Updated on 30.10.2016.
Evidence based unbiased information
Inherited Thrombophilia is a group of inherited genetic defects leading to hypercoagulable state. It includes activated protein C (APC) resistance, hyperhomocysteinaemia, prothrombin gene G20210A mutation, protein C deficiency, antithrombin III deficiency, protein S deficiency, heparin cofactor II (HC II) deficiency, plasminogen or tissue plasminogen activator (TPA) deficiency, elevated plasminogen activator inhibitor-1 (PAI-1), dysfibrinogenemia, abnormal thrombomodulin etc.
It is associated with up to 60% of women who developed thrombosis during pregnancy. The risk of thromboembolism increases with multiple defects. It is associated with several pregnancy complications such as recurrent miscarriage, second trimester miscarriage, intrauterine fetal death (IUFD), fetal growth restriction (FGR), pre-eclampsia, placental abruption and neonatal complications.
This is an overview of the conditions prepared after thorough review of the literature.
Overview of Protein C, Protein S and Antithrombin III deficiencies,
Factor V Leiden, Hyperhomocysteinaemia and
Prothrombin gene G20210A mutation
* A group of inherited genetic defects leading to hypercoagulable state
* Associated with up to 60% of women who developed thrombosis during pregnancy
* Risk of thromboembolism increases with multiple defects 1, 2
* Activated Protein C resistance (Factor V Leiden)
* Prothrombin gene G20210A mutation
II. Extremely rare
* Protein C deficiency
* Antithrombin III deficiency (Type I – quantitative; Type II – qualitative)
* Protein S deficiency
* Heparin cofactor II (HC II) deficiency
* Plasminogen or tissue plasminogen activator (TPA) deficiency
* Elevated plasminogen activator inhibitor-1 (PAI-1)
* Abnormal thrombomodulin 1, 3, 13,14
14, 45, 53
Activated protein C (APC) resistance
Activated protein C + protein S (co-factor)
–> FactorVa –> Prothrombin –> Thrombin
–> Factor VIIIa –> Factor X –> Factor Xa
I. Inherited due to factor V Leiden ( 95% )
* Single point mutation in the gene coding for factor V
* Substitution of arginine by glutamine at position 506 (A506G)
* Alteration of the cleavage site for factor Va inactivation
* Factor V Leiden resistant to inactivation by APC 1
* First demonstrated by Betrina et al in 1994 16
* Autosomal recessive condition
i> Heterozygous – 5 to 10 fold increased risk of venous thromboembolism
ii> Homozygous – 30 to 140 fold increased risk of venous thromboembolism
* Thrombosis occurs at a younger age than heterozygotes 1, 17, 18, 19
* Deep vein thrombosis is the commonest clinical presentation 1
* Thromboses at unusual sites less common 1
* Prevalence 1, 3, 8, 10, 11, 18-26
i> General population – 3 to 15% (3-5% in the UK and Germany, 12% in Greece and Sweden, <1% in SE Asia and almost unknown in Africa )
ii> First episode of TED – 20%
iii> Recurrent TED, family history – 10-64%
iv> TED during pregnancy – 20-60%
v> Recurrent fetal loss – 49%
vi> Recurrent spontaneous miscarriage – 20%
vii> Preclinical miscarriage – 35%
viii> Placental abruption – 30%
ix> H/O pre-eclampsia – 22%
x> H/O severe pre-eclampsia – 8.9%
* The HR2 haplotype – Recently identified factor V genetic pleomorphism 27
* Factor V Cambridge – A new mutation in the factor V gene. Substitution of arginine by threonine at position 306 (Arg306Thr) 28
* Pregnancy, antiphospholipid antibodies, oral contraceptive pill 29-33
* An increase in factors Vc and VIIIc is the cause of protein C resistance during pregnancy 3, 33
Screening for factor V Leiden
* The APC ratio = aPTT with APC : aPTT without APC
* APC resistance –> APC ratio <2
* Not useful in patients on warfarin or heparin and acquired APCR
(Modified tests using factor V depleted plasma are useful. Two tests are available: Coatest APCR V and Accelerimat, the latter is not influenced by the factor VIII by the adjunction of factor Xa and is probably more efficient during pregnancy.) 34, 35
* Diagnosis: By oral methionine loading. Total homocysteine concentration greater than 97.7 centile of the controls at 6 h after oral methionine loading 4
* Homocysteine levels fall by about 50% in normal pregnancy 4
* Homocysteine metabolism
i>Remethylation to methionine – A vitamin B12-dependent remethylation involving 5-methyltetrahydrofolate which is formed from 5,10 methylenetetrahydrofolate by the enzyme methylenetetrahydrofolate reductase (MTHFR)
ii> Trans-sulfuration to cysteine – Cystathione is formed by the enzyme cystathione beta synthase (CBS) 47
i> Homozygous cystathionine beta synthase (CBS) deficiency (Homocysteinuria, severe hyperhomocysteinaemia)
ii> Homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (Moderate hyperhomocysteinaemia). The enzyme MTHFR is responsible for synthesis of 5-methyltetrafolate, the primary methyl donor in the conversion of homocysteine to methionine)
iii>Autosomal recessive condition
i> Deficiencies of folate, vitamin B6 and vitamin B12
ii> Renal failure
iii> Anti-folate drugs – anti-convulsants, inhaled nitrous oxide, methotrexate 1, 4, 48
* Increased risk of venous (2 to 3 fold) and arterial thrombosis
* Women are more susceptible to thrombosis than men 47, 49, 50, 51
* Increased risk of recurrent miscarriage, FGR, IUFD, placental abruption and infarction, and severe early onset pre-eclampsia 36, 45, 46, 52-54
* Mechanism of thrombosis
i> Endothelial cell injury
ii> Inhibition of thrombomodulin expression
iii> Decreased protein C activation 1
i> General population – 2 to 9%
ii> First episode of TED – 10%
iii> Recurrent early miscarriage – 21%
iv> Early-onset severe pre-eclampsia – 18%
v> Placental abruption or infarction – 31%
vi> FGR, IUFD – 24% 45, 50-53
Prothrombin gene G20210A mutation
* Guanine to Adenine nucleotide substitution at position 20210 of the 3’ untranslated region of the prothrombin gene 36
* Elevated mean plasma prothrombin levels (mechanism not known) 37
* First described by Poort et al in 1996
* Autosomal recessive condition
* 3 to 5 fold increased risk of venous thromboembolism 38
* No significant association with recurrent miscarriage 39
* Associated with severe pre-eclampsia, placental abruption, FGR and stillbirth (10% vs 3% in controls) 36
i> General population – 1.2 to 2.6% (very low in non-Caucasians)
ii> First episode of TED – 5.5 to 6.2%
iii> Recurrent TED, family history – 18%
iv> Pregnancy complications – 10% 40, 41
* No screening test available
* Detected by polymerase chain reaction 3
Protein C, protein S and antithrombin III deficiency
* Protein C, protein S and antithrombin III are natural anticoagulants
* Activated protein C, together with its co-factor protein S degrades Factors VIIIa and Va and reduces thrombin generation
* Antithrombin III inhibits thrombin and factors IXa, Xa and XIa 1
* During pregnancy plasma Protein S levels decrease but Protein C and antithrombin III levels remain unchanged 3
* Autosomal dominant conditions 3
* 10 fold increased risk of venous thromboembolism 43
* Antithrombin III deficiency has a relatively high thrombotic risk 1
* Deep vein thromboses in the lower limbs and pulmonary embolism are commonest presentation 1
*Thrombosis tends to occur at a young age, at unusual sites (e.g. axillary, mesenteric, portal and cerebral veins and in inferior vena cava) and recurrent 1, 13,42
* Lifetime prevalence of thromboembolism in patients with a positive family history is >50% 1
* Increased risk of FGR, IUFD, pre-eclampsia and placental abruption (risk of stillbirth – 3.3 fold for protein S and 5.2 for antithrombin III deficiency) 44
* Increased neonatal complications (purpura fulminans, vitreous haemorrhage and CNS thrombosis) in homozygous protein C deficiency 9
i> General population – 0.3%
ii> First episode of TED – 5%
iii> Recurrent TED, family history – 5 to 10% 15
iv> Pre-eclampsia – 25% (protein S deficiency) 45
v> FGR, placental abruption – 26% (protein S deficiency) 46
* Role of thromboprophylaxis during pregnancy to reduce the incidence of adverse pregnancy outcome – not yet established in clinical practice 3
* Thromboembolism: Risk in pregnancy increased by 2-10 fold 1, 3
* Mortality and morbidity: Associated with thromboembolism, its management, thromboprophylaxis and post-thrombotic syndrome 3
* Pregnancy complications: Increased risks of recurrent miscarriage, second trimester miscarriage, fetal death, FGR, pre-eclampsia, placental abruption and neonatal complications 4, 5, 6, 7, 8, 9, 10, 11
* Non-traumatic osteonecrosis: Increased prevalence 12
i>Thromboprophylaxis to prevent thromboembolism
ii> ?Thromboprophylaxis to decrease adverse obstetric outcome 4
* Screening – Debatable issue 3, 4
1. Tan J, de Swiet M. Thromboembolism and thrombophilia in pregnancy and the puerperium. In: Studd J ed. Progress in Obstetrics and Gynaecology Vol 13. Edinburgh: Churchill Livingstone. 1998:73-86.
2. Hiller E, Pihusch R. Thrombophilia caused by congenital disorders of blood coagulation. Fortschr Med 1998; 116(29):26-28, 30, 32.
3. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106:756-66.
4. Nelson-Piercy C. Inherited thrombophilia and adverse pregnancy outcome: has the time come for selective testing? Br J Obstet Gynaecol 1999; 106:513-15.
5. Blumenfeld Z, Brenner B. Thrombophilia-associated pregnacy wastage. Fertil Steril 1999; 72(5):765-74.
6. Souza SS, Ferriani RA, Pontes AG, Zago MA, Franco RF. Factor V leiden and factor II G20210A mutations in patients with recurrent abortion. Hum Reprod 1999; 14(10):2448-50.
7. Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82(1):6-9.
8. Tal J, Schliamser LM, Leibovitz Z, Ohel G, Attias D. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure. Hum Reprod 1999; 14(6):1624-7.
9. Hattenbach LO, Begg T, Kreuz W, Zubcov A. Ophthalmic manifestation of congenital protein C deficiency. J Aapos 1999; 3(3):188-90.
10. Weiner-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998; 179 (6 Pt 1):1565-7.
11. Arias F, Romero R, Joist H, Kraus FT. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern Fetal Med 1998; 7(6):277-86.
12. Jones JP Jr. Coagulopathies and osteonecrosis. Acta Orthop Belg 1999; 65 Suppl 1:5-8.
13. Chrobak L, Dulicek P. Thrombophilic states. Vnitr Lek 1998; 44(8):481-6.
14. Rao AK, Kaplan R, Sheth S. Inherited thrombophilic states. Semin Thromb Hemost 1998; 24 Suppl 1:3-12.
15. Rosendaal FR. Risk factors for venous thrombosis – prevalence, risk and interaction. Semin Hematol 1997; 34:171-87.
16. Betrina RM, Koeleman BP, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein c. Nature 1994; 369:64-7.
17. Moland L, Sandset PM. Activated protein C resistance – a recently discovered hereditary thrombophilia. Tidsskr Nor Laegeforen 1998; 118(23):3590-5.
18. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85:1504-8.
19. Dahlback B. Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigations and clinical management. Semin Hematol 1997; 34:217-34.
20. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost 1998; 24(4):367-79.
21. Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996; 92:489-90.
22. Brenner B, Mandel H, Lanir N et al. Activated protein C resistance can be associated with recurrent fetal loss. Br J Haematol 1997; 97:551-4.
23. Lindoff C, Ingmarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Pre-eclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176:457-60.
24. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90:1004-8.
25. Koster T, Rosendaal FR, De Ronde H et al. Venous thrombosis due to a poor anticoagualant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342:1503-6.
26. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346:1133-4.
27. Bernardi F, Faioni E, Castoldi E et al. A factor V genetic component differing from factor VR506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90:1552-7.
28. Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation
(Arg 306 Thr) associated with resistance to activated protein C. Blood 1998; 91:1140-4.
29. Ehrenforth S, Radtke KP, Scharrer I. Acquired activated protein C resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 74:797-8.
30. Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CRM. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90:725-7.
31. Peek MJ, Nelson-Piercy C, Manning RA, de Swiet M, Lesky EA.Activated protein C resistance in normal pregnancy. Br J Obstet Gynaecol 1997; 104:1084-6.
32. Olivieri O, Friso S, Manzato F et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91:465-70.
33. Schneider DM, von Tempelhoff GF, Hoppenstaedt D, Fareed J, Heilmann I. Acquierd resistance to activated protein C in pregnancy. Z Geburtshilfe Neonatol 1998; 202(3):107-10.
34. Lane DA, Mannucci PM, Bauer KA et al. Inherited thrombophilia: Part 2. Thromb Haemost 1996; 76:824-34.
35. Magdelaine A, Soubrier F, Berkane N, Uzan S, Verdy E. Comparison of three reactants for the detection of activated protein C resistance due to mutation of factor V Leiden during pregnancy. Ann Biol Clin 1998; 56(4):445-50.
36. Kupfermine MJ, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Eng J Med 1999; 340(1):9-13.
37. Kyrle PA, Mannhalter C, Beguin S et al. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol 1998; 18:1287-91.
38. Poort Sr, Rosendaal FR, Reitsma PH, Betrina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88:3698-703.
39. Souza SS, Ferriani RA, Pontes AG, Zago MA, Franco RF. Factor V leiden and factor II G20210A mutations in patients with recurrent abortion. Hum Reprod 1999; 14(10):2448-50.
40. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated associated with a G to A transition at position 20210 in the 3’-untranslated region of the prothrombin gene. Br J Haematol 1997; 98:907-9.
41. Cumming AM, Keeney S, Salden A, Bhavnani M, Shure KH, Hay CRM. The prothrombin gene G20210A variant: prevalance in a UK anticoagulant clinic population. Br J Haematol 1997; 98:353-5.
42. Eby CS. A review of the hypercoagulable state. Hematol Oncol Clin North Am 1993; 7:1121-42.
43. Simioni P, Sanson Bj, Prandoni P et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81(2):198-202.
44. Preston FE, Rosendaal FR, Walker ID et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348:913-6.
45. Dekker GA, de Vries JIP, Doelizsch PM et al. Underlying disorders associated with severe early-onset pre-eclampsia. Am J Obstet Gynecol 1995; 173:1042-8.
46. De Vries JIP, Dekker GA, Huijgens PC et al. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997; 104:1248-54.
47. Boers G. Hyperhomocysteinaemia as a risk factor for arterial and venous disease: a review of evidence and relevance. Thromb Haemost 1997; 78:520-2.
48. Frosst P, Blom HJ, Milos R et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 1995; 10:111-3.
49. Cattaneo M. Hyperhomocysteinaemia: a risk factor for arterial and venous thrombotic diseases. Int J Clin Lab Res 1997; 27:139-44.
50. Den Heijer M, Blom HJ, Gerrits WBJ et al. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345:882-5.
51. Den Heijer M, Koster T, Blom HJ et al. Hyperhomocysteinaemia as a risk factor for deep vein thrombosis. N Eng J Med 1996; 334:759-62.
52. Wouters MGAJ, Boers GHJ, Blom HJ et al. Hyperhomocysteinaemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993; 60:820-5.
53. Goddijn-Wessel TAW, Wouters MGAJ, van derMolen EF et al. Hyperhomocysteinaemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Rep Biol 1996; 66:23-9.
54. Nelen WLDM, Steegers EAP, Eskes TKAB, Blom HJ. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997; 350:861.
Notice from themedideas.com to all using paid services/reading
All paid services/reading are non-refundable under any circumstances.
© Dr Sudipta Paul, themedideas.com, 2012
Tags: Activated Protein C resistance (Factor V Leiden) exam Tips, Antithrombin III deficiency exam Tips, Hyperhomocysteinaemia exam Tips, Inherited Thrombophilia Best Tips, Inherited Thrombophilia exam Tips, Protein C deficiency exam Tips, Protein S deficiency exam Tips, Prothrombin gene G20210A mutation exam Tips, Thromboembolism exam Tips