Hyers, Arch Intern Med, 163, 759-768, 2003 A timeline from approximately 1960 to the present indicates the seminal clinical trials that have influenced the use of emerging drugs for VTE prevention and treatment. HFS indicates hip fracture surgery; HITTS, heparin-induced thrombocytopenia thrombosis syndrome; LMWH, low-molecular-weight heparin; OA, oral anticoagulants; PE, pulmonary embolism; THR, total hip replacement; TKR, total knee replacement; and UFH, unfractionated heparin. Management milestones in venous thromboembolism (VTE).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing General Surgery (I) No specific prophylaxis other than early ambulation is recommended in low-risk general surgery patients: those who are undergoing minor procedures, are <40 years of age, and have no additional risk factors (grade 1C). Prophylaxis with low-dose UFK, LMWH, ES, or IPC is recommended in moderate-risk general surgery patients: those who are undergoing minor procedures but have additional risk factors or are between 40–60 years of age or those who are undergoing major operations but are younger than 40 years of age and have no additional risk factors (grade 1A).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing General Surgery (II) Prophylaxis with low-dose UFH, LMWH, or IPC is recommended in high-risk general surgery patients: those who are undergoing nonmajor surgery who are older than 60 years or have additional risk factors or those who are undergoing major surgery who are older than 40 years of age or have additional risk factors (grade 1A). ES or IPC is recommended in higher-risk general surgery patients with a greater-than-usual risk of bleeding (grade 1C). Low-dose UFH or LMWH combined with ES or IPC is recommended in very high-risk patients with multiple risk factors (grade 1C). Consider postdischarge LMWH or perioperative warfarin (INR 2.0–3.0) in selected very high-risk patients (grade 2C).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing Gynecologic Surgery Early ambulation is recommended for brief procedures for benign disease (grade 1C) Patients having major surgery for benign disease without additional risk factors should be treated with low-dose UFH twice daily (grade 1A); alternatives include LMWH once daily or IPC started just before surgery and continued for several days postoperatively (grade 1C+) Patients having extensive surgery for malignancy should be treated with low-dose UFH three times daily (grade 1A); alternatives include low-dose UFH plus ES or IPC or higher doses of LMWH (grade 1C).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing Urologic Surgery. Early ambulation is recommended in patients undergoing transurethral or other low-risk procedures (grade 1C) Low-dose UFH, LMWH, ES, or IPC is recommended for major procedures (grade 1B) Low-dose UFH or LMWH combined with ES or IPC is recommended for patients at the highest risk (grade 1C).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing Major Orthopedic Surgery (I) For patients undergoing elective hip replacement, LMWH should be started 12 hours before surgery, 12–24 hours after surgery, or 4–6 hours after surgery at half the usual high-risk dose, should be used and then continued with the usual high-risk dose the following day or warfarin (INR 2.0–3.0) started preoperatively or immediately after surgery (grade 1A) For patients undergoing elective knee replacement, LMWH or warfarin (INR 2.0–3.0) is recommended (grade 1A); optimal use of IPC is an alternative option (grade 1B); low-dose UFH is not recommended (grade 1C+)
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing Major Orthopedic Surgery (II) For patients undergoing hip fracture surgery, use LMWH or warfarin (INR 2.0–3.0) (grade 1B); low-dose UFH is an alternative option (grade 2B) At least 7 to 10 days of prophylaxis is recommended after total hip replacement or total knee replacement (grade 1A) LMWH prophylaxis beyond 7 to 10 days after surgery is recommended for high-risk patients undergoing major orthopedic surgery (grade 2A) Routine duplex ultrasonography screening is not recommended at the time of hospital discharge or during outpatient follow-up in asymptomatic total hip replacement or total knee replacement patients (grade 1A).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing Neurosurgery. IPC with or without ES is recommended in patients undergoing intracranial neurosurgery (grade 1A) Low-dose UFH or postoperative LMWH are acceptable alternatives (grade 2A because of concerns about clinically important intracranial hemorrhage) ES or IPC and LMWH or low-dose UFH prophylaxis may be more effective than either modality alone in high-risk patients (grade 1B).
Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing Trauma Surgery Trauma patients with a risk factor for thromboembolism should receive prophylaxis if possible. LMWH should be used as soon as it is considered safe to do so (grade 1A) Use ES and/or IPC if LMWH prophylaxis will be delayed or is contraindicated (grade 1C) In patients at high risk for thromboembolism who have received suboptimal prophylaxis, consider screening with duplex ultrasound (grade 1C) Insert an inferior vena cava filter if proximal deep vein thrombosis is documented and anticoagulation is contraindicated (grade 1C+); do not use an inferior vena cava filter for primary prophylaxis (grade 1C).
Aronow WS, J. Gerontology A: Biological Sciences and Medical Sciences 59:M42-M47 (2004) Abbreviations: UFH = unfractionated heparin; LMWH = low-molecular-weight heparins; IPC = intermittent pneumatic compression; ES = elastic (graduated compression) stockings; INR = international normalized ratio. GradeStrength of Recommendation 1A - Strong recommendation applicable to most patients with risk/benefit clear based on high-quality randomized controlled studies 1B - Strong recommendation likely to apply to most patients with risk/benefit clear based on randomized controlled studies with limitations 1C+ - Strong recommendation likely to apply to most patients with risk/benefit clear based on extrapolation from randomized controlled studies or on strong evidence from observational studies 1C - Intermediate-strength recommendation with risk/benefit clear based on observational studies only 2A - Weaker recommendation with risk/benefit unclear based on high-quality randomized studies 2B - Weak recommendation with risk/benefit unclear based on randomized studies with limitations; alternate approaches may be better in some patients 2C - Very weak recommendation with risk/benefit unclear based on observational studies only; alternatives may be equal or better in most patients
A schematic representation of blood coagulation Initiation: tissue factor (TF) is exposed by vessel damage; coagulation factor VIIa (FVIIa) binds to TF and activates small amounts of FX to FXa and FIX to FIXa. This leads to trace amounts of thrombin. Amplification: the trace amounts of thrombin activate the co-factors FV and FVIII to FVa and FVIIIa and platelets (via cleavage of protease-activated receptors, PAR1 and PAR4), which leads to the formation of complexes of factors for more efficient thrombin generation. Propagation: more thrombin is available leading to activation of FXI (to FXIa) for more thrombin generation, fibrin formation, activation of FXIII (to FXIIIa) to reinforce the fibrin structure and activation of thrombin activatable fibrinolysis inhibitor (TAFI) for prevention of fibrinolysis. Termination: thrombin leaking out of the clotting area activates protein C (to APC), which inactivates FVa and FVIIIa. This is important because it restricts the blood coagulation to the area of vessel damage. Amber arrows: direct effects of thrombin; green arrows: indirect effects of thrombin that stimulate plasma coagulation and platelet aggregation; red arrows: indirect effects of thrombin that inhibit plasma coagulation and fibrinolysis. Gustafsson et al., Nature Reviews Drug Discovery 3, 649-659 (2004)
AgentsMechanism of Action Onset of Action and Route of administration ApplicationControindications Heparin With ATIII, prevents thrombin activity (anti- IIa) and to a lesser extent thrombin generation (anti-Xa) Ineffective on clot- bound thrombin Immediate IV or subcutaneous Prevention and treatment of VTE Severe active bleeding; documented hypersensitivity HIT LMW heparins and heparinoids With ATIII, inhibits thrombin generation by an effect on Xa, to a lesser extent on IIa Ineffective on clot- bound thrombin Immediate Subcutaneous Prevention of VTE Severe active bleeding; documented hypersensitivity HIT Hirudin and direct thrombin inhibitors Inhibits thrombin activity directly Immediate IV Prevention and treatment of VTE; treatment of HIT Severe active bleeding; documented hypersensitivity Warfarin Inhibits proper synthesis of vitamin K- dependent coagulation factors (II, VII, IX, X) 4-5 days Oral Long-term treatment of VTE; prevention of VTE Severe active bleeding; pregnancy; documented hypersensitivity
Agents Mechanism of Action Onset of Action and Route of administration ApplicationControindications Streptokinase Activates plasminogen, dissolves fibrin; degrades fibrinogen and several other plasma proteins Immediate IV Treatment of severe or life- threatening PE or DVT Active bleeding; recent surgery; stroke; or severe trauma; any hemorrhagic disease; recent streptococcal infection or treatment with streptokinase documented hypersensitivity Urokinase Activates plasminogen, dissolves fibrin; degrades fibrinogen and several other plasma proteins Immediate IV Treatment of severe or life- threatening PE or DVT Active bleeding; recent surgery; severe trauma; any hemorrhagic disease Alteplase, Reteplase Activates plasminogen bound to fibrin; dissolves fibrin Immediate IV Treatment of severe or life- threatening PE or DVT Active bleeding; intracranial pathologic condition; recent surgery; severe trauma; any hemorrhagic disease
Eparina Glicosaminoglicano (mucopolissaccaride solfatato) di origine naturale Non frazionata: 3000-30000 Da LMWH: < 7000 Da Forma complessi con alcuni fattori della coagulazione, attivandoli (antitrombina) o inattivandoli (trombina) Attiva delle lipasi con effetto chiarificante del sangue
A molecular model of the ternary complex of ATIII, thrombin and heparin. Heparin acts as a template to facilitate ATIII-mediated inhibition of thrombin. Heparin forms a bridge of six to eight monosaccharide units. ABD = Antithrombin Binding Domain TBD = Thrombin Binding Domain De Kort et al., Drug Discov Today. 10:769-779, 2005
Indicazioni terapeutiche Eparina Onset: immediato Durata dazione: 3-6h Dosi: 35000 U/die suddivisa ogni 8-12h s.c.; 5000 U (bolo iniziale), poi 1200-1600 U/hr in infusione (DVT). aPTT (activated partial thromboplastin time) = 2-2.5 volte il normale. Trattamento della trombosi venosa profonda ed embolismo polmonare (infusione, anche 5000 U/2-3 die) Tromboprofilassi in chirugia (5000 U/2-3 die) Dopo un intervento di fibrinolisi Leffetto non è strettamente dose-dipendente. La biodisponibilità s.c. è 30%.
Indicazioni terapeutiche LMWH (Eparina a basso peso Molecolare) Onset: immediato Durata dazione: 3-6h Dosi: 5000 U/die suddivisa ogni 8-12h s.c. Profilassi trombosi venosa profonda ed embolismo polmonare Tromboprofilassi in chirugia Dopo un intervento di fibrinolisi Risposta dose-dipendente. Biodisponibilità: 90% s.c.
French & Faxon, Rev Cardiovasc Med. 3: 176-182, 2002
FeatureLMWHFondapari nux Idrapari nux Bioavailability80-90%100% Half-life (hours)41780 TargetFXa, THRFXa Renal clearanceYes Neutralized by PF4LittleNone Potential for HITLowNone Neutralized by protamine sulfate PartialNo Comparison of the properties of LMWH, fondaparinux and idraparinux
Effetti collaterali Sanguinamento (2 – 33%) Trombocitopenia (eparina non frazionata) Con le LMWH si hanno meno effetti collaterali Le eparine non sono attive sulla generazione di trombina nel coagulo.
Model of the interaction of the blood protein platelet factor 4 with a sulfated heparin polysaccharide. The basic residues of platelet factor 4 (PF4) are colored blue. PF4 is released by activated blood platelets and contains many basic amino acids on its surface, which can form strong interactions with UFH. HIT is caused by antibodies formed by the antigenic complex of heparin and PF4. De Kort et al., Drug Discov Today. 10:769-779, 2005
Table 1. Limitations of heparin and their consequences Limitation Consequence Binds to plasma proteins Variable anticoagulant response so monitoring is required Neutralised by platelet Reduced activity in the vicinity factor 4 of platelet-rich thrombi Forms complexes with platelet Causes heparin-induced factor 4 thrombocytopenia with or without thrombosis Limited capacity to inhibit Incomplete attenuation of factor Xa within the Thrombus growt prothrombinase complex or trhombin bound to fibrin Crowther & Weitz Expert Opin. Investig. Drugs (2004) 13 (4):403-413
Warketin TE, Best Pract Res Clin Haematol. 17:105-125, 2004
Warfarin (anticoagulante orale) Blocca la sintesi dei fattori della coagulazione vit. K dipendenti (II, VII, IX, X) Il INR (international normalized ratio, una misura standardizzata del tempo di protrombina-TP) deve essere tra 2 e 4 (TP 1.5 –2 quello normale)
Warfarin Leffetto del warfarin si osserva normalmente dopo 4-5 giorni di terapia La dose è di 1.5 mg/die che determina un INR (international normalized ratio, una misura standardizzata del tempo di protrombina-TP) tra 2 e 4 (TP 1.5 –2 quello normale). Molte molecole interferiscono con il warfarin. Esistono varianti genetiche del CYP2C9 (enzima che metabolizza il warfarin). Nei pazienti con dette varianti alleliche (10-20% Caucasici), la dose deve essere diminuita per ottenere un INR tra 2 e 4. In questi pazienti aumenta il rischio di emoraggie.
Effetti collaterali warfarin Effetto collaterale grave: sanguinamento, emorragie (5%). Antidoto: vit.K, ma poiché occorrono circa 24h per la de novo sintesi dei fattori vit.K dipendenti, trasfusioni. Leffetto è potenziato da antiaggreganti e da tutti i farmaci che spiazzano il warfarin dalle proteine plasmatiche (il warfarin si lega per il 95-98%). Una volta spiazzato dalle proteine plasmatiche è metabolizzato più rapidamente con una perdita di efficacia
Indicazioni terapeutiche Warfarin Profilassi trombosi venosa profonda ed embolismo polmonare Tromboprofilassi in chirurgia ortopedica (femore, bacino) e nella fibrillazione atriale Profilassi trombosi nei pazienti con valvole cardiache Onset: dopo almeno 24h almeno Durata: 3-5 die
Rivaroxaban, an oral direct factor Xa inhibitor Piccini et al., Expert Opin.Investig. Drugs 2008, 17: 925-937
Rivaroxaban Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists. Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation.