eMedicine Specialties > Neurology > Neuro-vascular Diseases

Blood Dyscrasias and Stroke

Souvik Sen, MD, MS, FAHA,, Associate Professor of Neurology, Founding Director of UNC Hospital Stroke Center, Director of Neurovascular Residency, Department of Neurology, University of North Carolina at Chapel Hill

Updated: Jul 14, 2009

Introduction

Background

Hematologic abnormalities lead to thrombosis in the cerebral vasculature, causing ischemic cerebrovascular events. However, the majority of patients with ischemic cerebrovascular events do not have a well-defined hematological abnormality. Coagulation disorders that predispose to strokes remain poorly defined. They have been implicated in venous strokes (cerebral venous thrombosis) rather than arterial strokes. Platelet function abnormality, inherited hemostatic abnormality, and vascular injury promote thrombosis.

The aim of this article is to highlight the significance of these factors in stroke, to assess their impact on long-term prognosis, and to outline an approach to the patient with stroke for evaluation of hemostatic abnormalities. The specific factors discussed in this article include factor V Leiden (ie, resistance to activated protein C [APC]¹ ); deficiencies of proteins C and S² and antithrombin III; sickle cell anemia; hyperhomocystinemia; and antiphospholipid antibody syndrome (aPLS).

Pathophysiology

Hemostasis means prevention of blood loss. Hemostasis is provided by an interaction of normal vessel responses, platelet plug formation, and activation of the coagulation cascade. The coagulation cascade involves activation of blood coagulation factors with formation of prothrombin activator, which catalyzes the conversion of prothrombin to thrombin. Thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form a clot.

Counteracting hemostasis are normal vascular endothelial cells, which inhibit platelet adhesion and aggregation, and proteins such as thrombomodulin. Thrombomodulin activates protein C, which in turn activates protein S; together, the 2 factors play a role in inactivating factors V and VIII. Antithrombin III also plays a role in inactivating factor X and thrombin, thus inhibiting thrombosis. In this way, interactions among multiple plasma proteins, protein C, and protein S; resistance to APC; antithrombin III; and normal vascular endothelial cells form an important barrier to thrombosis.

Factors that accelerate the hemostatic mechanism or inhibit mechanisms that counteract hemostasis contribute to an increased state of thrombogenicity (ie, hypercoagulability) and thereby play an etiological role in strokes.

Frequency

United States

Known hematologic abnormalities are estimated to account for about 4% of all strokes. This proportion may be higher in younger people.

Factor V Leiden (ie, APC resistance) occurs in 5-7% of the normal population, 20% of patients with deep vein thrombosis (DVT), and 60% with recurrent DVT. The incidence of this factor in patients with stroke is not known; in general, however, this factor correlates more with venous mechanisms of thrombosis than arterial ones. Factor V Leiden is suspected, therefore, to be associated with paradoxical emboli or with venous sinus thrombosis more than with arterial mechanisms of stroke.

Protein C and S and antithrombin III deficiencies are all extremely rare. The frequency of occurrence ranges from 1 per 1000 to 1 per 5000 in the general population.

Sickle cell anemia is a significant etiologic factor in stroke. The incidence of stroke in patients with hemoglobin SS is 10%; in those with hemoglobin SC, 2-5%.

Hyperhomocystinemia is a factor in stroke. Patients with stroke have homocysteine levels 1.5 times those of age- and sex-matched controls.

aPLS (ie, presence of aPL or lupus anticoagulant) occurs in 10% of patients with acute ischemic stroke. This number is higher in younger patients.

International

Incidence is not known.

Mortality/Morbidity

In general, patients with blood dyscrasias and stroke are prone to recurrent cerebrovascular events. These patients are usually younger than stroke patients in the general population and do not have the vascular risk factors.

Race

African American patients are at higher risk of sickle cell anemia. None of the other blood dyscrasias have strong racial associations.

Sex

Blood dyscrasias that commonly lead to stroke occur equally in men and women.

Age

Blood dyscrasias are suspected if a patient younger than 50 years suffers an unexplained stroke. However, older age does not preclude the presence of blood dyscrasias that may lead to stroke.

Clinical

History

• Blood dyscrasias or hypercoagulability should be suspected in patients with ischemic stroke who have the following characteristics:
  • Younger than 50 years with no obvious cause of stroke
  • History of multiple unexplained strokes
  • Prior history of venous thrombosis
  • Family history of thrombosis
  • Abnormalities on routine screening coagulation tests
• In addition, aPLS must be suspected in patients with history of multiple miscarriages, dementia, optic neuropathy, and thrombocytopenia, as well as lupuslike syndromes and "complicated migraine."

Physical

Few physical findings point toward the diagnosis of blood dyscrasias in stroke. Blood dyscrasias more commonly predispose to thrombosis in the large arteries. Uncommonly, blood dyscrasias may lead to lacunar stroke or cardioembolic stroke, as seen in aPLS. In patients diagnosed with blood dyscrasias, a search should be made for clinical findings of thrombosis elsewhere, including venous thrombosis. In a few instances, aPLS is associated with Sneddon syndrome, which is manifested by livedo reticularis and cerebrovascular disease.

Causes

• Factor V Leiden
  • The most common inherited defect leading to venous thrombosis is hereditary resistance to APC, which is caused by a mutation in factor V (factor V Leiden) that renders activated factor V unable to be cleaved by APC.^3,4
  • No study has established a relationship between factor V Leiden and arterial strokes. Factor V Leiden has been associated primarily with venous events. Heterozygous state, unlike homozygous state, has not been shown to be a risk factor for recurrent venous thromboembolism.
  • Clinical assays for factor V Leiden are available. More than 95% of patients with resistance to APC have the Arg506Gln mutation defect, which is readily identifiable by DNA amplification and analysis (Quest Diagnostics).
• Protein C, protein S, and antithrombin III deficiencies
  • Cerebral vein thrombosis is a more frequent presentation than arterial stroke. No clear-cut association has been found between protein C or antithrombin III deficiency and arterial strokes, though patients with low protein C levels at the time of acute stroke have had poor outcomes.
  • 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 antithrombin III is identified, differentiating between congenital and acquired cases is important.
• Hereditary abnormalities of fibrinolysis
  • Dysplasminogenemia results in hypofibrinolysis by various mechanisms, including a decreased level of circulating plasminogen, an abnormally functioning plasminogen, an increase in the concentration of plasminogen activator inhibitor, or a decrease in the level of plasminogen activator.
  • Although an association with stroke per se has yet to be described, these abnormalities should be considered in a young patient with stroke and a history of recurrent DVT.
  • Dysfibrinogenemia is caused by genetic mutations that produce fibrinogen molecules that form clots resistant to fibrinolysis or that bind with increased avidity to platelets to promote thrombosis. These mutations thereby increase the risk of venous and arterial thrombotic episodes, including stroke.
  • Most strokes result from cerebral venous occlusion, but large arterial thrombotic strokes also are described in relatively young individuals and in those without other recognized risk factors.
• Sickle cell disease
  • Sickle cell disease causes a vasculopathy that, along with stasis in small arteries, is a principal mechanism by which it causes strokes. 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 also is noted.
  • The incidence of brain infarction peaks around age 10 years.
  • Erythrocyte disorders besides sickle cell anemia, such as polycythemia vera, cause hyperviscosity-related diminished cerebral blood flow.
  • Essential thrombocythemia and paroxysmal nocturnal hematuria also cause cerebrovascular thrombotic events. Paroxysmal nocturnal hematuria has been associated primarily with venous thrombosis.
• Hyperhomocystinemia
  • Hyperhomocystinemia is associated with vasculopathy. Unlike most prothrombotic states, it causes more arterial strokes than venous.
  • Elevated levels of homocysteine and related disulfide compounds are clear risk factors for stroke.
  • 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.
  • 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 deficiencies of folate and vitamin B-12. MTHFR C677T, homozygous TT, or A1298C are not risk factors for cerebral arterial or venous thrombosis.
  • Prospective and case-control 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.
  • The range for a normal serum homocysteine is controversial, but levels above 14 µmol/L, the highest quartile of homocysteine levels, significantly increase the risk of stroke.
  • Folate and vitamin B-12 levels should be checked, since 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.
• Antiphospholipid antibody syndrome
  • aPLs are polyclonal and polyclass antibodies that bind to anionic and neutral phospholipid-containing moieties.
  • Recognizing aPLs is important, as they are associated with a hypercoagulable state characterized by fetal loss, thrombocytopenia, and venous and arterial thrombosis.
  • Initially associated with systemic lupus erythematosus (SLE), these antibodies now are known to be found also in patients without SLE; patients without SLE who have these antibodies are diagnosed as having the primary antiphospholipid antibody syndrome (aPLS).
  • Currently, the 3 major types of clinically relevant aPLs are anticardiolipin (aCL) antibodies, lupus anticoagulant (LA), and anti-β2-GP-I antibody. In a patient with aPS, the concordance of aCL and LA may be up to 70%. Up to 10% of patients with aPLs are solely positive for anti-ß2-GP-I antibody.
  • About 10% of all patients with ischemic stroke harbor aPL, and the figure is much higher in younger patients.
  • Cerebrovascular symptoms associated with aPLS include amaurosis fugax, occlusion of retinal arteries and veins, transient ischemic events of the brain, thrombosis of cerebral arteries and veins, and dementia. Although strokes of all sorts are noted, involvement of the cerebral cortex and subadjacent white matter by platelet-fibrin microthrombi is most commonplace.
  • The mechanisms of thrombosis are heterogenous 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 aPLS was updated.⁵ Clinical criteria include the following:
    • Vascular thrombosis
    • Pregnancy morbidity
    • Laboratory criteria on 2 or more occasions more than 12 weeks apart include the following:
      • Anticardiolipin Ab (IgG or IgM, medium or high titer of >40 GPL/MPL or >99 percentile)
      • Anti-ß2-glycoprotein-1 Ab (IgG or IgM, >99 percentile)
      • Lupus anticoagulant
• Disorders associated with abnormal platelet function
  • Thrombotic thrombocytopenic purpura (TTP) is a thrombotic illness of obscure origin, more common in women, causing stroke with associated fever, Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Most of the microvascular occlusions are secondary to multiple microvascular platelet-fibrin thrombi that involve small arteries and capillaries. Most studies of coagulation and fibrin degradation products are normal, but elevated plasma levels of fibrinogen often are found. The disorder is caused by large aggregates of von Willebrand factor and platelets. An antibody prevents normal cleavage of these complexes. The treatment usually involves plasmapheresis, which is often life saving.
  • Heparin-induced thrombocytopenia is a disorder in which patients develop antibodies against heparin that are directed toward platelets, causing activation. Two types have been identified: type I develops 1-5 days after institution of heparin therapy and is a benign condition that results in platelet aggregation. Type II develops 6-10 days after institution of heparin therapy and is a risk factor for recurrent stroke. The incidence of heparin-induced thrombocytopenia may be reduced by using low-molecular-weight (LMW) heparin, such as enoxaparin (Lovenox). However, if a patient has heparin-induced thrombocytopenia, the antibodies to heparin cross-react with LMW heparin. After the onset of heparin-induced thrombocytopenia, danaparoid may be used as an alternative. However, the role of danaparoid in stroke prevention is not known.
  • Myeloproliferative disorders, particularly essential thrombocytosis and polycythemia vera, place patients at higher risk of thrombotic events, including stroke. Atherosclerosis and dysfunctional platelets, more than elevated platelet count, are believed to contribute to the cerebral thrombotic events. Antiplatelet therapy, usually aspirin, is advocated. Additional pharmacological measures, such as lowering of platelet counts with hydroxyurea or anagrelide, also have been reported to benefit patients. These treatments are better accomplished in conjunction with hematologic consultation.
• Lipoprotein (a) elevation
  • Recent evidence identifies at least one lipoprotein, lipoprotein (a) [Lp(a)], whose levels are elevated in selected populations with cerebrovascular disease. Many studies have shown elevated levels to be a potent risk factor for stroke, especially in young individuals.
  • A clear role for the treatment of elevated levels of Lp(a) in preventing strokes still is not established.
  • Prothrombin gene mutation: Reports indicate that a G-to-A transition at nucleotide position 20210 (G20210A) in the prothrombin gene is considered a risk factor for cerebral venous thrombosis. Heterozygous state, unlike homozygous state, has not been shown to be a risk factor for recurrent venous thromboembolism. This mutation has not been associated clearly with acute ischemic strokes.

Differential Diagnoses

Other Problems to Be Considered

Transient ischemic attacks
Carotid disease and stroke

Workup

Laboratory Studies

• Laboratory tests recommended for all patients in whom a hypercoagulable state is suspected include the following:
  • Prothrombin time (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. It usually is expressed in terms of a standardized international normalized ratio (INR).
  • Partial thromboplastin time (aPTT) is used to diagnose deficiencies or inhibitors of factors VIII, IX, XI, and XII, and to diagnose deficiency of von Willebrand factor. It also is used to monitor heparin therapy and as a screening test for LA.
• The following tests are optional and should be done if a specific hypercoagulable state is suspected:
  • Thrombin time is used to diagnose fibrinogen deficiencies, to detect heparin resistance, and to monitor fibrinolytic therapy.
  • aPL of the immunoglobulin G (IgG) class and LA are tested in patients with or without clinical lupus in whom hypercoagulability is suspected. These include patients with stroke who have a history of thrombocytopenia, fetal loss, dementia, optic change, and recurrent venous thrombosis.
  • Protein C activity is used to screen for protein C deficiency or to diagnose protein C deficiency secondary to dysproteinemia. Hereditary heterozygous protein C deficiency is associated with recurrent venous thrombosis. To confirm protein C deficiency and to differentiate it from dysproteinemia, the protein C antigen is measured. Protein C deficiency is noted in liver disease, disseminated intravascular coagulation (DIC), vitamin K deficiency, and warfarin therapy.
  • Protein S acts as a cofactor of protein C. Protein S activity is used to screen for protein S deficiency or to diagnose the presence of a dysfunctional protein. Hereditary heterozygous protein S deficiency is associated with recurrent venous thrombosis. To confirm protein S deficiency and to differentiate it from dysproteinemia, the protein S antigen is measured. Protein S deficiency is noted following acute thrombotic events; in liver disease, DIC, vitamin K deficiency, warfarin therapy, l-asparaginase therapy, and pregnancy; and with oral contraceptives.
  • Antithrombin III is an inhibitor of thrombin. Antithrombin III activity is used to screen for antithrombin III deficiency or to diagnose dysfunctional antithrombin III. Hereditary heterozygous antithrombin III deficiency is associated with recurrent venous or arterial thrombosis. To confirm antithrombin III deficiency and to differentiate it from dysproteinemia, the antithrombin III antigen is measured. Antithrombin III deficiency is noted following acute thrombotic events or surgery; in liver disease, nephrotic syndrome, DIC, heparin therapy, l-asparaginase therapy, and pregnancy; and with oral contraceptives.
  • Resistance to APC is the most common inherited risk factor for thrombosis. It may be tested on plasma from patients on heparin or warfarin. A value <2.2 indicates a high likelihood of APC resistance, and DNA-based testing for factor V Leiden then should be performed. Testing for factor V Leiden is not confirmation of the fact that APC resistance is expressed.
  • 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.
  • Lp(a) is an atherogenic molecule. High levels of Lp(a) have been correlated with atherosclerosis of the cerebral and other vasculature.
  • Hemoglobin electrophoresis enables detection of hemoglobin SS and SC, both of which are risk factors for arterial strokes. The test should be ordered in African Americans and others whose ethnicity puts them at particular risk of sickle cell anemia. Although sickle cell disease itself does not alter hemostasis, it currently is believed to be a risk factor for stroke by vascular damage.

Imaging Studies

The following studies may be helpful in assessment of suspected stroke or stroke risk:

• MRI of the brain (T1-, T2-, and diffusion-weighted images)
• Magnetic resonance angiogram or computed tomography angiogram in cases of arterial stroke
• Magnetic resonance venogram if cerebral venous thrombosis is suspected
• Transcranial Doppler ultrasonography to assess stroke risk in sickle cell anemia^6,7
  • This 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.
  • It is also helpful in the assessment of intracranial arterial stenosis or occlusion.
• Carotid ultrasonography if extracranial stenosis or occlusion is suspected
• Cerebral angiogram if noninvasive tests yield inconclusive results

Treatment

Consultations

Hematologic consultation may be requested in the following complicated situations:

• When clinical diagnosis is uncertain
• To clarify abnormal test results
• For recommendations on management of the blood dyscrasia

Diet

Dietary issues with blood dyscrasias resulting in stroke include the following:

• Hyperhomocystinemia has been attributed to dietary deficiency of vitamin B-6, 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.

Medication

Treatment of blood dyscrasias that may cause stroke remains controversial. The risks and benefits of treatment have to be considered in the context of the number of episodes of thrombosis. In patients who are not treated with anticoagulants, prophylaxis should be considered during times of high risk such as pregnancy, immobilization, or the postoperative period.

Patients with hypercoagulable states such as APC resistance; protein C, protein S, and antithrombin III deficiencies; or aPS are treated with anticoagulants for stroke prophylaxis, especially if deep vein thrombosis is present or recurrent thrombotic events have occurred. The anticoagulation regimen usually is started with IV heparin, maintaining the aPTT at 2-3 times normal, until an oral anticoagulant (ie, warfarin) is able to achieve a therapeutic PT (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, one retrospective study had reported that an INR of 3.0-3.5 was more effective than the routinely used INR of 2.0-3.0; however, two prospective studies have shown that an INR of 2.0-3.0 is sufficient in aPS. 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 APASS study showed that there was no difference between aspirin and warfarin for treatment of patients with anticardiolipin antibody (aCL) or lupus anticoagulant (LA). It is important to emphasize that the APASS study did not look specifically at antiphospholipid antibody syndrome. However, it was noticed that the risk of recurrent thrombosis was increased in patients who had both aCL and LA. Besides, patients enrolled in the APASS study had low aCL titer and had low INR and the study was criticized for the limitations. Thus, in deciding whether patients need to be treated with warfarin, their LA status and high-titer aCL 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 antiphospholipid antibody syndrome and high titers of aCL and LA with high-intensity regimen of warfarin would probably answer the issue.

Patients with sickle cell anemia and stroke are treated with antiplatelet agents such as aspirin. Other methods of treatment that are advocated are blood transfusion and hydroxyurea⁸ . The role of bone marrow transplantation is, at best, experimental.⁹ The roles of other antiplatelet agents, such as ticlopidine and clopidogrel, or combination therapy with aspirin and dipyridamole specifically in prevention of strokes that result from blood dyscrasias have not been evaluated.

Hyperhomocystinemia is treated with vitamin supplementation, usually folic acid and sometimes pyridoxine (vitamin B-6) and vitamin B-12, as well. The Vitamin in Stroke Prevention trial (VISP) addressed the issue.¹⁰ Results of the VISP trial did not show any significant benefit of treatment with high doses of folic acid, pyridoxine, and vitamin B-12 in reducing vascular outcomes in patients with nondisabling strokes and elevated homocysteine compared with low doses of these vitamins. However, it did show that there was a persistent and graded association between total homocysteine and outcomes irrespective of the treatment group. A larger study with high baseline homocysteine levels and longer follow up may help resolve the issue.

Several new oral anticoagulant medications are in the final stages of clinical trials for use in the prophylaxis of ischemic thromboembolic stroke. Once approved for use, the potential of such drugs in the arena of stroke treatment is significant.

Anticoagulants

These agents are used for hypercoagulable states such as APC resistance; protein C, protein S, and antithrombin III deficiencies; and aPS. Insufficient evidence exists to make a recommendation. The most recent scientific statements state the following evidence-based recommendations:

1. Patients with ischemic stroke or TIA with thrombophilia should be evaluated for DVT (Class I, Level of Evidence A)
2. IF no VTE is present, long-term anticoagulants of antiplatelet therapy is reasonable (Class IIa, Level of Evidence C);
3. Recurrent event: Consider long-term anticoagulation¹¹ (Class IIb, Level of Evidence C).

For antiphospholipid antibody (APLA) syndrome, the following have been stated:

1. Cryptogenic stroke or TIA and possible APLA — antiplatelet therapy is reasonable (Class IIa, Level of Evidence B);
2. Cryptogenic stroke or TIA and APLA syndrome with venous and arterial occlusive disease in multiple organs, miscarriages, and livedo reticularis — oral anticoagulation is reasonable (INR 2-3) (Class IIa, Level of Evidence B).

Heparin

Inhibits reaction that leads to clotting of blood; in combination with antithrombin III (heparin cofactor), inhibits thrombosis by inactivating activated factor X, thus preventing formation of thrombin from prothrombin and fibrin from fibrinogen; also prevents formation of fibrin-stabilizing factor.

Dosing

Adult

800-1200 U/h IV; dosage adjusted according to aPTT

Pediatric

Not established

Interactions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity

Contraindications

Documented hypersensitivity, subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock; caution in elderly patients and women >60 y

Warfarin (Coumadin)

Inhibits synthesis of vitamin K-dependent clotting factors (ie, factors II, VII, IX, and X, proteins C and S); resultant suppression of extrinsic clotting pathway leads to its anticoagulant property.

Dosing

Adult

5-10 mg PO on day 1; on subsequent days, dosages determined by daily monitoring of PT (INR) until therapeutic INR for particular indication achieved

Pediatric

Not established

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate
Medications that may increase anticoagulant effects include oral antibiotics, salicylates, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; risk of hemorrhage, threatened abortion; recent surgery, during and immediately following major surgery or spinal tap; bleeding diathesis (inherited or acquired)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not switch brands after achieving therapeutic response; caution in active TB or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; elderly patients (>60 y)

Antiplatelet agents

Used for stroke prophylaxis in blood dyscrasias that lead to ischemic stroke. This includes hypercoagulable states with minor symptoms (ie, anticoagulation not indicated), sickle cell anemia with risk of stroke.

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Potent inhibitor of prostaglandin synthesis and platelet aggregation. Enteric coated aspirin is preferred, as it minimizes adverse GI effects.

Dosing

Adult

81-1300 mg/d PO with food; popular doses include 81-325 mg/d in Europe and 325-1300 mg/d in US (FDA in 1999 changed recommendation to 50-325 mg/d)
Most effective dose for stroke prophylaxis not known
Pregnancy: Used only if benefits clearly outweigh risks; low dose (<150 mg/d) used in second and third trimesters

Pediatric

Not established

Interactions

Effects may decrease with antacids and urinary alkalinizers; serum levels decreased by corticosteroids; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; concomitant anticoagulants; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, severe anemia, asthma; children <16 y with flu, due to association with Reye syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease

Follow-up

Further Outpatient Care

Patients being treated with an oral anticoagulant need to be monitored with outpatient blood testing for PT (INR). Initially, PT (INR) must 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.

Patient Education

For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

Miscellaneous

Medicolegal Pitfalls

• Supratherapeutic oral anticoagulation without monitoring can lead to intracranial and extracranial hemorrhage. Common reasons for such a state include overdosage, interaction with other drugs, and variation in dietary vitamin K. Subtherapeutic anticoagulation can lead to ischemic stroke. These potential pitfalls need to be discussed with the patient before initiating anticoagulation.
• Another pitfall is starting a patient with a known history of life-threatening bleeding disorder and a hypercoagulable state on either an antiplatelet agent or an anticoagulant. Treatment needs to be individualized for each patient, and the benefits of any treatment need to outweigh the risks.
• At the time of acute thrombotic events, certain coagulation parameters have acquired deficiencies (protein S and antithrombin III). In addition, patients on warfarin can have low protein C and S values, while patients on heparin have low antithrombin III values. Other conditions known to affect coagulation parameters are liver disease (protein C and S and antithrombin III), estrogens, pregnancy, and inflammatory disease (protein S).
• More than 100 mutations account for each deficiency; thus, genetic testing is not performed in clinical practice.
• Caution is advised to check candidates for oral anticoagulation for amyloid angiopathy with a higher propensity to bleed in the brain. MRI sequences such as gradient echo (GRE) are useful tools to detect multiple bleeds, a feature suggestive of amyloid angiopathy.

References

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10. Toole JF, Malinow MR, Chambless LE, 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. Feb 4 2004;291(5):565-75. [Medline].

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Keywords

hypercoagulable state, cerebrovascular event, cerebrovascular accident, coagulation disorder

Contributor Information and Disclosures

Author

Souvik Sen, MD, MS, FAHA,, Associate Professor of Neurology, Founding Director of UNC Hospital Stroke Center, Director of Neurovascular Residency, Department of Neurology, University of North Carolina at Chapel Hill
Souvik Sen, MD, MS, FAHA, is a member of the following medical societies: American Academy of Neurology, American Heart Association, and Association for Patient Oriented Research
Disclosure: Nothing to disclose.

Medical Editor

Draga Jichici, MD, FRCP, Associate Clinical Professor, Department of Medicine, Division of Neurology and Critical Care Medicine, McMaster University, Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health & Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Concentric Medical Consulting fee Review panel membership; Abbott Consulting fee Consulting; Sanofi  Consulting

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Anand Vaishnav, MD to the development and writing of this article.

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