Coagulopathies cause a predisposition to thrombosis and therefore an increased risk of ischaemic stroke. Although the frequency of coagulopathies in patients with stroke is low, the yield for diagnosing coagulopathies is typically greatest in young patients, those with family history of thrombosis, those with repeated unexplained strokes and patients with no vascular risk factors, as Omer H T Ali with Drs Bella Richard and Pradeep Khanna explain.
First published February 2007, updated October 2021
- Coagulopathies account for one to four per cent of ischaemic stroke.
- APL patients tend to have a high stroke recurrence rate.
- Factor V Leiden mutation is the most common inherited disorder leading to venous thrombosis.
- Cerebral venous thrombosis and ischaemic stroke are associated with increased mortality.
Stroke is defined as a focal (or at times global) neurological impairment of sudden onset, and lasting more than 24 hours (or leading to death) and of presumed vascular origin1. Cerebral ischaemia accounts for 85 per cent of presentation and primary intra-cerebral haemorrhage for 15 per cent2. Coagulopathies have been implicated in one to four per cent of ischaemic stroke3. Disorders of coagulation may occur as a result of an alteration in the amount or function of the protein cascade due to either congenital or acquired aetiologies. This causes a predisposition to thrombotic events (hypercoagulable state) and, therefore, an increased risk of ischaemic stroke. Thrombosis can be divided anatomically into venous and arterial thrombosis. The inherited hypercoagulable syndromes primarily affect veins, and only rarely causes arterial thrombosis. The acquired hypercoagulable states, such as the antiphospholipid antibody syndrome, are more implicated in arterial stroke4. The aim of this article is to provide a detailed review of the literature to date on the role of coagulopathies in arterial and venous thrombosis.
Antiphospholipid antibodies: anticardiolipin antibodies (ACL)/lupus anticoagulant (LA) Antiphospholipid antibodies (APL) are a heterogeneous family of antibodies that react to negatively charged membrane-bound phospholipids or phospholipid-protein complexes5. Even though antiphospholipid antibodies are associated with both arterial and venous thrombosis, they are more commonly implicated in arterial stroke4. The prevalence of APLs has been estimated to occur in two to seven per cent6 of the normal population. However, there is an increased prevalence with age, rising to 51.6 per cent among patients aged between 67 and 95 years7. Among patients with APL, 20 per cent present with stroke4. Several controlled studies of ACL or LA found a significant association with ischaemic stroke8-10. Brey et al, reported detectable levels of APL in 21 of 46 (46 per cent) subjects under 50 years of age presenting with stroke or TIAs, compared with only two of 26 (eight per cent) in controls11. The association between ACL/LA and ischaemic stroke is well known in patients with antiphospholipid antibody syndrome and systemic lupus erythematosus12. APL patients tend to have a high stroke recurrence rate, those who present with arterial stroke are also likely to have recurrent arterial stroke12. Despite the strong association between APL and stroke, the precise mechanism by which they promote thrombosis remain unknown. Many problems exist in interpreting the reported studies, including the lack of standardisation of laboratory tests or criteria for a positive result.
Hyperhomocysteinemia is now recognised as a risk factor for arterial disease, including carotid artery stenosis and stroke13,14. The pathogenesis of homocysteine-induced arterial disease is not well elucidated, however several mechanisms have been proposed including: an increase in adhesiveness of platelets; activation of the coagulation cascade; conversion of low density lipoprotein (LDL) cholesterol into proatherogenic forms; and endothelial damage with increased tissue factor expression4. It has also been suggested elevated levels of homocysteine increases the odds of carotid intimal thickening by more than threefold15. A case-controlled study suggested as many as 30 per cent of subjects with ischemic stroke had higher homocysteine levels compared with the controls16. Clarke R et al reported 42 per cent of stroke reported 42 per cent of stroke patients had elevated levels of homocysteine17. In another meta-analysis 11 of 27 studies concerned with cerebrovascular diseases, concluded elevated levels of homocysteine is an independent risk factor for stroke18. Supplemental folate, and to a lesser extent vitamin B6 and vitamin B12, can lower serum homocysteine levels, and vitamin supplementation is currently being investigated as a preventive treatment for patients with elevated homocysteine levels at risk for arterial disease19.
Sickle cell anaemia
Stroke is common in patients with sickle cell anaemia. It has been suggested 10 per cent of individuals with HbSS (sickle cell anaemia) and two to fi ve per cent of those with HbSC (haemoglobin-sickle cell disease) will experience symptomatic stroke, and an additional 13 per cent may develop asymptomatic stroke20. As sickle cell disease develops, there is a progressive narrowing of the distal internal carotid artery, portions of the circle of Willis and proximal branches of the major intracranial arteries21. Sickle cell plugging of microcirculation and cerebral veins can also occur22. Blood transfusion is the mainstay of treatment and is highly effective in reducing the risk of stroke23. Untreated patients tend to have an exceptionally high stroke recurrence rate of 67 per cent, compared with 10 per cent in those receiving frequent transfusion24.
Factor V Leiden mutation (FVL) By far the most common inherited disorder leading to venous thrombosis is the clinical syndrome of activated protein C (APC) resistance caused by the mutation in factor V (factor V Leiden)25. A single point mutation (G to A transition of nucleotide 1691) in exon 10 of factor V gene leads to the substitution of arginine 506 by glutamine (factor V Leiden) and results in a factor V molecule that is resistant to cleavage by APC26. This mutation is present in the majority of the patients with activated protein C resistance. Resistance to APC or factor V Leiden has been estimated to occur in two to 15 per cent of Caucasians27. Molecular studies have shown that FV Leiden homozygotes are exposed to a higher risk of thrombosis, an eightyfold increase compared with heterozygotes at a sevenfold increased risk28. A study of 19 patients with cerebral venous thrombosis has reported an incidence of factor V Leiden in 21 per cent29. In another study of families with factor V Leiden, the risk of thrombosis in asymptomatic carriers has been estimated to be one per cent per year between the ages of 20–50 years compared with 0.1 per cent for those without the mutation30. Notably several case control and prospective studies have failed to find evidence of a significant association between factor V Leiden mutations and arterial stroke31,32.
Antithrombin III deficiency (AT)
Antithrombin inhibits thrombin and factors X, IXa, XIa, XIIa and Kallikrein by forming an irreversible complex25. There are two major types of antithrombin deficiency. Type I is characterised by a quantitative reduction of functionally normal antithrombin protein. Type II is due to the production of qualitatively abnormal protein. In both types antithrombin activity is reduced to a variable extent33. Type II is further stratified according to the molecular defect: reactive site (thrombin binding site); heparin binding site; and pleiotropic effect (characterised by multiple functional defects)25. The distinction between the subtypes of antithrombin is of clinical importance as the incidence of thrombosis is higher in association with type I deficiency (relative risk twenty-five- to fi ftyfold)34, and type II deficiency in where mutation affects the reactive site33. The prevalence of antithrombin deficiency in the general population is 0.18 per cent35. In studies of patients with ischaemic stroke, antithrombin deficiency was reported in 4.6 per cent36.
Protein C and protein S deficiencies
Both protein C and protein S are vitamin dependent glycoproteins synthesised in the liver. By degrading activated clotting factors Va and VIIIa, activated protein C functions as one of the major inhibitors of the coagulation system33. Protein S is a cofactor for activated protein C and is required for protein C to have its full effect36. While the prevalence of protein S deficiency remains unknown33, protein C deficiency in the general population has been estimated to occur in 0.2per cent37. In studies of patients with ischaemic stroke, protein C deficiency was reported in 1.4 per cent and protein S in 0.9 per cent36. Even though venous thrombosis has been well documented as being caused by abnormalities in protein C and protein S, evidence supporting the role of deficiencies in protein C and protein S in arterial infarction are limited38.
Prothrombin gene mutation
Prothrombin is the final step in fibrin formation. Mutation in prothrombin gene leads to a gain of function of prothrombin and hence an increased risk of venous thrombosis. Even though several studies have shown an association between the prothrombin gene mutation and venous thrombosis, there is no compelling evidence indicating this mutation is a significant cause of arterial stroke38.
Prognosis and management
In general, despite an increased risk for thrombosis, the prognosis of most hypercoagulable states is excellent and currently there is no data showing increased mortality with protein C, FVL or AT deficiency compared with the general population36. However, presentations associated with increased mortality include cerebral venous thrombosis and ischaemic stroke. The optimal management of a patient with a hypercoagulable state after a single episode of venous or arterial stroke is unknown39. In patients with acquired coagulopathy, treatment of the underlying conditions may reverse the risk. In patients with hereditary deficiencies, and those with recurrent ischaemic episodes, warfarin is often recommended36. Levine et al, investigated the efficacy of warfarin compared with aspirin for thrombosis prevention in subjects with antiphospholipid antibodies. They concluded that there was no significant difference in stroke recurrence between those receiving aspirin or warfarin40. In order to identify the risk reduction with specific therapy, there is a need for more randomised control trials comparing long term anticoagulation to oral antiplatelet therapy in patients with coagulation disorders.
The role of coagulopathies has been well established in arterial and venous thrombosis leading to ischaemic stroke. However, because of the low frequency of coagulopathies in patients with stroke, it is difficult to justify screening all stroke patients. Specialised coagulation testing may be beneficial in young patients, those with a family history of thrombosis, those with repeated unexplained strokes and patients with no vascular risk factors. Additional prospective controlled studies of stroke patients are necessary to assess the prevalence rates and to further increase our knowledge of the role of coagulopathies in the aetiology of ischaemic stroke.
- The WHO STEPwise approach to stroke surveillance. 2005
- Philip M, Bath W, Lees KR. ABC of arterial and venous disease. BMJ 2000;320:920-923
- Haberl RL, Biniasch O, Ott M et al. Infrequency of stroke caused by specifi c coagulation disorders. Cerebrovascular Disease 1995; 5:391-396
- Moster ML. Coagulopathies and arterial stroke. Journal of NeuroOphthalmology Ophthalmology 2003;23:63-71
- Tuhrim S. Antiphospholipid antibodies and stroke. Current Cardiology Reports 2004; 6:130- 134
- McCrae KR, Feinstein DI, Cines DB. Antiphospholipid antibodies and the antiphospholipid syndrome. In:Colman RW, Hirsh J, Marder VJ, et al eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 4th edition. Philadelphia: Lippincott Williams& Wilkins; 2001;1339-56
- Manoussakis MN, Tzioufas AG, Silis MP et al. High prevalence of anticardiolipin and other autoantibodies in a healthy elderly population. Clinical Experimental Immunology Immunology 1987;69:557-65
- Tuhrim S, Rand JH, Wu XX et al. Elevated anticardiolpin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999; 30:1561-1565
- Camerlingo M, Casto L, Censori B et al. Anticardiolipin antibodies in acute non-hemorrhagic stroke seen within six hours after onset. Acta Neurologica Scandinavica 1995;92:69-71
- Montalban J, Codina A, Ordi J et al. Antiphosphlipid antibodies in cerebral ischemia. Stroke 1991; 22:750-753
- Brey RL, Hart RG, Sherman TG, Tegeler CH. Antiphospholipid antibodies and cerebral ischemia in young people. Neurology 1990; 40:1190-6.
- Levine SR, Brey RL, Sawaya KL et al. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Annals of Neurology 1995; 38:119-124.
- Aronow WS, Ahn C, Schoenfeld MR. Association between plasma homocysteine and extracranial carotid arterial disease in older persons. American Journal of Cardiology Cardiology 1997;79:1432-1433
- Perry IJ, Refsum H, Morris RW et al. Prospective study of serum total homocysteine concentarion and risk of stroke in middle aged British men. Lancet 1995;346:1395-1398
- Barnett H, Mohr JP, Stein BM et al. Stroke : Pathophysiology, Diagnosis and Management, 3rd edition. Churchill Livingstone;1998
- Coull BM, Malinow MR, Beamer N et al. Elevated plasma homocysteine concentration as a possible independent risk factor for stroke. Stroke 1990; 21:572
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- Moser FG, Miller ST, Bello JA. The spectrum of brain abnormalities in the sickle cell disease: a report from the Cooperative Study of Sickle cell Disease. AJNR 1996;17:965-972
- Stockman JA, Nigro MA, Mishkin NM et al. Occlusion of large cerebral vessels in sickle cell anaemia. NEJM 1972; 287:846 1972; 287:846
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- Goldstein LB, Adams R, Becker K et al. Primary prevention of ischemic stroke: a statement for health care professionals from the Stroke Council of the American Heart Association. Stroke 2001;32:280-299
- Powars D, Wilson B, Imbus C et al. The natural history of sickle cell disease. American Journal of Medicine 1978;65:461-471
- Roa AK, Sheth S, Kaplan R. Inherited hypercoagulable states. Vascular Medicine 1997;2:313- 320
- Bertina RM, Koeleman BP, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369:64- 67
- Rees DC, Cox M, Clegg JB. World distribution of FV Leiden. Lancet 1995;346:1133-1134
- 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; 85:1504-1508
- Zuber M, Toulon P, Marnet L, Mas J-L. Factor V Leiden mutation in cerebral venous thrombosis. Stroke 1996; 27:1721-1723
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- Ridker PM, Hennekens CH, Lindpaintner K et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke and venous thrombosis in apparently healthy men. NEJM 1995: 332;912-17
- Press RD, Liu XY, Beamer N, Coull BM. Ischemic stroke in the elderly- role of the common factor V mutation causing resistance to activated protein C. Stroke 1996;27:44-48
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