A. Altay Şahin, MD Hacettepe University Medical School Department of Chest Diseases

Prevention of VTE in Pregnancy and with Thrombophilia

VTE is a chronic disease which causes reccurence and complications

To minimze the risk of reccurrence?

RECCURRENCE Hypercoagulability,

Other modifiable/acquired risk factors

VTE

Reccurrence rates related to

Risk factors,

Hypercoagulability,

Hereditary factors,

Acquired factors, Immobility

VTE - INCIDENCE

-PE 1.43 / 1000 patient/yr (95%CI=1.33-1.54),

-DVT 0.93 / 1000 patient/yr, -PE and DVT Mortality 9.7% ve 4.6% (Naes IA. et al. J Thromb Haemost 2007;in

press)

-VTE incidence 1.92 / 1000 patient/yr,

-28 days’ mortality rate after the first VTE insult %11, -Thrombosis in cancer 25%, reccurrence during the 2 years’ follow-up

7.7%/yr (Cushman M et al. Am J Med 2004;117:19)

-Annual incidence 117/100 000, for DVT 48, for PE 69 - (Silverstein MD, et al. Arh Intern Med 1998;158:5859

Hypercoagulability

Quantitative and qualitative defects in coagulation inhibitors -AT, -PC, -PS, -Heparin cofactor II deficiency, -TFPI

deficiency, -Thrombomodulin deficiency,Increased level or function of coagulation factors -APC resistance (FVL), -Protein G20210A gen mutation -Hyperfibrinogenemia, -Inreased Factor VII, VIII, IX, XI,

XII, Defect in the fibrinolytic System -Plasminogen, -Tissue plasminogen activator, -Thrombin activatable fibrinolysis inhibitor, -FXII,Platelet Function Defect -Platelet glycoprotein GP1b-Ix, -GPIa-Iıa, GPIIb-IIIa

Hypercoagulability

Cause Risk General Popl (%) Thrombosis (%)

AT 20 0.2 1 – 3

PC 10 0.2 - 0.4 3 – 5

PS 10 0.03 – 0.1 1 – 5

FVL 5 5 10 – 50

Prot 3 2 – 5 6 – 18

FVIII 5 11 25

Thrombophilia

Figures related to thrombosis from Turkey,

-FVL (15/61 patients) 24.6%, Homozygous 1.6%, Heterozygous 22.9%, PT G20210A Mutation (4/61) 6.5%, healthy population 2.5%,

-FVL (45/146 patients), 7/45 4.8% Heterozygous , 38/45 26% Homozygous ,

PT G20210A Mutation 10/146 6.8%,

(Kalkankı S, et al. Angiology 2006;57:193, Gürgey A, et al. Am J Hematol 2001;67:107,

Ayyıldız O, et al. Heart Vessel 2004;19:164)

Experience of the Pediatrics Dept of Hacettepe University Medical School

Thrombosis rate during childhood among hospitalized patients 6/1000.

The most frequent age at thrombosis 1-3 years. Underlying chronic diseases found in 154 68%) of the patients. The most frequently associated factor with thrombosis was

infection. F V G1691A mutation was found in 15%, PT G20210A in 4%. Increased FVIII was found in 52%. According to the risk classification 173 (76%) patients were in the

high risk group. Reccurrence rate and poor response to treatment was more

frequent in the high risk group patients.

Experience of the Pediatrics Dept of Hacettepe University Medical School

Retrospective analysis of the clinical and laboratory charactersitics of the 474 patients followed during HÜTF 1998-2006.

% F V Leiden mutation Homozygous 1 Heterozygous 14 PT 474 patients Heterozygous 4

ATIII↓ 15

PC ↓ 45

PS ↓ 30

Lipoprotein a 15

Homosistein 10

FVIII   52 D-dimer 50  Antiphospholipid antibody+ 3    Anticardiolipin antibody + 2  

VTE and Reccurrence

-Reccurence rate decreases over time and stabilizes in the 9th month-Unrelated to the duration of VKA (Cochran Review 2005)

-Monthly incidence for the short course of treatment,1 and 3. months 3.3% (CI=2.34%-4.59%) 3 and 6. months 1.23% (CI=0.79%-1.83%),- Monthly incidence for the long course of treatment,6-9 months 0.99%, (CI=0.62%-1.49%)9-12 months 0.71% (CI=0.40%-1.18%),-Monthly reccurrence rate after the cessation of VKA,9. and 12. months 0.50%-0.71%,12. and 18. months 0.42%-0.59%(Cochran Review 2006)

VTE and Reccurrence

-Reccurrence rates, AT, PC, PS, FVL carriers 4.5%, controls 0.6%

(spontaneous rates are also high)(Vossen CY et al. J Thromb Haemost 2005;3:459)

-3 months anticoagulation, during 8 years follow-up reccurrence within 2 years 17.5%,

5 years 25%, 8 years 30%, - Reccurrence rate decreases with the duration of

anticoagulation, major bleedding 3%(Prandoni P, et al. NEJM 1998;338:409, Kearon C, et al. NEJM 1999;340:901, Agnelli G, et al.NEJM

2001;345:165)

VTE and Reccurrence

-3 months’ follow-up VTE reccurrence rate: 3% (CI=1.8-4.6), of the reccurrences 79% fatal, (11/14), 3 months’ mortality rate 8.2%, (Nijkenter M, et al. Chest 2007;146:278)

-10 years’ follow-up after anticoagulation

Cummulative reccurrence:

after 1 year 11%,

after 3 years 19.6%,

after 5 years 29.1%,

after 10 years 39.9% (Prandoni P, et al. Haematologica 2007;92:199)

VTE and Reccurrence

Reccurrence after 6 months’ treatment among the anticardiolipin carriers 29%, mortality 15%, others 14% and 6%, respectively

Among those who receive VKA for 6 months and continuously after the second VTE reccurrence and bleeding rates %20.7- %8.6, and %2.6-%2.7, respectively

(Büller HR, et al. Chest 2004;126:401S)

Prevalent risk factors for thrombophiliaAPC resistance (FVL), Protein G20210A mutation andAT, PC ve PS

inadequacies. Annual reccurrence rates among these patients after short and long term anticoagulation 5% and 1.1%, spontaneous reccurrence 75% and 57%, major bleeding 0.8%,

(Vossen CY, et al. Arterioscler Thromb Vasc Biol 2005;25:1992)

VTE and Reccurrence

Thrombophilia in the idiopathic thrombosis 25%, thrombophilia is associated with higher reccurrence rate. Though, some authors do not share this view. Reccurrence rate decreases after the 1st year. These authors suggest that provacating factors, residual thrombosis in DVT and highly positive D-dimer as the more important risk factors.

Incidence is higher in men than in women. (Prandoni P et al. BMJ 2004;329:484, van den Belt AG, et al. Arch Intern Med 1997;157:2227,

van den Belt AG, et al. Thromb Haemost 2000;84:758, Simioni P, et al. NEJM 1997;336:399, Christiansen SC, et al. JAMA , 2005;293:2352, Cosmi B, et al. Seminars in Vasc Med 2005;5:365, Kyrle PA, et al. NEJM 2004;350:2558)

Hypercoagulability and Prophylaxis

AT, PC, PS, and combined (heterozygous FVL+G20210A Mutation)Deficieny: risk high, relatively low in the others, (Vossen CY,et al. J Thromb Haemostn2004;2:1526, Samama MM, et al. Haematologica 2003;88:1410,

Makris M, et al. Blood 2000;95:1935)

Acquired hematological abnomalities Lupus Anticoagulant andanticardiolipin antibodies: reccurrence high and mortality rate high

after the cessation of anticoagulation, (Schulman S, et al. NEJM 1997;336:373)

Benefits of long term prophylaxis after the firs insult is not clear for hereditary thrombophilia and asymptomatic relatives of the symptomatic patients.

Prophylaxis must be given in case of a risk factor after the first insult. (Nicolaides AN. Int angiol 2006;25:101)

Hypercoagulability and Prophylaxis

After the second VTE attack 6 months, RR as compared to long term treatment is 8.0, but higher major bleeding rate in the long term treatment (Ginsberg JS, et al. 2001;161:2105, Prandoni P, et al. Ann Intern Med 2004;141:249)

Long term, low dose VKA in idiopathic reccurrence rate 1 / 100 patient/yr as compared to 4.6 / 100 patient/yr, Complication is more frequent in the long term treatment group (Decousus H, et al. NEJM 1998;338:409, Schulman S, et al. NEJM 1997;336:393)

For the most common genetic thrombohilia FVL ve G20210A gen mutation reccurrence rate has not been found to increase, (Ho Wk, et al. Arch Intern Med 2006;166:729)

Hypercoagulability and Prophylaxis

-First VTE attack with reversible risk in the 3 months,-First idiopathic VTE 6-12 months, indefinite (life long)?,-with cancer first VTE LMWH 3-6 months, then VKA, till

the cure is established,-APLS or thrombophilia, reversible risk, first VTE 6-12

months, idiopathic 12 months, indefinite (life long)?, - idiopathic PE reccurrence 12 months, indefinite (life long)?,

evaluation of the patient and the modifiable risk factors during the prophylaxis and evaluation of the patient is required during the prophylaxis.

Pregnancy and VTE

-thrombophilia rate ~15% in general,- thrombophilia could be detected in ~ 30%-50% of VTE ,- -VTE rate similar in antenatal and postpartum periods,-First VTE insult usually spontaneous and related to thrombophilia,-Risk of VTE in thrombophilia changes according to patients’ series, other risk

factors are also important,-There is no randomized controlled study for prophylaxis in congenital and

acquired thrombophilia ,-Maternal trombophily is a risk factor for early fetal loss?

(McColl MD, et al. Thromb Haemost 1997;78:1183, Robertson L, et al. Curr Opin Obstet Gynecol 2005;17:113, Doyle NM. Obstet Gynecol Clin N Am 2004;31:319, Greer IA. Lancet 1999;353:1258, Roque H, et al. Thromb Haemost 2004;91:290)

Pregnancy and VTE

Levels of fibrinogen, factors II, VII, VIII, IX, X, XII and plasminogen increase, venous stasis, APC resistance, Platelet activation develops.

Free PS, factors XI, XII, fibrinolytic activity decreases, Obesity, hereditary or acquired thrombophilia, C/S, surgery, age>35,

previous VTE, family history of VTE before age 50, increase the risk of VTE in pregnancy.

Women with the histroy of hiperemezis and preeclampsia, abortion should be investigated for the risk factors,

Fetal loss in FVL, G20210A, PC, PS: RR=1.4Risk of VTE in AT deficiency 30%, Risk of DVT reccurrence 2%-3%, with thrombophilia 6%, (Pabinger I, et al. Blood 2002;100:1060, Brill-Edwards P, et al. NEJM 2000;343:1439, Vossen CY et al. J

Thromb Haemost 2004;2:592)

Pregnancy and VTE

-VTE 1/1500 births, Post-partum: 3-8 times increased, PE mortality ~ 15%,

-Pregnancy and postpartum period RR=4.29 (CI=3.49-5.22)-Pregnant women as compared to other women have 5-6 times

increased risk,-Antepartum and Postpartum periods have similar rates,-Risk increases by 3.5 times in women with histroy of previous VTE,-Rate of VTE in thrombohily including APLS, FVL, FII G20210A,PC, PS, not on anticoagulation 32%-34%

(Heit JA, et al. Ann Intern Med 2005;143:697, Doyle NM, et al. Obstet Gynecol Clin NAm 2004;31:319, Conrad J, et al. Thromb Haemost 2003;29:131, Zotz et, al. Sem Thromb Hemost

2003;29:143 )

Pregnancy and VTE

-Previous history of VTE,

-Obesity,

-Age>35,

-Surgery, C/S delivery,

-History of VTE in a young-middle aged family member,

-Late fetal loss,

-Preeclampsia,

-Intrauterine growth retardation and still birth,

-Previous history of 2 or more abortions

RİSK FOR VTE

Pregnancy and Prophylaxis

Clinical characteristics Suggested treatment

Previous VTE with a modifiable risk factor

No additional risk factor

Antenatal follow-up, Postpartum 4- 6 weeks Prophylaxis

Previous VTE with a modifiable risk factor with thrombophilia or idiopathic or an additional risk factor

Antenatal LMWH Prophylaxis , Postpartum 4- 6 weeks Prophylaxis

Previous VTE without long term anticoagulation

Antenatal Prophylaxis? , Postpartum 4- 6 weeks Prophylaxis

Previous VTE and receiving anticoagulation (+ thrombohily)

Switch LMWH to VKA. Postpartum 4- 6 weeks Prophylaxis

Pregnancy and Prophylaxis

-LMWH is the drug of choice in pregnancy,

-Common concensus suggests that Warfarin is not to be used during pregnancy, in the first trimester, particularly in the first 6-12 weeks of pregnancy,

-Heparin is stopped 24 hours before delivery,

initiated 12 hours after delivery with Warfarin

Hiperkoagülabilite

AT (Serin proteaz inh.(serpin) single-chain glycoprotein’dir) -Aktive F Xıa, Xa, Xıa, XIIa ve thrombin’i inaktive eder, Tip I de antijen kantitatif

,Tip II de antijen N, ama a-reaktif trombin bağlanma kısmında, b-Heparin bağlanma kısmında, c-her iki kısımda anormallik,

PC (Vit. K bağımlı Kc.de sentezlenir yarı ömrü çok kısadır) -Thrombin-thrombomodulin tarafından aktive edilince Fva ve FVIIIa yı proteolitik

olarak parçalar. 150 den fazla mutasyonu, Tip I de kantitatif, Tip II de kalitatif eksiklik vardır. Akut tromboz Kc. Hastl., Renal hastl., DIC, warfarin kul. azalır,

PS (Taşıyıcısı C4PB’ye bağlı ve serbest halde bulunur) -Fva ve FVIIIa’nın yıkımında PC’nin cofaktörüdür, FVa ve FXa’ yı direkt

inaktive edebilir. Gebelik akut tromboz ve inflamasyonlarda C4PB artar. Tip I fonksiyon ve seviye düşük, Tip II seviye N, fonksiyon düşük, Tip III serbest PS az çoğu bağlı,

Hiperkoagülabilite

Heparin co-factor II (Kuvvetli bir protrombotik faktör değildir. Heparin varlığında trombini inhibe eder.),

Tissue Factor Pathway Inhibitor(TFPI) (FVII/TFP’i inhibe eder etkisi çok iyi bilinmez)

Thrombomodulin (Endoteliyal hücre reseptörüdür, trombin ve PS ile interaksiyona girerek antikoagülan etki gösterir, KAH ile ilişkisi olabilir, venöz trombozlarla ?)

APC Rezistansı (FVL= amino asit değiş. Arg506 to Gln) (Homozigot ve heterozigot olabilir, Heterozigot’un başka protrombotik faktörlerle birlikte olduğu durumlarda risk artar, Bu hastaların plazmalarına PC eklendiğinde APTT leri uzamaz,

Prothrombin Gen Mutasyonu (G20210A)

Hiperkoagülabilite

Dysfibrinogenemia ve Hyperfibrinogenemia (Venöz trombozda etkisi ? KAH da belki)

Seviyeleri Yükselmiş Pıhtılaşma Faktörleri (F VII, VIII, IX, XI, XII, Özellikle FVIII bağımsız risk taşır-Kyrle PA et al. NEJM 2000;343:457, Kraaijenhagen RA, et al. Thromb Haemost 2000;83:5, Aynı zamanda akut faz rektanıdır, Yüksek FIX ve FXI seviyeleri VTE ile ilişkilidir, FXII ?)

Hyperhomocysteinemia (Methionine metebolizmasıyla üretilen aminoasit, ilk yol B6

vit. ile cystathionine β-synthase (CBS), ikinci yol methionine synthase, B12 vit. ile Methyltetrahydrafolate reductase la yapılır. Folat, B12 , B6 ‘nın diyetteki yetersizliği, CBS veya MTHFR gen mutasyonu ile seviyesi yükselir. Yüksek olmayan venöz ve arteriyel tromboz riskine yol açar,

VTE’li her hasta kişisel ve aile öyküsü yönünden dikkatle taranmalı

Doyle NM, et al. Obstet Gynecol Clin N Am 2004;31:319

GEBELİK VE PROFİLAKSİ

Doyle NM, et al. Obstet Gynecol Clin N Am 2004;31:319

Doyle NM, et al. Obstet Gynecol Clin N Am 2004;31:319