Venous Thromboembolism:Pathophysiology and Management Gerald A. Soff M.D.
Thrombosis• A thrombosis is a pathological clot that forms within the lumen of a blood vessel or the heart.• Thromboses may form on the arterial or venous sides of the circulation.• Deep Vein Thrombosis – May embolize to form a pulmonary embolism.• Arterial Thrombosis – May cause ischemia or necrosis of the affected tissues. – Myocardial infarction and cerebral infarctions (ischemic stroke) result from arterial thrombosis.• We will focus on venous thrombosis
Normal Vein Function• Veins move blood against gravity by use of a series of valves and compression of the vein by surrounding muscles, especially in the legs.• There are superficial and deep veins that tend to run in parallel and are connected by perforating veins. Deep are of much larger capacity.
Deep Vein Thrombosis• Thrombus typically forms at venous valves.• Legs may be swollen, painful, warm, and erythematous. But often the signs are much more subtle, or case may be asymptomatic.
Pulmonary Embolism• Part of thrombus breaks off (usually from leg, pelvic, or inferior vena cava), travels through the right heart, and lodges in pulmonary artery.• Direct obstruction of pulmonary circulation and vaso-spasm cause decreased pulmonary blood flow.• Associated with pain, decreased oxygen delivery, and in severe cases vascular collapse and death.• Calf DVT are much less likely to embolize.
Post-Thrombotic (Phlebitic) Syndrome• Venous incompetence (Varicose veins);• Recurrent thrombosis and pulmonary embolism.• This complicates 25-75% of DVT.
Virchow’s Triad Risk Factors For Thrombosis• Altered Blood Flow/Venous stasis – Immobilization – Obesity – Heart disease• Vessel wall damage – Accidental trauma – Surgical trauma – Prior history of DVT – Advanced Age• Increase In Blood Coagulability – Increase in tissue factor – Presence of activated factors – Decrease in coagulation inhibitors
Physiologic Anticoagulants• Several physiologic anticoagulant systems exist.• All are dependent upon an intact endothelium.• Where endothelial cell lining of vessels is intact (and healthy) anticoagulant systems prevent blood from clotting.
Endothelial Cell-Dependent Anticoagulant Processes• Heparan Sulfate: AT III• Thrombomodulin: Protein C: Protein S• ADPase (CD39)• Tissue Factor Pathway Inhibitor• Nitric Oxide
Heparan:Antithrombin III Deficiency first described in 1965. – (Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 13:516-30, 1965) AT III neutralizes the active enzymes in the coagulation system. Dominant Inheritance.
Protein C/Protein S System • Constituents; – Protein C – Protein S – Thrombomodulin • Activated Protein C (With cofactor Protein S) inactivates Va and VIIIa, the cofactors of the cascade – (Probable role in augmenting fibrinolysis.) • Dominant Inheritance. • Homozygous individuals have purpura fulminans.
Factor V:Leiden/Activated Protein C Resistance • Reduced neutralization of Factor Va by Activated Protein C. • Genetically a balanced Polymorphism. • Found predominantly in European populations (~3-7%), with ~1% in Indian subcontinent and Arabs. • Heterozygotes (in isolation); ~3-4-fold increase risk in thrombosis. • Homozygotes; ~ 50 fold increase in thrombotic risk.
Prothrombin Gene Mutation: (Prothrombin G20210A)• Genetic polymorphism affects the terminal 3 nucleotide of the 3 untranslated region (UTR) region of the prothrombin mRNA and causes elevated levels of prothrombin in the plasma.• Heterozygous: Prothrombin levels that are increased by approximately 30%.• Homozygous: : Prothrombin levels that are increased by approximately 30%.• Increased prothrombin levels are associated with increased thrombin generation and correlate with an increased risk of venous thromboembolic disease.
Population Genetics Of Factor V:Leiden Rees DC. Brit. J. Haemat. 95:579, 1996.Country Allele Freq Country Allele (%) Freq(%)Greece 7.0 India 1.2Sweden 5.9 China 0Germany 3.6 Indonesia 0U.K. 3.4 Japan 0Spain 2.0 New Guinea 0Basques 0.0 Aboriginal Australia 0France 2.0 Sub-Saharan Africa 0Greenland 0.0 Vancouver Island 0 IndiansSaudi Arabia 1.0 Peruvian Indians 0
Polymorphism, Not Mutation• Factor V:Leiden and prothrombin G20210A are common among healthy whites but are extremely rare among Asians and Africans.• Founder effects have been demonstrated for both mutations, suggesting that they occurred after the separation of non- Africans from Africans and after the divergence of whites and Asians. – Zivelin et al. Blood 89:397, 1997. – Zivelin et al. Blood 92:92:1119, 1998.• Genetics suggest a balanced polymorphism, not new mutations (i.e. sickle cell vs. hemophilia).• Factor V:Leiden: Reduced blood loss observed in peripartum period, improved embryonic implantation rates, protection from sepsis.
Fibrinolytic System Constituents
Homocysteine Metabolism• Elevated Homocysteine levels associated with increased incidence of both arterial and venous thrombosis.
Vitamin Supplementation Reduces Blood Homocysteine Levels den Heijer et al. Arterioscler Thromb Vasc Biol. 18:356, 1998.• Homocysteine (tHcy) levels decreased with folic acid or combinationvitamin therapy.• Multivitamin Tablets – 5 mg folic acid, – 0.4 mg hydroxycobalamin – 50 mg pyridoxine.• Dietary supplementation with ~0.4 mg folate daily, since 1996, mainly to prevent neural tube defects.
Clinical and Diagnostic Laboratory Criteria for Antiphospholipid Syndrome (aPL)• Clinical criteria (one or more) – Vascular thrombosis • Arterial, venous, or small vessel thrombosis. – Pregnancy morbidity • Unexplained fetal death (>10 week gestation) • Premature birth of morphologically normal neonates at or before the 34th week of gestation, because of severe preeclampsia or eclampsia, or severe placental insufficiency. • Three of more unexplained consecutive spontaneous abortions before the 10th week of gestation.• Laboratory criteria – Anticardiolipin IgG or IgM at moderate to high levels (>20 U) on 2 or more occasions separated by at least 6 weeks – Lupus anticoagulant, Twice or more separated by at least 6 weeks.
Pathophysiology of Thrombosis and Antiphospholipid Syndrome• “Several hypotheses have been proposed to explain the molecular basis of the prothrombotic state associated with these antibodies.”• Antibodies to Beta 2 Glycoprotein 1 (apolipoprotein H) are functional component?• However, the clinical significance of any one (or more) of these pathways remains unclear. – Ortel. ASH Education Program, 2005
Molecular/Biochemical Risk Factors Of Thromboembolic Disease• Common – G1691A mutation in the factor V gene (factor V Leiden) – G20210A mutation in the prothrombin (factor II) gene – Homocysteinemia• Rare – Antithrombin III deficiency – Protein C deficiency – Protein S deficiency• Very rare – Dysfibrinogenemia – Homozygous homocystinuria – Alterations in fibrinolysis.• Probably inherited – Increased levels of factors VIII, IX, XI, or fibrinogen.
Synergy of “Risk” Factors For Thrombosis • Most patients with a hereditary or other underlying risk for thrombosis do not experience a thrombosis. • Thrombosis usually develops when there are multiple risk factors at the same time. • Therefore need to consider a series of inherited and acquired risk factors. Risk Ratio of Thrombosis Estrogen Containing Contraceptives ~3-4-fold risk Factor V:Leiden ~3-4-fold riskEstrogen Containing Contraceptives Plus ~40-Fold risk Factor V:Leiden
Hypercoagulable Work-up• Why work-up? – Mostly for decision on duration (life-long) anticoagulation – Avoidance of oral contraceptives – Family knowledge• BIG Debate in Hematology: To test or not to test? – Some recommend life-long anticoagulation after initial episode of idiopathic thrombosis, regardless of molecular/biochemical risks. – Therefore, is it necessary to test? – More recent studies suggest presence of thrombophilia may warrant longer duration of therapy.
Risk of Recurrence Dependent on Risk at Time of Intial Venous Thromboembolism. Baglin et al. The Lancet. 362: 523-526, 2003. Unprovoked Non-surgical triggers Post-operative• Post-operative thrombosis have very low recurrence rate. (Removal of risk)• Non-surgical triggers (Reduced risk)• Unprovoked: No reduction in risk factors, presumably hereditary.
Risk of Recurrence Dependent on Underlying Thrombophilia. Baglin et al. The Lancet. 362: 523-526, 2003.• Presence of thrombophilia does predict risk of recurrence of thrombosis.• Supports hypercoagulable testing for patients with an “unprovoked” initial thrombosis.
Consider Thrombophilia Testing in VTE Patients With the Following: (Cushman, ASH Education Book, 2005)• Idiopathic first event• Secondary, non-cancer-related first event and age < 50, including thrombosis on contraceptives or postmenopausal hormones• Recurrent idiopathic or secondary, non-cancer, events• Thrombosis at an unusual site
Hypercoagulable Work-Up (By Gerald A. Soff M.D.)• Thrombophilia Genetic polymorphism – Factor V:Leiden, Prothrombin G20210A Mutation – MTHFR (Not worth doing)• Protein C• Protein S• Antithrombin III• Homocysteine• Lupus Anticoagulant/Anticardiolipin Antibody• Except for DNA analysis, do not work-up during acute event, pregnancy, oral contraceptives, acute medical/surgical illness.
Acute Management of Venous Thromboembolic Disease: Heparin or Low Molecular Weight Heparin.• Cofactor for Antithrombin III, neutralizes the activated enzymes. (LMWH is specific of FXa).• Heparin dosed to prolong aPTT by approximately two-fold• Low Molecular Weight Heparin dosed based on body weight.• Need to treat for at least 5 days and until warfarin is stably therapeutic. (In non-cancer patients.)
Vitamin K Pathway/Warfarin
Management of Venous Thromboembolic Disease: Chronic Oral Vitamin K Antagonists• Warfarin (coumadin) – An oral vitamin K antagonist. – Blocking vitamin K metabolism results in reduced production of functional zymogens. – Does not adequately treat acute thrombosis, but reduced risk of recurrence. – Dose by INR (Internationalized Normal Ratio), a derivative of the prothrombin time. – Target INR: 2.0-3.0. – Usually treat 6 to 12 months for first episode.
How Long To Treat DVT?• Short-term treatment to help resolve initial VTE.• Long-term treatment to reduce risk of recurrent VTE.• Recurrent DVT or PE during anticoagulant treatment: – Recurrent DVT/PE: 8.8%, (95% CI: 5.0-14.1%) – Case-fatality rate of only 0.4% (95% CI : 0.2-0.6%).• Recurrences more likely during the initial 3 weeks of treatment. – Cancer (odds ratio 2.7), – Chronic cardiovascular disease (OR 2.3), – Chronic respiratory disease (OR 1.9) – Other clinically significant medical disease (OR 1.8). – Bounameaux & Perrier. ASH Education Book, 2008.
How Long To Treat DVT?• The PROLONG study: Persistently elevated D-Dimer after 3 months of Vit. K antagonist helps identify high risk patients. – Palareti et al., NEJM 2006; 355:1780• The DACUS study: Utility of Repeat Ultrasound – First, idiopathic or provoked, VTE – Excluded: active cancer, APLS, ATIII, PC, PS, homozygote FVL/PGM, or compoud heterozygote FVL/PGM – Residual vein thrombosis (RVT)= >40% of lumen obstructed by clot. – Patients without residual thrombus at 3 months, may be safely discontinued from anticoagulation. – Siragusa et al., Blood 2008; 112:511
Utility of Repeat Ultrasound (DACUS) Events per 100 person-yearsInitial Event Residual Residual No Residual Thrombosis, Thrombosis, Thrombosis Continued Discontinued Anticoagulation AnticoagulationProvoked VTE 10.4 9.9 0Idiopathic VTE 10.0 16.9 1.9 Siragusa et al., Blood 2008; 112:511
How Long To Treat DVT? Indication 8th ACCP GuidelineFirst episode of VTE secondary 3 months to a transient risk factor First episode of idiopathic At least 3 months. (unprovoked) VTE At 3 months, if favorable risk-benefit ratio, consider long-term treatment.Other (recurrent, active cancer, Long term (Grade 1A). etc.)
Bleeding With Anticoagulants• Heparin: – Major bleeding: 0.8% per day – Fatality rate: 0.05% per day• Oral anticoagulants: – Major bleeding: 0.4% per month. – Bounameaux & Perrier. ASH Education Book, 2008
Compression Hose Reduces Development of Post-Thrombotic Syndrome Prandoni et al. Ann. Intern. Med. 141:249-245, 2004. • Anticoagulation was continued for those with underlying/persistent risks. • Hose used for two years, and reevaluation done at 5 years. • Control: 40% PTS • Hose: 21% PTS • (OR 52%)
Thrombolysis In Pulmonary Embolism• For massive Pulmonary Embolism: – Shock – Right heart strain – Thrombolytics indicated for reduction in short-term mortality.• For submassive PE: – Improved rate of resolution with thrombolytics, but benefit does not persist after one month.
Event-Free Survival In Acute Submassive Pulmonary Embolism: tPA Plus Heparin Vs. Heparin: More Rapid Resolution Within 30 DaysKonstantinides S et al. N Engl J Med 2002;347:1143-1150
CLOT Study Lee et al. NEJM 349:146-53, 2003• Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT)• Compared LMWH, (Dalteparin) with warfarin (vitamin K antagonist).• All got LMWH (Dalteparin 200 IU/kg, SQ, daily for 5-7 days, then randomized to: – 6 months of Warfarin (INR target 2.5) or – 6 months of LMWH: • 200 IU/kg, SQ, daily for 1 month, then 150 IU/kg for 5 months.
Dalteparin Resulted in Approximately 50% Reduction in Thrombosis Recurrences Lee, A. Y.Y. et al. N Engl J Med 2003;349:146-153
Low Molecular Weight Heparin in Obese or Mildly Renal Impairment• The literature is not clear on dosing in obese (i.e. over >120 Kg), or those with mild renal impairment.• One should monitor and adjust therapy, in these patients with anti-Xa assays.• Anti-Xa:Treatment Dose: 0.7-1.1 units/mL• Anti-Xa: Prophylactic Dose: 0.2-0.3 units/mL.
Inferior Vena Cava Filters• Mechanical device inserted into the IVC to “catch” emboli, and prevent life-threatening pulmonary emboli.• Short-term protection from Pulmonary Embolism,• Long-term increased risk of thrombosis.• New generation of removable filters.
“An once of prevention is worth a pound of cure.” Benjamin Franklin• Many medical and surgical patients are at very high risk for developing a thrombosis.• Pulmonary embolism remains a major cause of deaths in hospitalized patients.• Prophylaxis with anticoagulants and pneumatic compression devices is highly effective in reducing the risk of thrombosis.
Fibrinolytic Pathway Plasminogen; – PAI-1, PAI-2; Plasminogen Activator Inhibitors – Activated to Plasmin (a serine proteinase) – α2-Antiplasmin. – Plasmin proteolyzes fibrin and fibrinogen Plasminogen Activators; – t-PA (Tissue-Plasminogen Activator) – u-PA (Urokinase-Plasminogen Activator) – Released by endothelial cells. Serpins
Ethnic Distribution of Factor V Leiden In U.S.A. (Ridker PM et al, JAMA 277:1305, 1997) Racial Group Incidence Of Factor V:Leiden Whites 5.27% Hispanic Americans 2.21% African Americans 1.23% Asian Americans 0.45% Native Americans 1.25%
57 Year Old Chinese-American Woman• Diagnosed with early stage breast cancer. – Second primary (Past left mastectomy)• Planned for bilateral mastectomy with flap reconstruction.• Hematology consult for clearance for the flap reconstruction.• No past history of thrombosis.• No other significant co-morbidities.• Physical exam: negative, except for prior left sided mastectomy without reconstruction.• What else do you need to know?
Family History• Twin brother in China, at age 27, developed unprovoked leg DVT. While being transferred to hospital, by 4 hour taxi ride, developed acute dyspnea, complained of “choking” and died!
Patient NormalPT 9.6” 9.4-12.8”PTT 27.6” 24-35.7”Lupus Anticoagulant, DRVVT 0.9 <1.2Lupus Anticoagulant, SCT 1.06 <1.2Anticardiolipin Antibodies, IgG, IgM, IgA NegativeAT III 99% 70-111%Protein C Antigen 48% 60-150%Protein C Functional 56% 83-144%Protein C Chromogenic 52% 74-164%Protein S Functional 119% 70-145%Factor VII 166% 63-125%Homocysteine 9.0 5.0-12.0 mcM/L mcM/L