Section 2 - General Knowledge
Chapter 18. Coagulation and Thromboembolism
A. Coagulation cascade
1. The coagulation cascade is a series of enzymatic reactions that lead to the eventual formation of fibrin.
2. Fibrin forms a lattice that traps platelets to form a clot and stem bleeding (
3. Each step in the cascade involves the activation of a clotting factor that, in turn, activates the next step in the cascade.
4. There are two pathways for the initiation of clot formation, the intrinsic and extrinsic pathways.
a. Intrinsic pathway
i. Activated by the exposure of collagen from the subendothelium of damaged blood vessels to factor XII
ii. Measured using partial thromboplastin time (PTT)
b. Extrinsic pathway
i. Activated by the release of thromboplastin (via cell damage) into the circulatory system
ii. Measured by prothrombin time (PT)
c. Platelet dysfunction can be identified by prolongation of the bleeding time.
B. Fibrinolytic system
1. The fibrinolytic system acts to stem clot formation and maintain vascular patency.
2. The key step is the formation of active plasmin from plasminogen.
*Craig J. Della Valle, MD, or the department with which he is affiliated has received research or institutional support from Zimmer, miscellaneous nonincome support, commercially-derived honoraria, or other nonresearch-related funding from Zimmer and Ortho Biotech, and is a consultant for or employee of Zimmer and Ortho Biotech.
3. Plasminogen dissolves fibrin.
1. Hereditary factor deficiency that leads to abnormal bleeding (
2. Recurrent hemarthrosis and resultant synovitis of the large joints can lead to joint destruction (the knee is most commonly affected).
3. Treatment options
a. Initial treatment consists of factor replacement, aspiration, initial splinting, and physical therapy.
b. If bleeding continues despite prophylactic factor infusion, radioisotope or arthroscopic synovectomy is indicated if the cartilaginous surfaces are relatively preserved.
c. Total knee arthroplasty (TKA) in these patients can be complex secondary to severe preoperative stiffness and contracture.
4. These patients are at high risk for infection.
5. Use of factor replacement
a. If surgical intervention is planned, intravenous factor replacement is required to maintain factor levels of 100% immediately preoperatively and for 3 to 5 days postoperatively for soft-tissue procedures and for 3 to 4 weeks postoperatively for bony procedures such as total hip arthroplasty (THA) and TKA.
b. Although plasma derivatives were commonly used for factor replacement in the past (associated with a high risk of infection with blood-borne pathogens such as hepatitis and HIV), recombinant derived factor currently is used.
6. Inhibitors—Circulating antibodies that neutralize factor VIII or IX.
a. These antibodies are suspected when a patient fails to respond to increasing doses of factor replacement.
b. Diagnosis is confirmed via an in vitro assay,
[Figure 1. The coagulation pathways. PT measures the function of the extrinsic and common pathways, whereas PTT measures the function of the intrinsic and common pathways. HMWK = high-molecular-weight kininogen; KAL = kallikrein; FPA = fibrinopeptide A; FPB = fibrinopeptide B.]
whereby the addition of normal plasma or factor concentrate fails to correct a prolonged PTT.
c. Although they previously were considered a contraindication to elective surgery, presently they can be overwhelmed to counteract the effect of the inhibitor.
D. von Willebrand disease
1. von Willibrand disease is a collection of genetic coagulopathies secondary to a deficiency of von Willebrand factor (vWF).
2. Role of vWF
a. Integral to normal platelet adhesion and the functioning of factor VIII
b. Normally found in platelets and in the vascular endothelium
3. Types of deficiencies
Type 1 (quantitative; decreased vWF levels)—A milder form that presents as heavy menstrual bleeding or excessive bleeding from the gums, easy bruising, or excessive surgical bleeding.
[Table 1. Factor Deficiencies Causing Bleeding Disorders]
Type 2 (qualitative; abnormal vWF)
Type 3 (quantitative; no vWF produced)—The most severe form of the disease, which is very rare (1 in 500,000).
4. Diagnosis is made via measuring the bleeding time, factor VIII activity, and both quantitative and qualitative tests for vWF.
a. Desmopressin, usually administered via a nasal spray, works via increased endogenous release of vWF from the vascular endothelium.
b. Factor VIII concentrates combined with vWF may be required in patients with more severe deficiencies (types 2 and 3).
1. Coagulopathies are caused by high blood loss secondary to major trauma or extended surgical procedures.
2. Fluid volume and packed red blood cells must be replaced.
3. The need for platelet and fresh frozen plasma transfusion must be assessed by monitoring platelet counts and coagulation parameters.
II. Venous Thromboembolic Disease
A. Pathophysiology—Deep venous thrombosis (DVT) is the end result of a complex interaction of events including activation of the clotting cascade and platelet aggregation.
B. Virchow triad (predisposing factors)
1. Venous stasis
a. Impaired mobility
b. Intraoperative vascular congestion
2. Endothelial damage secondary to injury or surgical trauma
a. Release of tissue factors and procoagulants (such as collagen fragments, fibrinogen, and tissue thromboplastin)
b. Large release of thrombogenic factors during preparation of the femur during THA, particularly if a cemented femoral component is used
C. Epidemiology and risk factors
1. Without prophylaxis, patients with a proximal femur fracture have a reported prevalence of fatal pulmonary embolism (PE) as high as 7%.
2. Patients undergoing elective THA and TKA have been described as having rates of symptomatic PE without prophylaxis of up to 20% and 8%, respectively.
3. Patients undergoing TKA seem to be at higher risk for venographically identified DVT but at lower risk for symptomatic PE than THA patients.
4. Risk factors for thromboembolism (
a. May have a cumulative effect; a combination of risk factors present in a given patient may greatly increase the risk.
b. Patients with a prior history of a thromboembolic event deserve special attention, given the numerous inherited hypercoagulable states
[Table 2. Risk Factors for Thromboembolic Disease]
(such as factor V Leiden) that have recently been identified. Preoperative consultation with a hematologist may be appropriate.
A. Given the high risk of thromboembolism in patients undergoing major orthopaedic surgery, the difficulty in diagnosing these events, and their potential for morbidity and mortality (approximately two thirds of patients who sustain a fatal PE die within 60 minutes of the development of symptoms), some form of prophylaxis is often necessary. Prophylaxis is required for all THA and TKA patients and for hip fracture patients.
B. The optimal duration of prophylaxis is unclear; however, patients may be at risk for thromboembolism for several weeks postoperatively.
C. Mechanical approaches
1. Sequential compression devices
a. Act via increasing peak venous flow to decrease venous stasis
b. Stimulate the fibrinolytic system
c. Present no risk of bleeding
d. Poor patient compliance and/or inappropriate application is common.
e. Good efficacy has been shown in patients who undergo TKA.
2. Plantar compression devices
a. Compression of the venous plexus of the foot produces pulsatile flow in the deep venous system of the leg (simulates walking).
b. Inadequate data are available to recommend these devices alone.
Table 3. Pharmacologic Agents for Thromboembolic Prophylaxis]
3. Graduated compression stockings
a. These stockings produce a pressure differential between the distal and proximal portions of the lower extremity, decreasing venous stasis.
b. These stocking should be used as an adjunct only and not as the sole means of prophylaxis.
4. Prophylactic inferior vena cava (IVC) filters
a. JVC filters are retrievable devices that are typically placed before surgery and then electively removed 10 to 14 days later.
i. Patients who require surgery in the context of a recent thromboembolic event
ii. Critically ill multiple-trauma patients (relative indication)
iii. May be considered in patients at high risk for a thromboembolism (eg, those with a hereditary hypercoagulable state). Consultation with a hematologist is useful in these cases.
D. Pharmacologic approaches (Table 3)
1. Unfractionated heparin (UFH)
a. Binds to antithrombin III, potentiating its inhibitory effect on thrombin (factor IIa) and factor Xa
b. Higher risk of bleeding and lower efficacy than low-molecular-weight heparin (LMWH)
c. Increased risk of heparin-induced thrombocytopenia, which is secondary to heparin-dependent antibodies that activate platelets
d. Fixed low-dose heparin (5,000 U administered subcutaneously twice daily) generally is not effective in orthopaedic patients.
e. Reversed using protamine sulfate
2. Low-molecular-weight heparin
a. LMWH is derived from the fractionation of UFH into smaller, more homogeneous molecules.
b. LMWH is unable to bind both antithrombin III and thrombin simultaneously and thus has a greater inhibitory effect on factor Xa than factor IIa (thrombin).
c. Provides superior protection against DVT and does not inhibit hemostasis as vigorously at surgical sites as to UFH
d. Less inhibition of platelet function and less vascular permeability than UFH
e. Improved bioavailability (90% versus 35% for UFH)
f. Longer half-life (less frequent dosing)
g. Laboratory monitoring is not required.
h. First full dose 12 to 24 hours postoperatively or until hemostasis obtained at the surgical site
i. Should not be used in conjunction with an indwelling epidural catheter or in patients who have had a traumatic neuraxial anesthetic placed (secondary to a risk of epidural bleeding). Neuraxial anesthesia can be performed 12 hours after administration of LMWH.
j. Compared with warfarin, LMWH is associated with a decreased risk of venographically identified DVT but a higher risk of bleeding complications.
k. Excretion is primarily renal and thus dosing needs to be adjusted in patients with chronic renal failure.
l. Several agents are presently available, and pharmacokinetics, dosing, and outcomes differ among agents.
a. Synthetic pentasaccharide and an indirect factor Xa inhibitor
b. Dosing is 2.5 mg/day subcutaneously; first dose is given 6 to 12 hours postoperatively.
c. Decreased incidence of venographically identified DVT compared with enoxaparin in hip fracture and TKA patients
d. Trend toward an increased risk of bleeding complications
e. Not recommended for patients who weigh less than 50 kg or those with renal insufficiency; has not been used in conjunction with indwelling epidural catheters.
Table 4. Common Drug Interactions With Warfarin]
Antagonizes vitamin K, which prevents the γ-carboxylation of glutamic acid required for the synthesis of factors II, VII, IX, and X and proteins C and S.
Typical dosing regimens start on the night of surgery, as soon as the patient can tolerate oral pain medication.
The anticoagulant effect is delayed for 24 to 36 hours after the initiation of therapy, and the target International Normalized Ratio (INR) is often not achieved until 3 days postoperatively.
The target level of anticoagulation has been controversial; however, a target INR of 2.0 is appropriate for orthopaedic patients.
Advantages—Low cost, oral administration, and efficacy in reducing symptomatic thromboembolic events.
Disadvantages—Difficulty in dosing and need for frequent blood monitoring. Patients with impaired hepatic function may be sensitive to the drug and thus must be dosed and monitored carefully.
Warfarin interacts with many other medications that can augment its effect (Table 4).
Not recommended for use in conjunction with NSAIDs secondary to a higher risk of bleeding at surgical and nonsurgical sites (particularly gastrointestinal bleeding)
Patients who ingest large amounts of vitamin K-rich foods (eg, green, leafy vegetables) may require increased doses to achieve the target INR.
Reversible with vitamin K administration; complete reversal can take several days. Fresh frozen plasma is given if immediate reversal is required.
a. Aspirin irreversibly binds to and inactivates cyclooxygenase (COX) in both developing and circulating platelets, which blocks the production of thromboxane A2, the necessary prostaglandin for platelet aggregation.
b. Advantages—Low cost, ease of administration, and low risk of bleeding-related complications.
c. The role of aspirin when used alone as a prophylactic agent is controversial given lower efficacy compared with other agents when venographic evidence of DVT is used as an end point. Randomized trials assessing the efficacy of aspirin are necessary.
6. When combined with neuraxial anesthetics and particularly hypotensive epidural techniques, aspirin seems to be associated with a lower risk of postoperative thromboembolic events secondary to enhanced blood flow in the lower extremities.
7. The Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy's highest recommendations for patients undergoing THA and TKA include warfarin (goal INR 2.0 to 3.0), LMWH, or fondaparinux for a minimum of 10 days. Routine screening with a duplex ultrasound at the time of hospital discharge is not recommended.
8. Data exist to support prolonged prophylaxis (up to 35 days) in THA patients, but prolonged prophylaxis has not been shown to have an effect in TKA patients.
IV. Diagnosis of Thromboembolic Events
A. Approach to diagnosing thromboembolism
1. No clinical signs are specific for diagnosis of DVT or PE.
2. Calf pain, swelling, and pain on forced dorsiflexion of the foot (Homans' sign) are common in the perioperative period secondary to postoperative pain, swelling, and abnormal gait patterns leading to muscular strain.
B. Initial patient evaluation
1. Chest radiograph—To rule out alternative causes of hypoxia such as pneumonia, congestive heart failure, and atelectasis.
2. Electrocardiogram (ECG)—To rule out cardiac pathology; tachycardia is the most common ECG finding in PE, although a right ventricular strain pattern can be seen.
3. Arterial blood gas measurements on room air
4. Assessing oxygenation
a. Most patients are hypoxic (PAO2 < 80 mm Hg), hypocapnic (PACO2 < 35 mm Hg), and have a high A-a gradient (> 20 mm Hg).
b. The A-a gradient (indicative of poor gas exchange between the alveolus and arterial blood supply) can be calculated as
c. Pulse oximetry is not an adequate alternative to arterial blood gas measurements on room air; patients can hyperventilate to maintain adequate oxygenation.
5. Ventilation/perfusion (V/Q) scanning
a. V/Q scanning has been the standard of care for diagnosing PE for many years.
b. Scans are compared to identify "mismatch defects": areas that are ventilated without associated perfusion.
c. Graded as normal, low, intermediate, or high probability based on criteria determined from prior studies that compared V/Q scans and pulmonary angiograms
i. Patients with normal or low-probability scans should be evaluated for alternative sources of hypoxemia (particularly if a search for lower extremity DVT is negative).
ii. Patients with high-probability scans require treatment.
iii. If the scan is intermediate and clinical suspicion is high, the lower extremities should be assessed for DVT; if negative, a high-resolution chest CT or pulmonary angiogram is indicated to rule out PE.
6. High-resolution (helical or spiral) chest CT angiography
a. Widely adopted as the first-line study for diagnosing PE, given the high rate of indeterminate V/Q scans and the accuracy of this technique compared with other imaging modalities
b. Advantage—Ability to identify alternative diagnosis if PE is not identified.
c. Requires contrast
d. Radiation dose can be a concern in certain patient populations (eg, pregnant women).
e. Sensitivity may be such that high rates of smaller, peripheral emboli are identified that are not clinically relevant, leading to overtreatment.
7. Pulmonary angiography
a. Pulmonary angiography is considered the gold standard for diagnosing PE
b. It is both expensive and invasive and therefore is rarely used in clinical practice.
8. Duplex ultrasonography
a. Noninvasive, simple, and inexpensive
b. Accuracy has been shown to be operator dependent.
c. Accurate in diagnosis of symptomatic proximal clots. Ability to visualize veins in the calf and pelvis is limited.
d. Routine screening for DVT before hospital discharge has not been shown to be cost effective.
9. Lower extremity contrast venography
a. Still considered the gold standard for diagnosing lower extremity DVT
b. Expensive and invasive; therefore, rarely used in clinical practice
10. D-dimer testing
a. D-dimer testing can be used as an adjunct to diagnosing thromboembolic events.
b. Elevated D-dimer levels indicate a high level of fibrin degradation products (which also can be seen following a recent surgery).
c. A low D-dimer level indicates a low risk for DVT (high negative predictive value).
C. Approach to diagnosing PE
1. PE is difficult to diagnose based on classic symptoms of dyspnea and pleuritic chest pain because these are rarely seen.
2. Vague symptoms such as cough, palpitations, and apprehension or confusion are common.
3. The most common sign seen in diagnosed PE is tachypnea followed by tachycardia and fever; therefore, even vague signs and symptoms require a thorough evaluation.
4. If chest radiograph and ECG do not point to an alternative diagnosis, a D-dimer level can be obtained; if negative, the likelihood of PE is low.
5. Depending on availability, chest CT or V/Q scan is obtained.
6. If the V/Q scan is low or intermediate probability and clinical suspicion is high, duplex ultrasonography of the lower extremities can be used.
7. If the ultrasound is negative and suspicion is still high, pulmonary angiography can be used to determine the presence or absence of PE.
D. Treatment of a thromboembolic event
1. Continuous intravenous heparin for at least 5 days, followed by oral warfarin. LMWH is now commonly used because it is simple and the patient may not need to be admitted to the hospital.
a. It prevents clot propagation while allowing the fibrinolytic system to dissolve clots that have already formed.
b. It decreases mortality in these patients compared with those who are not anticoagulated.
c. Risk of bleeding at the surgical site has been related to supratherapeutic levels of anticoagulation and initiation of therapy within 48 hours after surgery.
d. Intravenous heparin is adjusted to maintain a goal PTT of 1.5 to 2.5 times the control value for 5 days.
e. Avoiding the use of a bolus dose of intravenous heparin in the early postoperative period can reduce bleeding.
f. Warfarin is initiated with a target of INR of 2.0 to 3.0 maintained for a minimum of 3 months.
2. In patients who have sustained a PE, elective surgery should not be considered for at least 3 months after the event, and a thorough evaluation is needed to ensure that the clot has resorbed and that there are no residual effects (such as pulmonary hypertension).
3. LMWH is an alternative to intravenous UFH therapy (dosed at 1 mg/kg administered subcutaneously twice daily).
a. LMWH has more predictable onset, but it is associated with the potential for a higher risk of bleeding at the surgical site.
b. Although commonly used to treat orthopaedic patients, no studies to date have specifically examined the use of LMWH for the treatment of diagnosed thromboembolic events in patients who have had orthopaedic surgery.
4. IVC filters
i. When anticoagulation is contraindicated (eg, recent spinal surgery or head injury)
ii. Bleeding complication secondary to anticoagulant therapy
iii. Patients who have sustained a thromboembolic event despite adequate prophylactic anticoagulation
iv. Patients with poor cardiopulmonary reserve and at high risk for further morbidity and mortality if clot extension or recurrence occurs
b. Emboli can recur as either small emboli that pass through the filter, as collateral circulation develops, or as propagation of a large thrombus above the filter.
c. Complications include insertional problems, distal migration or tilting, vena cavae occlusion (which can lead to severe lower extremity swelling and rarely complete venous outflow obstruction) and vena cavae or aortic perforation.
d. In current practice, the IVC filter is often retrieved within 3 weeks, but certain designs allow for retrieval up to 1 year postinsertion.
5. DVT isolated to the calf is rarely associated with PE; proximal extension can occur in 10% to 20% of patients. In isolated calf vein thrombosis, serial ultrasonography can be performed and anticoagulant treatment withheld unless proximal extension is identified.
Top Testing Facts
1. LMWH inhibits factor Xa activity.
2. Fondaparinux is a synthetic pentasaccharide and an indirect inhibitor of factor X activity.
3. Both LMWH and fondaparinux are metabolized in the kidneys; warfarin is metabolized primarily in the liver.
4. Patients undergoing major elective orthopaedic surgery such as hip and knee arthroplasty and those who have sustained multiple trauma and proximal femoral fractures are at high risk for thromboembolic events.
5. The selection of a prophylactic agent requires balancing efficacy and safety.
6. The diagnosis of thromboembolic events can be difficult to make postoperatively; clinical signs and symptoms are unreliable for diagnosis.
7. Initial evaluation of the patient suspected of PE includes an arterial blood gas (ABG) on room air, a chest radiograph, and an ECG to rule out an alternative diagnosis.
8. Pulse oximetry is not an adequate alternative to an ABG as patient hyperventilation can maintain adequate oxygenation.
9. Treatment of thromboembolic events with intravenous heparin or LMWH followed by oral warfarin is effective at reducing morbidity and mortality.
10. IVC filters are indicated for patients diagnosed with a pulmonary embolus in whom anticoagulation is contraindicated or a bleeding complication has occurred, or if cardiopulmonary reserve is poor.
Colwell CW, Hardwick ME: Venous thromboembolic disease and prophylaxis in total joint arthroplasty, in Barrack RL, Booth RE, Lonner JH, McCarthy JC, Mont MA, Rubash HE (eds): Orthopaedic Knowledge Update: Hip & Knee Reconstruction 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2006, pp 233-240.
Conduah AH, Lieberman JR: Thromboembolism and pulmonary distress in the setting of orthopaedic surgery, in Einhorn TA, O'Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 105-113.
Della Valle CJ, Mirzabeigi E, Zuckerman JD, Koval KJ: Thromboembolic prophylaxis for patients with a fracture of the proximal femur. Am J Orthop 2002;31:16-24.
Geerts WH, Pineo GF, Heit JA, et al: Prevention of venous thromboembolism: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126: 338S-400S.
Luck JV, Silva M, Rodriguea-Mercan EC, Ghalambor N, Zabiri CA, Finn RS: Hemophilic arthropathy. J Am Acad Orthop Surg 2004;12:234-245.
Morris CD, Creevy WS, Einhorn TA: Pulmonary distress and thromboembolic conditions affecting orthopaedic practice, in Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 307-316.
Shen FH, Samartzis D, De Wald CJ: Coagulation and thromboembolism in orthopaedic surgery, in Vaccaro AR (ed): Orthopaedic Knowledge Update 8. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2005, pp 169-176.
Turpie AGG, Eriksson BI, Bauer KA, Lassen MR: Fondaparinux: Advances in therapeutics and diagnostics. J Am Acad Orthop Surg 2004;12:271-375.
Whang PG, Lieberman JR: Low-molecular-weight-heparins: Advances in therapeutics and diagnostics. J Am Acad Orthop Surg 2002;10:299-302.
Zimlich RH, Fulbright BM, Frieman RJ: Current status of anticoagulation therapy after total hip and knee arthroplasty. J Am Acad Orthop Surg 1996;4:54-62.