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Nonarteriosclerotic Disorders of the Arterial System


Pathophysiology of Arterial Thrombosis

In general, venous thrombosis is caused by disturbances in the plasma coagulation system, with platelet participation playing a minor role, whereas in arterial thrombosis, platelets play the major role with limited participation of the plasma coagulation system. This pattern helps explain why coagulation protein abnormalities—such as the presence of factor V Leiden (FVL), the prothrombin 20210 mutation, and deficiencies of protein C, protein S, and antithrombin III (ATIII)—predominantly lead to venous thromboembolism (VTE). It also helps explain why antiplatelet drugs are effective in the prevention of arterial thrombosis but less so in the prevention of VTE. Thrombus formation in the cardiac ventricles and atria is often attributed to stagnant blood flow in dyskinetic or aneurysmal parts of the heart chambers or in fibrillating atria. Arising in a slow-flow environment, these thrombi are more likely caused by mechanisms similar to those that lead to venous thrombosis.

Arterial clots usually form in areas of atherosclerotic vascular damage. The events leading to atherosclerosis, mainly lipid disturbances, oxidative stress, and inflammation, have recently been well reviewed elsewhere. The composition and vulnerability of plaque rather than its volume and the severity of stenosis are the most important determinants of the development of arterial ischemic syndromes. Plaques have a high content of tissue factor (TF), expressed on monocytes and macrophages. Disruption of the fibrous cap or endothelium overlying an atheromatous plaque leads to the exposure of collagen and of TF, which leads to platelet adhesion and aggregation and local thrombin formation, with subsequent thrombus development.

Atherosclerosis, Atrial Fibrillation, and Other Cardioembolic Sources

This chapter focuses on nonarteriosclerotic arterial occlusive disease and, thus, does not cover primary and secondary prevention of occlusive arteriosclerotic vascular disease, atrial fibrillation (AF), and other cardiac causes of arterial thromboembolism. Good and comprehensive evidence-based consensus guidelines on these topics, including the use of antiplatelet and anticoagulant drugs, exist to assist the clinician in patient management ( Table 22.1 ).

TABLE 22.1
Key Resources for the Use of Antithrombotic Drugs in Arteriosclerotic Occlusive Arterial Disease, Atrial Fibrillation, Valvular Heart Disease, and Patent Foramen Ovale
Antithrombotic Therapy Recommendations (Last Updated)
Peripheral arterial disease (2013)
Transient ischemic attack and stroke (2014)
Coronary artery disease and myocardial infarction (2014 and 2016)
Atrial fibrillation (2015)
Valvular heart disease (2014)
Patent foramen ovale a (2016)

a See Chapter 39 in this text.

A key point whenever one evaluates a patient with an “unexplained” nonarteriosclerotic arterial thromboembolic event is to fully rule out a cardioembolic source. Evaluation must include (1) a detailed medical history, to determine whether symptoms of AF have been present; (2) electrocardiography, including consideration of Holter monitoring to investigate whether asymptomatic or intermittent AF is present; (3) echocardiography, to look for an intracardiac embolic source, including a normal saline bubble study with the patient performing a Valsalva maneuver to assess for a right-to-left shunt. Management of cryptogenic stroke or a transient ischemic attack (TIA) is addressed in a recent (2016) “Practice Advisory” from the American Academy of Neurology.

Nonarteriosclerotic Arterial Occlusive Disease

Evaluation

When evaluating a patient with arterial thromboembolism, it is helpful to apply a systematic thought process regarding causality so that all possible causes are truly considered, including uncommon ones. Box 22.1 presents the four major lines of investigation in identifying cause, and this chapter discusses the various disease entities associated with nonarteriosclerotic arterial occlusive disease. Of course, a thorough medical history and physical examination are the first key steps in determining a possible etiology.

Box 22.1
Structured Approach to the Evaluation of a Patient With Unexplained Arterial Thromboembolism

  • A.

    Determine whether arteriosclerosis is the underlying problem.

    • Are arteriosclerotic changes demonstrated on imaging or pathologic studies (CT, contrast arteriography, or other radiologic imaging; pathologic analysis of specimens)? Review the imaging with an expert radiologist.

    • Are arteriosclerosis risk factors present?

    • Cigarette smoking

    • High blood pressure

    • High LDL cholesterol level

    • Low HDL cholesterol level

    • High lipoprotein (a) level

    • Diabetes mellitus

    • Obesity

    • Family history of arterial problems in young relatives (<50 years of age)

  • B.

    Evaluate the heart as an embolic source.

    • Is atrial fibrillation present (cardiac monitoring for up to 30 days: initial electrocardiography; ambulatory Holter or event monitoring)?

    • Does the patient have a patent foramen ovale (transthoracic ± transesophageal echocardiography with bubble study while patient is coughing and performing a Valsalva maneuver)?

  • C.

    Look for other causes.

    • Is the patient receiving estrogen therapy (contraceptive pill, ring, or patch; hormone replacement therapy)?

    • Is the patient on exogenous testosterone replacement therapy; if yes, what are hemoglobin/hematocrit and on-therapy testosterone serum levels?

    • Does the patient use cocaine or anabolic steroids?

    • Is there evidence of Buerger disease (does the patient smoke tobacco or use cannabis)?

    • Does the patient have cancer? Is the patient up to date with recommended cancer screening?

    • Does the patient have symptoms suggestive of a vasospastic disorder (Raynaud phenomenon) or migraine?

    • Were anatomic abnormalities seen in the artery leading to the ischemic area (web, fibromuscular dysplasia, dissection, vasculitis, external compression)?

    • Does the patient have sickle cell disease?

    • Does the patient have evidence of a rheumatologic or autoimmune disease (arthritis, skin rashes, etc.)? (Consider laboratory workup for vasculitis and immune disorder.)

    • Is there a suggestion of an infectious arteritis?

    • Could the patient have hyperviscosity or cryoglobulins?

  • D.

    Consider a thrombophilia evaluation.

    • Hemoglobin level and platelet count

    • Antiphospholipid antibodies

      • Anticardiolipin IgG and IgM antibodies

      • Anti–β 2 -glycoprotein I IgG and IgM antibodies

      • Lupus anticoagulant

    • Protein C activity

    • Protein S activity and free protein S antigen level

    • ATIII activity

    • Homocysteine level

    • Factor V Leiden and prothrombin 20210 mutation (purpose of testing is to detect the homozygous or double heterozygous state)

    • Do not test for MTHFR polymorphisms, plasminogen activator inhibitor 1, tissue plasminogen activator levels or polymorphisms, increased fibrinogen or factor VIII levels.

AT , Antithrombin; CT , computed tomography; HDL , high-density lipoprotein; Ig , immunoglobulin; LDL, low-density lipoprotein; MTHFR , methylenetetrahydrofolate reductase.

An arterial thromboembolic event can, of course, be the first presentation of underlying asymptomatic permanent or paroxysmal AF detected only by ECG monitoring techniques. Prolonged ambulatory ECG monitoring for up to a month is therefore appropriate.

For the interpretation of radiologic vascular imaging studies, the consulting physician may be well advised to personally review the imaging studies with a trusted radiologist, as the written radiologic report may not provide the details the clinician needs to know for a solid assessment of the etiology of the thromboembolic event. Questions to ask are what the quality of the study and the contrast bolus timing were, whether all vessels supplying the ischemic area were fully visualized, whether evidence of arteriosclerosis or other anatomic abnormalities were seen, and whether a stroke was lacunar or nonlacunar.

It is important to recognize that contrast angiography, such as coronary angiography, is far from the ideal technique for evaluating the type of atherosclerosis that leads to plaque rupture and acute ischemic events; thus it is not an optimal predictor of ischemic events. Alternative techniques to assess for plaques at risk of rupture are now being investigated, including intravascular ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Furthermore, it is important to realize that what may be termed an “angiographically normal” vessel may not actually be a normal vessel, because arteriosclerotic plaques may expand toward the outer layer of the vessel, not causing visible lumen narrowing yet creating plaques that are prone to rupture, resulting in acute ischemic events. An “unexplained” arterial thromboembolic event may thus in reality be caused by arteriosclerosis, particularly if the patient has risk factors for arteriosclerosis. In these patients the most common cause of “unexplained” arterial thromboembolism may well be some underlying arteriosclerosis with plaque rupture.

Spontaneous and traumatic cervical artery dissection is a common cause of “unexplained” stroke in the young. Arterial dissections can be missed on arterial imaging studies. The medical history taking should therefore always include an inquiry about unusual physical activities, particularly in the case of neck artery occlusions, to identify triggers for dissections (e.g., neck or cervical spine intervention by a chiropractor or sudden jerking head movements, as during athletic activities). Sometimes underlying vascular diseases, such as vascular Ehlers-Danlos syndrome (EDS) and others, first manifest as acute ischemic events secondary to arterial dissections.

Treatment

If an arterial ischemic event has occurred, secondary prevention of arterial ischemic events (if arteriosclerosis is the underlying cause) is classically accomplished through antiplatelet therapy and modification of arteriosclerosis risk factors (weight loss, discontinuation of smoking, treatment of hypertension, optimization of lipid and diabetes management, etc.). Revascularization procedures (angioplasty, stenting, arterial bypass) also play a role. This chapter does not discuss these treatments, nor will it discuss management of arterial thrombosis secondary to AF or a cardioembolic source (see Chapter 37 ).

The term embolic stroke of undetermined source (ESUS) was proposed in 2014 to designate patients with unexplained (cryptogenic) nonlacunar ischemic strokes in whom embolism is the likely mechanism of the stroke. The criteria for ESUS are listed in Box 22.2 . The concept does justice to the fact that many cryptogenic strokes are thought to be embolic from an unestablished source. Thus, it has been hypothesized that anticoagulation may be more efficacious than antiplatelet therapy for secondary stroke prevention in ESUS patients. Accordingly, several diagnostic studies are ongoing or planned to determine how often patients with ESUS have underlying covert paroxysmal AF or abnormalities of the heart or aorta; there are also large therapeutic intervention studies comparing one of the direct oral anticoagulants (DOACs) against aspirin for secondary stroke prevention in ESUS. Results of these studies will be paramount in influencing how we will treat patients with ESUS in the future. No similar concept exists for unexplained arterial thrombotic events in organs other than the brain (e.g. extremity, renal, splenic, mesenteric, hepatic, or coronary artery thromboembolism), even though it can be postulated that the same mechanisms might predispose to and explain such events. These types of unexplained arterial thromboses other than strokes could be termed EATUS (embolic arterial thrombosis of undetermined source). Criteria for definition would have to be established. Treatment options would likely be the same as discussed for ESUS—that is, anticoagulant versus antiplatelet therapy.

Box 22.2
Criteria for Embolic Stroke of Undetermined Source

  • 1.

    Ischemic stroke detected by CT or MRI that is not lacunar a

    a A lacunar stroke is defined as a subcortical infarct in the distribution of the small, penetrating cerebral arteries of the cerebral hemispheres and pons, measuring ≤1.5 cm (or ≤2.0 cm on MRI diffusion images) in largest dimension.

  • 2.

    Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia

  • 3.

    No major cardioembolic source of embolism b

    b Permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic heart valve, atrial myxoma or other cardiac tumors, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction <30%, valvular vegetations, or infective endocarditis.

  • 4.

    No other specific cause of stoke identified (e.g., arteritis, dissection, migraine/vasospasm, drug abuse)

CT , Computer tomography; MRI , magnetic resonance imaging.

Hart RG, Catanese L, Perera KS, et al. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke . 2017;48(4):867–872.

Thrombophilia in Arterial Disease

Although the events that lead to arterial thromboembolism are significantly better understood than those that lead to VTE, just the opposite is true for the thrombophilic abnormalities that predispose to arterial and venous events. Multiple inherited abnormalities are known that increase a person's risk of VTE, but only few are known that predispose to arterial events.

Factor V Leiden

Risk Factor for Arterial Thromboembolism

A meta-analysis has demonstrated no statistically significantly increased risk of arterial thromboembolism in FVL carriers compared with noncarriers (odds ratio [OR], 1.21; 95% confidence interval [CI], 0.99 to 1.49). Although patients younger than 55 years of age were at greater risk of arterial ischemic events than older patients with FVL (OR, 1.37; 95% CI, 0.96 to 1.97), this difference was not statistically significant. Thus, for practical clinical purposes, no association between FVL and arterial thromboembolic events in adults has been shown. Because the vast majority of FVL individuals in these studies are heterozygotes, the conclusion regarding a lack of association and relevance applies to individuals with heterozygous FVL status.

Whether the homozygous state for FVL is a risk factor for arterial thromboembolism is not known. The largest study to date evaluating the role of FVL homozygosity in cardiovascular disease included only eight patients homozygous for FVL. To create a somewhat meaningful analysis, these 8 patients were grouped together with 37 double heterozygote patients (with heterozygosity for FVL and the prothrombin 20210 mutation). It was found that this merged group had a 1.6-fold (95% CI, 0.7 to 3.9) increased risk of cardiovascular disease compared with single FVL or single prothrombin 20210 mutation carriers. Although these results did not reach statistical significance, they may suggest that these “stronger” thrombophilias are mild risk factors for arterial disease. However, the number of individuals with FVL homozygosity or a double heterozygous state was obviously too low to provide risk estimates with narrow confidence intervals. Thus one can conclude that it is not clear whether homozygosity for FVL is a risk factor for arterial thromboembolism.

In the pediatric population, FVL has been shown in a meta-analysis and systematic review to be a risk factor for incident stroke, with an odds ratio of 3.26 (95% CI, 2.59 to 4.10). However, the impact of FVL on outcome and recurrence risk is not known.

Clinical Consequences

Because there does not appear to be an association between heterozygosity for FVL and arterial occlusive disease, the finding of a heterozygous mutation in a patient with unexplained arterial thrombotic disease does not lead to any treatment changes from standard therapy in patients experiencing a noncardiogenic thrombotic event; that is, antiplatelet therapy is the appropriate choice. Whether a patient with unexplained arterial thromboembolic disease who is found to be homozygous for FVL should be treated differently is not clear. One can well argue for antiplatelet therapy, as for most patients with noncardiogenic arterial thromboembolism, because platelets play a major role in arterial thrombosis; or one could argue that an anticoagulant may be preferable (i.e., more effective in secondary prevention), because the homozygous FVL state may exert its arterial thrombotic effect through its role in the plasmatic coagulation pathway, which an anticoagulant blocks. Uncertainty regarding the best treatment options—antiplatelet versus anticoagulant therapy—and the risks associated with either treatment must be discussed with the patient.

Prothrombin 20210 Mutation

Risk Factor for Arterial Thromboembolism

A very slight association between the prothrombin 20210 mutation and arterial thromboembolism has been demonstrated in a meta-analysis: the risk of an arterial event was 1.32-fold higher in carriers of the mutation than in noncarriers (95% CI, 1.03 to 1.69). It is not likely that this is a meaningful, clinically relevant association. However, there is some suggestion of a somewhat stronger association between the prothrombin 20210 mutation and stroke and myocardial infarction (MI) in younger patients who do not have arteriosclerosis risk factors but experience arterial events before the age of 50 years: in a 72-patient study, heterozygous genotype was associated with a 3.8-fold increased risk of cerebral ischemia (95% CI, 1.1 to 13.1). Insufficient data exist to assess whether the uncommon homozygous prothrombin 20210 state is a risk factor for arterial thromboembolism. As discussed in the section on FVL, the double heterozygous state (FVL plus prothrombin 20210 mutation) may be a mild risk factor for arterial disease.

In the pediatric population, the prothrombin 20210 mutation has been shown in a systematic review and meta-analysis to be a risk factor for incident stroke, with an odds ratio of 2.43 (95% CI, 1.67 to 3.51). However, the impact on outcome and recurrence risk is not known.

Clinical Consequences

Because of its lack of clinical relevance, finding the heterozygous prothrombin 20210 mutation in a patient with arterial thromboembolism leads to the same discussion and decision regarding treatment as outlined earlier for the heterozygous FVL state: antiplatelet therapy is the appropriate treatment for prevention of recurrent arterial thromboembolism. In respect to the homozygous prothrombin 20210 mutation status and the double heterozygous state (FVL plus prothrombin 20210 mutation), the treatment approach is the same as discussed earlier for FVL homozygosity.

Protein C, Protein S, or Antithrombin III Deficiency

Risk Factor for Arterial Thromboembolism

A number of case reports and small case series over the years have suggested that deficiencies of protein C, protein S, and ATIII may be risk factors for arterial thromboembolism. However, a well-designed large retrospective study of thrombophilic families investigated this issue systematically: 552 individuals belonging to 84 different kindreds were enrolled, and detailed information on previous episodes of arterial thromboembolism, VTE, anticoagulant use, and atherosclerosis risk factors was collected. The primary study outcome was objectively verified symptomatic arterial thromboembolism. Of the 552 subjects, 308 had a deficiency of protein S (35%), protein C (39%), or ATIII (26%). After adjustment for atherosclerosis risk factors and clustering within families, it was found that individuals with a deficiency had a 4.7-fold higher risk of arterial thromboembolism before 55 years of age (95% CI, 1.5 to 14.2; P = .007) and a 1.1-fold higher risk thereafter (95% CI, 0.5 to 2.6) compared with family members without a deficiency, which indicates that these deficiencies are risk factors for arterial thromboembolism in younger persons but not older ones. For separate deficiencies, the arterial thromboembolism risks were 4.6-fold higher in protein S–deficient subjects (95% CI, 1.1 to 18.3), 6.9-fold higher in protein C–deficient individuals (95% CI, 2.1 to 22.2), and 1.1-fold higher in ATIII-deficient subjects (95% CI, 0.1 to 10.9) before 55 years of age. A history of VTE was not related to subsequent arterial thromboembolism. Thus, given the present knowledge, it appears that protein C and protein S deficiencies are moderate risk factors for arterial thromboembolism, whereas ATIII deficiency is not. The latter finding is surprising, because ATIII deficiency is typically viewed as a stronger risk factor for thrombophilia than either protein C or protein S deficiency, at least when it comes to VTE risk. The authors of the study discuss a number of possible pathophysiologic reasons why ATIII deficiency may not be an arterial thromboembolism risk factor, but, in short, the answer is not known. It is possible that less thrombogenic ATIII deficiency variants were studied (i.e., heparin-binding defect deficiencies). Further data need to be collected to clarify whether ATIII deficiency is an arterial thromboembolism risk factor or not.

In the pediatric population, deficiencies of protein C, protein S, and ATIII have been shown in a systematic review and meta-analysis to be risk factors for incident stroke, with an odds ratio of 8.76 for protein C (95% CI, 4.53 to 16.96), 3.20 for protein S (95% CI, 1.22 to 8.40), and 7.06 for ATIII deficiency (95% CI, 2.44 to 22.42). However, the impact on outcome and recurrence risk is not known.

Clinical Consequences

Whether the patient with protein C or protein S deficiency and a nonarteriosclerotic arterial thrombotic event is more effectively treated with antiplatelet or anticoagulant therapy to prevent recurrent arterial thromboembolism is not known. Thus the discussion with the patient with such a deficiency who has had a nonarteriosclerotic arterial thrombotic event mirrors the discussion outlined earlier for patients with FVL homozygosity, homozygosity for prothrombin 20210 mutation, and the double heterozygous state (FVL plus prothrombin 20210 mutation). However, in view of the stronger association of protein S and protein C deficiency with arterial thromboembolism and the pathogenic role that these two natural anticoagulants play in the coagulation process, one can make a stronger theoretical argument for prescribing anticoagulant therapy for patient with protein S or protein C deficiency and arterial thromboembolism. Nevertheless, it is not known whether this is more effective than antiplatelet therapy, or whether the clotting benefit outweighs the bleeding risk to justify the use of anticoagulant over antiplatelet therapy. A patient-specific assessment of bleeding risk and a patient's treatment preference need to be incorporated into the decision making.

Hyperhomocysteinemia, Homocystinuria, Methylenetetrahydrofolate Reductase Polymorphisms

Risk Factor for Arterial Thromboembolism

Elevated plasma homocysteine levels are associated with an increased risk of arterial thromboembolism. Although certain polymorphisms in the methylenetetrahydrofolate reductase ( MTHFR ) gene—the 677C>T (cytosine to thymine substitution at nucleotide 677) and the 12298A>C polymorphisms—can lead to increased serum homocysteine levels, meta-analyses show that in North America, where food is supplemented with folic acid, the MTHFR polymorphisms are not a risk factor for arterial thromboembolism. A number of prospective studies, summarized in several meta-analyses, have shown that lowering homocysteine levels does not decrease the risk of primary or recurrent arterial thromboembolic events.

A number of rare inherited metabolic disorders can lead to arterial thrombotic events, often together with multiorgan damage. They are often single-gene genetic diseases, such as Fabry disease, mitochondrial myopathy, homocystinuria, organic acidurias, and urea cycle disorders. The pediatric hematologist or vascular medicine physician may encounter such patients.

Clinical Consequences

Because the presence of MTHFR polymorphisms is not a thrombophilic state, there is no indication to screen patients with arterial thromboembolism for these mutations. Because lowering of homocysteine levels has no demonstrated clinical benefit with regard to thrombotic risk, there is no indication for treatment of elevated homocysteine levels with B vitamin or folic acid supplementation. Finally, because a finding of elevated homocysteine levels has no clinical management consequences, there is no rationale for testing for homocysteine levels in thrombophilia evaluations. An exception could be for younger patients with arterial thrombosis or VTE in whom homocystinuria is suspected.

Antiphospholipid Syndrome

Risk Factor for Arterial Thromboembolism

Clinical diagnosis of antiphospholipid syndrome (APLS) requires a history of venous or arterial thrombosis, or unexplained recurrent early pregnancy losses, or one or more late pregnancy losses together with persistent laboratory evidence of antiphospholipid antibodies (APLA) in blood samples drawn at least 12 weeks apart. The criteria for definite APLS have been described as the so-called updated Sapporo or Sidney criteria. The syndrome occurs as primary APLS not associated with any other disease and as secondary APLS associated with autoimmune diseases, malignancy, or the use of certain drugs. APLS is highly thrombophilic and is associated with both arterial and venous thrombosis. The risk of thromboembolism associated with anticardiolipin and anti–β 2 -glycoprotein-1 antibodies increases on a continuous scale, with higher titers associated with a higher risk. In addition, a positive result on all three antiphospholipid antibody tests—for lupus anticoagulant, anticardiolipin, and anti–β 2 -glycoprotein 1 (referred to as “triple positivity”) is associated with the highest risk.

Recommendations regarding which tests to perform to assess for APLS vary among different expert panels. The 2012 “International Consensus Guidelines on Anticardiolipin and Anti–β 2 -Glycoprotein-1 Testing” recommend (1) testing the immunoglobulin G (IgG) and IgM isotypes for both anticardiolipin and anti–β 2 -glycoprotein-1 and (2) testing the IgA isotype for both anticardiolipin and anti–β 2 -glycoprotein-1 when the results of all other tests are negative. The 2012 British Committee for Standards in Haematology guideline, on the other hand, is more restrictive and (1) recommends testing for IgG anti–β 2 -glycoprotein-1 antibodies in patients with thrombosis, but for not IgM antibodies, because IgM antibodies do not “add useful information”; (2) recommends performing either an IgG anti–β 2 -glycoprotein 1 or anticardiolipin antibody test but does not indicate whether it is useful or appropriate to obtain both tests; and (3) recommends against IgA isotype testing.

Clinical Consequences

Whether patients with arterial thrombosis and APLS are most effectively treated with antiplatelet therapy, anticoagulant therapy, or a combination of both is not known. In the absence of prospective randomized trial data, no consensus exists, and a variety of treatment approaches have been discussed and recommended. These have included (1) warfarin with a target international normalized ratio (INR) of 1.4 to 2.8 for cerebral arterial events and a target INR of 2 to 3 for noncerebral arterial events ; (2) warfarin with a target INR above 3 or combination anticoagulant and antiplatelet therapy for patients with APS and arterial thromboembolism ; (3) warfarin with a target INR of 2 or 3 or aspirin with or without dipyridamole or clopidogrel for cerebral arterial events, aspirin plus clopidogrel for coronary arterial events, and warfarin with a target INR of 2 to 3 for cerebral arterial events. The 2012 British Committee for Standards in Haematology guideline concludes in its recommendation that “young adults (<50 years) with ischaemic stroke and APLS may be at high risk of recurrence and cohort studies suggest that anticoagulation with warfarin should be considered, but there is no strong evidence that it is better than antiplatelet therapy.” Currently, if the conclusion is that an anticoagulant is indicated, insufficient data exist to determine whether one of the DOACs can be used instead of warfarin.

Fibrinogen Abnormalities

Fibrinogen Plasma Level and Polymorphisms

Risk factor for arterial thromboembolism.

Increasing fibrinogen levels are associated with an increased risk of arterial thromboembolism. Although part of this association is due to the effect of several established arterial thromboembolic and arteriosclerotic risk factors (smoking, elevated blood pressure, hyperlipidemia, age, etc.), adjusting for these risk factors shows that elevated fibrinogen levels by themselves constitute an arterial thrombotic risk factor. Because levels of fibrinogen and C-reactive protein correlate strongly, part of the interindividual variations in fibrinogen levels is likely explained by low-grade inflammation. However, other determinants of fibrinogen levels, many of them yet unknown, exist. Certain single-nucleotide polymorphisms (SNPs)—such as 455G/A in the fibrinogen β chain (FGB) gene as well as several SNPs in genes encoding proteins that play a role in inflammation—are associated with increased plasma fibrinogen levels. However, such SNPs explain less than 2% of the total variance in plasma fibrinogen levels. Association studies between various SNPs and arterial occlusive disease have yielded contradictory or controversial results, as summarized by de Moerloose.

Clinical consequences.

Neither fibrinogen levels nor fibrinogen polymorphisms are useful for clinical management purposes, and routine testing in arterial occlusive disease is not indicated. However, in the case of a patient with unexplained arterial thromboembolism, obtaining a fibrinogen level may be of interest to determine whether it is markedly elevated. Nevertheless, finding such elevated levels does not have treatment implications, because no fibrinogen-lowering medications are in clinical use. Owing to the inconsistent results of genetic testing for the 455G/A FGB gene polymorphism, testing for this SNP is not indicated.

Dysfibrinogenemia and Afibrinogenemia

Inherited disorders of fibrinogen are rare. They can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Patients with dysfibrinogenemia have an unpredictable clinical phenotype. A compilation of data for 250 patients revealed that 55% were asymptomatic (the disorder was detected by chance), 25% had a tendency to bleeding, and 20% were reported to have a tendency to thrombosis. Thrombotic events appear to be mostly venous, but arterial events have also been reported. Because there is a clear link between certain dysfibrinogenemia-causing mutations and thrombosis, genetic workup of individuals and families with dysfibrinogenemia with gene sequencing may be advisable.

Thromboembolism has also paradoxically been reported in patients with afibrinogenemia. Possible explanations have been put forward, such as that these patients have increased circulating thrombin levels because fibrin, which normally acts as antithrombin I (ATI) and binds and sequesters thrombin, is missing. At present there is no clear relationship between the genetic defect of afibrinogenemia and thrombosis; thus gene sequencing in asymptomatic individuals, although scientifically worthwhile, does not appear to be helpful clinically.

Elevation of Factor VIII and Von Willebrand Factor

Risk Factor for Arterial Thromboembolism

Several prospective studies of the role of factor VIII and von Willebrand factor (VWF) in arterial thrombosis (mainly coronary heart disease) have been performed in healthy individuals and patients with previous cardiovascular disease, and the data have been summarized. Although the majority of studies showed an association between high levels of factor VIII and VWF and arterial thrombosis, others have failed to confirm such findings. Elevations in factor VIII have a familial-inherited component, as documented by studies in families with thrombophilia and in monozygotic twins. No genetic polymorphism has been identified to explain elevations in factor VIII level. Factor VIII levels are higher in persons with non-O blood types.

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