoiesis, particularly in the spleen (1,2).

 
The mechanism of tear drop cell formation may be multifactorial but appears to involve distortion of the red cells as they pass through marrow or splenic sinusoids. Teardrop cells resulting from conditions such as cancer metastatic to the bone marrow likely involve primarily a marrow origin of the cells whereas primary myelofibrosis with prominent extramedullary hematopoiesis include a splenic mechanism of tear drop cell formation (2).

 
Supporting the possible splenic contribution to teardrop cell formation is the observation that teardrop cells may be reduced in number or eliminated entirely after splenectomy in patients with myelofibrosis and autoimmune hemolytic anemia (1,4).

Teardrop

Figure. Teardrop cells

References

1. DiBella NJ, Sliverstein MN, Hoagland HC. Effect of splenectomy on teardrop-shaped erythrocytes in agnogenic myeloid metaplasia. Arch Intern Med 1977; 137: 380-381. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/586447
2. Gutgemann I, Heimpel H, Nebe CT. Significance of teardrop cells in peripheral blood smears. J Lab Med 2014; DOI: 10.1515/labmed-2014-0005 https://www.researchgate.net/publication/272430111_Significance_of_teardrop_cells_in_peripheral_blood_smears
3. Korber C, Wolfler A, Neubauer M, Robier Christoph. Red blood cell morphology in patients with β-thalassemia minor. J Lab Med 2016-12-10 | https://www.researchgate.net/publication/311564128_Red_blood_cell_morphology_in_patients_with_b-thalassemia_minor DOI: https://doi.org/10.1515/labmed-2016-0052
4. Robier C, Klescher D, Reicht G,Amouzadeh-Ghadikolai O, Quehenberger F, Neubauer M. Dacrocytes are a common morphologic feature of autoimmune and microangiopathic haemolytic anaemia. Clin Chem Lab Med. 2015;53:1073-6. https://www.ncbi.nlm.nih.gov/pubmed/25503671

Contributed by Tom Spitzer, MD, Director of Cellular Therapy and Transplantation Laboratory,  Massachusetts General Hospital, Boston, MA.
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What is the significance of teardrop cells (dacrocytes) on the peripheral smear of my patient with newly-discovered pancytopenia?

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

Absolutely! Although tracheobronchial calcification (TBC) is often found as part of normal aging process in the elderly, especially women, long-term warfarin use has also been implicated as a cause of TBC, even among those with less advanced age (1-4).

In a cohort of patients 60 years of age or older, radiographic evidence of trachea and bronchi calcification was found in 47% of patients on warfarin (mean age 64 years, mean duration of treatment 6 years) compared to 19% of controls (1). A positive correlation between the duration of warfarin therapy and increased levels of calcification was also found.  Fortunately, TBC is a benign finding and has no health consequences.

As for the mechanism for this rather intriguing phenomenon, the inhibition of a vitamin K-dependent protein that prevents calcification of cartilaginous tissue seems to be the most plausible (1). Although we often think of vitamin-K dependent factors in relation to the coagulation cascade, several vitamin K-dependent proteins also play an important role in the inhibition of calcification in soft tissues and blood vessels (eg, matrix Gla protein-MGP) (5,6).

In fact, rats maintained on warfarin undergo calcification of cartilage and elastic connective tissue, while exposure of the fetus to warfarin during pregnancy is associated with calcifications in and around joints, airway and nasal cartilages (4,7). These observations further support a causative role of warfarin in inducing TBC.

 

Bonus Pearl: Did you know that MGP deficiency in humans is known as the Keutel syndrome, a rare autosomal recessive disease characterized by several characteristic physical features, including severe cartilage calcifications and depressed nasal bridge?

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References

  1. Moncada RM, Venta LA, Venta ER, et al. Tracheal and bronchial cartilaginous rings: warfarin sodium-induced calcification. Radiology 1992;184:437-39. https://pubs.rsna.org/doi/10.1148/radiology.184.2.1620843
  2. Thoongsuwan N, Stern EJ. Warfarin-induced tracheobronchial calcification. J thoracic Imaging 2003;18:110-12. https://journals.lww.com/thoracicimaging/Abstract/2003/04000/Warfarin_Induced_Tracheobronchial_Calcification.12.aspx
  3. Nour SA, Nour HA, Mehta J, et al. Tracheobronchial calcification due to warfarin therapy. Am J Respir Crit Care Med 2014;189:e73. https://www.atsjournals.org/doi/full/10.1164/rccm.201305-0975IM
  4. Joshi A, Berdon WE, Ruzal-Shapiro C, et al. CT detection of the tracheobronchial calcification in an 18 year-old on maintenance warfarin sodium therapy. AJR Am J Roentgenol 2000;175:921-22. https://www.ajronline.org/doi/full/10.2214/ajr.175.3.1750921
  5. Wen L, Chen J, Duan L, et al. Vitamin K-dependent proteins involved in bone and cardiovascular health (review). Molecular Medicine Reports 2018;18:3-15. https://www.spandidos-publications.com/mmr/18/1/3/abstract \
  6. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr 2012; 3:166-173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648717/pdf/166.pdf

7.      Price PA, Williamson MK, Haba T, et al. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci  U.S.A 1982;79:7734-8. https://www.ncbi.nlm.nih.gov/pubmed/6984192

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

My patient with primary Sjogren’s syndrome has now been diagnosed with COPD despite lack of a significant smoking history. Is there a connection between Sjogren’s syndrome and COPD?

Increasing body of evidence suggests that COPD in patients with primary Sjögren’s syndrome (PSS) is not uncommon even among those who never smoked (1).

 
A 2015 study of patients with PSS reported that overall 41% of patients with PSS, including 30% of those who never smoked, fulfilled the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD. More specifically, pulmonary function tests (PFTs) showed decreased vital capacity (VC), forced expiratory volume in 1 second (FEV-1)  and DLCO in patients with PSS. Importantly, lab inflammatory and serological features were poorly associated with PFT results, while radiographic signs of interstitial lung disease (ILG) were absent in one-half of patients with PSS and COPD (1).

 
A longitudinal study with a mean follow-up of 11 years found a 37% rate of development of COPD among patients with PSS (2). Another related study reported a poor correlation between respiratory symptoms and COPD disease as assessed by PFTs in PSS, with the authors recommending that PFTs be performed “liberally” in all patients with PSS regardless of symptoms (3).

 
Lastly, a population-based cohort study of female adults found significantly higher rate of COPD among patients with PSS compared to controls (4).

 
Although the exact pathogenic mechanism behind PSS-associated COPD is unclear, xerotrachea and impaired mucocilliary clearance, as well as inflammatory infiltrates in the exocrine glands of the airways, all leading to physical obstruction and bronchial hyperreactivity have been suggested (1).

 

Bonus Pearl: Did you know that COPD is associated with many other autoimmune diseases (eg, rheumatoid arthritis and systemic lupus erythematosus), and a genetic link has been implicated between COPD and autoimmunity? (5,6).

 

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References
1. Nilsson AM, Diaz S, Theander E, et al. Chronic obstructive pulmonary disease is common in never-smoking patients with primary Sjögren’s syndrome. J Rheumatol 2015;42:464-71. https://www.researchgate.net/publication/270907531_Chronic_Obstructive_Pulmonary_Disease_Is_Common_in_Never-smoking_Patients_with_Primary_Sjogren_Syndrome
2. Mandl T, Diaz S, Ekberg O, et al. Frequent development of chronic obstructive pulmonary disease in primary SS-result of a longitudinal follow-up. Rheumatology 2012;51:941-46. https://www.researchgate.net/publication/221760110_Frequent_development_of_chronic_obstructive_pulmonary_disease_in_primary_SS-results_of_a_longitudinal_follow-up
3. Bolmgren VS, Olssson P, Wollmer P, et al. Respiratory symptoms are poor predictors of concomitant chronic obstructive pulmonary disease in patients with primary Sjögren’s syndrome. Rheumatol Int 2017;37:813-18. https://link.springer.com/content/pdf/10.1007/s00296-017-3678-5.pdf
4. Shen TC, Wu BR, Chen HJ, et al. Risk of chronic obstructive pulmonary disease in female adults with primary Sjögren’s syndrome. A nationwide population-based cohort study. Medicine 2016; 95:1-6. http://europepmc.org/abstract/MED/26962839
5. Hemminki K, Liu X, Ji J et al. Subsequent COPD and lung cancer in patients with autoimmune disease. Eur Respir J 2011;37:463-74. https://www.ncbi.nlm.nih.gov/pubmed/21282811
6. Ji X, Niu X, Qian J, et al. A phenome-wide association study uncovers a role for autoimmunity in the development of chronic obstructive pulmonary disease. Resp Cell Mol Biol 2018;58:777-79. https://www.atsjournals.org/doi/10.1165/rcmb.2017-0409LE

My patient with primary Sjogren’s syndrome has now been diagnosed with COPD despite lack of a significant smoking history. Is there a connection between Sjogren’s syndrome and COPD?

My patient with inferior myocardial infarction with Q-waves 2 years ago now has no evidence of Q waves on his EKG. Can Q-waves from myocardial infarction really regress over time?

Short answer: Yes! Q-waves may regress following transmural myocardial infarction (ATMI) and in fact this phenomenon may not be as unusual as once thought, occurring in 7-15% of patients (1,2).

 
A prospective study involving patients with ATMI evaluated by coronary angiography and followed for an average of 65 months found an 11% rate of loss of Q-waves over an average of 14 months after ATMI. Factors associated with loss of Q-waves included lower peak creatine kinase values, lower left ventricular end-diastolic pressures, higher ejection fractions, fewer ventricular aneurysms and lower rate of congestive heart failure, all leading to the authors’ conclusion that Q-wave loss may be related to a smaller infarct size (1).

 
Similar findings were reported from patients enrolled in the Aspirin Myocardial Infarction Study with a loss of a previously documented diagnostic Q-wave confirmed in 14.2% of participants over an average of 38 months. Mortality among patients who lost Q-waves was not significantly different than among those with persistent Q-waves in a single infarct location (2).

 
These observations suggest that Q-waves in the setting of ATMI may not necessarily be pathognomonic of myocardial necrosis and, at least in some instances, may be due to tissue ischemia, edema and inflammation causing reversible myocardial and electrical stunning (3). Of interest, reversible Q-waves have also been reported in acute myocarditis (4).

Bonus Pearl: Did you know that the EKG waves P and Q were likely named by Einthoven, the inventor of EKG, after the designation of the same letters by Descartes, the father of analytical geometry, in describing refraction points? (5). 

 

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References
1. Coll S, Betriu A, De Flores T, et al. Significance of Q-wave regression after transmural acute myocardial infarction. Am J Cardiol 1988;61:739-42.
2. Wasserman AG, Bren GB, Ross AM, et al. Prognostic implications of diagnostic Q waves after myocardial infarction. Circulation 1982;65:1451-55.
3. Barold SS, Falkoff MD, Ong LS, et al. Significance of transient electrocardiographic Q waves in coronary artery disease. Cardiol Clin 1987;5:367-80.
4. Dalzell JR, Jackson CE, Gardner RS. Masquerade: Fulminant viral myocarditis mimicking a Q-wave anterolateral myocardial infarction. Am J Med 2009. Doi:10.1016/j.amjmed.2009.01.015.

5. Hurst, JW.  Naming of the waves in the ECG, with a brief account of their genesis. Circulation 1998;98:1937-42. 

 

My patient with inferior myocardial infarction with Q-waves 2 years ago now has no evidence of Q waves on his EKG. Can Q-waves from myocardial infarction really regress over time?

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

Although there may always be hesitation in resuming anticoagulation (AC) in patients with non-valvular atrial fibrillation (NVAF) and recent fall(s), the weight of the evidence suggests that most patients are still more likely to benefit from AC than be adversely impacted by intracranial hemorrhage.

 
An often-quoted systematic review article on the risks and benefits of anti-thrombotic (AC or aspirin) therapy in patients with NVAF at risk estimated that persons taking warfarin must fall 295 times in 1 year for warfarin to not be the optimal therapy for reducing the risk of stroke (1). The authors concluded that “a history of and/or the presence of risk factors for falls should not be considered important factors in the decision whether to offer antithrombotic (especially warfarin) therapy to elderly patients with atrial fibrillation”.

 
In another study involving older adults with NVAF, although a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage, this risk did not differ among patients treated with warfarin, aspirin or no antithrombotic therapy (2).

 
Ultimately, the decision to prescribe AC in patients with NVAF at risk for falls should be made based on shared decision making with patients and caregivers. However, in the absence of absolute contraindications for AC in these patients (eg, intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders), perceived or actual risk of falls by itself should not automatically exempt a patient from receiving AC in NVAF (3).

 

Although much of the data on the relative risk of bleeding against prevention of strokes has been derived from studies involving warfarin, it is reassuring that the risk of intracranial bleed has been lower than that of warfarin for several newer non-vitamin K antagonist direct oral anticoagulants (NOACs or DOACs),  including dabigatran, rivaroxaban, edoxaban and apixaban (4). 

 

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References

1. Man-Son-Hing M, Nichol G, Lau A, et al. Choosing antithrombotic therapy for elderly patiets with atrial fibrillation who are at risk for falls. Arch Intern Med 1999;159:677-685.
2. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005;118:612-617.
3. Hagerty T, Rich MW. Fall risk and anticoagulation for atrial fibrillation in the elderly: a delicate balance. Clev Clin J 2017;84:35-40.

4. Lopez RD, Guimaraes PO, Kolls BJ, et al. Intracranial hemorrhage in patietns with atrial fibrillation receiving anticoagulation therapy. Blood 2017;129:2980-87. 

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

My patient with diabetes mellitus is now admitted with pneumonia. Does diabetes increase the risk of pneumonia requiring hospitalization?

The weight of the evidence to date suggests that diabetes mellitus (DM) does increase the risk of pneumonia-related hospitalization.1-3

A large population-based study involving over 30,000 patients found an adjusted relative risk (RR) of hospitalization with pneumonia of 1.26 (95% C.I 1.2-1.3) among patients with DM compared to non-diabetics.  Of note, the risk of pneumonia-related hospitalization was significantly higher in type 1 as well as type 2 DM and among patients whose A1C level was ≥9.1  Another population-based study found a high prevalence of DM (25.6%) in patients hospitalized with CAP, more than double that in the population studied.2  A 2016 meta-analysis of observational studies also found increased incidence of respiratory tract infections among patients with diabetes (OR 1.35, 95% C.I. 1.3-1.4).

Not only does DM increase the risk of pneumonia-related hospitalization, but it also appears to adversely affect its outcome with increased in-hospital mortality.2 Among patients with type 2 DM,  excess mortality has also been reported at 30 days, 90 days and 1 year following hospitalization for pneumonia. 4,5 More specifically, compared to controls with CAP, 1 year mortality of patients with DM was 30% (vs 17%) in 1 study. 4

Potential reasons for the higher incidence of pneumonia among patients with DM include increased risk of aspiration (eg, in the setting of gastroparesis, decreased cough reflex), impaired immunity (eg, chemotaxis, intracellular killing), pulmonary microangiopathy and coexisting morbidity. 1,3,5,6

Bonus Pearl: Did you know that worldwide DM has reached epidemic levels, such that if DM were a nation, it would surpass the U.S. as the 3rd most populous country! 7

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References

  1. Kornum JB, Thomsen RW, RUS A, et al. Diabetes, glycemic control, and risk of hospitalization with pneumonia. A population-based case-control study. Diabetes Care 2008;31:1541-45. https://www.ncbi.nlm.nih.gov/pubmed/17595354
  2. Martins M, Boavida JM, Raposo JF, et al. Diabetes hinders community-acquired pneumonia outcomes in hospitalized patients. BMJ Open Diabetes Research and Care 2016;4:e000181.doi:10.1136/bmjdrc-2015000181. https://drc.bmj.com/content/4/1/e000181
  3. Abu-Ahour W, Twells L, Valcour J, et al. The association between diabetes mellitus and incident infections: a systematic review and meta-analysis of observational studies. BMJ Open Diabetes Research and Care 2017;5:e000336. https://drc.bmj.com/content/5/1/e000336. 
  4. Falcone M, Tiseo G, Russo A, et al. Hospitalization for pneumonia is associated with decreased 1-year survival in patients with type 2 diabetes. Results from a prospective cohort study. Medicine 2016;95:e2531. https://www.ncbi.nlm.nih.gov/pubmed/26844461
  5. Kornum JB, Thomsen RW, Rus A, et al. Type 2 diabetes and pneumonia outcomes. A population-based cohort study. Diabetes Care 2007;30:2251-57. https://www.ncbi.nlm.nih.gov/pubmed/17595354
  6. Koziel H, Koziel MJ. Pulmonary complications of diabetes mellitus. Pneumonia. Infect Dis Clin North Am 1995;9:65-96. https://www.ncbi.nlm.nih.gov/pubmed/7769221
  7. Zimmet PZ. Diabetes and its drivers: the largest epidemic in human history? Clinical Diabetes and Endocrinology 2017;3:1 https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-016-0039-3  

 

My patient with diabetes mellitus is now admitted with pneumonia. Does diabetes increase the risk of pneumonia requiring hospitalization?