Documentos de Académico
Documentos de Profesional
Documentos de Cultura
Protein C, protein S, and antithrombin III (ATIII) deficiencies are all extremely rare, with a
frequency ranging from 1 per 1000 to 1 per 5000 in the general population. In a study by
Martinez et al, 10 of 60 patients (17%) had an acute ischemic stroke that was attributed to
deficiencies in protein C, protein S, or ATIII.[4]
Cerebral vein thrombosis is a more frequent presentation than arterial stroke. No clear-cut
association has been found between protein C or ATIII deficiency and arterial strokes,
although patients with low protein C levels at the time of acute stroke have poor outcomes.
However, a prospective study did find free protein S deficiency in 23% of young patients
with stroke of uncertain cause, but this finding could be associated with higher levels of C4b
(an acute phase reactant that decreases free protein S levels).
Once a deficiency of protein C, protein S, or ATIII is identified, differentiating between
congenital and acquired cases is important.
Erythrocyte disorders
Although sickle cell disease itself does not alter hemostasis, it is believed to be a risk factor
for stroke by vascular damage. The mechanism is a progressive, segmental narrowing of the
distal internal carotid artery and portions of the circle of Willis and proximal branches of the
major intracranial arteries. Sickle cell plugging of microcirculation and cerebral veins has
also been noted.
The incidence of stroke in patients with hemoglobin SS is 10%; in those with hemoglobin
SC, it is 2-5%. The incidence of brain infarction peaks around age 10 years.
Other erythrocyte disorders, such as polycythemia vera, cause hyperviscosity-related
diminished cerebral blood flow.
Hyperhomocystinemia
Hyperhomocystinemia is associated with vasculopathy. Patients with stroke have
homocysteine levels 1.5 times those of age- and sex-matched controls. Prospective and casecontrol studies have found that the incidence of stroke increases with increasing
homocysteine levels. Thus, all young persons with unexplained stroke, especially those with
atherosclerosis, should have homocysteine levels checked. Unlike most prothrombotic states,
hyperhomocystinemia causes more arterial strokes than venous.
Individuals who are homozygous for cystathionine beta synthase deficiency develop
premature atherosclerosis and often experience a stroke early in life. Homozygous patients
clinically manifest a marfanoid habitus, lenticular dislocations, and other skeletal
abnormalities, in addition to strokes. These patients excrete homocysteine in the urine and
have 20-fold or greater elevations of homocysteine and related amino acids in the plasma.
However, patients who are heterozygous for cystathionine beta synthase deficiency can
develop a mild clinical picture.
A mutation in methylenetetrahydrofolate reductase (MTHFR) in the folate pathway has been
correlated with an increase in plasma homocysteine and may be a cardiovascular disease risk
factor. However, hyperhomocystinemia is more commonly acquired; the most common
acquired cause of hyperhomocystinemia is dietary deficiency of folate and vitamin B-12.
MTHFR C677T, homozygous TT, or A1298C are not risk factors for cerebral arterial or
venous thrombosis.
The range for a normal serum homocysteine is controversial, but levels greater than 14
mol/L, the highest quartile of homocysteine levels, significantly increase the risk of stroke.
Folate and vitamin B-12 levels should be checked, as evidence that folate and B-12
deficiencies can lead to elevated homocysteine levels is definite.
Older age and renal insufficiency can lead to elevated homocysteine levels, as can the use of
antiepileptic drugs such as phenytoin.
Autoantibody syndromes
Antiphospholipid syndrome (APS) (ie, presence of antiphospholipid [aPL] antibodies or
lupus anticoagulant [LA]) occurs in 10% of patients with acute ischemic stroke. This number
is higher in younger patients. Recognizing aPL antibodies is important, as they are associated
with a hypercoagulable state characterized by fetal loss, thrombocytopenia, and venous and
arterial thrombosis.
The 3 major types of clinically relevant aPL antibodies are anticardiolipin (aCL) antibodies,
LA, and anti2 -glycoprotein I (anti-2 GPI) antibodies. In a patient with APS, the
concordance of aCL and LA may be up to 70%. Up to 10% of patients with aPL antibodies
are positive solely for anti-2 GPI antibodies.
The mechanisms of thrombosis are heterogeneous and include cardiac valve lesions that
embolize, hypercoagulable states, and cerebral vascular endotheliopathy. They tend to
interfere in some way with normal endothelial cell functions via the protein C and protein S
anticoagulant pathway.
In 2006, the Sapporo Criteria for APS were updated.[8] Clinical criteria include vascular
thrombosis and pregnancy morbidity. The laboratory criteria on 2 or more occasions more
than 12 weeks apart include the following:
LA
There is evidence that at least one lipoprotein, lipoprotein(a) (Lp(a)), is elevated in selected
populations with cerebrovascular disease. Many studies have shown elevated Lp(a) to be a
potent risk factor for stroke, especially in young individuals. However, a clear role for the
treatment of elevated Lp(a) in preventing strokes has yet to be established.
Diagnosis
In patients diagnosed with blood dyscrasias, a search should be made for clinical findings of
thrombosis elsewhere, including venous thrombosis. In a few instances, antiphospholipid
syndrome (APS) is associated with Sneddon syndrome, which is manifested by livedo
reticularis and cerebrovascular disease.
Other conditions that should be considered when evaluating blood dyscrasias and stroke
include cardioembolic stroke; dissection syndromes; fibromuscular dysplasia; lacunar
syndromes; anterior circulation stroke; cerebral venous thrombosis; cerebellar, intracranial,
and subarachnoid hemorrhage; epidural and subdural hematomas; seizures and epilepsy;
atherosclerotic disease of the carotid artery; and transient ischemic attack.
Metabolic diseases have also been associated with stroke, including
hyperglycemia/hypoglycemia; syndrome of mitochondrial encephalomyopathy, lactic
acidosis, and strokelike episodes (MELAS); methylmalonic acidemia; and propionic
acidemia.
Coagulation Studies
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are recommended
tests for all patients in whom a hypercoagulable state is suspected.
PT is used to diagnose deficiencies or inhibitors of factors I, II, V, VII, and X. It also is used
to monitor warfarin therapy and screen for vitamin K deficiency. PT results are usually
expressed in terms of a standardized international normalized ratio (INR).
APTT is used to diagnose deficiencies or inhibitors of factors VIII, IX, XI, and XII, as well as
to diagnose deficiency of von Willebrand factor. This study is also used to monitor heparin
therapy and as a screening test for lupus anticoagulant (LA).
Additional testing is aimed at specific hypercoagulable states that may be suspected on the
basis of patient history and findings (see Evaluation of Patients With Blood Dyscrasia and
Stroke).
Thrombin time
Thrombin time is used to diagnose fibrinogen deficiencies, to detect heparin resistance, and
to monitor fibrinolytic therapy.
Homocysteine levels
Fasting homocysteine level is measured most commonly by high-performance liquid
chromatography (HPLC) with fluorescence detection. Hyperhomocystinemia is associated
with arterial and venous thrombosis and is to be distinguished from autosomal recessive
homocystinuria. Elevated homocysteine levels are encountered in the elderly; in patients with
nutritional deficiency of vitamin B-6, B-12, or folate; and in renal insufficiency and other
disorders.
Hemoglobin electrophoresis
Hemoglobin electrophoresis enables detection of hemoglobin SS and SC. The test should be
ordered in black individuals and others whose ethnicity puts them at particular risk of sickle
cell anemia.
Angiography
Obtain a cerebral angiogram if noninvasive tests yield inconclusive results. Magnetic
resonance angiography (MRA) or computed tomography angiography (CTA) may be helpful
in cases of arterial stroke.
Ultrasonography
Transcranial Doppler ultrasonography is used to assess stroke risk in patients with sickle cell
anemia.[9, 10] This imaging modality is most useful in children, as it allows detection of
increases in mean blood velocities within the circle of Willis and middle cerebral artery as the
arteriopathy of sickle cell disease develops. Transcranial Doppler ultrasonography is also
helpful in the assessment of intracranial arterial stenosis or occlusion.
Consider carotid ultrasonography if extracranial stenosis or occlusion is suspected.
The recent evidence-based guidelines have made recommendations on topics that are relevant
to stroke/transient ischemic attack (TIA) patients with hypercoagulable state, as follows[11] :
Patients should be fully evaluated for alternative mechanisms of stroke. In the absence
of venous thrombosis in patients with arterial stroke or TIA and a proven
thrombophilia, either anticoagulant or antiplatelet therapy is reasonable (Class IIa;
level of Evidence C).
For patients with cryptogenic ischemic stroke or TIA in whom an APL antibody is
detected, antiplatelet therapy is reasonable (Class IIa; level of Evidence B).
For patients with ischemic stroke or TIA who meet the criteria for the APL antibody
syndrome, oral anticoagulation with a target international normalized ration (INR) of
2-3 is reasonable (Class IIa; level of Evidence B).
For adults with sickle cell disease and ischemic stroke or TIA, the general treatment
recommendations cited above are reasonable with regard to control of risk factors and
the use of antiplatelet agents (Class IIa; level of Evidence B).
In the absence of trial data to define the optimal duration of anticoagulation for acute
central venous thrombosis, it is reasonable to administer anticoagulation for at least 3
months, followed by antiplatelet therapy (Class IIa; level of Evidence C).
For pregnant women with ischemic stroke or TIA and high-risk thromboembolic
conditions such as hypercoagulable state, the following options may be considered:
adjusted-dose unfractionated heparin (UFH) throughout pregnancy, for example, a
For women who have had ischemic stroke or TIA, postmenopausal hormone therapy
(with estrogen with or without a progestin) is not recommended (Class III; level of
Evidence A).
Consultations
Hematologic consultation may be requested when the clinical diagnosis is uncertain, when
abnormal test results require clarification, and when recommendations on the management of
the blood dyscrasia is needed.
Anticoagulation
Patients with hypercoagulable states such as activated protein C (APC) resistance; protein C,
protein S, or antithrombin III (ATIII) deficiencies; or antiphospholipid syndrome (APS) are
treated with anticoagulants for stroke prophylaxis, especially if deep vein thrombosis (DVT)
is present or recurrent thrombotic events have occurred. The anticoagulation regimen usually
is started with intravenous (IV) heparin, maintaining the activated partial thromboplastin time
(aPTT) at 2-3 times normal, until an oral anticoagulant (ie, warfarin) is able to achieve a
therapeutic prothrombin time (PT) (international normalized ratio [INR]).
In protein C and S deficiencies, starting heparin before warfarin is imperative to avoid
warfarin-induced skin necrosis. The level of anticoagulation in terms of PT (INR) required
for stroke prophylaxis is uncertain. In the treatment of APS, a retrospective study reported
that an INR of 3.0-3.5 was more effective than the routinely used INR of 2.0-3.0[12] ; however,
2 prospective studies showed that an INR of 2.0-3.0 is sufficient in APS.[13, 14] A sizable
fraction of neurologists avoid treating patients with stroke with a heparin bolus, as this is
thought to increase the risk of intracranial bleed.
Results of the Antiphospholipid Antibodies in Stroke Study (APASS) demonstrated that there
was no difference between aspirin and warfarin for treatment of patients with anticardiolipin
(aCL) antibodies or lupus anticoagulant (LA).[15] It is important to emphasize that APASS did
not look specifically at APS. However, it was noted that the risk of recurrent thrombosis was
increased in patients who had both aCL antibodies and LA. In addition, patients enrolled in
APASS had low aCL antibody titers and a low INR, and the study was criticized for these
limitations.
Thus, in deciding whether patients need to be treated with warfarin, their LA status and hightiter aCL antibodies should also be borne in mind, and high-intensity anticoagulation (target
INR > 3.0) should be considered in appropriate patients. A clinical trial with defined APS and
high titers of aCL antibodies and LA with high-intensity regimen of warfarin would probably
answer the issue.
Currently, 3 new oral anticoagulants are available: Dabigatran (oral thrombin inhibitor),
rivaroxaban (factor X inhibitor), and apixaban (factor X inhibitor). These agents are FDA
approved to prevent thromboembolic events, including stroke/TIA in patients with atrial
fibrillation. Their role in the prevention of stroke/TIA in patients with hypercoagulable state
is yet to be determined.
Vitamin Supplementation
Hyperhomocystinemia is treated with vitamin supplementation, usually folic acid and
sometimes pyridoxine (vitamin B-6) and vitamin B-12, as well. Although the Vitamin in
Stroke Prevention (VISP) trial results did not show any significant benefit of treatment with
high doses of folic acid, pyridoxine, and vitamin B-12 in reducing adverse vascular outcomes
in patients with nondisabling strokes and elevated homocysteine (relative to low doses of
these vitamins), it did show that there was a persistent and graded association between total
homocysteine and outcomes, irrespective of the treatment group.[18] A larger study with high
baseline homocysteine levels and longer follow-up may help resolve the issue.
Dietary Issues
Hyperhomocystinemia has been attributed to dietary deficiency of vitamin B-6, vitamin B-12,
or folic acid, especially in older patients with poor nutritional intake.
Patients with hypercoagulable states that may cause stroke typically take the oral
anticoagulant warfarin. For these patients, monitoring vitamin K in the diet is important, as it
may alter the efficacy of warfarin.
Outpatient Monitoring
Patients being treated with an oral anticoagulant must be monitored with outpatient blood
testing for prothrombin time (PT) (international normalized ratio [INR]). Initially, PT (INR)
should be tested frequently to determine the maintenance dose (ie, daily to twice a week);
once a regular maintenance dose is determined, PT (INR) may be checked monthly.
Special Considerations
7. Reuner KH, Ruf A, Grau A, Rickmann H, Stolz E, Jttler E, et al. Prothrombin gene
G20210-->A transition is a risk factor for cerebral venous thrombosis. Stroke. 1998
Sep. 29(9):1765-9. [Medline]. [Full Text].
8. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al.
International consensus statement on an update of the classification criteria for
definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb. 4(2):295306. [Medline].
9. Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, et al. The use of
transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med.
1992 Feb 27. 326(9):605-10. [Medline]. [Full Text].
10. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a
first stroke by transfusions in children with sickle cell anemia and abnormal results on
transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2. 339(1):5-11.
[Medline]. [Full Text].
11. [Guideline] Furie K, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al.
Guidelines for prevention of stroke in patients with ischemic stroke or transient
ischemic attack: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2011. 42(1):227-276. [Medline].
[Full Text].
12. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The
management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J
Med. 1995 Apr 13. 332(15):993-7. [Medline]. [Full Text].
13. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A
comparison of two intensities of warfarin for the prevention of recurrent thrombosis in
patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18.
349(12):1133-8. [Medline]. [Full Text].
14. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. A
randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic
therapy for the prevention of recurrent thrombosis in patients with the
antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May. 3(5):848-53.
[Medline].
15. Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR, et al.
Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients
with ischemic stroke. JAMA. 2004 Feb 4. 291(5):576-84. [Medline]. [Full Text].
16. Ware RE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to blood
transfusions for the prevention of recurrent stroke in children with sickle cell disease.
Blood. 1999 Nov 1. 94(9):3022-6. [Medline]. [Full Text].
17. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, et al.
Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996 Aug 8.
335(6):369-76. [Medline]. [Full Text].
18. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al.
Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke,
myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention
(VISP) randomized controlled trial. JAMA. 2004 Feb 4. 291(5):565-75. [Medline].
[Full Text].
http://emedicine.medscape.com/article/1160261-overview#showall