Cerebral Venous Thrombosis

Background

Thrombosis of the venous channels in the brain is an uncommon cause of cerebral infarction relative to arterial disease, but it is an important consideration because of its potential morbidity. (See Prognosis.)

Knowledge of the anatomy of the venous system is essential in evaluating patients with cerebral venous thrombosis (CVT), since symptoms associated with the condition are related to the area of thrombosis. For example, cerebral infarction may occur with cortical vein or sagittal sinus thrombosis secondary to tissue congestion with obstruction. (See Presentation.)

Lateral sinus thrombosis may be associated with headache and a pseudotumor cerebri–like picture. Extension into the jugular bulb may cause jugular foramen syndrome, while cranial nerve palsies may be seen in cavernous sinus thrombosis as a compressive phenomenon. Cerebral hemorrhage also may be a presenting feature in patients with venous sinus thrombosis. (See Presentation.)

Imaging procedures have led to easier recognition of venous sinus thrombosis (see the images below), offering the opportunity for early therapeutic measures. (See Workup.)

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Left lateral sinus thrombosis demonstrated on magnetic resonance venography (MRV). This 42-year-old woman presented with sudden onset of headache. Phy....

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Axial view of magnetic resonance (MR) venogram demonstrating lack of flow in transverse sinus.

The following guidelines for CVT have been provided by the American Heart Association and the American Stroke Association^[1] :

• In patients with suspected CVT, routine blood studies consisting of a complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time should be performed.
• Screening for potential prothrombotic conditions that may predispose a person to CVT (eg, use of contraceptives, underlying inflammatory disease, infectious process) is recommended in the initial clinical assessment.
• Testing for prothrombotic conditions (including protein C, protein S, or antithrombin deficiency), antiphospholipid syndrome, prothrombin G20210A mutation, and factor V Leiden can be beneficial for the management of patients with CVT. Testing for protein C, protein S, and antithrombin deficiency is generally indicated 2-4 weeks after completion of anticoagulation. There is a very limited value of testing in the acute setting or in patients taking warfarin.
• In patients with provoked CVT (associated with a transient risk factor), vitamin K antagonists may be continued for 3-6 months, with a target international normalized ratio of 2.0-3.0.
• In patients with unprovoked CVT, vitamin K antagonists may be continued for 6-12 months, with a target international normalized ratio of 2.0-3.0.
• For patients with recurrent CVT, venous thromboembolism (VTE) after CVT, or first CVT with severe thrombophilia (ie, homozygous prothrombin G20210A; homozygous factor V Leiden; deficiencies of protein C, protein S, or antithrombin; combined thrombophilia defects; or antiphospholipid syndrome), indefinite anticoagulation may be considered, with a target international normalized ratio of 2.0-3.0.
• For women with CVT during pregnancy, low-molecular-weight heparin (LMWH) in full anticoagulant doses should be continued throughout pregnancy, and LMWH or vitamin K antagonist with a target international normalized ratio of 2.0-3.0 should be continued for ≥6 weeks postpartum (for a total minimum duration of therapy of 6 months).
• It is reasonable to advise women with a history of CVT that future pregnancy is not contraindicated. Further investigations regarding the underlying cause and a formal consultation with a hematologist or maternal fetal medicine specialist are reasonable.
• It is reasonable to treat acute CVT during pregnancy with full-dose LMWH rather than unfractionated heparin.
• For women with a history of CVT, prophylaxis with LMWH during future pregnancies and the postpartum period is reasonable.

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Etiology

Many causative conditions have been described in cerebral venous thrombosis (CVT). These may be seen alone or in combination. For example, a prothrombin gene mutation in association with oral contraceptive use raises the odds ratio for developing CVT.

Sinusitis

Infection may occur by extension from the paranasal sinuses. These cases also may be associated with subdural empyema. Bacterial meningitis as a coexistent condition should be considered in these cases. Frontal sinuses are the most common source of infection, with spread through the emissary veins between the posterior sinus mucosa and the meninges. Rarely, sphenoid sinusitis may be associated with cavernous sinus thrombosis. Multiple organisms are to be considered, Staphylococcus aureus being the most common. In chronic infections, gram-negative organisms and fungi such as Aspergillus species may be found.

Trauma and surgery

Trauma may also be an etiologic event. Cerebral sinus thrombosis easily may be overlooked in cases of minor head trauma. Neurosurgical procedures such as dural taps and infusions into the internal jugular vein have been implicated as well.

Hypercoagulable states

Many medical conditions have been associated with CVT. For example, hypercoagulable states associated with the antiphospholipid syndrome, protein S and C deficiencies, antithrombin III deficiency, lupus anticoagulant, and the Leiden factor V mutation may result in CVT. Antibodies against the fibrinolytic receptor, annexin A2 (titer >3 standard deviations), are significantly associated with CVT.^[2] Pregnancy also is associated with a hypercoagulable tendency. Malignancies may be associated with hypercoagulable states as well, and therefore may be risk factors.

Intracranial hypotension

Isolated cortical venous thrombosis has been associated with intracranial hypotension syndrome, but only rarely. In a study, Schievink and Maya found that CVT was present in only 3 (2.1%) out of 141 patients with spontaneous intracranial hypotension.^[3]

Lumbar puncture

A few cases of CVT have been reported after lumbar puncture (LP), suggesting a causal association. In a study by Canhao et al, LP induced a sustained decrease in mean blood flow velocity (BFV) in the straight sinus (SS), suggesting that the decrease in venous blood flow is a possible mechanism contributing to the occurrence of CVT. In the study, the investigators used transcranial Doppler ultrasonography to register the mean BFV of the SS before, during, and after LP. LP induced a decrease of 47% in mean BFV in the SS, with the mean decrease being significant immediately at the end, 30 min after, and more than 6 hours after LP.^[4]

Medications

Several medications are reported to increase the risk of CVT, including the following:

• Oral contraceptives - Including the third-generation formulations
• Corticosteroids
• Epsilon-aminocaproic acid
• Thalidomide
• Tamoxifen
• Erythropoietin
• Phytoestrogens
• L-asparaginase
• Heparin - Heparin therapy has been reported to produce thrombotic thrombocytopenia with associated venous sinus thrombosis

Additional disease risk factors

Other diseases that have been described as risk factors for CVT include the following:

• Inflammatory bowel diseases, such as Crohn disease and ulcerative colitis, are described as risk factors for venous thrombosis^[5] ; corticosteroids used in treatment of these conditions may play a causative role
• Pregnancy and puerperium are important considerations in women of childbearing age
• Hematologic conditions, including paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, sickle cell disease, and polycythemia, are to be considered
• Collagen-vascular diseases, such as systemic lupus erythematosus, Wegener granulomatosis, and Behçet syndrome, have been reported to be associated with CVT
• Hyperhomocysteinemia is a strong and independent risk factor for CVT, being present in 27-43% of patients with CVT but in only 8-10% of the general population; whether treatment with folate, pyridoxine, and/or cobalamin reduces the risk of CVT is unclear
• Nephrotic syndrome
• Dehydration
• Spontaneous intracranial hypotension
• High altitude
• Hepatic cirrhosis
• Sarcoidosis

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Epidemiology

International occurrence

The incidence of cerebral venous thrombosis (CVT) is difficult to determine, but generally, it is believed to be an uncommon cause of stroke, with the reported ratio of venous to arterial strokes being 1:62.5. In 1973, Towbin reported CVT in 9% of 182 autopsies,^[6] while in 1995, Daif reported a frequency in Saudi Arabia of 7 cases per 100,000 hospital patients.^[7]

However, with the advent of newer imaging techniques, the reported incidence of CVT is likely to increase as less severe cases are found.

Sex- and age-related demographics

CVT is believed to be more common in women than in men. In a series of 110 cases, Ameri and Bousser found a female-to-male ratio of 1.29:1.^[8]

In 1992, Ameri and Bousser reported a uniform age distribution in men with CVT, while 61% of women with CVT were aged 20-35 years.^[8] This difference may be related to pregnancy or the use of oral contraceptives.^[9]

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Prognosis

Smith demonstrated the efficacy of anticoagulant and thrombolytic therapy in patients with cerebral venous thrombosis (CVT). In his study, he compared outcomes of patients who were treated with heparin and local infusion of urokinase (12 patients) with those of patients who received no treatment (21 patients).^[10] The results appear in the Table, below.

Table. Patients With Cerebral Venous Thrombosis Treated With Heparin and Local Infusion of Urokinase vs Nontreated Group

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See Table

Morbidity and mortality

Herniation attributable to unilateral mass effect is the major cause of death in CVT. In CVT patients with large parenchymal lesions causing herniation, decompressive surgery has been lifesaving and often results in good functional outcome, even in patients with severe clinical conditions.^[11]

Mortality in untreated cases of venous thrombosis has been reported to range from 13.8-48%; this high mortality rate may be a reflection of clinical severity at entrance into the study. Between 25% and 30% of patients have full recovery.

In a Portuguese study that prospectively analyzed 91 patients with CVT over a mean 1-year follow-up interval, the majority of patients experienced complete recovery.^[12] Of the patients analyzed, 7% died in the acute phase, 1% died during the one year follow-up, 82% recovered completely, and 1% were dependent; 59% developed thrombotic events during the follow-up, 10% had seizures, 11% complained of severe headaches, and 1 patient experienced severe visual loss.

In 2003, Buccino et al found a good overall outcome in their reinvestigation of a series of 34 patients with confirmed CVT.^[13] However, 10 patients (30%) had episodic headaches, 3 patients (8.8%) had seizures, 4 patients (11.7%) had pyramidal signs, and 2 (5.9%) had visual deficits. Mild nonfluent aphasia was seen in 3 patients. Working memory deficit and depression of mood were seen in 6 patients (17.6%).

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History

Patients with cerebral venous thrombosis (CVT) may present with headache.^[14] Although thunderclap headache usually indicates subarachnoid hemorrhage (SAH), it may also be seen in sinus thrombosis.

SAH has been described as the presenting event with CVT. CVT should be considered in the workup of SAH, especially when the basilar cisterns are not involved.^[15]

Patients with lateral sinus thrombosis may present with a pseudotumor cerebri–like syndrome. Using a technique called auto-triggered elliptic-centric-ordered 3-dimensional gadolinium-enhanced magnetic resonance venography (MRV), Farb et al found that 27 of 29 patients with idiopathic intracranial hypertension had bilateral sinovenous stenosis; this was seen in only 4 of 59 control subjects.^[16]

Nausea and vomiting may also be associated with CVT. In some cases, seizures, which can be recurrent, occur. Some patients may experience a decreased level of consciousness that progresses to coma.

Focal neurologic deficit may develop, depending on the area involved. Hemiparesis may occur, and in some cases of sagittal sinus thrombosis, weakness may develop in the lower extremity. This also may occur as bilateral lower extremity involvement. Aphasia, ataxia, dizziness, chorea, and hemianopia all have been described.

Cranial nerve syndromes are seen with venous sinus thrombosis. These include the following:

• Vestibular neuronopathy
• Pulsatile tinnitus
• Unilateral deafness
• Double vision
• Facial weakness
• Obscuration of vision

Site of headache versus location of sinus involvement

Wasay et al found little association between headache location and the site of sinus involvement in patients with CVT. In their study, the authors described the pattern and location of headache in 200 consecutive patients with a proven diagnosis of CVT to identify an association between the site of the headache and location of sinus involvement. The quality of headache was reported as throbbing (9%), bandlike (20%), thunderclap (5%), and other (pounding, exploding, stabbing, etc) (20%).

The authors found no association between headache location and the site of sinus thrombosis except in cases of sigmoid sinus thrombosis, in which 17 of 28 patients (61%) with involvement of the sigmoid sinus alone or in combination with the transverse sinus had pain in the occipital and neck region. There was no association between lateralization of pain and the site of thrombosis.^[17]

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Physical Examination

The effect of cerebral venous thrombosis (CVT) on mental status is quite variable, with some patients showing no change in alertness, others developing mild confusion, and still others progressing to coma.

Cranial nerve findings may include papilledema, hemianopia, oculomotor and abducens palsies, facial weakness, and deafness. If the thrombosis extends to the jugular vein, the patient may develop involvement of cranial nerves IX, X, XI, and XII with the jugular foramen syndrome.

Thrombosis of the superior sagittal (longitudinal) sinus may present with unilateral paralysis that then extends to the other side secondary to extension of the clot into the cerebral veins. Because of the location, this may present as a unilateral lower extremity weakness or paraplegia.

Cavernous sinus thrombosis with obstruction of the ophthalmic veins may be associated with proptosis and ipsilateral periorbital edema. Retinal hemorrhages and papilledema may be present. Paralysis of extraocular movements, ptosis, and decreased sensation in the first division of the trigeminal nerve often are observed.

Although unusual, cortical vein thrombosis may be seen in the absence of dural sinus involvement. These cases are associated with varied focal deficits, including aphasia, hemiparesis, hemisensory loss, and hemianopia.

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Approach Considerations

The diagnosis of cerebral venous thrombosis (CVT) is made on the basis of clinical presentation and imaging studies (see the images below), while clinical laboratory studies are useful for determining the possible causes of CVT.

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Axial view of magnetic resonance (MR) venogram demonstrating lack of flow in transverse sinus.

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Coronal view of magnetic resonance (MR) venogram demonstrating lack of flow in the left transverse and sigmoid sinuses.

Lab studies

A complete blood count (CBC) is performed to look for polycythemia as an etiologic factor. Decreased platelet count would support thrombotic thrombocytopenic purpura; leukocytosis might be seen in sepsis. (If heparin is used as treatment, platelet counts should be monitored for thrombocytopenia.)

Antiphospholipid and anticardiolipin antibodies should be obtained to evaluate for antiphospholipid syndrome. Other tests that may indicate hypercoagulable states include protein S, protein C, antithrombin III, lupus anticoagulant, and Leiden factor V mutation. These evaluations should not be made while the patient is on anticoagulant therapy.

Sickle cell preparation or hemoglobin electrophoresis should be obtained in individuals of African descent.

Erythrocyte sedimentation rate and antinuclear antibody studies should be performed to screen for systemic lupus erythematosus, Wegener granulomatosis, and temporal arteritis. If levels are elevated, further evaluation, including of complement levels, anti-deoxyribonucleic acid (DNA) antibodies, and neutrophil cytoplasmic antibodies (ANCA), could be considered.

Urine protein should be checked and, if elevated, nephrotic syndrome considered. Liver function studies should be performed to rule out cirrhosis.

EEG

An electroencephalogram (EEG) may be normal, show mild generalized slowing, or show focal abnormalities if a unilateral infarct occurs. An EEG is helpful in evaluating a seizure focus.

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Procedures

Lumbar puncture (LP) is helpful in evaluating for meningitis as an associated infectious process in cerebral venous thrombosis (CVT). However, a large, unilateral hemispheric lesion or posterior fossa lesion demonstrated on CT or MRI scan is a contraindication for LP.

In the past, compression of the jugular vein unilaterally with pressure measurement was utilized. Pressure may be elevated if thrombosis of the contralateral transverse sinus is present. However, collateral circulation or incomplete compression of the jugular vein may yield a false-negative result. Moreover, elevation of the intracranial venous pressure is a concern, as it may precipitate herniation. As the maneuver adds little to the diagnosis, it usually is not performed.

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D-Dimer Levels

D-dimer values may be beneficial in screening patients who present in the emergency department for headache evaluation.

In a study of 18 patients with cerebral venous thrombosis (CVT), Tardy et al reported that D-dimer levels of less than 500 ng/mL had a negative predictive value for ruling out the diagnosis in patients with acute headache.^[18]

In a prospective study of 54 consecutive patients with headache suggestive of CVT, Lalive found that 12 had CVT and, of those, 10 had D-dimer levels greater than 500 ng/mL.^[19] The 2 patients with confirmed CVT and a D-dimer level of less than 500 ng/mL had a history of chronic headache lasting longer than 30 days.

In a study by Kosinski et al, D-dimers were positively correlated with the extent of thrombosis and negatively correlated with the duration of symptoms in patients with cerebral sinus thrombosis. The investigators prospectively studied 343 patients with symptoms suggesting cerebral sinus thrombosis.^[20] The diagnosis was confirmed in 35, with 34 of these patients showing elevated D-dimer levels greater than 500 mcg/L. Of the 308 patients not having CVT, 27 had positive values. Sensitivity was 97.1%, with a negative predictive value of 99.6%. Specificity was 91.2%, with a positive predictive value of 55.7%.

The D-dimer test does not establish the diagnosis of CVT, and more definitive studies, such as magnetic resonance venography (MRV), are necessary. Likewise, if a high suspicion for CVT exists, the test cannot definitely exclude the diagnosis but can indicate that the presence of CVT is very unlikely.

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CT Scanning

Computed tomography (CT) scanning is an important imaging technique, as it is often the first imaging study obtained. It may show evidence of infarction that does not correspond to an arterial distribution. However, in the absence of a hemorrhagic component, demonstration of the infarct may be delayed for as long as 48-72 hours. (See the image below.)

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Computed tomography (CT) scan demonstrates a left posterior temporal hematoma in a 38-year-old woman on oral contraceptives (the only identified risk ....

CT scanning is also useful for ruling out other conditions, such as neoplasm, and in evaluating coexistent lesions, such as subdural empyema. CT scanning of the sinuses is useful in evaluating sinusitis, while CT scanning of the mastoids may be helpful in lateral sinus thrombosis.

An empty delta sign appears on contrast scans as enhancement of the collateral veins in the superior sagittal sinus (SSS) walls surrounding a nonenhanced thrombus in the sinus. However, the sign is frequently absent. Early division of the SSS can give a false delta sign. The dense triangle sign formed by fresh coagulated blood in the SSS and the cord sign representing a thrombosed cortical vein are extremely rare.

CT angiography

CT angiography has also been used to visualize the cerebral venous system. Ozsvath et al compared CT and MR projection in the identification of cerebral veins and thrombosis.^[21] CT venography was superior to MR in identification of cerebral veins and dural sinuses. CT was equivalent to MR in identification of dural sinus thrombosis and therefore is a viable alternative to MRV in the examination of patients with suspected dural sinus thrombosis. The maximum-intensity-projection technique used, however, did not allow direct visualization of the thrombus by CT or MR technique.

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MRI

MRI shows the pattern of an infarct that does not follow the distribution of an expected arterial occlusion. It may show absence of flow void in the normal venous channels. Mas et al described MRI findings of increased intraluminal signal on all planes and with all pulse sequences in patients with lateral sinus thrombosis. (See the image below.)^[22]

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Contrast-enhanced magnetic resonance imaging (MRI) scan showing lack of filling of left transverse sinus.

MRV

MRV is an excellent method of visualizing the dural venous sinuses and larger cerebral veins. (See the images below.)

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Left lateral sinus thrombosis demonstrated on magnetic resonance venography (MRV). This 42-year-old woman presented with sudden onset of headache. Phy....

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Same patient as in the previous image. One week after treatment with heparin, the magnetic resonance (MR) venogram displayed increased flow in the lef....

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Magnetic resonance venogram (MRV) - axial view; A = lateral (transverse) sinus; B = sigmoid sinus; C = confluence of sinuses; and D = superior sagitta....

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Magnetic resonance venogram (MRV) - sagittal view; A = lateral (transverse) sinus; C = confluence of sinuses; D = superior sagittal sinus; and E = str....

Since thunderclap headaches are not limited to SAH and may be seen with cerebral venous thrombosis (CVT), lack of evidence of SAH in a patient with such headaches should prompt examination with MRV.

SSPCA

Single-slice phase-contrast angiography (SSPCA) takes less than 30 seconds and provides rapid and reliable information. Many neurologists now consider it to be the procedure of choice in diagnosing cerebral venous thrombosis. In a study of 21 patients, Adams demonstrated a specificity and sensitivity of 100% for SSPCA when compared with alternative imaging techniques.^[23]

Flow gap versus thrombosis in MRV

Ayanzen described transverse sinus flow gaps in 31% of patients with normal MRI findings who were studied with MRV; 90% of these were in the nondominant transverse sinus, and 10% were in the codominant sinuses. None was seen in the dominant sinus.^[24] These should not be mistaken for thrombosis.

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Contrast Studies

Carotid arteriography with delayed filming technique to visualize the venous system was the procedure of choice in the diagnosis of venous thrombosis prior to the advent of MRV. It is an invasive procedure and is therefore associated with a small risk.

If MR studies are not diagnostic, conventional angiography should be considered. Direct venography can be performed by passing a catheter from the jugular vein into the transverse sinus, with injection outlining the venous sinuses.

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Approach Considerations

With regard to stabilization, medical management of patients with cerebral venous thrombosis (CVT) is similar to that of patients with arterial stroke.

Specific therapy for CVT involves anticoagulation or thrombolytic therapy.^{[25, 26, 31]}  However, the use of anticoagulation in CVT has been a subject of consternation among neurologists as concern has been expressed over the possibility of increasing hemorrhage in patients treated in this manner. Existing data support the use of systemic anticoagulation as an initial therapy in all patients, even in the presence of intracranial hemorrhage.^[25]

Studies by Einhaupl in 1991^[27] and by de Bruijn and Stam in 1999^[28] indicated that anticoagulation can be used safely in CVT.

Frontal sinusitis

Frontal sinusitis should be aggressively treated before it leads to subdural empyema or CVT

Altered mental status or hemiplegia

Patients with altered mental status or hemiplegia should be given nothing by mouth to prevent aspiration. Intravenous (IV) fluids should not be hypotonic solutions. Normal saline is recommended at a rate of approximately 1000 mL in 24 hours. To decrease intracranial pressure, the patient’s head should be elevated 30-40° at all times. In the treatment of stroke patients, supplemental oxygen has not been shown to be beneficial unless the patient’s level of consciousness is decreased.

Surgical care

In cases of severe neurologic deterioration, open thrombectomy and local thrombolytic therapy have been described as beneficial.^{[25, 26, 29, 30]}

Herniation attributable to unilateral mass effect is the major cause of death in cerebral venous thrombosis (CVT). In CVT patients with large parenchymal lesions causing herniation, decompressive surgery has been lifesaving and often results in good functional outcome, even in patients with severe clinical conditions.^[11]

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Thrombolytic Therapy

Thrombolytic therapy has been described in several case reports as beneficial in patients with cerebral venous thrombosis (CVT). These patients were treated with infusion of a thrombolytic agent into the dural venous sinus, utilizing microcatheter technique. This treatment at present is limited to specialized centers but should be considered for patients with significant deficit.

A report describes the use of a rheolytic catheter device in a patient who had not responded to microcatheter instillation of urokinase. The rheolytic catheter was designed for use in the coronary circulation and delivers 6 high-velocity saline jets through a halo device at the tip of the catheter. This leads to a Bernoulli effect that breaks up the thrombus. In addition, the particulate debris is directed into an effluent lumen for collection in a disposable bag. The catheter was advanced into the sagittal sinus, resulting in restoration of venous flow and reduction of intracranial pressure.

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Anticonvulsant Therapy

Seizures should be treated with appropriate anticonvulsants. Fosphenytoin is recommended for the treatment of seizures in patients who require a parenteral formulation. Alternatively, phenobarbital or sodium valproate injection may be utilized if the patient is allergic to phenytoin. Diazepam or lorazepam may be used to treat status epilepticus, but the patient also should be given an anticonvulsant with a longer duration of action to prevent recurrent seizures.

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Consultations

Consultation with a neurosurgeon is indicated in patients with subdural empyema or brain abscess. Consultation should also be considered for patients who have severe deterioration despite aggressive medical management.

Consultation with an infectious disease specialist is to be considered for patients with cerebral venous thrombosis (CVT) who have an associated infection, such as meningitis or sinusitis. Consultation with an otolaryngologist may also be helpful in patients with associated sinusitis.

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Guidelines Summary

European Stroke Organization

In 2017, the European Stroke Organization updated the previous guidelines from the European Federation of Neurological Societies.^[31] Current recommendations include the following:

• Magnetic resonance or computed tomographic angiography is recommended for confirming the diagnosis of CVT; routinely screening patients with CVT for thrombophilia or cancer is not recommended.
• Use parenteral anticoagulation in acute CVT and decompressive surgery to prevent death due to brain herniation.
• Use low-molecular-weight heparin in the acute phase and not direct oral anticoagulants.
• Do not use steroids and acetazolamide to reduce death or dependency.
• Antiepileptics are recommended in patients with an early seizure and supratentorial lesions to prevent further early seizures.
• Avoid contraceptives containing oestrogens in women who have suffered a previous CVT.
• Subsequent pregnancies are safe, but use of prophylactic low-molecular-weight heparin should be considered throughout pregnancy and puerperium.

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Medication Summary

Heparin should be considered seriously in the management of cerebral venous thrombosis (CVT), with subsequent conversion to warfarin as maintenance therapy suggested. Subcutaneous low ̶ molecular-weight heparin (Lovenox) also has been used in patients with venous sinus thrombosis.

Thrombolytic therapy may be effective in CVT, but all studies so far describe its use only with local instillation by microcatheter or direct instillation at the time of surgical thrombectomy.

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Heparin

• Dosing, Interactions, etc.

Clinical Context:  Heparin increases the action of antithrombin III, leading to inactivation of coagulation enzymes thrombin, factor Xa, and factor IXa. Thrombin is the enzyme that is most sensitive to inactivation by heparin.

Because heparin is not absorbed from the GI tract, it must be given parenterally. When given intravenously, its effect is immediate. Metabolism of heparin is complex; rapid zero-order metabolism is followed by slower first-order renal clearance. The saturable phase of heparin clearance is thought to be due to binding to endothelial cell receptors and macrophages in which it is depolymerized. Zero-order process is saturable, leading to an increase in half-life from 30 minutes with a low dose bolus to 150 minutes with a high dose bolus. Weight-based protocol is now often used for dosing. When choosing this therapy, the risks of its contraindications must be weighed against the potential benefits of the drug.

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Enoxaparin (Lovenox)

• Dosing, Interactions, etc.

Clinical Context:  Enoxaparin is a low-molecular-weight heparin (LMWH) produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). It binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). LMWH differs from UFH by having a higher ratio of anti–factor Xa to anti–factor IIa.

Enoxaparin does not actively lyse thrombi but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis. Its advantages include intermittent dosing and a decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. There is no point in checking the aPTT; the drug has a wide therapeutic window, and aPTT does not correlate with anticoagulant effect.

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Warfarin (Coumadin, Jantoven)

• Dosing, Interactions, etc.

Clinical Context:  Warfarin interferes with the action of vitamin K, a cofactor essential for converting precursor proteins into factors II, VII, IX, and X. Warfarin does not affect the activity of coagulation factors synthesized prior to exposure to warfarin. Depletion of these mature factors by normal metabolism must occur before the therapeutic effects of the newly synthesized factors can be seen; thus, warfarin may take several days to become effective.

The dose of warfarin administered is influenced by differences in absorption, metabolism, and hemostatic responses to given concentrations; the dose must be monitored closely by following the prothrombin time (PT) and international normalized ratio (INR). Higher initial doses do not appear to improve the time required to achieve therapeutic levels but do increase the bleeding risk.

The expert opinion is that warfarin treatment should be maintained for 3-6 months, but no randomized, placebo-controlled trials have addressed this issue.

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Class Summary

These medications are used to prevent propagation of the clot to more extensive areas of the cerebral venous system. Studies indicate a tendency toward better outcome in patients treated with anticoagulant therapy than in those who are not treated with anticoagulants. In Einhaupl's study, even patients with cerebral hemorrhage appeared to benefit from anticoagulation.^[27]

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Alteplase (Activase)

• Dosing, Interactions, etc.

Clinical Context:  Alteplase is a biosynthetic form of human tissue plasminogen activator. Tissue plasminogen activator exerts an effect on the fibrinolytic system that results in the conversion of plasminogen to plasmin. Plasmin degrades fibrin, fibrinogen, and procoagulant factors V and VIII.

Alteplase is not given as an IV infusion to treat CVT. Refer the patient to a facility with the expertise to perform venous sinus catheterization.

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Reteplase (Retavase)

• Dosing, Interactions, etc.

Clinical Context:  Reteplase is a recombinant tPA that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, it has been shown to be comparable with tPA in achieving patency at 90 minutes. Heparin and aspirin are usually given concomitantly and afterwards.

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Tenecteplase (TNKase)

• Dosing, Interactions, etc.

Clinical Context:  Tenecteplase is a modified version of alteplase that is made by substituting 3 amino acids. It has a longer half-life than alteplase and thus can be given as a single bolus infused over 5 seconds (as opposed to the 90 minutes required for alteplase). It appears to cause less non–intracranial bleeding than alteplase but carries a comparable risk of intracranial bleeding and stroke.

Base the dose on the patient's weight. Initiate treatment as soon as possible after the onset of AMI symptoms. Because tenecteplase contains no antibacterial preservatives, it must be reconstituted immediately before use.

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Class Summary

These agents cause the lysis of clots. All studies concerning the use of these agents in cerebral venous thrombosis (CVT) involve either direct instillation into the sinus at the time of surgery or the use of microcatheters to reach the venous sinus.

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