Page 2394 - Hematology_ Basic Principles and Practice ( PDFDrive )

2136 Part XII Hemostasis and Thrombosis

Meta-analyses of observational studies have failed to demonstrate a characterized by a pentad of thrombocytopenia, microangiopathic
significant association between the factor V Leiden mutation and hemolytic anemia, fever, renal failure, and neurologic abnormalities
ischemic stroke in adults, although some small case-control studies including ischemic stroke (see Chapter 134)
have reported an increased risk of ischemic stroke in women with
factor V Leiden using oral contraceptives. Two large prospective
population studies, the Physicians’ Health Study and the Cardiovas- Paraproteinemias
cular Health Study, failed to demonstrate a significant association
between the prothrombin G20210A mutation and ischemic stroke The paraproteinemias, including Waldenström macroglobulinemia,
risk, although a large meta-analysis of 19 case-control studies reported multiple myeloma, and POEMS syndrome (characterized by a
a modest association. There is no evidence to support an association plasma-cell proliferative disorder, typically myeloma, polyneuropathy,
between protein C, protein S, or antithrombin deficiency and ische- with involvement of multiple other organ systems) are also associated
mic stroke risk in adults. with an increased risk of ischemic stroke and hemorrhagic stroke
(because of thrombocytopenia).

Antiphospholipid Syndrome
Genetic Risk Factors
Antiphospholipid syndrome is reviewed in Chapter 141. Stroke is the
main acute arterial thrombotic complication of antiphospholipid A substantial body of evidence from twin, family, and animal
syndrome, and is reported to be the initial clinical manifestation in studies supports a genetic contribution to stroke risk. A recent
13% of patients subsequently diagnosed with antiphospholipid meta-analysis of genome-wide association studies from more than
syndrome. However, the overall association between antiphospholipid 12,000 patients with ischemic stroke identified three loci with
antibodies (without other features of the syndrome) and ischemic genome-wide significance for ischemic stroke—PITX2 and ZFHX3,
stroke is less certain. Anticardiolipin antibodies have been associated previously associated with an increased risk of atrial fibrillation,
with ischemic stroke in some studies, especially in young women, but were associated with an increased risk of ischemic stroke, whereas
not in others. The lupus anticoagulant is a more potent risk factor HDAC9 was associated with an increased risk of large-artery stroke.
for ischemic stroke. For example, in the Risk of Arterial Thrombosis Another meta-analysis reported that APOEε2 carrier status was
in Relation to Oral Contraceptives (RATIO) study, the odds ratio associated with an increased burden of white matter hyperintensities
(OR) for an association between the lupus anticoagulant and ischemic (a marker for prior cerebrovascular disease) and risk of ischemic
stroke was 43.1 (95% CI, 12.2–152.2) compared with an OR of 2.3 stroke
(95% CI, 1.4–3.7) for anti-β 2 -glycoprotein I antibodies and no sig- The concordance rate for stroke is 65% higher in monozygotic
nificant association reported for anticardiolipin antibodies. Current twins compared with dizygotic twins, with a range of 12.8%–19.0%
AHA guidelines recommend antiplatelet therapy for secondary pre- in monozygotic twins and 3.6%–13.0% in dizygotic twins. Family
vention of ischemic stroke in patients with cryptogenic ischemic history of stroke increases the risk of ischemic stroke by about
stroke who do not meet the criteria for antiphospholipid syndrome 75% and the presence of a first-degree relative with a history of
but have antiphospholipid antibodies. For patients with cryptogenic hemorrhagic stroke is associated with a sixfold increase in risk of
ischemic stroke who meet the diagnostic criteria for antiphospholipid hemorrhagic stroke. A number of monogenic disorders have been
syndrome and who have persistently moderate-to-high antiphospho- associated with an increased risk of ischemic stroke, including Marfan
lipid antibody titers for more than 12 weeks, oral anticoagulant syndrome, Fabry disease, familial moyamoya disease, homocyste-
therapy for secondary prevention of ischemic stroke can be consid- inuria, sickle cell disease, and MELAS. Rare Mendelian forms of
ered. The most recent American College of Chest Physicians (ACCP) stroke have been described such as CADASIL and CARASIL, which
guideline recommends oral anticoagulant therapy with a target manifest as small-vessel ischemic stroke. However, most monogenic
international normalized ratio (INR) of 2–3 for the latter group disorders are infrequent and thus have limited impact on the wider
population, despite their marked effect on individual risk in young
populations.
Sickle Cell Disease

Sickle cell disease is associated with an increased risk of stroke, par- CLINICAL MANIFESTATIONS
ticularly in those homozygous for the sickle cell gene. The risk of
stroke is 11% at 20 years of age, 15% at 30 years, and 24% at 45 Clinical Presentation
years. The most common mechanism underlying ischemic stroke in
sickle cell disease is believed to be large-artery arteriopathy secondary Stroke is a clinical diagnosis, supported by the results of neuroimag-
to hyperplasia of the intima from repeated endothelial injury. ing (computed tomography [CT] or MRI of the brain). CT of the
brain may be normal in patients with acute ischemic stroke, and cases
of MRI-negative stroke also occur. With advances in neuroimaging,
Myeloproliferative Disorders an increasing proportion of patients (about one-quarter) presenting
with transient neurologic deficits (previously diagnosed as TIA) have
Myeloproliferative disorders, such as polycythemia vera and essential small infarcts identifiable on high-quality MRI. Clinically, stroke is
thrombocytopenia, are uncommon conditions associated with an characterized by the sudden onset of typically a focal neurologic
increased risk of stroke. In a randomized controlled trial of daily deficit, lasting more than 24 hours or leading to death because of a
aspirin in 518 patients with polycythemia vera, the combined rate of presumed vascular cause. Common presenting features are lateralizing
ischemic and hemorrhagic stroke was 1.2% in the aspirin group weakness of the upper extremities and/or lower extremities, facial
compared with 3.8% in the control group over 3 years. Defective weakness, speech abnormalities (aphasia, dysarthria), visual loss
platelet function in these disorders also results in an increased risk (monocular visual loss or homonymous hemianopia), reduced level
of ICH. of consciousness, ataxia, diplopia, vertigo, and headache. A number
of clinical conditions can mimic stroke. Among patients admitted to
a hospital with suspected stroke, only about two-thirds are subse-
Thrombotic Thrombocytopenic Purpura quently diagnosed with stroke. Common stroke mimics include
migraine, seizure, syncope, hypoglycemia, primary or secondary brain
Thrombotic thrombocytopenic purpura is an uncommon systemic tumors, transient global amnesia, and toxic-metabolic disturbances
disorder associated with an increased risk of ischemic stroke. It is with delirium.