Increased attention has been paid recently to the possible relationship between arterial thrombosis Table 12.1 Inherited thrombophilias
Gene Variant Function Phenotype
Factor V Factor V Leiden (R506Q) Increased factor V coagulant activity
Venous thromboembolism [147,148], miscarriages [149], obstetrical complications [150]
Factor V R2 (H1299R) Incompletely characterized [146]
Prothrombin G20210A Increased thrombin DVT, PE [151–155]
Plasminogen activator inhibitor-1
4G/5G promoter Reduced fi brinolysis Portal vein thrombosis [156]
Estrogen receptor beta 1730A > G Unknown DVT [157]
JAK-2 V617F Unknown Budd-Chiari, portal, splanchnic and
mesenteric vein thrombosis, catastrophic intra-abdominal thrombosis (reports inconsistent) [158–160]
Endothelial protein C receptor
Haplotype 1 (H1, tagged by rs9574) Impaired activation protein C functionality
VTE; VTE in carriers of factor V Leiden [161–165]
Haplotype 3 (H3)
Haplotype 4 (H4) 4600AG, 4678CC
Factor XIIIA Val34Leu Changes FXIII activation rate
and fi brin structure/function
DVT, MI, CVA [40,166,167]
Fibrinogen Aα Thr312Ala Changes fi brin structure/
function and FXIII cross-linking
Pulmonary embolism [168]
Thrombomodulin Several missense mutations Various VTE [169–172]
Tissue-factor pathway inhibitor
Pro151Leu Unknown VTE (contradictory reports) [173,174]
CVA, cerebrovascular accident; DVT, deep vein thrombosis; JAK-2, janus kinase-2; MI, myocardial infarction; PE, pulmonary embolism; VTE, venous thromboembolism.
and VTE risk [94]. Observational studies have found associations between arterial thrombotic risk factors, such as metabolic syndrome [95], diabetes [96], waist circumference, and smoking [97], and the development of VTE, and between statin use and lower incidence of VTE [98]. VTE has also been associated with subclinical atherosclerosis: one study found that patients with a prior history of VTE had a higher risk of carotid plaque on ultrasound imaging [99], and another found a higher incidence of coro- nary artery calcium in patients with idiopathic VTE than in matched controls without VTE [100].
Studies have also suggested an increased risk of development of subsequent arterial thrombotic events after VTE [94,101,102]. One prospective study of 1,919 consecutive patients followed for a median of 4 years after a fi rst episode of VTE found that patients with idiopathic VTE had a 60%
higher risk of experiencing at least one arterial thrombotic event [99], suggesting the presence of a common risk factor contributing to a shared pro- thrombotic state. While FVL, prothrombin G20210A, and APCR have been associated with both VTE and, much less commonly, arterial thrombosis, further studies are necessary to better understand this relationship.
Acquired thrombophilias and stroke risk
The acquired thrombophilic disorders include uncommon but not rare conditions such as drug- induced thrombocytopenia, autoimmune diseases, and myeloproliferative disorders (Table 12.2). Each contributes to the risk of venous and arterial throm- bosis to varying degrees. In some cases, familial clus- tering and genetic infl uences are discernible [103]
(Figures 12.3 and 12.4). Pregnancy, estrogens and estrogen receptor antagonists intake, smoking, drugs of abuse including cocaine and methamphetamines, and fi ne particulate air pollution can cause profound changes in coagulation [104–106].
Thrombotic disorders associated with thrombocytopenia
Heparin-induced thrombocytopenia (HIT) occurs in 1–3% of patients receiving unfractionated heparin for 5 or more consecutive days [107]. Recent hospi- tal-based registries suggest that the true incidence has been underestimated due to under-recognition in clinical practice [108].
Many patients with platelet factor (PF)4/heparin antibodies remain asymptomatic, implying that host-specifi c factors infl uence the development of clinical thrombosis in HIT [107]. When it does occur, thrombosis most often involves the venous circulatory system; however, arterial thrombosis to include stroke is not a rare occurrence.
Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy characterized by profound thrombocytopenia, systemic platelet aggregation, erythrocyte fragmentation, and multi- organ ischemia [109]. The mental status changes inherent to the diagnosis of TTP may represent microvascular thrombosis of the brain; while fi xed neurological defi cits are not common, ischemic strokes can occur. TTP must be considered in any patient receiving ticlopidine (or rarely clopidogrel) who develops a platelet count <100 × 109 per liter, and either MI or stroke. Most cases of TTP are caused by a severe functional defect of the plasma metalloprotease ADAMTS13, which fails to degrade unusually large vWF multimers. ADAMTS13 regu- lates platelet adhesion and aggregation through cleavage of vWF multimers. Two recent studies have demonstrated the prognostic value of inhibitory ADAMTS13 antibodies in adult-acquired TTP [110,111]. Patients with TTP and detectable inhibi- tory anti-ADAMTS13 antibodies had delayed plate- let count recovery, higher plasma exchange volume requirements, and a trend toward more frequent fl are-ups [110]. High levels of inhibitory ADAMTS13 IgG at presentation were associated with the persis- tence of an undetectable ADAMTS13 activity in remission, the latter being predictive for relapses within an 18-month period [111].
Autoimmune disorders, myeloproliferative disorders, and malignancy
The antiphospholipid syndrome (APS) is strongly associated with atherothrombosis, with several studies indicating that patients with APS experience an increased incidence of atherosclerosis and its complications compared with the general popula- tion [112]; however, a major concern is the increased risk of venous and arterial thrombotic events, including stroke. This was, in fact, the diagnosis for the example patient. The overall risk of arterial thrombosis among patients with systemic lupus ery- thematosus and APS may be heightened in those
Table 12.2 Association of hypercoagulable states with arterial disease
Inherited hypercoagulable states Association with arterial disease
Coagulation proteins
Fibrinogen level CAD [175], stroke [175]
β-chain – 455 G/A CAD [176] stroke [177]
β-chain – 854 G/A CAD [178]
β-chain – 1420 G/A CAD [179]
β-chain Bcl1 CAD [178] PAD [179]
β-chain C448 Stroke [180]
α-chain Thr312Ala Stroke [181]
Prothrombin G20210A variant CAD [176], stroke [182], PAD [183]
Factor V Leiden (G1691A) CAD [176], stroke [184]
Tissue factor Ag level CAD [185]
Tissue factor pathway inhibitor CAD [186]
Factor VII level CAD [185]
FVII Arg353Gln, FVII HRV4, FVII-401G/T, FVII-402G/A CAD [187]
Factor VIII level CAD [187], stroke [187]
Factor IX level CAD [188]
Factor XI level (paradoxical) CAD [188]
Factor XII level (paradoxical) CAD [189]
FXII C46T CAD [189]
FXIII Val34Leu CAD [190], stroke [191]
von Willebrand factor (vWF) Ag level CAD [192]
vWF Thr789Ala CAD [192]
vWF SmaI polymorphism in intron 2 CAD [192], stroke [192]
Thrombomodulin Ag level CAD [193]
Thrombomodulin Ala455Val, Ala25Thr CAD [193]
Fibrinolytic system
Plasminogen activator inhibitor level Stroke [194]
PAI-1 -6754G/5G CAD [195]
Thrombin-activatable fi brinolysis inhibitor (TAFI)level CAD [196]
TAFI Ala147Thr, 1542C/G CAD [196]
Tissue-type plasminogen activator (tPA) CAD [197], stroke [198]
tPA Alu insertion/deletion CAD [196]
tPA – 7351C/T CAD [196], stroke [199]
Platelets
Platelet hyperreactivity CAD [200]
GPIIIa Leu33Pro CAD [176]
GP1BA – 5C/T CAD [201]
GP1a C807T CAD [200]
GP6 T13254C CAD [61,201]
Biochemical
Hyperhomocysteinemia§ CAD [72], stroke [72,202]
MTHFR C677T CAD [203], Stroke [204]
Inherited hypercoagulable states Association with arterial disease Acquired hypercoagulable states
Thrombotic thrombocytopenic purpura MI [103], stroke [103]
Heparin-induced thrombocytopenia MI [107], stroke [107]
Antiphospholipid syndrome CAD [112], stroke [112]
Rheumatoid arthritis CAD [113,114], stroke [113]
Nephrotic syndrome MI [121]
Solid organ malignancy MI [205], stroke [205]
Myeloproliferative disorders MI [122], stroke [122]
Essential thrombocytosis, polycythemia vera, chronic myeloid leukemia and myelofi brosis
Oral contraceptives MI [106], stroke [106]
Hormone replacement therapy CAD [125,126], stroke (125,126]
Pregnancy and puerperium MI [116]
Air pollution CAD [129], stroke [130]
History of venous thrombosis CAD [94,99], stroke [94,99]
CAD, coronary artery disease; PAD, peripheral arterial disease; MI, myocardial infarction; MTHFR, methyltetrahydrofolate reductase.
Table 12.2 Continued
Genetic factors Phenotype/biological effects
Environmental factors
Atherothrombosis (clinical disease) 1 Acute coronary syndrome 2 Ischemic stroke 3 Acute limb, visceral ischemia Malignancy and myeloproliferative
diseases (PV,ET)
Viral infections (SLE/APS/NS/RA) Drugs (thienopyridines-TTP, heparin-HIT, cocaine, OCP, antifibrinolytics, prothrombin complex concentrates) DM/metabolic syndrome Diet
Smoking Sedentary lifestyle Pregnancy and puerperium Air pollution
Drugs of abuse:
1 Cocaine 2 Methamphetamine
Fc gamma RIIA polymorphisms (HIT) ADAMTS13 mutations (TTP) SNPs of genes regulating cytokines, B cell activation, apoptosis and complement (SLE) Viscosity (TTP)
LA, aCL, β2-GPI (APS)
Fc gamma RIIA, anti-PF4 antibodies (HIT) CRP, IL-6, TNF-α, E-selectin, P-selectin, ICAM-1, VCAM-1, and oxidized LDL (DM/MS, SLE/NS) Endothelial dysfunction, Accelerated atherosclerosis
(smoking/DM/MS/SLE/RA)
Fig. 12.3 Pathophysiology of acquired hypercoagulable states.
anti-PF4, antiplatelet factor 4; APS, antiphospholipid syndrome; CRP, C reactive protein; DM, diabetes mellitus; ET, essential
thrombocythemia; GP, glycoprotein; HIT, heparin- induced thrombocytopenia; ICAM, intercellular adhesion molecule; IL-6, interleukin-6; LDL, low-density lipoprotein; MS, metabolic syndrome; NS, nephritic syndrome; OCP, oral contraceptive pill; PV, polycythemia vera; RA, rheumatoid arthritis; SNP, single nucleotide polymorphism; SLE, systemic lupus erythematosus; TNF, tumor necrosis factor; TTP, thrombotic thrombocytopenic purpura; VCAM, vascular cell adhesion molecule.
with a circulating lupus anticoagulant, high-titer antibodies to anticardiolipin, particularly if persis- tently high, and prior thrombotic events [112].
Rheumatoid arthritis (RA) is associated with an increased risk of coronary and cerebrovascular ath- erosclerotic disease and ischemic stroke. In the Nurses’ Health Study, the incidence of the compos- ite end point of MI and stroke was signifi cantly higher among those with RA of more than 10 years’
duration compared with normal controls (incidence of 272 vs. 96 per 100,000 person years) [113]. This increased risk of atherothrombosis appears to be the result of heightened infl ammation and coagulation rather than concomitant rheumatoid vasculitis [114]. MI as a direct consequence of large- or medium-sized vessel vasculitis is uncommon [115].
There have been isolated reports of acute thrombo- sis within coronary artery aneurysms in patients with polyarteritis nodosa [116,117] or a history of childhood Kawasaki’s disease, but chronic angina due to progressive arterial narrowing is, by far, the more common presentation of coronary or aortic arteritis [118,119].
Patients with the nephrotic syndrome (NS), espe- cially membranous nephropathy, have a relatively high incidence of both arterial and venous throm- bosis [120]. In an analysis of 142 patients with NS and 142 matched healthy controls, the adjusted rela- tive risk of MI and coronary death with NS was 5.5 and 2.8, respectively [121]. Although the actual mechanism leading to increased coronary thrombo- sis in NS is unclear, possible pathogenic factors
include hyperlipidemia, platelet hyperreactivity, endothelial dysfunction, and functional and quanti- tative changes in plasma coagulation proteins [120].
Myeloproliferative disorders often elicit unique clinical features such as a tendency toward both hemorrhagic and thrombotic events, including stroke, splenomegaly (which is occasionally massive), and clinical manifestations of microcirculatory disturbances such as ocular migraine, Raynaud’s phenomenon, and erythromelalgia [122]. Throm- bocytosis (>450,000 platelets/mm3) is a main feature of essential thrombocytosis and an important diagnostic feature of polycythemia vera, with con- comitant increases of both erythrocyte and leuko- cyte cell lines in the latter disorder [123]. The added presence of the janus kinase-2 mutation may have important diagnostic and management implications [124].
Environmental factors
Estrogen exerts numerous effects on the hemostatic system, including modulation of platelet function and endogenous levels of physiological anticoagu- lants [125]. Pregnancy and oral contraceptive use are more prevalent in women with acute MI and stroke.
The association between hormone replacement therapy (HRT) and arterial thrombosis is particu- larly complex. In randomized trials including over 20,000 women followed over 4.9 years, HRT users had a signifi cantly increased incidence of stroke and Inherited factors
Male Female
Relative contribution
Age OCP use
pregnancy /puerperium
Sixth decade of life Menopause Single gene
Polygenic Acquired factors
Fig. 12.4 Relative infl uence of inherited and acquired factors in determining hypercoagulable risk with age. Due to the gendered contribution of pregnancy, puerperium, and menopause, women may have a distinct age-dependent risk profi le compared with men.
OCP, oral contraceptive pill.
pulmonary embolism but no signifi cant change in endometrial cancer or coronary heart disease [126].
Psaty and colleagues suggested an interaction with other inherited hypercoagulable states and acquired risk factors [127], while Rossouw et al. found that early initiation of HRT in relation to menopause might improve the risk–benefi t profi le [128]. Cur- rently, however, the weight of the evidence indicates that older women and those with subclinical or overt coronary heart or cerebrovascular disease should not take HRT [126]. Further data on HRT in younger women will come from the ongoing Kronos Early Estrogen Prevention Study (ClinicalTrials.gov identifi er: NCT00154180), which is evaluating 5 years of HRT versus placebo in 720 women aged 42–58 years within 36 months of their fi nal men- strual period, using the prevention of progression of carotid intimal medial thickness and accrual of cor- onary calcium as surrogate clinical end points.
Fine particulate air pollution has been linked to cardiovascular disease. In a study of postmenopausal women without previous cardiovascular disease living in cities exposed to varying levels of air pollu- tion, each increase of 10 μg/m3 was associated with a 24% increase in the risk of cardiovascular events and a 76% increase in the risk of death from cardio- vascular disease over 6 years [129]. The stroke risk may be increased by as much as 2-fold among indi- viduals exposed to particulate matter and nitrogen dioxide [130].
Diagnostic approach to suspected thrombophilias
Most patients experiencing recurrent arterial throm- botic events, including ischemic stroke, are more likely to have one or more traditional atherosclerotic risk factors than an inherited or acquired thrombo- philic disorder [104]. All patients who experience an arterial thrombotic event require a comprehensive history and physical examination, with particular attention given to taking a detailed past, family, and medication history. A recent hospitalization should raise the possibility of heparin exposure and the development of HIT, to include the delayed variant.
The following laboratory studies should be per- formed as they may provide valuable clues to an underlying thrombophilic state: a complete blood count with differential, prothrombin time, activated partial thromboplastin time, blood urea nitrogen/
serum creatinine, and a peripheral blood smear. A urinalysis to determine the presence of proteinuria or features of an “active” sediment is also recom- mended. Abnormal renal function is an early feature of TTP. Patients with “catastrophic” APS present acutely with thrombotic events involving multiple sites within the venous, arterial, and/or microvascu- lar systems – often in rapid succession.
Acute thrombosis can cause “false-positive”
results when testing for inherited thrombophilias:
proteins C and S and antithrombin III activity may be spuriously low, and factor VIII antigen or activity may be abnormally high (see Table 12.3). When unfractionated heparin or low molecular weight heparin is used for treatment, certain assays for APCR may be unreliable, and antithrombin activity may appear abnormally low. Vitamin K antagonists (VKAs) suppress protein C and S levels and factor IX activity or antigen levels, while antithrombin levels may appear abnormally high [131]. These observations serve as the basis for diagnostic testing to be performed at a minimum of 6 weeks after the acute thrombotic event, or for subjects prescribed VKA, a minimum of 6 weeks after cessation of therapy [131]. In contrast, a majority of laboratory studies employed in the evaluation of arterial throm- bophilias are much less susceptible to the effects of acute thrombosis and can therefore be performed early in the clinical course. Because of the highly variable effect of antiphospholipid antibodies on test reagents used to perform an evaluation of activated partial thromboplastin time (aPTT), young patients with a fi rst arterial thrombotic event should be screened for antiphospholipid antibodies and the presence of a circulating lupus anticoagulant even in the absence of a prolonged aPTT [131]. If these anti- bodies are present on initial testing, tests should be repeated at a 6-week interval to ascertain persistence of elevated antibody titers. If patients are being treated with anticoagulants during testing for lupus anticoagulant, test kits containing neutralizers that inactivate heparin or low molecular weight heparin should be used [131].
The generally modest link between thrombophilic disorders affecting the venous circulatory system and arterial thrombosis, the marginal effect that individual genetic polymorphisms, at least those described to date, have in predicting clinical pheno- types, and an overall low yield in the detection of
thrombophilias, form the rationale behind taking a highly selected approach to laboratory testing [1,39].
We recommend the algorithm modifi ed from Andreotti and Becker in which patients meeting any one of the fi ve criteria undergo further testing [104]
(Figure 12.5).
Therapeutic perspectives
Patients presenting with a fi rst episode of arterial thrombosis, who are subsequently found to have an inherited thrombophilic condition, should receive standard treatment for the acute thrombotic episode (Figure 12.6).
Despite an association between elevated serum homocysteine levels and clinical end points, there is no convincing evidence of a reduction in adverse clinical events with vitamin supplementation in patients with a modest elevation [132–134].
However, it may be reasonable to use vitamin B12,
vitamin B6, and folic acid supplementation among patients with hyperhomocysteinemia (serum homo- cysteine concentration >10 μmol/L) [1], especially those with markedly elevated homocysteine levels (>100 μmol/L) [135] (Table 12.4).
The importance of recognizing acquired causes of arterial thrombophilia relates directly to the avail- ability of benefi cial treatments and management strategies for many of these conditions. Long-term, intermediate-intensity anticoagulation with VKA, such as warfarin (international normalized ratio [INR] of 2.0–3.0), reduces the likelihood of recur- rent arterial thrombosis in patients with the APS to the same degree as high-intensity anticoagulation (INR 3–4) [1,136].
In essential thrombocytosis and polycythemia vera, increased platelet biosynthesis of thromboxane A2 is suppressible by low-dose aspirin [137]. A ran- domized trial in patients with polycythemia vera Table 12.3 Infl uence of acute thrombosis, heparin, and warfarin on thrombophilia test results
Test Acute thrombosis
Unfractionated heparin (UF)
Low molecular weight heparin (LMWH)
Vitamin K antagonists
Factor V Leiden genetic test Reliable Reliable Reliable Reliable
Activated protein C resistance assay Reliable* Caveat† Caveat† Reliable*
Prothrombin 20210 genetic test Reliable Reliable Reliable Reliable
Protein C activity or antigen Caveat‡ Reliable Reliable Low
Protein S activity or antigen May be low Reliable Reliable Low
Antithrombin activity May be low May be low May be low May be elevated
Lupus anticoagulant Reliable§ Caveat¶ Caveat¶ Caveat¶
Anticardiolipin antibodies Reliable§ Reliable Reliable Reliable
Homocysteine Reliable Reliable Reliable Reliable
Factor VIII antigen or activity High** Reliable Reliable Reliable
Factor IX antigen or activity Reliable** Reliable Reliable Low
Factor XI antigen or activity Reliable** Reliable Reliable Reliable
Adapted from Moll J. Thromb Thrombolysis. 2006;21:7–15.
*Reliable if the assay is performed with factor V depleted plasma [206]; thus, the clinician needs to inquire how the individual laboratory performs the assay.
†Depending on the way the assay is performed, results may be unreliable; the healthcare provider needs to contact the laboratory and ask how the specifi c test performs on heparin.
‡Probably reliable, but limited data in literature.
§Test is often positive or elevated at the time of acute thrombosis, but subsequently negative [207].
¶While many test kits used for lupus anticoagulant testing contain a heparin neutralizer that inactivates UF and possibly LMWH, thus making these tests reliable on UF and LMWH, clinicians needs to inquire with their laboratory how their individual test kit performs in samples with UF and LMWH.
**No indication for testing in the acute setting.
demonstrated the safety and effi cacy of low-dose aspirin in preventing both venous and arterial thromboses over a period of 3 years [138]. More- over, anagrelide or hydroxyurea added to mainte- nance antiplatelet therapy reduced the number of thrombotic events, compared with antiplatelet therapy without myelosuppressive therapy, in patients with essential thrombocythemia and high- risk clinical features for thrombosis [139].
Thrombophilia testing infl uences less than 25%
of physicians’ treatment of ischemic stroke [140].
Practically, performing these expensive tests is prob- ably not clearly indicated in patients with other reasons to be anticoagulated (i.e., atrial fi brillation) or in patients where anticoagulation is going to be contraindicated anyway. If making a diagnosis is going to affect therapy, then an investigation of a thrombophilia should be performed [1,141].
To improve cardiovascular health and reduce car- diovascular death, it has generally been recom- mended that patients get regular physical exercise.
One specifi c mechanism by which regular exercise could have benefi cial health effects is through reduc- ing prothrombotic factors [1,39,142]. This is in con- trast to the known effects of acute strenuous/intense activity linked to acute coronary occlusion/throm-
bosis. While acute exercise has been suggested to be able to induce a prothrombotic state from the acti- vation of platelets (shear-induced platelet aggrega- tion with increased GPIIb/IIIa expression and increased vWF binding to platelets), abnormal fi bri- nolysis, and increased P-selectin [143], large differ- ences in study methodologies preclude drawing strong conclusions. However, emerging literature suggests that regular exercise (8-week training program at 60% of VO2 max for 30 minutes a day for 5–7 days per week) can reduce shear-induced platelet aggregation, vWF binding, and P-selectin expression both at rest and during intense exercise [144]. A caveat is that studies have typically been performed in healthy young men. Future studies need to be conducted in a relevant population of older individuals with atherosclerosis disease and atherosclerotic risk factors. Further, given the link between stress and increased cardiovascular disease, stress-reduction strategies may also prove useful in reducing vascular occlusive events.
Triggers for a stroke associated with a thrombo- philia are usually unknown, but surgery, trauma, pregnancy, hormone use, and systemic illness have been proposed [1,141]. While avoidance of these triggers is recommended, therapy should be tailored Diagnostic
algorithm
An episode of arterial thrombosis with
≥1 of the following clinical features:
5
Screen for:
Antiphospholipid antibodies Lupus anticoagulant ET, PV, malignancy Cocaine and amphetamine metabolites
Lipoprotein (a)
Consider screening for:
Serum or plasma homocysteine
Factor V Leiden, PT 20210, and other candidate gene variants Platelet hyperreactivity 4 No significant coronary stenosis on
angiography
3 Age ≤55 (male) or ≤60 (female) with no other traditional risk factors present
2 Age ≤50 (male) or ≤55 (female) 1 Previous arterial thrombosis
Age ≤55 (male) or ≤60 (female) + strong family history*
Fig. 12.5 Proposed selection criteria for diagnostic testing.
Adapted from Andreotti F, Becker RC. Circulation. 2005;111:1855–1863.
*May be defi ned as at least one fi rst-degree relative affected at age ≤50 years if male or ≤55 years if female.
ET, essential thrombocythemia; PV, polycythemia vera.