Anticoagulant Pharmacology

Disease/Disorder

Definition

Pharmacological anticoagulation is the use of medications to decrease a patient’s risk for developing blood clots. There is prophylactic and therapeutic anticoagulation. Below we will discuss the different conditions that require anticoagulation and how to best manage them.

Etiology

The formation of thrombi is underpinned by Virchow’s triad which includes blood stasis, vascular injury and hypercoagulability. Important subsets of rehab patients with increased risk include those with immobility, trauma, especially orthopedic, and cancer.¹

Epidemiology including risk factors and primary prevention

Many different conditions require anticoagulation and often include venous thromboembolism, atrial fibrillation (AF), and mechanical heart valves.

Venous thromboembolism (VTE), often presents as deep vein thrombosis (DVT) or pulmonary embolism (PE). It has an estimated annual incidence of 1-2 per 1000 person years in the US and Europe.¹ 40-60% happen within three months of hospitalization.¹ See Table 1 for a summary of the risk of DVT after major rehabilitation diagnoses without thromboprophylaxis.²

Table 1 Incidence of DVT and DVT Prophylaxis Guidelines

DVT- deep vein thrombosis
UFH- unfractionated heparin
LWMH- low molecular weight heparin

It is estimated that atrial fibrillation affects more than 46.3 million worldwide as of 2016. It leads to a 5 time higher risk of stroke.³ Therefore it is important to provide anticoagulation for this condition.

18,000 patients a year get a mitral valve replacement or 11,000 a year get an aortic valve replacement in the US.⁴ About a third to a half are mechanical in the 50-year-old range but the proportion decreases with age.⁵ Mechanical heart valves necessitate anticoagulation to prevent thromboembolism.⁴

Patho-anatomy/physiology

Coagulation Cascade

The coagulation cascade can be broken into the extrinsic, intrinsic and common pathways as seen in Figure 1.⁶

• Warfarin is a vitamin K antagonist (VKA) that works by inhibiting the γ-carboxylation and activation of factors II, VII, IX, and X.⁶ Although a lot of foods contain vitamin K itis better to maintain a stable diet than restrict diet for the use of warfarin.⁷
• Heparin and related drugs like low molecular weight heparin (LMWH) and synthetic heparin work by the potentiation of antithrombin which inhibits thrombin and factors XIIa, XIa, Xa, IXa, and VIIa.⁸
• Direct Oral Anticoagulants (DOACs) have two classes, oral direct factor Xa inhibitors (apixaban and rivaroxaban) and direct thrombin inhibitors (dabigatran).⁹
• Aspirin is an irreversible inhibitor of COX-1 and COX-2 that normally help produce platelet activator Thromboxane A_2.¹⁰
• Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of ADP binding to its receptor.¹⁰
• Aggrenox is a combination of Aspirin and an extended-release Dipyridamole, which increases cyclic AMP, an inhibitor of platelet aggregation.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Venous stasis, vascular injury or a hypercoagulable state can lead to clot formation. Venous stasis is the most important and often related to valvular insufficiency in the deep veins of the legs that results in blood pooling, local hypoxia and expression of certain procoagulants. It manifests as swelling, redness and tenderness. Thrombi can rupture and migrate into the pulmonary vasculature leading to PE and shortness of breath (SOB).

Atrial fibrillation and valvular or septal defects can cause blood turbulence or stasis which can further embolize and lead to strokes.

Specific secondary or associated conditions and complications

Complications related to anticoagulants include thrombosis (insufficient anticoagulation) and hemorrhage (too much anticoagulation). Complications include DVT, PE, stroke or death. All anticoagulant medications have an increased risk of bleeding. Warfarin leading to a supratherapeutic international normalized ratio (INR) especially has a high risk and is likely due to drug interactions, and diet changes that can change levels of vitamin K.⁶ DOACs have demonstrated a statistically significant decreased risk of major bleeds including GI when compared to warfarin.⁶ DOACs are cleared by the kidney so kidney dysfunction can increase risk of bleed with DOACs.⁹ Reduced dosage is often used in this setting. Similarly, for LMWH, renal impairment can increase drug levels therefore dosage adjustment is needed for kidney dysfunction according to product labelling.

LMWH and unfractionated heparin (UFH) can cause heparin induced thrombocytopenia (HIT) if given for more than 4 days. The rate of this is low at less than 3%. It increases the risk of venous and arterial thrombosis. Instead thrombin-specific inhibitors like argatroban and fondaparinux should be used for several weeks.^8,12

Essentials of Assessment

History

Patients on anticoagulation may present with affected limb pain, swelling, redness, decreased pulses, arrhythmias, SOB, dizziness, new neurological deficits, bruising or other signs of bleeding (bloody vomit or bloody/dark urine).Changes in medications and diet should also be elicited.

Physical examination

Anticoagulation can often cause bleeding. Physical signs of bleeding can manifest as hematemesis, coffee ground emesis, hematochezia, melena, and ecchymosis. New stroke from hemorrhage can manifest as neurological changes.

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Patients affected by VTE, PE, CVA and other hypo/hypercoagulable states can present with impaired mobility and ADL’s. When a new proximal DVT is diagnosed, early mobilization after therapeutic anticoagulation is indicated over bed rest.^12,13 Studies have shown that when patients are first anticoagulated, this is safe.¹³ Meta-analyses have shown a lack of PE or other complications with early ambulation after DVT. It can also prevent postthrombotic syndrome.¹²

Laboratory studies

INR should be monitored regularly in all patients on warfarin with target ranges generally from 2-3 but can vary according to condition.

UFH should be monitored and adjusted based on activated partial thromboplastin time (aPTT).⁸

Anti-Xa measurements can be used to monitor LMWH with therapeutic levels at 0.5 to 1.0 U/mL.^8,12

Imaging

Choosing the correct imaging study depends largely on the differential diagnosis.

Imaging studies for VTE (DVT or PE) include

• Ultrasound
  • Venous duplex (non-invasive, can visualize arterial or venous clots)
• Radiologic Angiography (invasive, involves injection of radiopaque contrast dye into a blood vessel)
  • X-ray arteriography or venography
  • Computed tomography angiography (CTA)
  • Magnetic resonance angiography (MRA)
• Nuclear Studies
  • Ventilation/ Perfusion (V/Q) scan: high radiation exposure risk

Imaging to detect strokes

• Non-contrast Head CT: performed first, to exclude intracranial hemorrhage (ICH), detects some ischemic changes in 6-24 hours
• Head MRI: can detect ischemic changes within 3-30 minutes

Contrast Studies

• most accurate, but expensive, invasive, difficult to perform
• contrast materials can be nephrotoxic, irritating to vessel walls and can cause allergic reactions

EKG changes can uncover arrhythmias.

Supplemental assessment tools

Many factors should be taken into account when making a comprehensive treatment decision to anticoagulate, including patient’s age, medical history, interactions with other medications, fall risk, life expectancy, among others.

CHA2DS2-VASc score (0-9) is a tool that estimates stroke risk for AF, based on patient’s age, sex, history of HTN, CHF, stroke/TIA/VTE, vascular disease and diabetes. Age over 74 and prior stroke/TIS/VTE confer two points. Age between 65-74 confers 1 point.  Oral anticoagulation therapy is recommended for a score of 2 and above.¹⁴

HAS-BLED score (0-9) is a tool that estimates the risk for bleeding based on HTN, abnormal renal/liver function, stroke, labile INRs, elderly age (>65) and drugs or alcohol use (more than 7 drinks a week confers a point). A HAS-BLED score of ≥3 indicates that caution is warranted when prescribing oral anticoagulation for AF.¹⁴

Early prediction of outcomes

Predictors of reduced survival after VTE include increasing age, male sex, earlier event year, lower BMI, tobacco use, confinement to a hospital or nursing home at the onset of venous thromboembolism, and a history of congestive heart failure, chronic lung disease, neurologic disease, or malignancy.¹⁵

Risk factors for VTE include central venous catheters, higher illness intensity scores, history of VTE, higher BMI, and vasopressor therapy. The last three are associated with VTE prophylaxis failure.¹⁶

Cancer at baseline, older age, leukocytosis, diabetes mellitus, liver disease, female sex, and initial presentation with massive PE were all independent predictors of all-cause mortality after PE.¹⁷

Social role and social support system

Multidisciplinary teams and allied health professionals are essential in supporting patients on anticoagulation during the transition of care between healthcare settings and home. Point of care INR monitoring by general practitioners, pharmacists, combined with patient and family education is needed.

Professional issues

Warfarin treatment, though inexpensive, requires frequent INR testing. A strong patient-clinician relationship ensures patient compliance.

DOACs are more expensive but do not require frequent lab monitoring. Financial assistance programs are however available for those who qualify.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Currently, there is no “standard of care” specific to VTE prophylaxis within the acute inpatient rehabilitation setting. Depending on medical history, admitting diagnosis, weight and lab values, patients are usually started on Heparin or LMWH for the duration of the rehabilitation stay.¹⁸

Below are some anticoagulation recommendations by diagnosis with a summary in Table 1.

• Neurologic
  • Ischemic strokes
    • Dual-antiplatelet therapy with Aspirin 81 mg and Clopidogrel 75 mg daily for 21 days followed by mono-therapy with Aspirin is recommended to prevent future stroke.¹⁹
  • For acute ischemic stroke patients with limited mobility, DVT prophylaxis with LMWH or low dose UFH is recommended. Pharmacological DVT prophylaxis should be held for 24 hours after thrombolytic administration. Low dose UFH may be used safely in combination with aspirin.²⁰
  • Traumatic Brain Injury (TBI)
    • LMWH or low-dose unfractionated heparin (UFH) may be used in combination with mechanical prophylaxis for VTE based on low quality evidence.²¹
    • VTE prophylaxis should be started within 24–72 hours following TBI once the intracranial hemorrhage is stable and in conjunction with neurosurgery consultation.²²
    • The varied evidence suggests that oral anticoagulation for AF can be restarted between 4 and 10 weeks from ICH.¹⁴ The risk of bleeding versus the risk of thromboembolism must be weighed.
  • Spinal Cord Injury (SCI)
    • Mechanical prophylaxis combined with pharmacological prophylaxis should be used as soon as possible in the acute care phase.²³ There is low evidence to support the exact timing and type of pharmacological prophylaxis but within 72 hrs and with LMWH or fixed low dose UFH is suggested.²⁴
    • Pharmacological prophylaxis should be continued for 8 weeks after the injury in those with limited mobility. There is less evidence for the type of pharmacological prophylaxis but DOACs, warfarin (goal INR 2-3), or LMWH are suggested.²³
• Hip/Knee Surgery
  • Commonly used pharmacologic agents for VTE prophylaxis: LMWH, UFH, fondaparinux, rivaroxaban, apixaban, dabigatran, warfarin, or aspirin.³⁶
  • Aspirin or DOACs are preferred after total knee arthroplasty (TKA) or total hip arthroplasty (THA) for at least 10-14 days for VTE prevention.^25,26
  • LMWH, fondaparinux, UFH, warfarin, or aspirin are recommended to prevent VTE after hip fracture surgery for at least 10-14 days.²⁵ LMWH is preferred but with less evidence.²⁵ For all major orthopedic surgeries it is suggested that VTE prophylaxis be extended to 35 days.²⁵
  • For all major orthopedic surgery it is recommended that VTE prophylaxis be started 12hrs or more after surgery.²⁵
• Cancer
  • DOACs are recommended for cancer related VTE. Duration of more than 3 months are needed.²⁷
• VTE (DVT or PE) treatment
  • Proximal provoked VTE- 3 months, a DOAC is recommended.²⁷ Proximal unprovoked VTE- extended treatment greater than 3 months, a DOAC is recommended.²⁷
• Hospitalization
  • In 2018 the American Society of Hematology (ASH) recommended VTE prophylaxis for critically ill medical patients. It was only suggested for those acutely ill.²⁸ Low dose UFH or LMWH can be used.
• Atrial fibrillation (AF)/valvular disease
  • DOACs generally recommended over VKA for AF.³
• Mechanical Heart Valves
  • Lifelong treatment with warfarin is used.  Bridging with UFH or LMWH is needed. For aortic valves a median target INR of 2.5 is used when no other VTE risk factors are present. For mitral valves a median target INR of 3.0 is used.⁴
• COVID-19
  • As of 2025 the American Society of Hematology (ASH) suggests using standard prophylactic anticoagulation for patients with COVID-19 related critical illness.²⁹ CHEST agrees with this.
  • The ASH also suggested the use of therapeutic anticoagulation for hospitalized COVID-19 patients that are not critically ill.²⁹ The International Society on Thrombosis and Haemostasis agrees with this.

Common interventional pain procedures⁵³

• Prior to low-risk procedures (e.g., peripheral joints, trigger point injections, etc.) This is summarized in Table 2.
  • ASIPP reports you can continue or stop low dose aspirin for 3 days. ASRA recommends stopping for 4 days.
  • NSAID’s (COX1, COX2) – may continue or stop 1-10 days per ASIPP. ASRA recommends just stopping it for 1-10 days.
  • Clopidogrel can be continued.
  • For warfarin, INR should be checked to ensure it is <3.0. ASIPP recommends stopping it for 2 days but ASRA reports it can be continued.
  • For DOACs you can continue or stop for 1-2 days depending on the DOAC.
  • LMWH can be held for 24 hrs.
  • SC Heparin can be held for 8-10 hours.
• Prior to moderate-risk procedures (e.g., spinal facet joint injections, lower lumbar epidurals, etc.) This is summarized in Table 3.
  • ASIPP reports you can continue or stop low dose aspirin for 3 days. ASRA recommends stopping for 4 days.
  • NSAID’s (COX1, COX2) – may continue or stop 1-10 days per ASIPP. ASRA recommends just stopping it for 1-10 days.
  • Clopidogel can be continued or held for 3 days per ASIPP. Or it can be held for 7 days per ASRA.
  • Warfarin should be stopped for 2-5 days with a target INR of <1.5 per ASIPP or target INR of normal INR per ASRA.
  • DOACs should be stopped for 2-5 days depending on the DOAC.
  • LMWH can be held for 24 hrs.
  • SC Heparin can be held for 8-10 hours.
• Prior to high-risk procedures (cervical, thoracic, high lumbar epidurals, spinal cord stimulator trial/implant, sympathetic blocks etc.)
  • NSAID’s (COX1, COX2) – may continue or stop 1-10 days per ASIPP. ASRA recommends just stopping it for 1-10 days.
  • Low dose aspirin should be stopped for 5-6 days.
  • Clopidogrel should be stopped for 5-7 days.
  • Warfarin should be stopped for 2-5 days with a target INR of <1.5 per ASIPP or normal INR per ASRA.
  • DOACs should be stopped for 2-5 days depending on the DOAC.
  • LMWH can be held for 24 hrs.
  • SC Heparin can be held for 8-10 hours.
• LMWH bridge therapy during cessation of the anticoagulant – up to 24 hours before the procedure – can be used if VTE risk is high
• Anticoagulants may generally be resumed 12-24 hours after the interventional procedure

Table 2 How Long to Hold Anticoagulants Prior to Low Risk Procedures

ASIPP – American Society of Interventional Pain Physicians
ASRA – American Society of Regional Anesthesia and Pain Medicine
NSAID’s- nonsteroidal anti-inflammatory drugs
DOAC’s- direct oral anticoagulants
LMWH- low molecular weight heparin
UFH- unfractionated heparin

Table 3 How Long to Hold Anticoagulants Prior to Moderate Risk Procedures

ASIPP – American Society of Interventional Pain Physicians
ASRA – American Society of Regional Anesthesia and Pain Medicine
NSAID’s- nonsteroidal anti-inflammatory drugs
DOAC’s- direct oral anticoagulants
LMWH- low molecular weight heparin
UFH- unfractionated heparin

Management of bleeding in the setting of anticoagulation

Below we will focus on how to manage bleeding in the setting of anticoagulation.

• Oral anticoagulation reversal can be achieved many ways depending on the type of anticoagulation. Below is a summary of the different reversal strategies.^30,31
  • For warfarin-in the case of major bleeding, four-factor prothrombin complex concentrate or fresh frozen plasma is given with vitamin K 10 mg IV. With no significant bleeding and INR≤10 can omit a dose and monitor more frequently. If there is increased risk of bleeding though, you can also give vitamin K1(1-2.5 mg orally). For INR>10 give vitamin K1 5-10 mg orally along with holding warfarin.
  • For DOACs, give Andexanet alfa to reverse. If this is not available give prothrombin complex concentrate. Andexanet alfa is given as a bolus followed by an infusion.
  • For UFH, in major bleeding, protamine sulfate is used to reverse it. The dosing is based on timing from last heparin dose and how many units of heparin were given. Similarly for LMWH, protamine sulfate is also given.
• When a VTE is diagnosed but the patient has a contraindication to anticoagulation, an inferior vena cava filter is needed.³²

Coordination of care

Coordination of care as it relates to management of patient anticoagulation involves an interdisciplinary approach with other specialists such as neurologists, hematologists, cardiologists, surgeons, internists and pharmacists. Due to a lack of clear guidelines, a team discussion is warranted to reach a consensus on the initiation, duration and type of anticoagulation.

Patient & family education

Patient and family input along with education are essential for anticoagulation treatment as our patient population can often be older and more cognitively impaired.  They play a crucial role in providing informed consent, managing medications, managing diet, and adhering to lab and physician visits. Patients and family are also educated and counseled on risk, benefits and alternatives to anticoagulation.

Measurement of treatment outcomes including those that are impairment-based, activity participation-based and environmentally-based

N/A

Translation into practice:  Practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Anticoagulation management is an evolving topic with new medications that can change guideline recommendations. At this time there is no clear consensus regarding the anticoagulation treatment for many conditions encountered in rehabilitation medicine. Clinicians need to stay up to date on the latest available guidelines and work as a team to ensure optimal patient outcomes.

Cutting Edge/Emerging and Unique Concepts and Practice

There are new changes to the anticoagulation treatment and prevention of VTE for patients with BMI >40 kg/m2 and weight >120 kg from the previous 2016 guidance from the International Society of Thrombosis and Hemostasis (ISTH)

• The 2021 ISTH guidance regarding the use of DOACs suggest rivaroxaban or apixaban are among appropriate anticoagulant options regardless of high BMI or weight.
• Monitoring of peak or trough drug specific DOAC levels is not recommended
• Use of vitamin K antagonists (VKA), LMWH and fondaparinux can also be used in this patient population.
• Use of dabigatran, edoxaban or betrixaban is not suggested given the lack of sufficient data.³³

Gaps in the Evidence-Based Knowledge

Although many organizations have attempted to create algorithms and guidelines for anticoagulation use, clinicians of varying specialties must still face this ambiguous pathway. Especially ambiguous are the management of distal DVT’s and the type/dosing of VTE prophylaxis. Every case is unique and with newly emerging pathologies such as COVID-19, the decision process is further complicated. A patient-specific team-based approach to anticoagulation remains the best strategy.

References

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Original Version of the Topic

Laurentiu Iulius Dinescu, MD, Rachel Levihaiem, PharmD, Michael Schmidt, MD, Maksim Shmargun, MD, Noemi Olivero, MD, Bruce Metcalf, MD. Anticoagulant Pharmacology. 2/9/2022

Author Disclosure

Cynthia Hung, MD
Nothing to Disclose