Is my patient with varicose veins at higher risk of venous thromboembolism?

Although varicose veins are common and usually not associated with serious health complications, increasing scientific evidence suggests that they are associated with increased risk of subsequent incident deep venous thrombosis (DVT) and pulmonary embolism (PE). 1-3

A 2018 retrospective cohort study involving patients with the diagnosis of varicose veins and controls (>200,000 subjects each) based on claims data from Taiwan found a higher incidence rate of DVT among cases (hazard ratio [HR] 5.3, 95%C.I. 5.1-5.6). Increased risk of DVT with varicose veins was reported in all age groups but decreased with increasing age.  The HR was higher within the first year of the diagnosis of varicose veins. 1

In the same study, the incidence of PE was higher among participants with varicose veins (HR 1.7 95% C.I. 1.5-1.9).  Again, the association did not significantly differ by age.1  Other smaller studies have found similar association between DVT and varicose veins. 2,3

Although these studies at best demonstrate an association (not necessarily a cause and effect relationship) between varicose veins and venous thromboembolism, several possible explanations have been posited. Animal studies have demonstrated higher concentrations of macrophages, monocytes, neutrophils, lymphocytes, and matrix metalloproteinases in venous valves exposed to high pressure for prolonged periods.  The resultant inflammatory state in patients with varicose veins may in turn promote a prothrombotic state contributing to venous thromboembolism. 1,4

Bonus Pearl: Did you know that nearly 1 of 4  adults in the United States have been reported to have varicose veins?

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References

  1. Chang SL, Huang YL, Lee MC, et al. Association of varicose veins with incident venous thromboembolism and peripheral artery disease. JAMA 208;319:807-817. https://jamanetwork.com/journals/jama/fullarticle/2673551
  2. Muller-Buhl U, Leutgeb R, et al. Varicose veins are a risk factor for deep venous thrombosis in general practice patients. Vasa 2012;41:360-65. https://pubmed.ncbi.nlm.nih.gov/22915533/
  3. Engbers MJ, Karasu A, Blom JW, et al. Clinical features of venous insufficiency and the risk of venous thrombosis in older people. Br J Haematol 2015;171:417-23. https://pubmed.ncbi.nlm.nih.gov/26221838/
  4. Riva N, Donadini MP, Ageno W. Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation. Thromb Haemost 2015;113:1176-1183. https://pubmed.ncbi.nlm.nih.gov/25472800/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is my patient with varicose veins at higher risk of venous thromboembolism?

Is intermittent pneumatic compression effective in reducing the risk of deep vein thrombosis in non-surgical hospitalized patients at high risk of major bleed?

The weight of the evidence to date suggests that intermittent pneumatic compression (IPC) is effective in reducing the risk of deep venous thrombosis (DVT) in hospitalized patients with stroke. 1,2 Whether IPC is also effective in non-surgical hospitalized patients without stroke at high risk of DVT and major bleed needs further studies.

A 2013 multicenter randomized trial (CLOTS 3) involving over 2,000 immobile hospitalized patients post-stroke found a significantly lower risk of DVT in proximal veins or any symptomatic DVT in the proximal veins within 30 days of randomization (8.5% vs 12.1%; absolute reduction risk 3.6%, 95% C.I. 1.4-5.8). Of note, the rate of concurrent heparin or low molecular weight heparin (LMWH) prophylaxis was similar between the 2 groups (17%). 1

A meta-analysis including the CLOTS 3 study and 2 other smaller trials 2 in patients with stroke found a risk reduction for proximal DVT (O.R. 0.66, 95% C.I 0.52-0.84) with nearly significant reduction in deaths by the end of the treatment period (O.R. 0.81, 95% 0.65-1.01).1

Although IPC may also be effective in non-surgical hospitalized patients without stroke but at high risk of DVT and bleed, proper trials in this patient population is lacking. In fact, the 2012 American College of Chest Physicians guidelines on antithrombotic therapy and prevention of thrombosis classifies use of IPC in preventing DVT’s in non-surgical acutely ill hospitalized patients as category 2C recommendation (weak, low quality evidence). 3

The patient population and methodology of above studies should be distinguished from those of a 2019 published trial involving only critically ill patients—all receiving pharmacologic thromboprophylaxis—which reported no reduction in the incidence of proximal lower-limb DVT with the addition of IPC. 4

 

Bonus Pearl: Did you know that venous thromboembolism has been reported in up to 42% of hospitalized patients who have had a stroke? 1

 

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References

  1. Dennis M, Sandercock P, Reid J, et al. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicenter randomized controlled trial. Lancet 2013;382:516-24. https://www.thelancet.com/cms/10.1016/S0140-6736(13)61050-8/attachment/1a0438d2-86eb-4da1-8bdb-92c0aec18b8d/mmc1.pdf
  2. Naccarato M, Chiodo Grandi F, Dennis M, et al. Physical methods for preventing deep vein thrombosis in stroke. Cochrance Database Syst Rev 2010;8:CD001922. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001922.pub3/full
  3. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012;141 (suppl):7S-47S. http://www.sphcs.org/workfiles/CardiacVascular/7S-full.pdf
  4. Arabi YM, Al-Hameed F, Burns KEA, et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Engl J Med 2019;380:1305-15. https://pubmed.ncbi.nlm.nih.gov/30779530/

 

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is intermittent pneumatic compression effective in reducing the risk of deep vein thrombosis in non-surgical hospitalized patients at high risk of major bleed?

How does older people’s immune system place them at high risk of sepsis and death?

Increased risk of sepsis and death from infectious causes among the elderly is a well-known phenomenon—particularly as witnessed in the Covid-19 era— and is in part due to 2 major age-related alterations of their immune system: 1. Defective T and B cell functions in response to acute infections; and 2. Once infection sets in, inadequate control of sepsis-induced pro-inflammatory response and its attendant procoagulant state. Interestingly, the essential elements of the innate immunity (eg, neutrophils, dendritic cells, complements) are generally spared from the effects of aging.1,2

Increased susceptibility of the elderly to acute infections is in part caused by poorer T helper cell function and suboptimal B cell humoral response to neoantigens. Despite this, serum levels of pro-inflammatory cytokines such as IL-1, IL-6,TNF-alpha, and IFN-gamma are intact.  In fact, production of IL-6 and its duration of response is actually increased in the elderly.1,2

Poor control of the inflammatory state due to sepsis in older patients may be related to the difficulty in clearing a pathogen or dysfunction in the signaling by counter-regulatory cytokines, such as IL-10.2 Either way, unchecked inflammatory response is deleterious to the patient and is associated with increased risk of thrombosis and thromboembolism, multiorgan system failure, septic shock and death. 

Bonus Pearl: Did you know that even in the absence of infection, older people are more prone to thrombosis and thromboembolism , in part related to elevated plasma levels of fibrinogen, as well as factor VII, VIII, and IX, among others?2,3  

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 References

  1. Ticinesi A, Lauretani F, Nouvenne A, et al. C-reactive protein (CRP) measurement in geriatric patients hospitalized for acute infection. Eur J Intern Med 2017;37:7-12. https://pubmed.ncbi.nlm.nih.gov/27594414/
  2. Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis 2005;41: (Suppl 7) S504-12. https://pubmed.ncbi.nlm.nih.gov/16237654/
  3. Mari D, Coppola R, Provenzano R. Hemostasis factors and aging. Experimental Gerontology 2008;43:66-73. https://www.sciencedirect.com/science/article/abs/pii/S0531556507001404?via%3Dihub

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

How does older people’s immune system place them at high risk of sepsis and death?

What’s the evidence that patients with Covid-19 are at high risk of blood clots?

Although we often think of it as a respiratory disease, emerging evidence suggests that Covid-19, particularly when severe,  is also associated with high risk of thrombotic events, including pulmonary embolism, venous thrombosis, and arterial thrombotic events.1

A Chinese study found that ICU patients with severe Covid-19 had a venous thromboembolism (VTE) incidence of 25%, with disseminated intravascular coagulopathy (DIC) found in the majority of fatal cases.2

A prospective Dutch study involving critically ill ICU patients with Covid-19 reported VTE in 27% and arterial thrombotic events in another 3.7%, despite standard VTE prophylaxis.3 The authors suggested the use of “high prophylactic doses” of anticoagulants in these patients due to concern over hypercoagulability.

An ICU French study also found high frequency of thrombotic complications in Covid-19 patients with ARDS, with 11.7% of patients having pulmonary embolism vs 2.1% in non-Covid-19 patients with ARDS. As with the Dutch study, thrombotic complications occurred despite standard prophylactic anticoagulation.4

Postmortem studies have also shown marked changes in lung microvasculature with the presence of microthrombi, with some calling it “pulmonary intravascular coagulopathy” to distinguish it from DIC.1

A NEJM letter reported 5 Covid-19 patients less than 50 years of age who presented with large vessel stroke symptoms without an alternative explanation.5 Of interest, 2 of these patients had no other symptoms suggestive of Covid-19.  A pre-print article from China reported an acute stroke incidence of 5% in hospitalized patients with Covid-19.6

The finding of a hypercoagulable state in patients with severe Covid-19 is not surprising given the frequent association of this infection with a high inflammatory state and the well-known capability of SARS-CoV-2 to attack the endothelial surfaces of blood vessels. High inflammatory state can promote activation of blood coagulation through release of inflammatory cytokines (eg, IL-6, IL-8, and TNF-alpha).1

Perhaps even more intriguing is the finding of extremely high levels of factor VIII found in some Covid-19 patients which could make them hypercoagulable.7 This phenomenon should be suspected when a patient appears to be resistant to anticoagulation by heparin based on aPTT but not based on anti-Xa assay.7

 Bonus pearl: Did you know that the overall incidence of VTE is lowest among Asians-Pacific islanders, followed by Hispanics and Caucasians, with highest rate among African-Americans? 1 ,8

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References

  1. Fogarty H, Townsend L, Cheallaigh CN, et al. COVID-19 coagulopathy in Caucasian patients. Br J Haematol 2020, https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16749
  2. Cui S, Chen S, Li X, et al. Huang C, Wang Y, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haematol 2020, April 9. https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14830
  3. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020. https://www.sciencedirect.com/science/article/pii/S0049384820301201?via%3Dihub
  4. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf
  5. Oxley TJ, Mocco J, Majidie S, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020, April 28. https://www.nejm.org/doi/full/10.1056/NEJMc2009787?query=featured_home
  6. Li Y, Wang M. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study. 2020. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3550025
  7. Beun R, Kusadasi N, Sikma M, et al. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol 2020, April 20. https://onlinelibrary.wiley.com/doi/abs/10.1111/ijlh.13230
  8. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res 2009;123 Suppl 4:S11-S17. doi:10.1016/S0049-3848(09)70136-7

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the evidence that patients with Covid-19 are at high risk of blood clots?

My hospitalized patient with pneumonia has now suffered an acute myocardial infarction (MI). Can acute infection and MI be related?

Yes! Ample epidemiological studies implicate infection as an important risk factor for MI.1 The increased risk of MI has been observed during the days, weeks, months or even years following an infection.

A 2018 paper reported a several-fold risk of MI during the week after laboratory-confirmed infection caused by a variety of respiratory pathogens such as influenza virus (6-fold), respiratory syncytial virus (4-fold), and other respiratory viruses (3-fold). 2 Among patients hospitalized for pneumococcal pneumonia, 7-8% may suffer an MI.3,4 One study found a 48-fold increase in the risk of MI during the first 15 days after hospitalization for acute bacterial pneumonia.5 Similarly, an increase in the short-term risk of MI has been observed in patients with urinary tract infection and bacteremia.6

The risk of MI appears to be the highest at the onset of infection and correlates with the severity of illness, with the risk being the highest in patients with pneumonia complicated by sepsis, followed by pneumonia and upper respiratory tract infection. Among patients with pneumonia, the risk exceeds the baseline risk for up to 10 years after the event, particularly with more severe infections.1

Potential mechanisms of MI following infections include release of inflammatory cytokines (eg, interleukins 1, 6, tumor necrosis factor alpha) causing activation of inflammatory cells in atherosclerotic plaques, in turn resulting in destabilization of the plaques. In addition, the thrombogenic state of acute infections, platelet and endothelial dysfunction may increase the risk of coronary thrombosis at sites of plaque disruption beyond clinical resolution of the acute infection. 1

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References

  1. Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med 2019;380:171-6. https://www.ncbi.nlm.nih.gov/pubmed/30625066
  2. Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018;378:345-53. https://www.nejm.org/doi/full/10.1056/NEJMoa1702090
  3. Musher DM, Alexandraki I, Graviss EA, et al. Bacteremic and nonbacteremic pneumococcal pneumonia: a prospective study. Medicine (Baltimore) 2000;79:210-21. https://www.ncbi.nlm.nih.gov/pubmed/10941350
  4. Musher DM, Rueda Am, Kaka As, Mapara SM. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007;45:158-65. https://www.ncbi.nlm.nih.gov/pubmed/17578773
  5. Corrales-Medina VF, Serpa J, Rueda AM, et al. Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes. Medicine (Baltimore) 2009;88:154-9. https://www.ncbi.nlm.nih.gov/pubmed/19440118
  6. Dalager-Pedersen M, Sogaard M, Schonheyder HC, et al. Risk for myocardial infarction and stroke after community-acquired bacteremia: a 20-year population-based cohort study. Circulation 2014;129:1387-96. https://www.ncbi.nlm.nih.gov/pubmed/24523433

 

My hospitalized patient with pneumonia has now suffered an acute myocardial infarction (MI). Can acute infection and MI be related?