Prothrombin Time

Prothrombin time (PT) tests the efficacy of the extrinsic pathway of clotting involving factors, X, VII, V, prothrombin, and fibrinogen. Prothrombin, VII, and factor X are vitamin K dependent and therefore associated with Warfarin therapy (see section on anticoagulant therapies). The PT is measured using the International Normalized Ratio (INR) that measures the patient’s PT in relation to the PT control that is standardized to the World Health Organization value. ^, This technique adjusts the actual PT for variations in the reagents used to run the test among hospitals. Under normal conditions the INR is 1.0.

Partial Thromboplastin Time

Partial thromboplastin time (aPTT) tests the adequacy of the intrinsic pathway of clotting involving factors VIII, IX, XI and XII as well as the common pathway (factor V, X, prothrombin, and fibrinogen). Abnormalities of aPTT are often a result of factor deficiencies of the intrinsic and common pathways of clotting. This can be used to identify genetic origins of bleeding problems. The normal value ranges from 22 to 34. aPTT can be used to correlate the effect of anticoagulants and antiplatelets as well as dysfunction of liver physiology.

Qualitative/Quantitative Platelet Dysfunction

The normal range of platelets can vary from 150,000 to 450,000/μL of blood. Absolute counts can identify deficiency (ie, thrombocytopenia but not necessarily function). Platelet function analysis 100 (PFA-100) can be used as a measure of function. Qualitative dysfunction (ie, a problem in the structure/function of the platelet) is often caused by missing or defective proteins, either on the surface or granules of the platelet, that prevent events in aggregation and clotting. The manifestations are presented as easy bruising, nosebleeds, bleeding of the mouth or gums, heavy menstrual bleeding (periods), postpartum (after child birth) bleeding, and bleeding following dental work, surgical, or invasive procedures.

Bleeding Time

Bleeding time is evaluated as a measure of the time until bleeding stops after a 1 mm slit is made in the skin. Normal times range from 7 to 9 minutes. Although not very specific for ruling in a dyscrasia, bleeding time is used in conjunction with thrombin time, which measures the conversion of fibrinogen to fibrin. The normal range is less than 10 seconds. Other adjunctive tests for suspected bleeding dyscrasias include liver panels, hepatitis panels, complete blood count screening tests for HIV, and genetic testing.

Anticoagulants: Vitamin K Antagonists/Heparin/Direct Anticoagulants

Anticoagulants, which are agents that hinder the formation of blood clots, are the mainstay of treatment for many thromboembolic disorders including pulmonary embolism and stroke from atrial fibrillation and deep vein thrombosis. An estimated 30 million prescriptions are written annually in the United States for the anticoagulant warfarin alone. Anticoagulants fall into 3 major categories: vitamin K antagonists, heparins, and direct anticoagulants (direct thrombin inhibitors/direct factor Ax inhibitors). The anticoagulant that requires the most attention in regard to outpatient dental procedures is warfarin, a vitamin K antagonist, as it is the most widely prescribed and requires close monitoring. However, newer anticoagulants such as the direct thrombin inhibitors are gaining attention because of their broad therapeutic window. Box 2 describes a stepwise approach developed by Hasalszynki for perioperative workup of patients prescribed anticoagulants.

Vitamin K antagonists

The oral anticoagulants most often seen in practice are derivatives of Coumadin (warfarin) or vitamin K antagonists, which act by inhibiting vitamin K epoxide reductase, the enzyme needed for cyclic interconversion of vitamin K. Warfarin (Coumadin, Bristol-Meyers Squibb, New York, New York), which is derived from 4-hydroxycoumarin, is a competitive inhibitor of vitamin K and blocks the function of the vitamin K epoxide reductase complex in the liver. This inhibits the action of vitamin K-dependent factors II, VII, IX, and X and proteins C and S. Warfarin is metabolized in the liver by the cytochrome P450 system, and is administered in doses to achieve an INR of 2.0 to 3.0 for most clinical indications except in patients with mechanical heart valves and deep venous thromboses (DVT), where a higher INR is recommended (2.5–3.5). Warfarin is absorbed rapidly from the gastrointestinal (GI) system and has a peak activity at 90 minutes with a half-lie of 36 to 42 hours. The patients who are prescribed warfarin must be carefully evaluated, as dosing can be affected by diet, drug-drug interactions, and other chronic illnesses. As such, the assessment of perioperative bleeding involves an understanding of these risk predictors when considering invasive oral health care intervention. The HAS-BLED score was crafted as a decision-making strategy for patients who required anticoagulation for atrial fibrillation (AF). This pneumonic accounts for a history of hypertension, abnormal renal and liver function, stroke, bleeding predisposition, labile INR, elderly, and use of alcohol. ^, It also accounts for decisions on whether bridging should be considered to avoid thrombotic events. The CHAD52 and CHA2DS2-VASc scores are other models (congestive heart failure, hypertension, age >65, diabetes, and stroke/TIA) that predict increase risk of thrombotic events. The CHADS2 more precisely predicts whether bridging therapy needs to be initiated for those taking warfarin and requires a discontinuation of anticoagulation. ^,

Debate continues with respect to risk of altering dosing in patients who are on warfarin. Several studies have suggested that anticoagulation can continue without interruption. High-risk procedures, however, lack a consensus statement with respect to continuation of therapy. van Diermen and colleagues recommend discussion with the patient’s physician if the INR is greater than 3.5 and complicated oral surgery is planned. Other studies did not confirm the association of increased risk of bleeding and a high INR. Bajkin and colleagues ^, studied 54 patients with INR values 3.5 to 4.2 who had up to 3 teeth extracted and recorded postoperative bleeding at 3.7% (2 of 54 patients). Scully and Wolff found that uncomplicated extraction of 3 teeth was safe if the INR is less than 3.5, while Chugani suggested that periodontal flaps, implant placement, and apicoectomy were not recommended in patients with INR ranges of 3.0 to 4.0. ^, Several studies mentioned that along with INR values and surgical trauma, an important risk predictor that influences postoperative bleeding is inflammation of the dental tissue environment, which is associated with a greater chance of significant bleeding. ^, Ward and Smith reviewed the literature in comparison with current practice by oral and maxillofacial surgeons who perform dentoalveolar procedures for the anticoagulated patient. They concluded that for moderate-to-high-risk procedures, warfarin discontinuation is recommended to minimal therapeutic levels as determined by the INR. Future prospective trials are required, however, for stronger management guidelines in this population of patients.

The normal INR for a patient not on anticoagulation ranges from approximately 0.8 to 1.4. The target range of INR in the anticoagulated patient is 2.5, ranging from 2 to 3; however, some conditions such as the presence of an artificial heart valve require a higher target INR of 3 (range 2.5–3.5). ^{, ,} As a general rule, anticoagulation should not be discontinued prior to low-risk procedures, such as a simple dental extraction, if the INR on the day of surgery is within the therapeutic range, or less than 3.5. INR should be measured within 24 hours of surgery or within 72 hours for an INR stable patient. If the INR is above 3.5, then low-risk procedures are contraindicated as significant bleeding can occur. ^, Values greater than 3 warrant holding of warfarin for up to 5 days and retesting the INR. ^, Decisions to discontinue medication should always be done in conjunction with the patient’s physician. Warfarin can be discontinued 5 days prior to surgery, with an INR drawn up to 24 hours prior. INR is then rechecked on the day of surgery to ensure that it is normal or less than 1.4. Box 3 suggests the range of INR based on the condition being treated. ^{, , ,} The practitioner must also check for concurrent medications affecting hemostatic mechanisms such as antiplatelet drugs, ASA and NSAIDS that can hamper hemostasis and cause hematoma formation. ^{, ,} Postoperatively, warfarin can usually be restarted 12 to 24 hours following the procedure as long as the risk of significant postoperative hemorrhage has passed. Because warfarin takes approximately 5 to 10 days to reach therapeutic levels, patients with high risk of thromboembolism might require bridging therapy in which an anticoagulant with a shorter onset and offset is used perioperatively. Bridging therapy refers to anticoagulation using a short-acting blood thinner like low molecular weight heparin (LMWH) for 10 to 12 days around the time of the surgical intervention when warfarin is interrupted and the effect is outside of the therapeutic range. This will prevent the patient from risk of developing blood clots. Warfarin is stopped usually 5 to 6 days prior to surgery and restarted 24 hours after. ^{, ,}

Post-myocardial infarction patients with high risk of thromboembolism may also be taking low-dose antiplatelet medication. These patients on high-intensity anticoagulation have a fivefold greater risk for bleeding compared with low-intensity anticoagulation. Warfarin can be reversed with fresh-frozen plasma (10–15 mg/kg) as well as with a slow infusion of vitamin k (5–10 mg). The US Food and Drug Administration (FDA) is evaluating a 4-factor prothrombin complex concentrate containing factors II, VII, IX, X. Warfarin therapy can be resumed within 12 to 24 hours after procedure if hemostasis is well-controlled. If bridging was required, then this approach may be altered. The American College of Chest Physicians (ACCP) recommends the administration of an oral prohemostatic agent (eg, 5 mL tranexamic acid rinse 5–10 minutes before surgery and 3 or 4 times daily for the next 1–2 days), which is associated with a low risk (<5%) of a major bleeding event.

Heparin: unfractionated heparin/low molecular weight heparin

Heparin is a glycosaminoglycan found in the secretory granules of the mast cells. It serves as an anticoagulant that is activated by antithrombin, which binds to a 5-saccharide sequence on heparin, which then activates an antithrombin enzyme that will bind to factor Xa. Thrombin (factor II) inhibition will occur when antithrombin and thrombin both bind to sites on heparin. The heparin will then act as a catalyst, contributing to thrombin inhibition by activating antithrombin III. Unfractionated heparin is comprised of heterogeneous heparin molecules not degraded by the enzyme glucuronidase in the mast cells. It activates thrombin III and can be monitored with use of aPTT with a prolongation time 2 to 3 as therapeutic. Low molecular weight heparin (LMWH) activates thrombin III and inhibits factor Xa. It does not require monitoring of aPTT to be therapeutic. Fondaparinux is a synthetic derivative of the 5-chain binding sequence found on heparin. It selectively causes inhibition of factor Xa and similar to LMWH. Like LMWH, it is given subcutaneously once daily at a dose of 5.0 to 10.0 based upon weight (in kilograms), and it also does not respond to laboratory monitoring. Its half-life is 17 hours, and it is cleared by the kidneys. ^,

Heparin can be administered either by intravenous or subcutaneous approaches. Unfractionated heparin is often indicated as a bridging therapy (in the event that warfarin needs to be stopped) or as an inpatient anticoagulation therapy for thromboembolism, because the onset is immediate. Bridging can also be accomplished with LMWH, and either unfractionated heparin or LMWH can be initiated 24 to 48 hours after warfarin cessation with INR monitoring to a normal range. ^, Unfractionated heparin is discontinued at 6 to 8 hours prior to surgical intervention, and LMWH is administered at 50% of the dose 12 to 24 hours before surgery. Several local hemostatic measures can be applied to prevent hemorrhage; however, careful monitoring involves the extent of surgical exposure and systemic risks such as cerebral infarcts and acute coronary syndrome. ^{, ,} Other prophylactic approaches for hemostasis include external compression stockings in patients with high-risk criteria such as obesity, malignancy, immobility, smoking, and hypercoagulability. The perioperative management of patients who are on fondaparinux is less well studied. Recommendations include a discontinuation for 2 half-life time periods prior to minimal surgical intervention and a 3- to 4-day discontinuation period prior to major procedures. The drug is resumed 24 hours after.

Several contraindications of heparin-based therapy need to be addressed. Patients are often on several drugs at the same time, and as such they can affect hemostasis. Antiplatelet and other fibrinolytic agents can increase the risk of hemorrhage with subsequent need for transfusions. Other factors such as liver disease susceptibility to thrombocytopenia can cause adverse events during the perioperative period of treatment. The latter is a result of a heparin-induced thrombocytopenic (HIT) caused by antibodies that activate platelets in the presence of heparin. ^, Type I HIT is a nonimmunological-mediated response that usually appears within the first 2 to 3 days after the initiation of heparin treatment. It typically causes a mild and transient thrombocytopenia (rarely <100, 000/mm3), which occurs because of a direct interaction with platelets and heparin that causes clumping and is not associated with an increased risk of thrombosis. HIT type II, however, is associated with an immunologic response and does have an increased risk of thrombosis and can be detected via laboratory testing (heparin-induced platelet aggregation [HIPA] and the serotonin release assay). The treatment is immediate cessation of heparin therapy and monitoring until thrombocytopenia resolves.

The half-life of heparin and its coagents is short. In the event of a major bleeding episode, it can be neutralized with protamine sulfate (PS). PS binds to heparin as a complex that neutralizes the anticoagulant effect. 1 mg dosing of PR can neutralize 100 units of heparin. LMWH is partially neutralized by PS at the antifactor Xa portion of the protein chain. PS can elicit an adverse event because of its causation of histamine release and risk of a resultant anaphylactic event. Careful slow dosing intravenously should not exceed 50 mg. ^{, ,}

Direct anticoagulants:/thrombin inhibitors

The dynamic of thromboprophylaxis with anticoagulants is of the utmost importance in managing patients who are at risk for systemic embolization and catastrophic events. Newer anticoagulants have gained popularity over direct vitamin K antagonists because of their more predictable anticoagulation. ^, These direct thrombin inhibitors (DOAs) have broad therapeutic windows, allow fixed dosing, and lack interaction with cytochrome P450 enzymes, which eliminate the need for frequent monitoring. Their targets are enzymes that affect thrombin and factor Xa; they have shorter half-lives and as such are easier to discontinue and resume rapidly. These agents, however, were thought to lack a specific antidote, which raises concern for emergent management of patients who require hemostatic control (ie, maxillofacial trauma patients or those who require full mouth extractions prior to cardiothoracic intervention) and increased risk of a thromboembolic event (see below). The newer oral anticoagulants, whether they be direct thrombin inhibitors or antifactor Xa, have a peak anticoagulant effect within 2 to 3 hours that will potentially reduce the need for temporary bridging.

Thrombin inhibitors

These medications interrupt the proteolysis of thrombin by inactivating fibrin bound to thrombin and target factor IIa to cause direct inhibition of thrombin. Direct thrombin inhibitors prevent thrombin from cleaving fibrinogen to fibrin, which is involved in the formation of clots. This effect is exerted on the soluble and fibrin-bound forms of thrombin. Additionally, thrombin activates factors V, VIII, XI and XIII and binds to thrombomodulin and activating protein C. The term hirudins refers to a class of antithrombotic agents structurally derived from the medicinal leech salivary protein hirudin. These proteins prevent deep venous thrombosis and are often prescribed for patients who have had hip replacements who are at risk for deep vein thrombosis (DVT) or PE. Their half-life is 30 minutes to 3 hours, and they can be monitored using the aPTT, which is prolonged for thromboprophylaxis. ^, Dabigatran (PRADAXA, Boehringer-Ingelheim, Ridgefield, Connecticut) is the only widely available oral direct thrombin inhibitor, but parenteral drugs in this class are available and include lepirudin, desirudin, bivalirudin, and argratroban. They are currently approved for use in the prevention of venous thromboembolism and stroke in nonvalvular atrial fibrillation. ^,

The risk of perioperative bleeding in patients who are taking direct thrombin inhibitors is comparable to those on warfarin (ie, warfarin,4.6%; dabigatran, 5.1%). Monitoring. however, can be challenging, as no laboratory value can determine risk of bleeding with dabigatran, and as such a careful assessment of risk with surgical intervention is required. Several studies have characterized rare bleeding events in patients who were on dabigatron and received dental extractions, while other studies find it prudent to stop the medications except in those oral procedures that may result in minimal bleeding. ^, When on direct thrombin inhibitors, the risk of hemorrhage is comparable to anticoagulation with warfarin, with an INR of 2.0 to 3.0. When the risk of hemorrhage is significant, and anticoagulation needs to be discontinued, renal function should be considered, as 80% of the drug is excreted unchanged in urine; therefore, a patient with reduced creatinine clearance will require a longer drug hiatus prior to surgery. For low risk of bleeding, dabigatran can be held for 24 hours prior to surgery. For high risk of bleeding, it can be held 48 to 72 hours or longer if renal function is diminished. Postoperatively, because of its fast onset, dabigatran can be restarted once hemostasis is achieved or within 24 hours after a low-risk procedure and within 48 to 72 hours if the procedure is of high risk.

Bleeding complications from an interventional procedure such as nerve blocks and soft tissue procedures can result in hematomas, and subcutaneous ecchymosis require a formal risk assessment as described previously with the treating physician as to the need for altering the patient’s anticoagulant therapy when necessary. Patients who present emergently from maxillofacial trauma should have therapy discontinued and be placed on supportive measures to prevent hemorrhage. Laboratory values can be applied if they are on warfarin or dabigatran that will serve only to indirectly measure whether the drugs are in their system. Idarucizumab (Praxbind) is an antidote for patients taking Dabigatran and used against the risk of major bleeding in this patient group. ^,

Direct factor Xa inhibitors

The direct factor Xa inhibitors are a new group of anticoagulants that are being considered as substitutes for both vitamin K antagonists and LMWH in certain patient populations. These xabans (inhibitors) include rivaroxaban (XARELTO, Janssen Pharmaceuticals, Titusville, New Jersey, apixaban ELIQUIS, Pfizer, New York, New York), edoxaban (Savaysa), and Betrixaban (in development). Their monitoring is less needed because of quick onset and fewer drug and food interactions, thereby providing consistency in therapeutic blood levels. ^{, ,} Factor Xa inhibitors prevent the cleaving of prothrombin to thrombin. The inhibition of factor Xa is important and provides a robust response, because 1 molecule of factor Xa can cleave approximately 1000 molecules of prothrombin to thrombin. Additionally, factor Xa exists in both circulating and clot-bound forms, and direct Xa inhibitors are able to act on both. This is advantageous, as these inhibitors do not require a cofactor, act at a single step in coagulation, and are metabolized in the liver and kidney, which will prevent liver accumulation of the drug and prevent hepatic insufficiency. ^,

Generally speaking, dentoalveolar procedures that are simple; that is, extraction of up to 3 teeth require no monitoring of factor Xa. It is prudent, however, to know the level of anticoagulation in circumstances of trauma and the high-risk surgical patient. Rivaroxaban should be discontinued 48 hours in advance of a high-risk procedure and restarted as soon as hemostasis has been achieved (or in 48–72 hours if there is high risk of postoperative bleeding). For lower-risk bleeding procedures, rivaroxaban can be stopped as little as 1 day prior if renal function is normal. Moderate- to high-risk patients on apixaban (Eliquis) in the perioperative period should be managed individually. Apixaban is recommended to be discontinued 3 to 5 days in advance of a high-risk procedure in those with normal renal function. In low-risk procedures such as dental extractions (excluding multiple tooth extraction), apixaban can be continued. For patients who experience minor bleeding, consider local hemostatic measures (suturing, placement of gelatin sponge, and tranexamic acid rinse). In moderate-to-severe bleeding, mechanical compression, fluid replacement, hemodynamic support, oral charcoal (if recent ingestion <2 hours to remove the pro-drug from the gastrointestinal tract) or hemodialysis may be appropriate. In situations where there is major life-threatening bleeding, administration of a 4-factor prothrombin complex concentrate (factors II, VII, IX, X) is recommended (see section on postoperative hemostatic measures). ^, Table 1 lists the most recent guidelines for continuance/discontinuance of anticoagulant therapy.

Table 1

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Botox and Dermal Fillers
2. Neuropathic Pain and Burning Mouth Syndrome
3. Soft-Tissue Grafting Solutions
4. Role of Piezo Surgery and Lasers in the Oral Surgery Office
5. Intraoral Scanner, Three-Dimensional Imaging, and Three-Dimensional Printing in the Dental Office
6. Bone Regeneration

Stay updated, free dental videos. Join our Telegram channel

Join