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The Impact Of Oral Anticoagulants On Wound Healing And Development In An Aging Population

Many patients presenting to podiatric practices may be on anticoagulant therapy. Thus, it behooves the physician to understand the impact of these medications on both development and healing of wounds, especially in older populations. Here the author outlines the therapeutic pathways, diagnostic pearls and treatment recommendations in these challenging case scenarios.

The skin is the largest organ of the integumentary system. Our intact skin plays a major part in maintenance of our overall health and wellbeing. A crucial role of this highly developed organ is to provide a barrier for protection against physical, chemical or bacterial injury. As our population ages, skin frailty and fragility becomes more than just a cosmetic concern. Decreased dermal collagen integrity in the elderly can result in friable skin that easily becomes damaged with even the most trivial of traumas. Kaya and Saurat coined the term “dermatoporosis” in a manuscript published in 2007 to refer to the loss of this protective mechanical function seen in aging skin.1 As a result of dermatoporosis, or thinning of the skin, minor soft tissue traumas can lead to complications such as the formation of non-healing ulcers, lacerations and hematomas. The clinical manifestations of dermatoporosis begin to occur with increased incidence starting as early as age 60, but become more acutely problematic in patients aged 70-90.1

Falls are the second leading cause of accidental or unintentional injury worldwide.2 Elderly patients are at increased risk for trauma from falls, in fact, adults over the age of 65 suffer the greatest number of fatal falls annually.2 Concurrently, patients most at risk for dematoporosis are also among this demographic. It is estimated that 37.3 million falls per annum are so severe that they require medical attention.2 Patients that have signs of dermatoporosis may also have multiple comorbidities, such as diabetes or peripheral vascular disease (PVD), that further contribute to thinning of the skin in the lower extremity and can additionally contribute to the development of complex traumatic and nonhealing wounds.

In this same subset of the population, polypharmacy, or the use of multiple drugs, is not uncommon. Wound care patients are often on multiple medications for both acute and chronic health conditions. According to the Centers for Disease Control and Prevention, over 50 percent of Americans take at least one prescription drug per month and over 20 percent take three or more drugs monthly.3 Medications can aid in wound healing or considerably hinder it. Americans are living longer and chronic illness rates are on the rise, therefore one should not overlook the potential impact of pharmacological therapy on wound development and healing.

Anticoagulant Agents And Wound Healing

Blood clots consist of two key elements:4

• fibrin (a strand-shaped protein that forms a mesh that traps red blood cells); and

• platelets (tiny cell fragments that clump together).

Together, these components stabilize clots, keeping them from falling apart. Anticoagulation medications inhibit the coagulation cascade intrinsic and extrinsic pathways by limiting thrombin and preventing fibrin deposition.4 Anticoagulant medications prevent clot formation in a range of thromboembolic disease. It is common practice to prescribe these medications to patients to treat a variety of disorders such as deep venous thrombosis, atrial fibrillation, peripheral arterial disease, ischemic events of the central nervous system and cardiac disorders. These medications work through an anti-thrombin-mediated pathway to inhibit thrombin formation.4

Anticoagulants such as warfarin sodium (Coumadin), known widely as Vitamin K antagonists (VKAs), can accelerate bleeding and contribute to the severity of soft tissue damage sustained during even a minor fall, causing a potential delay in wound healing.4,5 VKAs inhibit the enzyme vitamin K epoxide reductase, therefore inhibiting vitamin K formation, thus preventing the hepatically synthesized coagulation factors II, VII, IX and X. This effect can last for several days, which complicates exact dosing and makes regular international normalized ratio (INR) monitoring necessary.4,5

Newer direct oral anticoagulants (DOACs) such as rivaroxaban (Xarelto®, Janssen) and apixaban (Eliquis®, Bristol-Meyers Squibb) recently emerged as alternative therapeutics that many consider to be effective, safe and convenient options. Blood contains a protein called Factor Xa that starts the clotting process. DOACs block Factor Xa, effectively halting the body’s production of a clotting enzyme known as thrombin.4 This action prevents blood clots from forming by preventing the clotting process from occurring.4 Because of their comparatively short half-life and fewer interactions DOACs are easier to control and do not require regular monitoring to ensure their efficacy.4

Wound healing is a dynamic process that involves a variety of complex overlapping mechanisms. A variety of external factors can affect essential cellular activities. The phases of wound healing proceed most efficiently when there is a fully functioning clotting system in place composed of active platelets and unhampered fibrin cross-linking.6 The first wound healing phase, hemostasis, begins upon initial injury.7 Damage to endothelium will precipitate the coagulation cascade through platelet activation and adhesion. The formation of a hemostatic plug relies on adequate amounts of thrombin.7 Physiological concentrations or thrombin in wounds can enhance connective tissue growth factor and vascular endothelial growth factor.7 These substances play an important role in stimulating fibroblasts, supporting collagen production, triggering cellular contraction and enhancing angiogenesis.7 These critical steps in wound repair contribute to connective tissue and new blood vessel formation.7 Existing evidence demonstrates the importance of adequate physiologic levels of thrombin in increasing the rate and quality of wound healing.8

Conversely, it stands to reason that interference in thrombin-mediated activities may interfere with wound healing and stall wound progression. In fact, a study published in Wounds UK found that patients with nonhealing wounds were taking a higher percentage of some drugs than patients with healing wounds.9 Those drugs most associated with delayed wound healing were antiplatelet and anticoagulant agents.9 Therefore, whether the benefits outweigh the risk of these drugs is debatable, and one should carefully review individual patient cases.

Do Anticoagulants Contribute To Wound Development?

Patients sustaining even low impact trauma while on anticoagulant therapy can develop extensive soft-tissue injuries that require medical or surgical attention. These medications can also contribute to wound healing complications such as bleeding and excessive wound exudate.10 Dermatoporosis, polypharmacy, fall risk, antithrombotic therapy creates the perfect storm for patients to suffer serious sequelae such as infection, skin loss, chronic non-healing wounds, the development of deep dissecting hematoma (DDH).10

DDHs of the lower extremity are a concerning complication seen as a result of dermatoporosis and concomitant anticoagulation therapy. Formation of a DDH occurs as a result of soft tissue trauma where substantial bleeding between the junction of the skin and subcutaneous tissue takes place.10 The use of anticoagulant therapy increases the likelihood of the formation of a DDH. As the DDH expands, the pressure within the hematoma exceeds the perfusion pressure of the capillaries and leads to the necrosis of the overlying skin and subcutaneous tissue.10 Urgent evacuation of the hematoma is necessary to release the increased tension placed on the skin by the expanding blood clot. Patients suffering from DDHs are frequently seen in outpatient wound centers with difficult to manage complex wounds at increased risk for deep space infection, tissue necrosis, skin loss and the need for surgical intervention. These wounds are often very painful and debilitating, especially in elderly patients with multiple comorbidities.11

According to the National Hospital Ambulatory Medical Care Survey, of the approximately 117 million visits to emergency departments in the United States in 2007, 14.6 percent were for lower extremity injuries, but the specifics of these injuries were not recorded.12 In order to further determine the anatomical location and disease categories of patients presenting to the ED, Lambers and colleagues used the National Electronic Injury Surveillance System (NEISS) to obtain a probability sample of all lower extremity injuries treated in US emergency departments during 2009.12 They found the incidence of lower extremity injuries caused by contusions/abrasions was 19 percent, fractures accounted for 18 percent and lacerations amounted to eight percent of US ED visits. All these injuries could lead to the development of deep dissecting hematomas. Post-traumatic hemorrhages, seen mostly in the lower leg accountted for 39 percent of reported cases in emergency departments.12 Early diagnosis and proper referrals to establish an effective treatment plan for post-traumatic hematomas may very well impact clinical outcomes in an at-risk population of patients.

One Podiatrist’s Protocol For Managing Deep Dissecting Hematomas

Once diagnosing hematoma, visual assessment should include evaluating the injured tissues for an open wound with active bleeding and denoting the color of the injured tissues. Dark or dusky tissue coloration along with signs and symptoms of hematoma formation extending greater than 10cm2 in the absence of an open wound is concerning. This may signify continued subdermal bleeding that can lead to development of a deep dissecting hematoma with increasing areas of devitalized tissue. Evacuating the hematoma under local anesthesia to minimize the risk of tissue necrosis is advisable. Use of a compression bandage along with a referral to a wound care specialist for follow up within 24 to 48 hours for reassessment of the injury is then indicated. If there is not an open wound and the area of hematoma formation measures less than 10cm2, the patient should adhere to the RICE protocol (rest, ice, compression and elevation) and follow up with a clinician if the symptoms do not improve within seven days.

When treating a post-traumatic hematoma in the presence of an open wound with active bleeding it is imperative to obtain hemostasis. One can accomplish this via localized pressure, limb elevation, electric/chemical cautery or with other topical hemostatic agents. If bleeding cannot be controlled, immediate referral to a trauma or wound care surgeon for vessel ligation is indicated. Once achieving hemostasis, steri-strips applied under zero tension can secure skin flaps, but still allow for wound exudate transfer into the secondary dressings. One can apply a non-adherent dressing under a compression bandage with a referral for the patient to follow up at a wound center within 48 to 72 hours. Often times these injuries are initially mismanaged and result in significant tissue necrosis needing surgical intervention.

Herein the author will detail two recent cases where the patients were on anticoagulation therapy, sustained a trauma of the lower extremity and developed DDH that subsequently needed surgical intervention and aggressive wound care.

When An Patient Suffers A Traumatic Laceration While On Anticoagulant Therapy

This 85-year-old male presented to the wound clinic nine days after sustaining a lower left extremity skin tear laceration secondary to blunt trauma from a fall off a ladder. The patient complained of persistent and worsening pain edema, and discoloration, resulting in a diagnosis of

DDH requiring surgical evacuation. The patient provided verbal and written consent to the use of wound photographs and non-identifying medical information for educational purposes.

The patient sought initial treatment in a local ED three hours post-initial injury. No labs were collected, and an X-ray of the left lower extremity was negative. There was no evaluation of the patient’s INR, and their anticoagulant, warfarin, was not dose-adjusted. Treatment consisted of irrigation of injured tissue, reapproximation of the traumatically avulsed tissue flap with interrupted polypropylene (Prolene®, Johnson and Johnson) stitches and a dry dressing. Discharge to home took place with prescription for oral antibiotics and instructions to follow-up with their primary care physician (PCP) in 10 days for stitch removal.

Five days post-trauma they returned to the same ED with continued pain, swelling and redness at the injury site. Labs showed a white blood cell count (WBC) of 4.6 x 109 L, and negative blood cultures. A duplex ultrasound was negative for worsening of his previously identified DVT. Due to a past history of MRSA, the ED discharged the patient with additional antibiotics, and again referred to primary care for stitch removal.

After wound clinic evaluation, we took the patient to the OR, removed the stitches and surgically evacuated the DDH (see first photo above). The wound extended deep to muscle and measured 8.2 cm x 6.4 cm x 1.0 cm post-operatively. With aggressive wound care consisting of cellular tissue product (CTP) application and compression bandages, the patient healed in 11 weeks (see second photo above).

When A Patient Taking Anticoagulants Sustains A Fall On Ice

We saw this 73-year-old male in the wound center two weeks after sustaining a fall on ice in his driveway, resulting in a large trauma to the left lower leg. Their medications included rivaroxaban 20mg daily for management of atrial fibrillation. Immediately after injury, the patient presented to a local emergency department, and after triage received discharge to home with orders to elevate the leg and apply heat to the area. The following week’s visit to our wound clinic revealed continued pain and a large deep dissecting hematoma extending into the entire lateral half of his calf (see photo above). We performed surgical evacuation of the hematoma, for which the wound measured 19.8 cm x 11.3 cm x 0.6 cm with undermining around the entirety of the wound. Aggressive wound care consisting of negative pressure wound therapy (NPWT), CTP applications and compression bandaging achieved complete healing 17 weeks postoperatively.

In Conclusion

Clinical studies evaluating the effects of various anticoagulants on wound healing are limited and future large clinical trials to assess wound healing outcomes for those on anticoagulant therapy are necessary. Wound care clinicians should obtain a baseline level of knowledge when it comes to pharmacotherapeutic effects on wound development and healing. Medications such as anticoagulants can contribute to skin and tissue damage and substantially impede wound healing. It is important for clinicians to be aware of a patient’s overall drug therapy profile.

Older adults at increased risk for dermatoporosis who present with full-thickness lower extremity wounds caused by post-traumatic hematomas while on therapeutic anticoagulation are indeed challenging to manage. Given the possibility of the development of complex wounds such as the DDH examples presented in this article, clinicians must weigh the pros and cons prior to initiating any anticoagulation therapy and carefully manage patients taking these common medications. 

Dr. Cole is the Medical Director of the Wound Care Center at University Hospitals Ahuja Medical Center in Beachwood, Ohio. She is also an Adjunct Professor and Director of Wound Care Research at the Kent State University School of Podiatric Medicine.

Features
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By Windy Cole, DPM, CWSP
References

1. Kaya G, Jacobs F, Prins C, Viero D, Kaya A, Saurat JH. Deep dissecting hematoma: an emerging severe complication of dermatoporosis. Arch Dermatol. 2008;144(10):1303–1308.

2. World Health Organization. Falls. Available at: https://www.who.int/news-room/fact-sheets/ detail/falls . Published April 26, 2021. Accessed May 6, 2021.

3. Centers for Disease Control and Prevention. Chronic Disease Overview. Available at: https:// www.cdc.gov/chronicdisease/about/index.htm . Accessed May 6, 2021.

4. Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015;16(1):11-17.

5. Sussman G. The impact of medicines on wound healing. Pharmacists. 2007;26(11):874–876.

6. Goldfine A, Eisenbud D. Biological mechanisms of wound healing. In: Eisenbud D (ed). Modern Wound Management. Columbus, Ohio:Anadem Publishing;1999:5-13.

7. Chanbers RC, Leoni P, Blanc-Brude OP, Wembridge DE, Laurent GJ. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1. J Biol Chem. 2000:275:35584- 35591.

8. Stienberg J, Norfleet AM, Redin WR, Warner NS, Fritz RR, Carney DH. Acceleration of full-thickness wound healing in normal rats by the synthetic thrombin peptide, TP508. Wound Repair Regen. 2000;8:204-215.

9. Wigston C, Hassan S, Turvey S, et al. Impact of medications and lifestyle factors on wound healing: A pilot study. Wounds UK. 2013;9(1):22-28.

10. Kaya G, Saurat JH. Dermatoporosis: a chronic cutaneous insufficiency/fragility syndrome. Clinicopathological features, mechanisms, prevention and potential treatments. Dermatology. 2007;215(4):284–294.

11. Pagen M, Hunter J. Lower leg hematoma: potential for complications in older people. Wound Practice and Research. 2011;19(1):21-28.

12. Lambers K, Ootes D, Ring D. Incidence of patients with lower extremity injuries presenting to US emergency departments by anatomic region, disease category, and age. Clin Orthop Relat Res. 2012;470(1):284–290.

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