An Inherited Risk Factor.ppt

1、Factor V Leiden:An Inherited Risk Factor for Venous Thromboembolism,Mary Ann Knovich, M.D. Internal Medicine Grand Rounds November 18, 1998,Case Presentation,RD - 32 WM with no medical problems 2 week h/o chest pressure and shortness of breath, some pleuritic chest pain worse with exertion. EKG - TW

2、I in anterior leads. Pt started on heparin drip, and transferred to CCU at NCBH.,Past Medical History,PMH/PSH: None MEDS: None Allergies: NKDA Cardiac Risk Factors: Tob, FH,History,SH: Tobacco pack per day x 14 yrs, No EtOH or drug use. Married 1 month ago. Works in management at a tractor supply st

3、ore. FH: Father - MI age 50. DVT age 20 with trauma. Sister with multiple miscarriages,Physical Exam,Gen: WD, WN WM, mildly anxious in NAD VS: HR120, BP 110/70, R 22, afeb, O2 sat 98% on 2l nc Neck: no JVD or carotid bruits Lungs: CTA Heart: Tachy S1, S2, no S3, S4, or m Extremities: No edema, cyano

4、sis, or calf tenderness,Studies,Labs: Creatinine kinase, electrolytes, renal function, CBC, PT nl, PTT 60 sec. EKG- TWI leads V1-V4. CXR: NACPD,Hospital Course,emergent cardiac catheterization - showed normal cors, normal LV systolic function. became hemodynamically unstable pulmonary angiography -

5、large b/l pulmonary emboli severe pulmonary HTN - PA systolic pressure 80mm Hg.,Hospital Course (cont),Pigtail catheter placed in PA-continuous urokinase infusion. Heparin was continued. Remained hemodynamically stable 2 follow-up PA grams showed continued resolution of thrombi. Started on Coumadin

6、for a goal INR 3 Discharged to home in stable condition after a 10-day hospitalization,Further Studies,Lower venous duplex negative for DVT b/l. CT chest, abdomen, and pelvis -no evidence of malignancy. Thrombophilia screen - normal activity of HepCofactor, Protein C, Protein S, plasminogen, ATIII.

7、Anti-Cardiolipin antibodies were normal. No detectable lupus inhibitor. Factor V Leiden - heterozygous by PCR,Questions,What is Factor V Leiden? How prevalent is this mutation? What is the associated risk for thromboembolic disease? What are the recommendations for anticoagulation in patients with F

8、actor V Leiden?,Importance of Factor V Leiden in Internal Medicine,Venous thromboembolism - 250,000 hospital admissions annually in US PE - cause of death in 50,000 to 100,000 persons per year 21% of older patients hospitalized for PE die during that admission Factor V Leiden is the most common inhe

9、rited risk factor thus far described for VTE,The Coagulation Cascade,The Protein C Anticoagulant system,Protein C is a key regulatory protein of the hemostatic system Vitamin K-dependent zymogen synthesized in liver circulates in plasma Inactivates activated forms of Factor V and Factor VIII,Model o

10、f anticoagulant Protein C system,Native Factor V,Large single-chain glycoprotein activated to Factor Va by thrombin Activated Protein C cleaves factor Va at 3 amino acid positions,Activation and Inactivation of Normal Factor V and Factor V Leiden,The Coagulation Cascade,Factor V Leiden,mutation in F

11、actor V gene Substitution of adenine for guanine at nucleotide position 1691 Results in replacement of arginine by glutamine at amino acid position 506,Mutated Factor V,Activated by thrombin in a normal way Impaired inactivation by Activated Protein C not cleaved at amino acid position 506 Maintains

12、 full cofactor activity until it is inactivated by the secondary cleavages at amino acid positions 306 and 679 Results in life-long hypercoagulability,Activation and Inactivation of Normal Factor V and Factor V Leiden,The Coagulation Cascade,Prevalence of Factor V Leiden Mutation,Varies widely from

13、one population to another Nearly 14% prevalence of the allele among healthy controls in Sweden and Greece Low prevalence (0.5%) in Japan, Australia, Africa, and Asia,Prevalence of Factor V Leiden Mutation,Large cross-sectional study in US ( Ridker et al, JAMA, 1997) Prevalence of Factor V Leiden mut

14、ation was determined in a cohort of 4047 men and women Caucasians - 5.27% Hispanic Americans - 2.21% African Americans - 1.23% Asian Americans - 0.45% Native Americans - 1.25% Overall carrier frequency of mutation was 3.71% Allele frequency was 1.89%,How did the mutation arise?,Confined geographical

15、 spread and genetic analysis support hypothesis that the mutation arose from a single individual,Evolutionary advantages of Factor V Leiden,advantages in fertility hypercoagulability reduces blood loss with menstruation postpartum hemorrhage trauma,What is the Risk for Arterial and Venous Thrombosis

16、 in Patients with the Factor V Leiden Mutation?,The Leiden Thrombophilia Study (Koster et al, 1993),Large, population-based, patient-control study 301 patients with 1st episode of objectively confirmed DVT selected from the files of thrombosis centers in Leiden, Rotterdam, and Amsterdam in the Nethe

17、rlands age 70 years DVT not related to malignancy 301 age and sex matched healthy controls patients asked to provide controls,The Leiden Thrombophilia Study,21% of patients vs. 5% of healthy controls had resistance to APC in clotting assays Estimated 7-fold increase (matched odds ratio of 6.6) in ri

18、sk for DVT in persons with APC resistance Provided evidence for the association of APC resistance with an increased risk for thrombosis,The Leiden Thrombophilia Study,Rosendaal et al, Blood, 1995 Risk for VTE among patients homozygous for Factor V Leiden mutation was increased 80-fold Homozygous pat

19、ients presented with initial VTE at a younger age (median age 31 yrs) vs. heterozygotes (median age 46 yrs),Relationship between Genotype to Severity of Thrombotic Events in 50 Families,Zoller et al, J. Clin Invest, 1994 Investigated 308 family members from 50 families with APC resistance 146 normal

20、s 144 heterozygotes 18 homozygotes,Thrombotic risk related to genotype in 50 families with inherited APC resistance,Physicians Health Study,large-scale epidemiologic assessment of the Factor V mutation in a healthy population of predominantly white men followed prospectively for the occurrence of CV

21、 disease, in particular arterial and venous thrombosis confirmed the association between Factor V Leiden mutation and the risk for VTE,Physicians Health Study (Ridker et al, NEJM, 1995),Random, Double-blinded, Placebo-controlled study 22,071 predominantly white male physicians randomly assigned to r

22、eceive ASA, beta-carotene, both, or neither 14,916 (68%) returned base-line blood samples Occurrence of DVT, PE, MI, or stroke during follow-up period of 8.6 years,Strengths of the Physicians Health Study,nested case control design allowed for detection of the Factor V Leiden mutation within the sco

23、pe of a much broader RCT performed in a large cohort of apparently healthy men (n=14,916),Strengths of the Physicians Health Study,not limited to thrombophilic patients or families Previous studies done in families with hypercoagulable defects pts with recurrent TE events pts referred for tx of DVTs

24、 subject to bias of case reports, case series, and retrospective studies of selected referral populations,Strengths of the Physicians Health Study,use of PCR, restriction-enzyme digest to detect Factor V Leiden mutation physicians as accurate reporters of their TE events, PMH, risk factors, family h

25、istory not limited to younger patients age of physicians ranged from 40-84, with a mean age of 60.3 years,Physicians Health Study (cont.),Of the 14,916 who returned base-line blood samples, 704 suffered a DVT, PE, MI, or stroke Each patient was matched to a control based on age smoking habits time s

26、ince randomization,Physicians Health Study (cont.),704 thrombotic events 704 controls free of cardiovascular disease Blood samples thawed DNA analyzed by PCR for Factor V Leiden Mutation,Prevalence of Mutation in 704 Controls Free of Cardiovascular Disease,94% homozygous for gene coding for Native F

27、actor V 6% were heterozygous for genes coding for Native and Mutated Factor V None were homozygous for Factor V Leiden mutation,Prevalence of Factor V Mutation in 1408 Apparently Healthy Men in the Physicians Health Study,Physicians Health Study (cont.),Relative risk of MI, Stroke, and DVT or PE in

28、subjects with the mutation was determined Analysis then adjusted for smoking status h/o HTN hypercholesterolemia body-mass index diabetes family history of CAD,Relative Risk of MI, Stroke, and Venous Thrombosis Associated with the Presence of the Factor V Mutation,Physicians Health Study (cont.),Sub

29、jects grouped according to age In men age 60 with a 1o DVT, prevalence of mutation was 25.8%, with a RR of 5.3,Men 60 years of age,Relative risk adjusted for:smoking, h/o HTN, hypercholesterolemia, Body Mass Index, DM, family h/o CAD Adjusted relative risk of any DVT was 4.0 Adjusted relative risk f

30、or primary DVT was 7.0 (p0.001),Adjusted Relative Risks for Future Venous Thromboembolism among Apparently Healthy Men with Factor V Leiden Mutation,Long-Term Management Issues,After a defined period of anticoagulation treatment for an acute thrombotic event, how should patients with this mutation b

31、e managed? Most information comes from anecdotal reports, cross-sectional studies, and uncontrolled clinical observations.,Long-Term Management Issues,Little reliable data regarding magnitude of thrombotic risk optimal intensity of anticoagulation duration of anticoagulant treatment No data from RCT

32、s to show that long-term prophylaxis will prevent recurrent thromboses in patients with the factor V Leiden mutation,Long-Term Management Issues,Must assess relative benefit of long-term anticoagulation to prevent thromboembolic complications vs. Potential side-effects, bleeding risk, cost, and inco

33、nvenience for patients,Long-Term Management Issues,Clinical trials designed to evaluate the benefit-to-risk ratio of screening for Factor V Leiden and subsequent long-term anticoagulation are needed Such studies will need to consider: different rates of mutation in various patient groups thrombosis with Factor V Leiden is not limited to young patients,Management Guidelines,High-Risk Classification 2 or more spontaneous thromboses 1 spo