Anticoagulant Pharmacology

Disease/ Disorder

Definition

Mechanical or pharmacological anticoagulation is the use of mechanical devices or medications to decrease a patient’s risk for developing blood clots often due to an underlying disorder. The goal of prophylactic and therapeutic anticoagulation is to find the optimal balance between the risk of thrombosis and the complication of anticoagulation. Below we will focus on pharmacologic anticoagulation.

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 caused by stroke, spinal cord injuries (SCI), surgeries especially orthopedic, as well as comorbidities such as cardiac conditions, cancer, lupus, factor V, C & S deficiency, and COVID-19. Other risk factors include drug therapy, (e.g., estrogen, tamoxifen, raloxifene, cancer therapy, heparin induced thrombocytopenia), pregnancy, and malignancy.¹

Epidemiology including risk factors and primary prevention

Venous thromboembolism (VTE), clinically presenting as Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), is the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke in the world,² and has been estimated to cause 1 out of every 4 deaths in 2010.³ The estimated annual incidence of VTE ranges from 142 to over 300 per 100,000 persons, increases with age and is more common in men after age 45. 30% may have a recurrence in 10 years.¹ 0.71% develop VTE in the 180 days following orthopedic surgeries.⁴ In acute spinal cord injury the 91-day cumulative incidence of VTE was 5.4% with appropriate prophylaxis. In SCI the incidence of asymptomatic VTE, can reach 48% to 100% among patients not given any medical thromboprophylaxis.⁵ In COVID-19 infection the incidence of VTE is thought to be 27-47% in hospitalized patients.⁶ In cancer among average-risk patients, the overall incidence of VTE has been estimated to be 13 per 1,000 person-years, with the highest risk among patients with cancers of the pancreas, brain, and lung.⁷

In the US, atrial fibrillation may be responsible for >70,000 strokes each year representing 10%–12% of all ischemic strokes.⁸

Patho-anatomy/physiology

Coagulation Cascade

The coagulation cascade can be broken into the extrinsic, intrinsic and common pathways.⁹

• Warfarin is the most commonly prescribed anticoagulant worldwide and is a vitamin K antagonist (VKA) that works by inhibiting γ-carboxylation of factors II, VII, IX, and X in the liver and can take up to 5 days for full effect.¹⁰
• Heparin and Low molecular weight heparin (LMWH) work by the potentiation of antithrombin leading to the inactivation of thrombin and factors II, VII, IX, and Xa.^2,10
• Direct Oral Anticoagulants (DOACs) such as Rivaroxaban and Apixaban work by directly inhibiting Factor Xa while Dabigatran is a direct thrombin inhibitor.^2,10
• Aspirin is a non-selective and irreversible inhibitor of COX-1 and COX-2.
• Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of ADP binding to its receptor.
• Aggrenox is a combination of Aspirin and an extended-release Dipyridamole, which inhibits adenosine uptake into cells, increases platelet cAMP, thereby decreasing platelet aggregation.

See tables 1 and 2 for additional information regarding DOACs and antiplatelet agents respectively

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).

Arterial thrombosis is thought to be caused by erosion of an arteriosclerotic plaque, which can rupture and further lead to clotting and embolization. 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). Both can lead to serious complications including DVT, PE, stroke or death. All anticoagulant medications have an increased risk of bleeding. Warfarin has the highest number of major bleeding events, likely due to the effect of various drugs and foods on CYP 450 enzyme, which breaks down warfarin and/or alters the intestinal absorption of vitamin K.¹⁰ Apixaban has demonstrated a statistically significant decreased risk of major bleeds including GI when compared to warfarin and other DOACS.¹¹ Importantly, DOACs are similarly affected by drugs that alter the CYP3A4 enzyme, namely, phenytoin, carbamazepine, phenobarbital and St. John’s wort.¹⁰

Essentials of Assessment

History

Patients may present with affected limb pain, swelling, redness, decreased pulses, arrhythmias, SOB, dizziness, new neurological deficits, ecchymoses or active bleeding.¹²

Additional history may reveal recent travel, surgeries or other conditions leading to prolonged immobility, infections such as COVID-19, cardiac arrhythmias, valvular or septal defects, history of hypercoagulable state, smoking, morbid obesity, administration of oral contraceptive, and history of VTE (history of DVT was an independent predictor of DVT recurrence) should also be obtained.

Physical examination

Typical findings of VTE are tenderness, warmth, erythema, cyanosis, edema, palpable cord (a palpable thrombotic vein), and superficial venous dilation of the lower extremity. These can occur in various combinations and evolve over hours to weeks.¹³ Though with a low specificity and sensitivity in diagnosing DVT, a positive Homan’s sign, described as presence of deep calf pain or tenderness upon palpation of calf during forced dorsiflexion of the foot with the knee flexed 10 degrees, may indicate the presence of a DVT.¹⁴

PE can manifest as tachypnea, tachycardia without significant findings on lung auscultation.

Tachy or brady-arrhythmias can be detected with precordial auscultation or by irregular pulses. Murmurs can indicate valvular or septal defects.

CVA signs include sudden neurological deficits affecting strength, sensation, speech, coordination, cognition.

Over-medication with anticoagulants can cause internal or external bleeding.

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. Furthermore, when a new DVT/ PE is diagnosed, the patient should be first anti-coagulated prior to restarting mobilization. Early mobilization after therapeutic anticoagulation is indicated over bed rest.¹⁵ Currently there is no specific guideline as to when to start mobilization/therapy when a new VTE is diagnosed. However, patients who were encouraged to ambulate within 3 days of diagnosis of VTE were not more likely to develop a progression of DVT, DVT related death or PE than those treated with bed rest after a new DVT/PE diagnosis.¹⁶

Laboratory studies

D-dimers (>500ng/ml) – low specificity; can be elevated in cancer, after recent surgery, trauma and other conditions.¹⁷

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) should be requested in all patients on warfarin, prior to a procedure, or with clinically relevant bleeding.

Quantitation tests of specific medications such as the dilute thrombin time, ecarin clotting time, and ecarin chromogenic assay for dabigatran and Anti-FXa assay for apixaban are not widely available.¹⁸

Imaging

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

Imaging studies for VTE, cardiac valvular/septal defects include:

• Ultrasound
  • Duplex compression vascular ultrasound (non-invasive, can visualize arterial or venous clots)
  • Cardiac ultrasound
• 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 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, comorbidities, interactions with other medications, fall risk, life expectancy, among others.

Pretest probability tools such as the Wells Score¹⁹ for PE in conjunction with D-dimer can help stratify patient categories based on risk/probability. The Wells score is calculated based on the presence of:

• clinical signs and symptoms of DVT
• tachycardia
• immobilization for >3 consecutive days or surgery in the previous 4 weeks
• previous PE or DVT
• hemoptysis
• malignancy

Assessment tools considered in the three-tier Wells score risk-model:¹⁹

• low risk (0-1): consider PE rule-out criteria (PERC) and D-dimer
• moderate risk (2-6): consider D-dimer or pulmonary CTA
• high risk (>6): consider CTA or V/Q scan, D-dimer not recommended

In the two-tier model:

• PE unlikely (<4): consider D-dimer
• PE likely (>4.5): consider pulmonary CTA

CHA2DS2-VASc score (0-9) is a tool that estimates stroke risk for atrial fibrillation, based on patient’s age, sex, history of HTN, CHF, stroke/TIA/VTE, vascular disease and diabetes. Oral anticoagulation therapy (OAC) is recommended for a score of 2 and above.²⁰

HAS-BLED score (0-9) is a tool that estimates the risk for bleeding based on patient’s age, bleeding predisposition, abnormal renal/liver function and a history of HTN, stroke, labile INRs and drugs or alcohol use. A HAS-BLED score of ≥3 indicates that caution is warranted when prescribing oral anticoagulation and regular review is recommended.²⁰

Early prediction of outcomes

Rehabilitation and medical outcomes may vary based on the patient’s comorbidities. Older age, tobacco use, CHF, chronic lung or kidney disease, cancer or atrial fibrillation can predict worse outcomes.²¹

Central venous catheters, higher illness intensity scores, history of VTE, higher BMI, and vasopressor therapy are all poor prognostic factors.²²

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.²³

Of the DVT prophylaxis methods, data has shown that sequential compression devices were superior to antiembolic stockings, and that chemoprophylaxis was efficacious in preventing VTE.²⁴

Environmental

N/A

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 was found to be beneficial in vulnerable patient groups taking anticoagulants such as warfarin or DOACs.²⁵

Professional issues

Warfarin treatment, though inexpensive, requires frequent INR testing. Adherence to INR testing strategies into clinical practice supports the patient-clinician relationship and ensures patient compliance.²⁶

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 anticoagulation within the rehabilitation setting. Depending on medical history, admitting diagnosis, weight and lab values, patients are usually started on Heparin or LMWH (i.e., Enoxaparin).²⁷

Below are some anticoagulation recommendations by diagnosis: 

• 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.²⁸ Aggrenox can be used as an alternative. 
    • DOACs are the preferred anticoagulation strategy for secondary prevention in patients with atrial fibrillation.²⁹
  • Traumatic Brain Injury (TBI)
    • LMWH or low-dose unfractionated heparin (UH) may be used in combination with mechanical prophylaxis for VTE.³⁰
    • VTE prophylaxis should be started within 24–72 hours following TBI if no contraindication.³¹
    • Weak evidence suggests that anticoagulation after intracranial hemorrhage (ICH) may be initiated between 14 days up to 30 weeks, and not earlier than 7 days post ICH, on a ‘case-by-case basis’.³²
  • Spinal Cord Injury (SCI)
    • LMWH for 3 months post SCI to prevent DVT/PE, after which the risk is similar to that of the general population;³³ based on the severity of neurological dysfunction LMWH may be continued for up to 6 months.³⁴
• Poly-trauma/Burns
  • Severely ill patients may require increased doses of anticoagulation to prevent VTE.
  • In severe burns with >20% total surface area, LMWH is recommended instead of DOACs.³⁵
• Hip/Knee/Spine Surgery
  • Commonly used pharmacologic agents for VTE prophylaxis: LMWH, UFH, fondaparinux, rivaroxaban, apixaban, dabigatran, warfarin, or aspirin.³⁶
  • LMWH and DOACs are preferred in orthopedic patients after total knee arthroplasty (TKA) or total hip arthroplasty (THA).³⁷
  • For low post-procedural bleeding risk, anticoagulation can be restarted 24 hours post-procedure. If the risk is higher, it should be delayed for 48 to 72 hours.³⁸
  • Start DVT prophylaxis within 12hrs or more post-operatively for a minimum of 10 to 14 days and extending for up to 35 days.^36,39
  • For patients after TKA or THA there was no significant difference on DVT or PE prophylaxis between aspirin and rivaroxaban.³⁹
  • No specific thromboprophylaxis is suggested for isolated lower-extremity injuries requiring immobilization and for patients undergoing knee arthroscopy without a history of VTE.
• Amputees
  • Currently there have only been two larger studies comparing heparin to LMWH which demonstrated no difference in efficacy or increased side effects.⁴⁰
• Cancer
  • LMWH has been the primary treatment choice for patients with VTE.⁴¹ More recently, Apixaban & Rivaroxaban have been recommended in addition to LMWH.⁴²
  • DOACs are associated with lower intracranial hemorrhage risk than warfarin.⁴¹
• DVT/PE
  • DVT/PE usually occurs within the first week after stroke and the first 2 weeks after SCI.¹²
  • Treatment duration:
    • First unprovoked isolated distal (calf) VTE/ VTE provoked by a reversible risk factor: 3 months
    • Second unprovoked VTE/ VTE associated with active cancer: indefinitely.⁴³
• Atrial fibrillation (Afib)/ valvular disease
  • DOACs generally recommended over VKA for Afib.⁴⁴
  • Warfarin (target INR 2.5-3.5) is preferred for mechanical heart valve assuming patient’s target therapeutic range (TTR) is > 65%, otherwise DOAC is preferred.
  • Warfarin is preferred in renal impairment if TTR is 65%-70%, otherwise apixaban is preferred.⁴⁵
• COVID-19
  • The data on VTE prophylaxis in COVID-19 is still evolving. A few studies were completed in 2021 that looked at the use of VTE prophylaxis in patients with COVID-19:
    • In a meta-analysis of 66 observational studies through August 2020, the overall prevalence of VTE in hospitalized patients with COVID-19 was 9.5% without screening, and 40% with ultrasound-screening.⁴⁶
    • In the ACTION trial, Lopes et al. did an efficacy and safety analysis by looking at therapeutic versus prophylactic anticoagulation in COVID-19 population with elevated D-dimer levels. They found that compared to prophylactic anticoagulation, in-hospital therapeutic dose anticoagulation with rivaroxaban or enoxaparin followed by 30 days of rivaroxaban did not improve clinical outcomes and was associated with increased bleeding.⁴⁷
    • In the RAPID trial, Sholzberg et al. did not find a significant reduction in the primary composite outcome of death, mechanical ventilation, or ICU admission with therapeutic heparin. However, therapeutic heparin decreased the odds of all cause death at 28 days with a low risk of major bleeding, suggesting that it is beneficial in moderately ill patients admitted with COVID-19 and increased D-dimer levels.⁴⁸ 
    • In the HEP-COVID trial, Spyropoulos et al. looked at VTE, arterial thromboembolism (ATE) and death from any cause within 30 ± 2 days after randomization to various heparin formulations. Therapeutic-dose LMWH was found to reduce the composite of thromboembolism and death compared to institutional standard heparin prophylaxis without an increased major bleeding among the patients hospitalized (not in the ICU) with elevated D-dimer levels.⁴⁹
• Renal Impairment
  • There is limited data to support DOAC use. Patients with renal impairment are at higher risk of developing stroke and major bleeds therefore appropriate anticoagulation is essential in this patient population.
  • Studies looking at the safety and effectiveness of apixaban versus warfarin in severe renal impairment found no significant difference in the occurrence of major bleeding as well as of stroke and VTE.
  • Another study found that patients who were prescribed the standard dose (5 mg twice a day) versus the reduced dose (2.5 mg twice a day) demonstrated that unlike the other DOACs, apixaban use in end stage renal disease (ESRD) was associated with a lower risk of major bleeding, thromboembolism and death compared with warfarin.^{50- 52}

Common interventional pain procedures:⁵³

• Prior to low-risk procedures (e.g., minor peripheral procedures, trigger point injections, etc.)
  • No need to hold anticoagulation
  • Consider holding Aspirin/ Aggrenox for 4 days, Heparin for 4-8hrs, LMWH for 24hrs prior to procedure
• Prior to moderate/severe-risk procedures (e.g., spinal facet joint injections, epidurals, spinal cord stimulators, pumps, catheters, etc.)
  • Medial Branch Blocks/ RFAs:
    • No need to hold anticoagulation
  • Epidural injections/ Spinal cord stimulator or pump trials/implants:
    • Aspirin – hold for 4-6 days
    • NSAID’s (COX1, COX2) – may continue or stop 1-10 days
    • Platelet Aggregation Inhibitors – hold for 5-7 days
    • DOACs – hold for 3-5 days
    • Warfarin – hold for 2-5 days
• LMWH bridge therapy during cessation of the anticoagulant – up to 24 hours before the procedure – can be used if VTE risk is high
• Anticoagulant may generally be resumed 12 hours after the interventional procedure

At different disease stages

Below we will focus on the management of common “diseases” that require anticoagulation:

Ischemic events

• New onset/acute ischemic events
  • potential curative interventions
    • clot extraction/ thrombectomies/ tPA
  • anticoagulant pharmacotherapy
    • IV UFH infusion – short half-life, available reversal agent (protamine sulfate)
    • oral/ SQ anticoagulation therapy
    • DOACS preferred for DVT/ PE (LMWH & warfarin as alternatives)
  • non-pharmacological therapy (for high bleeding risk patients)⁵⁴
    • left atrial appendage occlusion device
    • inferior vena cava filter (IVCF)
    • avoid sequential compression devices (SCDs)
  • symptom relief
    • pain: analgesics/ anti neuropathics
    • shortness of breath: oxygen supplementation
  • rehabilitation strategies
    • start early mobilization once therapeutic anticoagulation is achieved
    • avoid massage over the limb with DVT
• Subacute/chronic/stable
  • secondary VTE prevention with pharmacotherapy
  • symptom relief with analgesics
  • rehabilitation strategies – continue therapy while on anticoagulants to optimize function

Bleeding events

• Injectable anticoagulants²⁷
  • A meta-analysis showed that adjusted-dose LMWH decreased the risk of both DVT and PE but increased risk of ICH.
  • High-dose UFH (>15,000 units/dose) was associated with a reduction in PE but showed an increased risk of ICH/ extracranial hemorrhage (ECH).
  • Low-dose UFH (<15,000 units/dose) decreased the DVT risk, had no influence on PE and did not significantly increase the risk of hemorrhage (ICH/ECH).
• Oral antithrombotic reversal can be achieved using fresh frozen plasma, prothrombin complex concentrate, recombinant factor VIIa, factor VIII inhibitor bypassing activity or another specific antidote.
  • Hemodialysis is reported as being useful only for dabigatran.
  • If warfarin is used, INR ≥9 and no major bleeding events, a single oral dose of vitamin K (2.5‐5 mg) is needed. In case of major bleeding, vitamin K 10 mg is administered parenterally every 12 hours, along with prothrombin concentrate or recombinant factor VIIa.
  • For dabigatran, in case of life-threatening bleeding, the antidote Idarucizumab is indicated, with rapid effects after a single dose of 5 g IV.
  • Andexanet alfa was recently approved by FDA as a reversal agent for rivaroxaban and apixaban.⁵⁵

Coordination of care

Coordination of care as it relates to management of patient anticoagulation involves an interdisciplinary approach with other specialists such as neurologists, 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 they play a crucial role in providing informed consent, preventing complications, maintaining appropriate therapeutic levels and encouraging medication compliance. Patients and family are educated and counseled on risk, benefits and alternatives of anticoagulation and verbalize understanding. This is especially important in older patients, mentally impaired and those who are incapable of self-care.^{38, 56}

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.⁵⁷

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. 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.

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Author Disclosure

Laurentiu Iulius Dinescu, MD
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Rachel Levihaiem, PharmD
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Michael Schmidt, MD
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Maksim Shmargun, MD
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Noemi Olivero, MD
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Bruce Metcalf, MD
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