Hematologic Disorders and Stroke

Key Points

Patients with hematologic disorders, such as hereditary thrombophilias, are at higher risk for venous thrombosis than ischemic stroke, but these disorders account for a small, but important, percentage of stroke patients.
The hereditary causes of protein S, protein C, and antithrombin III deficiencies, in addition to antiphospholipid antibody syndrome, are considered to be very high risk for recurrent thromboembolic events.
There are no clinical trials to guide secondary prevention in the setting of thrombophilias, and therefore the majority of patients are treated with antiplatelet therapy, except in the case of primary antiphospholipid antibody syndrome, in which the general consensus is to treat with adjusted dose warfarin in the range of international normalized ratios 2 to 3 because of the high risk of recurrent thromboembolism.
Myeloproliferative disorders, including polycythemia rubra vera and essential thrombocythemia, are important causes of ischemic stroke, with high risk of morbidity and mortality. Hematology consultation is essential to guide therapy, monitoring for other leukemias, and genetic testing.
Heparin-induced thrombocytopenia (HIT) is an important consequence of heparin therapy and is important to recognize because of the risk of severe thrombosis. HIT type II is the most serious and requires stopping heparin and switching to alternative anticoagulation with heparinoids or hirudins.
Sickle cell anemia is associated with stroke primarily in children, but this can continue throughout an affected individual’s lifetime. In children, transcranial Doppler studies showing greater than 200 cm/s in the middle cerebral arteries studies can identify those at highest risk of stroke and therefore guide transfusions for prevention.
Testing for thrombophilias should be reserved for ischemic stroke patients who younger than age 55 years, with strong family or personal history of venous thrombosis, pregnancy complications, and no clear explanation for the stroke (i.e., vasculopathy, cardioembolic source, or absence of typical risk factors for stroke).

Introduction

The formation of a thrombus within an artery is a frequent consequence of vascular endothelial injury, such as happens with rupture of an atherosclerotic plaque or from relative stasis of blood in the auricle of the fibrillating left atrium. Abnormalities in hemostasis that predispose to thrombotic events are referred to as either a “hypercoagulable state” or a “thrombophilia,” whereas conditions in which thrombotic events are more prevalent, such as diabetes mellitus, are considered to be a prothrombotic state; however, these terms are frequently interchanged. A detailed understanding of the hypercoagulable state hones the mechanistic diagnosis of stroke and may also help to define treatment. Some measures of hemostatic function show promise as biomarkers for monitoring the risk of stroke.

Pathogenesis of Thrombosis

Vascular Injury

Hemostasis is a complex system of reactions that are normally held in check by a dynamic interplay between the normal blood vessel endothelial surface and certain regulatory plasma proteins that prevent activation of platelets and the prothrombin pathway. The circulating regulatory plasma proteins include protein C, protein S, antithrombin III (ATIII), tissue factor pathway inhibitor (TFPI), and protein Z. ^, On the vascular endothelium, a key protein, thrombomodulin, promotes the activation of protein C. The combination of activated protein C (APC) with another natural anticoagulant, protein S, results in a complex that can rapidly inactivate activated coagulation factors Va and VIIIa, thereby suppressing thrombin activation (see, for example, Fig. 42.1 ). Protein S is found in the plasma as both an active (free) and an inactive (C4b-binding protein) form. A member of the coagulation cascade, protein Z, along with protein Z–related protease inhibitor, directly degrades factor Xa.

Fig. 42.1, Regulation of factor V activity by thrombin and activated protein C. Thrombin activates protein C, which degrades factor V. Factor V Leiden is resistant to inactivation by protein C, which leads to a hypercoagulable state.

The vascular endothelium forms another key element in the regulation of hemostasis by expressing a number of regulatory molecules on the endothelial surface. Among these are thrombomodulin and the glycosaminoglycan, heparin, which by binding ATIII, greatly amplifies the ATIII functional ability to rapidly neutralize thrombin and other activated prothrombotic serine proteases, including factors Xa and IXa. ^, Healthy vascular endothelium also inhibits platelet adhesion and aggregation by several mechanisms. When the endothelium is stimulated by local injury, inflammation, or other thrombogenic processes, prostacyclin (PGI2) is released. PGI2 causes vasodilatation and inhibits platelet plug formation. Vascular endothelium also synthesizes and releases nitric oxide, a potent vasodilator and inhibitor of platelet activation. ^, Furthermore, if a clot does begin to form, the vascular endothelium promotes local fibrinolysis via the synthesis and release of tissue plasminogen activator (tPA).

Although usually a barrier against thrombosis, the normal vascular endothelium becomes a strongly prothrombotic surface when injured. Mediators of inflammation such as interleukin-1, tumor necrosis factor, and immune complexes can induce the endothelium to express tissue factor and other such substances, expose binding sites for clotting factors, and downregulate thrombomodulin expression. With severe injury, endothelial cells may be lost from the vascular surface altogether, thereby exposing thrombogenic subendothelial tissues, as happens with rupture of an atheromatous plaque. ^, The brain vascular endothelium also appears to vary in its effectiveness as a barrier against thrombosis because the expression of thrombomodulin within the cerebral circulation varies regionally and is limited in amount compared with systemic vessels.

Factor V Leiden, Antithrombin III, Protein C, Protein S, and Protein Z Deficiencies; Prothrombin G20210A Polymorphism; and von Willebrand Factor

Hereditary Deficiencies

Genetic modifications that affect function or concentration of the regulatory coagulation proteins in the hemostatic pathways are associated with an increased risk of stroke. As a general rule the risk is similar for both ischemic stroke and myocardial infarction (MI) in adults, but there are some exceptions. Abnormalities in proteins S, C, and ATIII are associated most strongly with stroke in neonates and young children. Their role in adult stroke is less certain, but recent studies suggest importance in selected populations. For example, the Atherosclerosis Risk in Communities (ARIC) study reported that the lowest quintile of protein C levels was associated with a 1.5-fold greater risk of ischemic stroke than the highest quintile, and that these levels were most likely associated with nonlacunar stroke subtype.

The presence of factor V Leiden, APC resistance, and the prothrombin G20210A gene mutation has been associated with stroke in children and young adults. In addition, low levels of protein Z have all been associated with increased risk of stroke. APCR, caused by a mutation in factor V (factor V Leiden), which renders factor Va unable to be cleaved by APC, is by far the most common inherited defect associated with venous thrombosis. This mechanism and the related role of thrombin activation and protein C are summarized in Fig. 42.1 . In white populations, the factor V Leiden defect is present in 5%–7% of the normal population and accounts for more than 95% of the total APC resistance. Although APC resistance due to factor V Leiden has a well-recognized association with cerebral venous thrombosis, the relationship to arterial stroke in adults is less certain; currently, the strongest evidence suggests a role in children with stroke. In adult populations, such as in the Physicians’ Health Study, the presence of factor V Leiden did not increase the risk of stroke or MI, and similar results have been found in some case-control studies. In addition, the recent FUTURE study did not find an association between prothrombotic factors, including factor V Leiden. However, one large study showed that in young patients with recurrent stroke, factor V Leiden was significantly more common in patients with large infarcts (13.6%; P < .025; confidence interval [CI], 1.16–4.34) than in the stroke-free control subjects (6.5%). Another recent study found that levels of factor V Leiden were elevated compared with healthy controls and similar in patients with acute ischemic stroke and venous thromboembolism. Furthermore, a meta-analysis of 18 case-control studies in adults with stroke, both young and those older than 50 years, found inconsistent results with such a heterogeneous mixture of subjects. Among unselected individuals with ischemic stroke, the odds ratio (OR) for factor V Leiden was 1.40 ( P = not significant), whereas the OR associating stroke with factor V Leiden was statistically significant at 2.73 ( P = .003) when individuals who were likely to have a prothrombotic state were specified. In the Genetics of Early Onset Stroke (GEOS) study, there was no significant association between the Factor V Leiden mutation and stroke in young men and women versus age-matched controls, and this relationship did not change when the analysis was restricted to strokes of undetermined etiology.

In adults with stroke, the association between inherited deficiencies in protein C, protein S, and ATIII and arterial thrombosis is less convincing. ^, Case-control and cohort studies provide inconsistent results: some show a positive relationship to stroke while others show a negative relationship. Such discrepancies reflect differences in the selection of subjects to be tested. In a prospective case-control study that initially enrolled subjects with acute MI, it was found on follow-up that individuals with low levels of protein C and/or antithrombin, even if in the low normal range, tended to have an increased risk of recurrent cardiovascular events including stroke (4 of the 35 patients with recurrent events). A recent study found no link between APC resistance and increased risk of subsequent stroke in patients with stroke or transient ischemic attack (TIA).

An increased risk of stroke is also reported with elevated levels of von Willebrand factor (vWF), factor VIIIc, and plasma fibrinogen. ^, Unlike the other regulatory proteins that interact with normal vascular endothelial function, vWF comes into play when endothelium is damaged, and the factor interacts with platelet activation. The levels of vWF are influenced by inflammation, genetics (e.g., ABO blood groups), and ADAMTS (A Disintegrin and Metalloprotease with ThromboSpondin motif) levels. When coupled with inflammation, high levels of vWF triple the relative risk of stroke compared with individuals with low vWF levels. Lip et al. found that constantly elevated vWF levels in persons with chronic atrial fibrillation were associated with an increased likelihood of cardioembolic-related stroke. From a clinical perspective, many of these studies emphasize the importance of the role of inflammation as a critical influence on levels and function. When considering the results of measurements obtained during the early phase of stroke, one must keep in mind that levels of these substances can be affected by the extent of the early inflammatory phase response. For example, one study reported that low protein S levels were common in patients hospitalized for any reason, which makes the role of this substance in stroke much more difficult to establish.

A single mutation in the 3′-untranslated region of the prothrombin gene resulting in a G-to-A (glycine-to-alanine) substitution has been associated with familial thrombophilia. Prothrombin, or factor II, is the precursor of thrombin. A vitamin K–dependent zymogen, this protein is produced by the liver and has a central role in the conversion of fibrinogen to fibrin. Prothrombin also has inhibitory functions that limit the hemostasis process (see Fig. 42.1 ). Thrombin also has regulatory functions that are important in the pathogenesis of atherosclerosis, such as initiating platelet aggregation and endothelial activation.

Factor II G20210A occurs in approximately 2.5% of the general population and in 6% of patients with a family history of venous thrombosis. This mutation is seen almost exclusively in white persons; in the presence of traditional vascular risk factors, the addition of factor II G20210A has a synergistic effect on the risk of MI, but results are conflicting. Few studies have investigated the role of factor II G20210A in stroke. A case-control study of consecutive patients with stroke or TIA found no difference in prevalence of the prothrombin mutation between the patients and control subjects. Another study of 72 young patients with stroke and without traditional vascular risk factors found an increased prevalence in patients compared with control subjects (9.7% of patients had heterozygous mutations versus 2.5% of control subjects; 2.8% of patients had homozygous mutations versus 0% of control subjects). The stroke risk associated with the heterozygous mutation was increased 3.8-fold, either mutation was increased 5.5-fold, and the homozygous mutation was increased 208-fold. According to a recent meta-analysis, a body of evidence is also developing that suggests G20210A mutations may be a risk factor for developing atrial fibrillation as well as stroke. From a clinical perspective, more studies are needed to clarify the role of this mutation in stroke from either a diagnostic or therapeutic perspective.

Combined Genetic Prothrombotic Factors and Association With Patent Foramen Ovale

In a cohort of young (aged 55 or younger) patients with ischemic stroke and nonstroke controls, genetic polymorphisms for factor V Leiden, G20210A prothrombin, C677T MTHFR, and 4G/5G PAI-1 were evaluated along with other traditional stroke risk factors. The prothrombotic gene mutations were added to provide a genetic sum score, which resulted in an independent association with ischemic stroke in this cohort (OR 2.31, 95% CI 1.64–3.25), in addition to decreased high-density lipoprotein (HDL) cholesterol, hypertension, obesity, and smoking. The authors concluded that these prothrombotic genetic abnormalities act synergistically to increase the risk of ischemic stroke in young patients.

Although patent foramen ovale (PFO) appears to be a conduit for paradoxical embolism in patients with prothrombotic disorders, one study showed that FII G20210A was associated with cryptogenic stroke regardless of the presence of PFO. In addition, there was no increased association with factor V Leiden mutation and PFO. There has also been an association between prothrombotic states and the development of left atrial appendage thrombus without documented atrial fibrillation. In these cases, patients had higher levels of plasminogen activator inhibitor (PAI), thrombin-antithrombin complexes, and vWF than controls. These findings suggest that prothrombotic blood alterations may play a role and potentially are the proximate causes in some cases of cardioembolic stroke from thrombus of left atrial appendage and PFO.

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