Clinical manifestations

Presentation and course

Patients with a hypercoagulable state usually present at an early age (younger than 50 years). The clinical manifestations of thrombophilic patients can be due to either venous thrombosis or (rarely) arterial thrombosis. In antiphospholipid antibody syndrome, pregnancy morbidity, including spontaneous abortions or preterm delivery due to placental insufficiency, is another clinical manifestation. The most common presentation of venous thrombosis is deep vein thrombosis of the lower extremity with or without pulmonary embolism. Thromboses are seen rarely in other sites, including cerebral veins, axillary veins, mesenteric veins, and renal veins. Arterial thrombosis manifests as ischemic stroke, myocardial infarction, and peripheral arterial thrombosis. If a patient with venous thrombosis has a right-to-left shunt such as a patent foramen ovale or pulmonary arteriovenous malformation, an embolus may dislodge from the thrombus and pass through this shunt to cause an arterial ischemic stroke, termed a “paradoxical embolus.”

Cerebrovascular manifestations of a hypercoagulable state are arterial ischemic stroke and cerebral venous thrombosis.

Arterial ischemic stroke. Arterial ischemic stroke manifests as acute onset focal neurologic deficits including paresis, numbness, aphasia, hemispatial neglect, dysarthria, vertigo, and/or visual disturbances including a hemianopia, quadrantanopia, or monocular blindness.

Thrombosis of the cerebral veins or dural sinuses. Thrombosis of the cerebral veins or dural sinuses is an uncommon form of stroke, usually affecting young individuals. It has a highly variable clinical presentation. The signs and symptoms can be grouped into three major syndromes:

	(1) Isolated intracranial hypertension syndrome: headache with or without vomiting, papilledema, and visual problems.
	(2) Focal syndrome: focal deficits, seizures, or both.
	(3) Encephalopathy: multifocal signs, mental status changes, stupor, or coma.

Isolated intracranial hypertension or papilledema are frequent presentations in chronic cerebral venous thrombosis rather than in those who present acutely (53).

Headache. Headache is the most common symptom of cerebral venous thrombosis and was present in 89% of patients in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort (52). Headache is usually described as diffuse pain that progresses in severity over days to weeks. Some patients have sudden explosive onset of severe headache (thunderclap headache), and the pain mimics that seen in subarachnoid hemorrhage. A migrainous type of headache with aura has also been reported (34). Cerebral venous thrombosis must be a diagnostic consideration in patients with persistent headache or in patients with headache and papilledema or diplopia (due to sixth nerve palsy).

Focal symptoms and signs. When focal brain injury occurs due to venous ischemia or hemorrhage, neurologic symptoms referable to the affected territory occur. Hemiparesis and aphasia are the most frequent focal symptoms. Sensory deficits and visual field defects are less common.

Seizures. Focal or generalized seizures are more frequent in cerebral venous thrombosis than in other cerebrovascular diseases. In the ISCVT cohort, 39.3% of patients presented with seizures (52).

Encephalopathy. Severe cases of cerebral venous thrombosis may present with disturbances of consciousness, cognitive dysfunction or delirium, apathy, frontal lobe syndrome, multifocal deficits, or seizures. Psychosis has been rarely reported in conjunction with focal neurologic signs (06). Isolated mental status changes such as somnolence or a confusional state without other focal neurologic abnormalities can occur (91), especially in the elderly.

Intracranial hemorrhage. Approximately 30% to 40% of patients with cerebral venous thrombosis present with intracranial hemorrhage (63; 161), usually along with other features such as prodromal headache, bilateral parenchymal abnormalities, and clinical evidence of a hypercoagulable state. Rarely, isolated subarachnoid hemorrhage can occur in cerebral venous thrombosis.

Clinical manifestations of cerebral venous thrombosis also depend on the location of thrombosis.

	• Superior sagittal sinus thrombosis may present with headache, increased intracranial pressure, and papilledema. It may also present with motor deficit with or without seizure. The deficit can be bilateral. Scalp edema and dilated scalp veins may be seen.
	• Cavernous sinus thrombosis presents with ocular signs, such as orbital pain, chemosis, proptosis, and oculomotor palsies.
	• Isolated transverse sinus thrombosis frequently presents with isolated headache or isolated intracranial hypertension. Less commonly, it may also present with focal deficits (hemianopia, contralateral weakness, and aphasia) or seizures. Aphasia may occur if the left transverse sinus is affected.
	• Isolated cortical vein thrombosis produces motor and/or sensory deficits and seizures (80).
	• Jugular vein or transverse sinus thrombosis may present with pulsating tinnitus (160).
	• Transverse sinus, jugular, or posterior fossa vein thrombosis may present with multiple cranial nerve palsies (92).
	• When the deep cerebral veins (internal cerebral vein, vein of Galen, and straight vein) are affected, the symptoms are usually severe, and there is rapid deterioration. There can be thalamic or basal ganglia involvement (158).

Antiphospholipid antibody syndrome. Frequent clinical manifestations of antiphospholipid antibody syndrome include deep vein thrombosis (32%), thrombocytopenia, livido reticularis, stroke (13%), superficial thrombophlebitis, pulmonary embolism, fetal loss, transient ischemic attack, and hemolytic anemia (26). The occurrence of livedo reticularis in association with a stroke is known as Sneddon syndrome.

Prognosis and complications

Despite an increased risk for thrombosis, the prognosis of most hypercoagulable states is excellent. Overall mortality is not higher in patients with protein C or antithrombin III deficiency than in the general population (03; 157) nor is mortality increased in patients with factor V Leiden (73). However, massive pulmonary embolism, cerebral venous thrombosis, and ischemic stroke are associated with increased mortality. Complications of ischemic stroke and cerebral venous thrombosis include long-term neurologic morbidity and seizures.

Retrospective studies in select families with factor V Leiden or deficiencies of protein C, protein S, or antithrombin III suggest a lifetime prevalence of thrombosis of over 50% (36; 73). Many patients remain asymptomatic, however, and prospective data indicate that the true prevalence of thrombosis in such patients may be considerably lower (39). The risk of recurrence of ischemic stroke in patients with the antiphospholipid antibody syndrome is not well established but is likely increased by the presence of lupus or multiple antiphospholipid antibodies.

Clinical vignette

A 49-year-old woman with active tobacco use was admitted to the hospital 5 years ago for acute infarcts in the right hemisphere. Stroke work-up was negative for large artery cervical or intracranial atherosclerosis, and transesophageal echocardiogram was negative for significant valvular disease or embolic source. Labs revealed triple-positive antiphospholipid syndrome. Based on the absence of clinical trial data regarding the use of direct oral anticoagulants (DOACs) for antiphospholipid syndrome at that time and patient preference, she was started on apixaban 5 mg twice daily. She successfully quit smoking. In 2018, an echocardiogram performed for shortness of breath revealed Libman-Sacks (culture negative) endocarditis and severe mitral valve regurgitation. In 2019, she underwent mechanical mitral valve replacement, and anticoagulation was switched to warfarin, INR goal 2.5 to 3.5, and aspirin 81 mg daily. She had one seizure in 2019 and was started on levetiracetam 500 mg twice daily. In 2020, she was diagnosed with undifferentiated connective tissue disorder and was started on hydroxychloroquine 400 mg daily. She remains neurologically stable without recurrent stroke since initial hospitalization in 2017.

Biological basis

Etiology and pathogenesis

Table 1. Thrombosis Risk Factors

Inherited thrombophilia
	(1) Factor V Leiden mutation (2) Prothrombin G20210A gene mutation (3) Protein C deficiency (4) Protein S deficiency (5) Antithrombin III deficiency (6) Dysfibrinogenemia (7) Hyperhomocysteinemia (MTHFR mutation) (8) Plasminogen activator inhibitor mutation
Acquired thrombophilia
	(1) Malignancy (2) Presence of central venous catheter (3) Surgery (4) Trauma (5) Pregnancy and puerperium (6) Ovarian hyperstimulation syndrome (7) Hormonal contraception (8) Hormone replacement therapy (9) Tamoxifen, thalidomide, lenalidomide (10) Prolonged immobilization (11) Congestive heart failure (12) Antiphospholipid antibody syndrome (13) Heparin-induced thrombocytopenia and thrombosis syndrome (14) Myeloproliferative disorders: polycythemia vera, essential thrombocytosis (JAK2 V617F mutation is typically a sporadically acquired somatic mutation, but a genetic predisposition has been identified) (15) Thrombotic thrombocytopenia purpura (16) Paroxysmal nocturnal hemoglobinuria (17) Inflammatory bowel disease (18) Nephrotic syndrome (19) HIV (20) Hyperthyroidism (21) Iron deficiency anemia with reactive thrombocytosis (22) Infection with SARS-CoV-2 (COVID-19)

Often, more than one risk factor may be present in a patient. Some patients have an inherited cause in addition to the acquired risk factor (surgery, bed rest, malignancy, etc.). There may be more than one inherited cause in a single patient.

Protein C resistance and factor V Leiden mutation. Activated protein C was originally discovered in thrombophilic families and was later shown to be associated with factor V Leiden mutation. This inherited resistance to protein C is the most common genetic risk factor for venous thrombosis. Carrier frequency of factor V Leiden is 5.3% in Caucasian Americans, 2.3% in Hispanic Americans, and 1.2% in African Americans (137). The relative risk for first venous thrombosis with factor V Leiden mutation compared to the general population is about 5 to 7 (101). Though many genetic and acquired conditions contribute to activated protein C resistance, factor V Leiden is the major cause. Factor V Leiden has autosomal dominant inheritance with incomplete dominance. Factor Va is a cofactor in conversion of prothrombin to thrombin. The transition of a single nucleotide (G1691A) of the factor V gene results in the replacement of arginine with glutamine at position 506. This missense mutation renders factor V Leiden insusceptible to cleavage by activated protein C (140). Decreased inactivation of factor Va causes increased generation of thrombin and, thereby, increased coagulation. This commonly manifests as deep vein thrombosis with or without pulmonary embolism.

Protein C deficiency. The thrombin-thrombomodulin complex activates protein C, and activated protein C inhibits factors Va and VIIIa, thus, preventing further thrombin generation (28). This action of protein C is enhanced by protein S. In addition, activated protein C enhances fibrinolysis. The deficiency of protein C leads to increased risk of venous thrombosis. The relative risk is 15 to 20 (101). There are two types of heterozygous protein C deficiency associated with more than 160 different gene abnormalities (135). Type 1 deficiency is more common, with plasma concentration approximately 50% of normal in both functional and immunologic assays. Type 2 deficiency individuals have normal protein C antigen level with decreased functional activity. Patients with protein C deficiency clinically present with venous thrombosis, arterial thrombosis, neonatal purpura fulminans, warfarin-induced skin necrosis, or fetal loss.

The first episode of venous thromboembolism occurs spontaneously in 70% of patients and along with other risk factors (trauma, surgery, pregnancy, oral contraceptives, etc.) in the remaining 30%. Cerebral vein thrombosis can occur in association with protein C deficiency, particularly when associated with other acquired risk factors such as oral contraceptives (38).

Arterial thromboses leading to nonhemorrhagic stroke have been rarely reported in young adults with hereditary protein C deficiency (24). Larger studies have not associated protein C deficiency with ischemic stroke in young adults (45; 59).

Warfarin-induced skin necrosis occurs in the first few days of treatment with loading dose of warfarin especially in protein C-deficient patients. The lesions occur as an initial central erythematous macule and progress to skin necrosis. The usual sites are the extremities, breast, trunk and penis.

Neonatal purpura fulminans affects infants with protein C deficiency and usually presents in the first day of life with ecchymoses and extensive venous and arterial thrombosis. Laboratory findings are consistent with disseminated intravascular coagulation and very low levels of protein C (less than 1%) (106).

Protein S deficiency. Protein S acts as a cofactor of activated protein C and together they form an anticoagulant complex that inactivates factor Va and factor VIIIa. It circulates in two forms—free form and bound form (bound to complement component, C4b binding protein). Only the free form has protein C cofactor activity. Protein S deficiency is inherited as an autosomal dominant trait. The gene of protein S (PROS1) resides in chromosome 3. Almost 200 mutations have been characterized in PROS1 (60). Based on total protein S concentration, free protein S concentration, and activated protein C cofactor activity, protein S deficiency is classified into three types: type I (decreased levels of both free and total protein S antigen), type II (normal levels of total and free antigen levels, but cofactor activity of protein S was decreased), and type III (decreased levels of free protein S with normal levels of total protein S antigen) (58). The clinical manifestations of protein S deficiency are similar to that of protein C and antithrombin deficiency, which include deep vein thrombosis, superficial thrombophlebitis, or pulmonary embolism (48). Thrombosis of axillary, mesenteric, and cerebral veins and warfarin-induced skin necrosis have been described in patients with protein S deficiency (74; 141).

Prothrombin gene mutation. Prothrombin or factor II is the precursor of thrombin, the end product of the coagulation cascade. Transition of guanine to adenine at 20210 position in the 3’ untranslated region of prothrombin gene leads to formation of prothrombin G20210A genotype (130). This G20210A variant leads to increased plasma prothrombin levels and increases thrombotic risk. Heterozygosity for the prothrombin gene mutation is present in 1.7% to 3% among European populations (139). The relative risk for first venous thrombosis is 2 to 3 (101). Heterozygous carriers were shown to have 30% higher plasma level than normal individuals. The prothrombin gene mutation carriers have an increased risk of deep vein and cerebral vein thrombosis. Oral-contraceptive use in patients with prothrombin gene mutation increases the risk of cerebral vein thrombosis further (107; 136).

Antithrombin deficiency. Antithrombin physiologically inactivates factors in the intrinsic pathway, namely activated forms of factor X, factor IX, factor XI, factor XII, and to a lesser extent Factor II and also the activated form of Factor VII from the extrinsic pathway. Deficiency leads to venous thrombosis and, rarely, arterial thrombosis. The relative risk is about 15 to 20 (101). Based on immunologic and functional activity, antithrombin deficiency is classified into two types. Type I has reduced activity of both immunologic and functional activity of about 50% of normal. Type II has markedly reduced functional activity but normal immunologic activity. Three subtypes of Type II have been described: those with heparin binding site defects, with thrombin binding site defects, and with pleiotropic defects. Venous thrombosis can occur in deep veins of legs, iliofemoral veins, mesenteric veins, and, less frequently, in vena cava, renal, retinal, cerebral (37), and hepatic veins. Arterial thrombosis has also been rarely reported in antithrombin deficiency.

Dysfibrinogenemia. Fibrinogen plays a pivotal role in hemostasis by acting as substrate for fibrin clot formation, binding to platelets to support platelet aggregation, and the fibrin clot acting as a template for both thrombin binding and fibrinolytic system. The clinical manifestations of abnormal fibrinogen or dysfibrinogenemia depend on which functions are affected and includes bleeding, thrombosis, both, or neither. Dysfibrinogenemia as a cause of thrombophilia is rare. It usually presents as venous thrombosis of a lower extremity. Arterial thrombosis, both arterial and venous thrombosis, postpartum thrombosis, and abortions have also been reported in association with dysfibrinogenemia (72).

Hyperhomocysteinemia. Hyperhomocysteinemia is a disorder characterized by elevation of plasma homocysteine, and it can be either genetic or acquired. The genetic defects in the enzymes involved in homocysteine metabolism, nutritional deficiencies in vitamin cofactors, some chronic medical conditions, and drugs can cause hyperhomocysteinemia. The most common genetic variety of hyperhomocysteinemia results from the production of thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) with reduced enzymatic activity. Several studies have shown that hyperhomocysteinemia is a risk factor for cardiovascular (02) and cerebrovascular disease (18) and venous thromboembolism (134). The risk for arterial ischemic stroke with an MTHFR mutation is not well established.

Plasminogen activator inhibitor mutation. The plasminogen activators (t-PA and u-PA) convert plasminogen to plasmin, which in turn degrades fibrin into fibrin degradation products. Plasminogen activator inhibitor mutation can lead to either bleeding from thrombosis deficiency or overexpression of the plasminogen activator inhibitor. An elevated level of plasminogen activator inhibitor is associated with a variety of pathological conditions, including thrombosis (159). The other associations include obesity and insulin resistance (84).

Antiphospholipid antibody syndrome. Antiphospholipid antibody syndrome is an acquired thrombophilia associated with specific laboratory criteria (lupus anticoagulant, anticardiolipin antibody, and anti-beta-2-glycoprotein 1) and a history of a venous or arterial thrombosis or fetal loss. Antiphospholipid antibody syndrome is characterized by antibodies directed against either phospholipids or plasma proteins that are bound to phospholipids. These include lupus anticoagulant, anticardiolipin antibodies, antibodies to beta-2 glycoprotein 1, prothrombin, annexin V, phosphatidylserine, phosphatidylinositol, and others. The various clinical manifestations of antiphospholipid antibody syndrome are proposed to be due to the effects of these antibodies on the coagulation pathway via disruption of the annexin A5 shield, increased oxidative stress and impaired function of endothelial nitric oxide synthase, actions on protein C, platelets, serum proteases, toll-like receptors, complement, and tissue factor as well as via impaired fibrinolysis (56; 88; 133; 155; 62). Beta 2-glycoprotein 1 is an endogenous regulator of fibrinolysis and is the most common target of antiphospholipid antibodies. Impairment of beta 2-glycoprotein 1-stimulated fibrinolysis by anti-beta 2-glycoprotein 1 antibodies may also contribute to the development of thrombosis in patients with antiphospholipid antibody syndrome (22). Anticardiolipin antibodies may be bound to cardiolipin either in the presence of beta 2-glycoprotein 1 or independent of beta 2-glycoprotein 1. Among different subtypes of antibodies, IgG antibodies (which are beta 2-glycoprotein 1-dependent) appear to be a more specific marker for thrombosis, especially in patients with ischemic stroke (19).

Heparin-induced thrombocytopenia. This complication of heparin therapy caused by immune mechanisms usually occurs within 5 to 10 days after heparin treatment has started (65). This syndrome should be suspected in patients who develop thrombocytopenia (platelet count less than 100,000/µL) 5 or more days after exposure to heparin. There is a high risk for life-threatening arterial or venous thrombosis with continued therapy in such patients.

Myeloproliferative disorders. Myeloproliferative disorders, including polycythemia vera, myeloid metaplasia, and essential thrombocytopenia, are acquired bone marrow disorders frequently associated with the JAK2 V617F mutation. JAK2 is a tyrosine kinase implicated in hematopoietic signaling pathways. Mutation of JAK2 contributes to an uncontrolled expansion of myeloproliferative disorder clones and increased red blood cell or platelet mass and abnormal platelet function (123). There is an imbalance of tissue factor and tissue factor inhibitor, thrombin upregulation, increased factor Xa production, hypersensitivity of megakaryocytes to fibrinogen, and increased platelet aggregation. JAK2 mutation is associated with increased risk of arterial ischemic stroke, myocardial infarction, cerebral venous thrombosis, and portal or splenic vein thrombosis. Additional somatic mutations causative of a myeloproliferative disorder include JAK2 exon 12, thrombopoietin receptor gene (MPL), and careticulin (CALR) gene. Originally thought to be a sporadic mutation, a familial predisposition toward development of the JAK2 V617F mutation is now recognized (83).

Thrombotic thrombocytopenic purpura. Thrombotic thrombocytopenia purpura is a rare acquired disorder of unknown cause characterized by fever, thrombocytopenia, and microangiopathic hemolytic anemia evidenced by the appearance of fragmented red blood cells (schistocytes) on the peripheral blood smear. The hallmark of thrombotic thrombocytopenic purpura is widespread microvascular thrombosis, which results in purpura, acute renal insufficiency, and CNS manifestations-seizures, delirium, or ischemic stroke (153).

HIV. There is a 2- to 10-fold increased risk of venous thromboembolism in patients with HIV compared to the general population. The association with venous thromboembolism becomes much stronger when it coexists with other risk factors such as low CD-4 count, clinical AIDS, and other prothrombotic conditions (15). Studies have shown an increased risk of stroke in HIV patients (31); the mechanisms of stroke in these patients are variable and include vasculitis or hypercoagulability (119).

SARS-CoV-2 (COVID-19). SARS-CoV-2, also called COVID-19, is an RNA coronavirus that initially causes symptoms of viral illness including fever, myalgias, fatigue, headache, and cough. It can progress to adult respiratory distress syndrome, systemic inflammatory response syndrome, cytokine storm, multiorgan failure, and thrombosis. Hematological laboratory abnormalities most frequently seen in COVID-19 include elevated D-dimer (a negative prognostic factor for ICU admission, mechanical ventilation, and death), elevated fibrinogen, and thrombocytopenia. Prolonged prothrombin time, elevated INR, and disseminated intravascular coagulation have also been reported (11; 16). Antiphospholipid antibodies have been described in the setting of the COVID-19 infection, though the persistence of these antibodies and clinical significance is not yet determined (71; 75; 168). On a pathological level, endotheliitis and focal microvascular thrombosis have been described (11). COVID-19 has been associated with increased risk for venous thromboembolism, systemic arterial thrombosis, arterial ischemic stroke, intracranial hemorrhage, and cerebral venous thrombosis (104; 105; 120; 138; 167). Cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia has been reported as an extremely rare side effect of the COVID-19 vaccination (151).

Pathophysiology of cerebral vein thrombosis. The two main pathologies leading to the clinical manifestations of cerebral venous thrombosis are (1) increased intracranial pressure and (2) brain parenchymal changes. Obstruction of dural sinuses causes an increase in venous pressure, which impairs CSF reabsorption and leads to raised intracranial pressure. The raised endocapillary pressure causes veins and capillaries to rupture, leading to parenchymal hemorrhage. It also causes blood-brain barrier disruption, leading to vasogenic edema. The increased intravenous pressure also lowers the cerebral perfusion pressure, leading to decreased cerebral blood flow and failure of Na+/K+ ATPase pump and consequent cytotoxic edema (64).

Epidemiology

Cerebral vein thrombosis. Hypercoagulable states associated with cerebral venous thrombosis in the literature include the antiphospholipid antibody syndrome, antithrombin III deficiency, protein C or S deficiency (47; 40), factor V Leiden mutation (102), prothrombin G20210A gene mutation (17), the JAK2 V617F mutation (124; 116; 122), hyperhomocysteinemia due to gene mutations in MTHFR (25), hormonal contraception use, cancer, hyperthyroidism (13), and SARS-CoV-2 (COVID-19) infection (77; 138).

Of 624 patients in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), 34% had an inherited or acquired prothrombotic condition, including antithrombin III deficiency, protein C deficiency, protein S deficiency, factor V Leiden, activated protein C resistance, prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibody syndrome (52). In the presence of a hypercoagulable state, patients are at higher risk of developing cerebral venous thrombosis when exposed to other acquired risk factors such as hormonal contraception, head trauma, lumbar puncture, jugular catheter placement, pregnancy or the puerperium, surgery, infection, and drugs. The VENOST study of 1144 patients with cerebral venous thrombosis found prothrombotic laboratory abnormalities in 26.4% of patients, including most frequently MTHFR or factor V Leiden homozygotes, protein S or C deficiency, hyperhomocysteinemia, and prothrombin gene mutation (46).

In children and neonates, thrombophilias associated with cerebral venous thrombosis in the literature include antithrombin III deficiency, protein C deficiency, protein S deficiency, factor V Leiden mutation, and a trend toward an association with prothrombin gene mutation and combined thrombophilic abnormalities (86).

Arterial ischemic stroke. The association between hereditary hypercoagulable disorders and ischemic stroke is not as well-established as with venous thrombosis. The cumulative odds ratios for activated protein C and factor V Leiden and prothrombin gene mutation in ischemic stroke patients was 1.6 (95% confidence interval 1.3 to 1.9) and 1.4 (1.03 to 1.9), respectively, based on controlled prevalence studies published prior to March 2000 (23). However, a well-designed prospective study found no significant association among deficiencies of protein C, protein S, or antithrombin III, activated protein C/factor V Leiden, or prothrombin gene mutation in ischemic stroke patients compared with controls (70). A nested case-control within the Copenhagen City Heart Study also found no difference in the prevalence of the factor V Leiden mutation in patients with myocardial infarction or ischemic stroke compared with controls (85). A study focused on young adults aged 16 to 39 years showed no association with activated protein C resistance, protein C, protein S, antithrombin III, factor V Leiden, or prothrombin gene mutation with either ischemic stroke or myocardial infarction compared with matched controls (143). A meta-analysis of 18 case-control studies of ischemic stroke in adults 50 years of age and younger found that in those studies selecting for patients with an increased likelihood of a hypercoagulable state, the factor V Leiden mutation was associated with an increased risk of ischemic stroke with an odds ratio of 2.73 (95% CI 1.98-3.75) (69). In the Genetics of Early Onset Stroke (GEOS) study, a case-control study of 830 unselected stroke patients aged 15 to 49 years with first ischemic stroke in a multiethnic cohort, there was no association between factor V Leiden and stroke (68). In a large Danish series of patients aged 18 to 50 years with stroke, transient ischemic attack, or amaurosis fugax tested for multiple genetic and acquired thrombophilias, only factor V Leiden heterozygosity was associated with a higher risk of transient ischemic attack/amaurosis fugax, and persistently positive lupus anticoagulant showed a nonsignificant trend toward increased risk of ischemic stroke (121). Finally, a systematic review and metaanalysis of case-control and cohort studies of adults with arterial ischemic stroke tested for inherited thrombophilias including approximately 11,000 patients and 96,000 controls found a small increased risk for stroke with protein S deficiency, protein C deficiency, prothrombin G20210A, and factor V Leiden, particularly in young patients (27).

In the GEOS study, in patients of European ancestry, an association was found between the prothrombin G20210A mutation and ischemic stroke (OR 5.9; 95% CI 1.2-28.1) only in those patients aged 15 to 42 years. A meta-analysis including the GEOS results and 17 other case-control studies of patients aged less than 55 years by the same authors showed an increased risk of ischemic stroke (OR 1.5; 95% CI 1.1-2.0) in those with prothrombin G20210A mutation (82).

The significance of plasminogen activator inhihibitor-1 polymorphisms as an independent risk factor for arterial ischemic stroke is inconsistently reported. An association study and meta-analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism failed to show a relationship between the polymorphism and ischemic stroke in the case-control part of the study but suggested an association between the 4G/4G genotype and ischemic stroke in the meta-analysis; however, the direction of the effect was not consistent from study to study (09). The largest metaanalysis to date reported a small increased risk for ischemic stroke in adults with the PAI-1 4G/4G genotype or the -844 A/A genotype (76).

There is considerable debate about whether the MTHFR C667T mutation is associated with ischemic stroke. A meta-analysis reported a mild association with ischemic stroke in the MTHFR TT genotype (abnormal homozygotes) (100), but this warrants further confirmation in prospective studies controlling for dietary and other vascular risk factors.

A retrospective review of consecutive stroke and transient ischemic attack patients aged 18 to 45 years at a tertiary stroke center found that hypercoagulable screening tests including protein C, protein S, antithrombin III deficiency, factor V Leiden mutation, and prothrombin gene mutation were abnormal in 30 out of 189 patients. In follow-up, only 8 of 23 patients with low protein S at the time of a cerebrovascular event had a persistently low level, underscoring that aside from the genetic mutations, other thrombophilic states may be transient. Two other single-center case series of arterial ischemic stroke patients who underwent thrombophilia testing reported at least one laboratory abnormality on initial testing in roughly 31% to 44% of patients; however, this led to a change in management (ie, anticoagulation) in less than 10% of patients (61; 115). Decisions regarding anticoagulation for these should be judicious, and repeat testing after the acute stroke period is important (81). In contrast, in a single-center small series of arterial stroke and cerebral venous thrombosis patients aged 16 to 50 years in Beirut without other conventional vascular risk factors, a strikingly high number of patients had multiple gene mutations, including most frequently the MTHFR mutation (94%), factor V Leiden mutation (49%), and plasminogen activator inhibitor-1 mutation (34%), suggesting that in a select young stroke population, a high incidence of multiple abnormal thrombophilia tests may be found, although the risk of each alone or in combination for cerebrovascular disease was not determined by comparison with controls (08).

In the pediatric population, a meta-analysis of 22 observational studies found significant associations between first arterial ischemic stroke and protein C deficiency, factor V Leiden mutation, prothrombin gene mutation, antiphospholipid antibodies, MTHFR homozygotes (C677 TT), and those with combined genetic defects. Antithrombin III deficiency and protein S deficiency did not meet statistical significance for an association with pediatric arterial ischemic stroke (86). In the Canadian Pediatric Ischemic Stroke Registry, prothrombotic disorders were found in 32% of the 516 patients tested out of 1129 total, with factor V Leiden, elevated lipoprotein (a), and activated protein C resistance being most frequent (41). A large international cohort of pediatric recurrent arterial ischemic stroke patients found antithrombin III deficiency, elevated lipoprotein (a) or the presence of more than one prothrombotic risk factor to be associated with stroke recurrence (42). Regarding perinatal stroke specifically, a case-control study found that perinatal stroke was not associated with an increased risk of thrombophilia, and suggested that thrombophilia testing in children with a history of perinatal stroke is not warranted (35).

A large epidemiological study reported that a history of deep venous thrombosis or pulmonary embolism significantly increased the risk of future stroke and myocardial infarction (146). After excluding patients with a prior history of cardiovascular disease, patients with unprovoked deep venous thrombosis or pulmonary embolism had a 74% increased risk of myocardial infarction (HR 1.74; 95% CI 1.42-2.13), a 2-fold increased risk of stroke (HR 2.01; 1.63-2.48), and a 60% increased risk of ischemic stroke (HR 1.60; 1.18-2.18) in the first year. Although the risk estimate decreased during the 2nd through 20th years of follow-up, it was still significant for both provoked and unprovoked stroke and myocardial infarction. The risk for myocardial infarction and ischemic stroke was even higher if patients had experienced a pulmonary embolus (146).

Hypercoagulable disorders typically associated with venous thrombosis are relevant in the setting of paradoxical embolus from a deep venous thrombosis through a patent foramen ovale or pulmonary arteriovenous fistula to the cerebral arteries, causing stroke. An increased risk of arterial ischemic stroke was observed in patients with patent foramen ovale and the prothrombin G20210A gene mutation in comparison to ischemic stroke patients without patent foramen ovale in a large meta-analysis (128). However, this finding was not reproduced in a large series (49). A metaanalysis of cryptogenic stroke patients with patent foramen ovale showed an increased risk for recurrent stroke in patients with inherited or acquired thrombophilia that just lost significance when looking specifically at patients treated with patent foramen ovale closure but conclusions could not be drawn about optimal secondary prevention antithrombotic regimen (78).

Antiphospholipid antibody syndrome. There is a strong association between antiphospholipid antibody syndrome and stroke. Earlier studies showed that 20% to 25% of young stroke patients had antiphospholipid antibodies (111; 66). The Honolulu Heart study examined antiphospholipid antibodies as a risk factor for ischemic stroke and myocardial infarction and found the relative risk of stroke at 15 years of follow-up was 2.2 in subjects with antiphospholipid antibodies, primarily in those subjects who had both beta 2-glycoprotein 1 and anticardiolipin IgG antibodies (19). In the Stroke Prevention in Young Women study, the relative odds of stroke for women with anticardiolipin antibodies or a lupus anticoagulant was 1.87 (95% CI, 1.24- 2.83; P=0.0027) (20). Two meta-analyses supported by the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) have attempted to determine the prevalence of antiphospholipid antibodies in patients with stroke, and whether they increase the risk for stroke. The first meta-analysis estimated that antiphospholipid antibodies including lupus anticoagulant, anticardiolipin, and anti-beta-2 glycoprotein 1 antibodies were present in approximately 13.5% of the general population of stroke patients (05).When the meta-analysis was limited to patients below age 50, the overall frequency of antiphospholipid antibodies in patients with cerebrovascular events was approximately 17%, and the presence of an antiphospholipid antibody increased the risk of cerebrovascular events by 5.48-fold (95% CI 4.42 to 6.79) (145). It is important to note that due to heterogeneity in inclusion criteria and antiphospholipid antibody testing in the studies included in these meta-analyses, these prevalence and risk estimates should be interpreted cautiously.

The mechanisms by which antiphospholipid antibodies predispose to thrombosis are not completely understood, but research has provided insights into which types of antibodies are most specific for cerebral thrombosis. In the RATIO study, a Netherlands case-control study of women younger than 50 years with first myocardial infarction or stroke, lupus anticoagulant (OR 43.1 95% CI 12.2-152.0) and anti-beta-2 glycoprotein 1 (OR 2.3 95% CI 1.4-3.7) were independently associated with ischemic stroke (156). Smoking or oral contraceptive use further increased the risk. Anti-phosphatidylserine and anti-prothrombin antibodies were not associated with thrombotic events in the RATIO study but were associated with ischemic stroke when combined with anti-cardiolipin and anti-beta-2 glycoprotein 1 in a study of Japanese patients with lupus (113). In a French cohort of antiphospholipid patients with isolated IgM anticardiolipin and/or IgM anti-beta-2 glycoprotein-1 (isolated-IgM-APS), when compared to those with IgM and IgG antibodies, IgG antibodies alone, and/or lupus anticoagulant (nonisolated-IgM-APS), stroke was more frequent at diagnosis in those with isolated-IgM-APS. Patients were older, had similar relapse rates to their nonisolated-IgM-APS counterparts, and had a higher relapse rate on antiplatelet therapy versus vitamin K antagonists. This underscores the importance of close follow-up and active management of patients with isolated IgM antiphospholipid antibodies, who are often assumed to have a more benign course (154). Other prothrombotic conditions may enhance the thrombosis risk in patients with antiphospholipid antibodies.

In one small case-control study of stroke patients, patent foramen ovale and atrial septal aneurysm were strongly associated with antiphospholipid syndrome patients, suggesting paradoxical embolus as a stroke mechanism of the antiphospholipid syndrome (149). In the PICSS-APASS study of patients with ischemic stroke, the presence of a lupus anticoagulant or anticardiolipin antibody on a single assay and a patent foramen ovale was not associated with an increased risk of recurrent stroke (132).

The literature inconsistently demonstrates antiphospholipid antibodies alone as a risk for recurrent stroke. Antiphospholipid antibodies in combination with lupus appear to increase the risk of recurrent stroke. The antiphospholipid titer level and presence of multiple antiphospholipid antibodies or other hereditary or acquired thrombophilias is relevant. In the APASS study, the presence of a lupus anticoagulant or anticardiolipin antibody on one occasion after stroke did not increase the risk of recurrent thrombotic events over 2 years (99). In an extension of the APASS study, persistently positive anti-beta 2-glycoprotein 1 antibodies, either alone or in combination with another persistently positive antiphospholipid antibody, significantly decreased the time to recurrent thrombo-occlusive events or death, but did not increase the overall rate of these events in a 2-year period (04). In the Italian Project on Stroke in Young Adults, only the presence of antiphospholipid antibodies, but not the factor V Leiden or prothrombin G20210A mutations, was predictive of recurrent ischemic arterial events (127). Notably, in 160 “triple positive” (lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein 1 positive) patients with antiphospholipid syndrome in a retrospective study, of whom 18.8% had lupus, the recurrence rate of thromboembolic events after 1 year was 26.1% (95% CI 22.3-29.9) and at 10 years was 44.2% (95% CI 38.6-49.8) (126). A retrospective study of 99 ischemic stroke patients with either definite antiphospholipid syndrome by modified Sapporo criteria or indefinite antiphospholipid syndrome (transiently positive antiphospholipid antibodies) followed for a mean of 51.6 months reported a recurrent thrombosis rate of approximately 30% in both groups, regardless of antithrombotic used (131). This underscores the high long-term risk for recurrent thrombosis with antiphospholipid syndrome despite current antithrombotic treatments.

Racial variation in risk of thrombosis. There is ethnic and racial variation in the incidence of venous thromboembolism. The incidence in the African American population is 30% higher compared to the Caucasian population, whereas it is 70% lower in Native and Asian-Americans. Hispanics have a significantly lower prevalence of venous thromboembolism compared to Caucasians but higher than Asians and Pacific Islanders (163). In populations of European descent, the factor V Leiden mutation is found in 3% to 6% of asymptomatic controls, in approximately 20% of unselected patients with venous thrombosis, and in up to 50% of patients with familial venous thrombosis. The prevalence of factor V Leiden is much lower in Asian, African, and native North and South American populations. Like factor V Leiden, prothrombin 20210A also is more prevalent in Caucasian populations (14; 139).

Table 2. Prevalence of Inherited Hypercoagulable States in Caucasian Populations

Factor V Leiden
	• Asymptomatic controls: 3% to 6% • Unselected patients with venous thrombosis: 19% • Patients with familial thrombosis: 46% • Patients with ischemic stroke: 4.6% (OR 2.1, 95% CI 0.6 to 6.8)*
Prothrombin 20210A
	• Asymptomatic controls: 1% to 2% • Unselected patients with venous thrombosis: 6.3% • Patients with familial venous thrombosis: 18% • Patients with ischemic stroke: 3.7% (OR 1.9, 95% CI 0.5 to 6.2)*
Protein C deficiency
	• Asymptomatic controls: 0.14% to 0.5% • Unselected patients with venous thrombosis: 3.2% • Patients with familial venous thrombosis: 4.9% • Patients with ischemic stroke: 1.4% (OR 0.7%, 95%CI 0.2 to 3.1)*
Protein S deficiency
	• Asymptomatic controls: 0.1% • Unselected patients with venous thrombosis: 2.2% • Patient with familial venous thrombosis: 5.1% • Patients with ischemic stroke: 0.9% (OR 0.9, 95% CI 0.1 to 6.7)*
Antithrombin III deficiency
	• Asymptomatic controls: 0.02% to 0.2% • Unselected patient with venous thrombosis: 1.1% • Patients with familial thrombosis: 4.2% • Patients with ischemic stroke: 5.2% (OR 1.3, 95% CI 0.5 to 3.3)*
*Percentages, odds ratios (OR), and 95% confidence intervals (CI) derived from a single case-control study of ischemic stroke patients (70). (Adapted from Hypercoagulable states and cerebrovascular diseases article.)

Prevention

Prenatal diagnosis using molecular methods is technically possible but not widely available for protein C deficiency, protein S deficiency, antithrombin III deficiency, prothrombin 20210A, and factor V Leiden. No preventive measures are known for antiphospholipid antibody syndrome, which is an acquired autoimmune disorder. There are limited data regarding the efficacy of antithrombotic medications for primary prevention of ischemic stroke in patients with thrombophilias diagnosed incidentally or as a result of venous thrombosis.

SARS-CoV-2 (COVID-19). Emerging data support the role of anticoagulation to prevent and treat the thromboembolic complications of COVID-19 infection. The reader is advised to refer to their own institutional policy on the prevention and treatment of COVID-19 associated coagulopathy and remain abreast of emerging guidelines.

The optimal regimen for the prevention of venous thromboembolism and other thrombotic complications of COVID-19 infection is an area of active research. Multiple organizations including the International Society of Thrombosis and Haemostasis, American College of Chest Physicians and the National Institutes of Health have issued guidelines. It is reasonable to measure D-dimer, prothrombin time, fibrinogen, and platelet count in hospitalized COVID-19 patients, although there is limited guidance about how these data should guide management. Prophylactic dose low molecular weight heparin (LMWH) or unfractionated heparin is advised for hospitalized noncritically ill and critically ill COVID-19 patients in the absence of any contraindications. Additionally, in noncritically ill patients with a low risk of bleeding and risks for thrombosis including significantly elevated D-dimer, therapeutic dose anticoagulation with low molecular weight heparin or unfractionated heparin can be considered. Extended anticoagulant treatment postdischarge is an area of active research, but there are some data to support the use of rivaroxaban 10 mg daily for approximately 30 days postdischarge in select high-risk patients (109; 112; 144).

Differential diagnosis

Confusing conditions

The thrombophilic patient presenting with cerebrovascular disease (cerebral venous thrombosis or arterial ischemic stroke) may mimic patients with other causes of acute neurologic deficits or headache. The differential diagnosis is broad and includes intracranial hemorrhage, aneurysm, seizure, structural brain lesions, migraine, intracranial infection, toxic-metabolic abnormalities, etc.

Diagnostic workup

In a patient presenting with cryptogenic cerebral venous thrombosis or arterial ischemic stroke, pertinent history includes immobilization or prolonged hospitalization, recent surgery, obesity, lower extremity trauma, malignancy, use of contraceptives or hormonal replacement therapy, pregnancy or puerperium, history of pregnancy morbidity, and personal and family history of venous thrombosis or stroke. This is supplemented with careful physical examination, echocardiographic evaluation for a right-to-left shunt, and laboratory testing to determine the presence of any inherited or acquired thrombophilias.

Routine blood studies. Complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time should be performed in all patients.

Evaluation for the cause of thrombosis. Screening for hypercoagulable conditions in arterial ischemic stroke patients in general is likely of low yield, and a thorough evaluation for conventional vascular risk factors in most patients first is warranted. Situations in which thrombophilia testing could be considered include patients with a personal or family history of venous thrombosis without an identifiable risk factor, young patients with cryptogenic stroke, clinical features suggestive of a paradoxical embolism (110), and patients with recurrent unexplained thrombosis or thrombosis in unusual areas, such as the portal, hepatic, mesenteric, or cerebral veins. Commonly available laboratory tests include protein C, protein S, antithrombin III, factor V Leiden, prothrombin G20210 gene mutation, MTHFR, lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein 1 antibodies. Other laboratory tests include anti-phosphatidylserine, annexin V resistance, plasminogen activator inhibitor, paroxysmal nocturnal hemoglobinuria, fibrinogen, and factor levels. Some tests, such as antithrombin III, protein C, and protein S, may be falsely abnormal in the setting of anticoagulation or by the presence of acute thrombus. Repeat testing after the acute stroke period in conjunction with hematology consultation is advised for interpretation of these tests.

Diagnosis of antiphospholipid antibody syndrome. Revised classification criteria for antiphospholipid antibody syndrome are as follows (108):

Antiphospholipid antibody syndrome is considered present if at least one of the following clinical criteria and at least one of the following laboratory criteria are satisfied. Classification of the antiphospholipid syndrome should be avoided if fewer than 12 weeks or more than 5 years separate the positive antiphospholipid test and the clinical manifestation.

Clinical criteria.
	(1) Vascular thrombosis:
		One or more episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (ie, unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.
	(2) Pregnancy morbidity:
		(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe pre-eclampsia or placental insufficiency, or (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded
	(3) Laboratory criteria:
		(a) Presence of lupus anticoagulant in plasma on two or more occasions at least 12 weeks apart. (b) Presence of medium or high titer (ie, higher than 40 GPL or MPL, or higher than the 99th percentile) of anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA. (c) Presence of anti-beta2-glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titer higher than the 99th percentile) on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA.

Diagnosis of cerebral venous thrombosis. In addition to evaluation for hereditary and acquired thrombophilias and identification of risk factors (eg, pregnancy, malignancy, or infection), neuroimaging is important in the diagnosis of cerebral venous thrombosis.

Neuroimaging. The cerebral venous system should be imaged in patients with clinical suspicion of cerebral venous thrombosis and in clinical scenarios in which misdiagnosis, or delay in diagnosis, of cerebral venous thrombosis occurs. Imaging should be done in patients with lobar intracerebral hemorrhage of otherwise unclear etiology, in cerebral infarction that crosses typical arterial boundaries, in patients with idiopathic intracranial hypertension, and in patients with headache associated with atypical features (142).

Computed tomography. Computed tomography is the widely used initial neuroimaging test. Plain CT is abnormal in about 30% of cerebral venous thrombosis cases (142), but the anatomic variability of cerebral venous sinuses makes CT insensitive.

On plain CT, a thrombosed cortical vein or dural sinus can appear as a hyperdense “cord sign” (129). A hypodensity consistent with venous congestion, sometimes with hemorrhagic component, may be seen. The lesion may cross the usual arterial boundaries or may be near a venous sinus (57). Rarely, subarachnoid hemorrhage localized in the convexity is seen (117).

In contrast-enhanced CT, slow or absent flow within the confluence of the sinuses may create a hypodensity in comparison to the surrounding contrast enhancement, termed the “empty delta” sign (57; 96).

Magnetic resonance imaging. MRI with and without contrast is more than CT in diagnosing cerebral venous thrombosis. Depending on the age of the thrombus, the MRI signal intensity will vary based on the breakdown of hemoglobin (44; 79). In the first week, the thrombosed sinus appears isointense on T1-weighted images and hypointense on T2-weighted images due to the increased deoxyhemoglobin in the thrombus. In the second week, the thrombus becomes more apparent and appears hyperintense in both T1- and T2-weighted images owing to the methemoglobin in the thrombus. After 4 weeks, the thrombosed sinus exhibits low signal on gradient-echo and susceptibility-weighted images.

Other signs suggestive of cerebral venous thrombosis on MRI include absence of a flow void signal in the sinus or a central isodense lesion in a venous sinus with surrounding enhancement on post-contrast MRI. The brain parenchymal lesions of cerebral venous thrombosis (cerebral swelling, edema, or infarction) appear as hypointense or isointense lesions on T1-weighted MRI and hyperintense lesions on T2-weighted MRI and FLAIR. Appearance on diffusion-weighted imaging varies. The location of the parenchymal lesion will correlate with the involved sinus; for example, parasagittal lesions can occur with superior sagittal thrombosis, and temporal lobe lesions can occur with transverse sinus thrombosis.

CT venography. CT venography is a rapid, reliable imaging modality with almost the same effectiveness as MR venography in diagnosing cerebral venous thrombosis (142). In subacute or chronic cerebral venous thrombosis, it can demonstrate heterogeneous density in thrombosed venous sinuses. The drawbacks of CT venography include low resolution of the deep venous system and cortical veins, radiation risk, risk of iodine contrast allergy, and renal complications in patients with poor renal function.

MR venography. Normal anatomic variants such as hypoplastic sinuses and asymmetric flow can confound the diagnosis of cerebral venous thrombosis. A time-of-flight (TOF) 2- dimensional MR venography may reveal the chronic thrombosed hypoplastic sinus, which appears as a markedly enhanced sinus with no flow, whereas the nonthrombosed but hypoplastic sinus will not have a low signal on other sequences, such as gradient echo or susceptibility weighted imaging.

Angiography. In rare cases, digital subtraction angiography may be necessary to confirm the diagnosis of cerebral venous thrombosis.

Lumbar puncture. Lumbar puncture is typically not helpful in patients with focal neurologic abnormalities when radiographic confirmation of cerebral venous thrombosis is already made unless there is clinical suspicion of meningitis. There are no specific CSF findings, but an elevated opening pressure and elevated cell counts and protein levels may be present.

D-dimer. A normal D-dimer value indicates that there is a low probability of cerebral venous thrombosis but does not exclude it, especially in patients having suggestive symptoms and predisposing conditions (32). An elevated D-dimer supports a cerebral venous thrombosis diagnosis (95; 90).

Management

Management of cerebrovascular disease associated with a hypercoagulable state depends on the clinical syndrome and underlying thrombophilia. For example, it would be reasonable to treat a patient with an arterial ischemic stroke and history of unprovoked deep venous thrombosis or stroke due to paradoxical embolism from deep venous thrombosis with anticoagulation according to current deep venous thrombosis guidelines (89). The duration of anticoagulation will depend on the underlying thrombophilia. In patients with arterial ischemic stroke and a thrombophilia that is not as strongly associated with arterial stroke, such as Factor V Leiden or protein S deficiency, the decision to anticoagulate will be made on a case-by-case basis, accounting for the patient’s clinical scenario and other comorbidities. In an adult with arterial stroke and a heterozygous MTHFR with normal homocysteine, this finding is unlikely to be relevant, and the patient will be treated according to standard ischemic stroke guidelines. Efforts should be made to reduce other provoking factors, such as smoking or hormonal contraception use. In general, randomized prospective studies on secondary stroke and cerebral venous thrombosis prevention are lacking, and guidelines are based on literature review and expert consensus statements. Below are excerpts from the guidelines for the management of cerebral venous thrombosis and arterial ischemic stroke in the setting of the antiphospholipid antibody syndrome and other hypercoagulable states.

Antiphospholipid antibody syndrome

The management and secondary prevention of arterial ischemic stroke in patients with antiphospholipid antibody is an area of active research. Results from earlier studies were conflicting regarding the benefit of anticoagulation. The APASS study showed no difference in thrombo-occlusive events associated with lupus anticoagulant or anti-cardiolipin antibody IgG at 2-year follow-up in stroke patients treated with either warfarin or aspirin (99). Of note, many of the patients in this study had low-grade titers and conventional vascular risk factors, and the diagnosis of antiphospholipid antibody syndrome was not confirmed by repeat titers after 12 weeks. In contrast, a retrospective observational study of 160 patients with “triple positive” antiphospholipid antibody syndrome (lupus anticoagulant, anti-cardiolipin and anti-beta-2 glycoprotein 1 positive) demonstrated a significantly higher thrombosis recurrence rate in patients taking aspirin or no antithrombotic than in those taking oral full-dose anticoagulation (HR=2.4 95% CI 1.3-4.1) (126). Regarding optimal goal INR, prospective studies have failed to show an increased benefit for secondary prevention with a goal INR greater than 3.0 when compared to a goal INR of 2 to 3. In one study, high-intensity warfarin increased risk of hemorrhage (33; 55).

Prospective clinical trials. The RAPS trial randomized patients with antiphospholipid syndrome and previous venous thromboembolism to warfarin (target INR 2.5) or rivaroxaban and measured their endogenous thrombin potential from randomization to day 42. Although by endogenous thrombin potential, rivaroxaban was inferior to warfarin in terms of anticoagulation intensity, peak thrombin generation was lower in the rivaroxaban group, and the authors concluded that the overall thrombogram did not indicate an increase in thrombotic risk with rivaroxaban (30). However, the TRAPS trial, which randomized patients with high-risk (triple-positive) thrombotic antiphospholipid syndrome to either full-dose rivaroxaban or warfarin, was stopped early due to an excess of thromboembolic and bleeding events in the rivaroxaban arm, indicating that rivaroxaban showed no benefit and increased risk in this population (125). Another prospective, randomized noninferiority trial comparing rivaroxaban to warfarin (which included approximately 60% triple-positive antiphospholipid syndrome patients) also demonstrated an increased risk for recurrent thrombosis in patients receiving rivaroxaban (118). The published ASTRO-APS trial, which randomized antiphospholipid syndrome patients (about 30% of whom had triple-positive antiphospholipid syndrome) to either apixaban or warfarin, was terminated early due to an excess of thrombotic events in the apixaban group (164).

A single-center prospective cohort study of 176 patients with antiphospholipid syndrome compared 82 patients taking a direct oral anticoagulant due to patient preference or unstable INRs on vitamin-K antagonists (VKAs) versus 94 patients taking a vitamin-K antagonists (103). Over a median of 51 months of follow-up, there were significantly more thromboembolic events and major bleeds in the direct oral anticoagulant group.

Several systematic reviews and metaanalyses have concluded that direct oral anticoagulants are associated with an increased risk of recurrent thromboembolic events, especially arterial events and in patients with triple-positive antiphospholipid syndrome, in comparison to vitamin-K antagonists (67; 98; 165). Current guidelines, excerpted below, recommend the use of vitamin-K antagonists as first-line therapy for antiphospholipid syndrome. Whether direct oral anticoagulants are an effective option for single- and double-positive antiphospholipid patients is an area of active research.

In addition to anticoagulants, hydroxychloroquine, which significantly reduced lupus anticoagulant and antiphospholipid antibody titers in retrospective studies of patients with antiphospholipid syndrome, is a promising area of research (21; 114). The HIBISCUS study is an ongoing trial of hydroxychloroquine in the secondary prevention of thrombotic and obstetrical events in patients with primary antiphospholipid syndrome (12).

Evidence-based recommendations for the prevention and long-term management of thrombosis in patients with antiphospholipid antibodies. American Heart Association/American Stroke Association (AHA/ASA) guidelines for the treatment of stroke in patients with antiphospholipid antibody syndrome (89):

	(1) In patients with ischemic stroke or TIA who have an isolated antiphospholipid antibody but do not fulfill the criteria for antiphospholipid syndrome, antiplatelet therapy alone is recommended to reduce the risk of recurrent stroke (Class of recommendation 1/Level of evidence B-nonrandomized).
	(2) In patients with ischemic stroke or TIA with confirmed antiphospholipid syndrome treated with warfarin, it is reasonable to choose a target INR between 2 and 3 over a target INR >3 to effectively balance the risk of excessive bleeding against the risk of thrombosis (Class 3a/LOE B-randomized).
	(3) In patients with ischemic stroke or TIA who meet the criteria for the antiphospholipid syndrome, it is reasonable to anticoagulate with warfarin to reduce the risk of recurrent stroke or TIA (Class 2a/LOE C-limited data).
	(4) In patients with ischemic stroke or TIA, antiphospholipid syndrome with history of thrombosis and triple-positive antiphospholipid antibodies (ie, lupus anticoagulant, anticardiolipin, and anti–β2 glycoprotein-I), rivaroxaban is not recommended because it is associated with excess thrombotic events compared with warfarin (Class 3:Harm/LOE B-randomized).

Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis:

	(1) We recommend that for the treatment of thrombotic antiphospholipid antibody syndrome among patients with any of the following (termed “high-risk” antiphospholipid antibody syndrome patients):
		- triple positivity
		- arterial thrombosis
		- small vessel thrombosis or organ involvement
		- heart valve disease according to Sydney criteria
	(2) Vitamin K antagonists should be used instead of direct oral anticoagulants.
	(3) We recommend that direct oral anticoagulants should not be used in antiphospholipid antibody syndrome patients with recurrent thrombosis while on therapeutic intensity vitamin K antagonist. In this circumstance, other therapeutic options may include an increased target INR range, treatment dose low molecular weight heparin, or the addition of antiplatelet therapy.
	(4) We recommend that direct oral anticoagulants should not be used in antiphospholipid antibody syndrome patients who are nonadherent to vitamin K antagonists. In this circumstance, other options may include education on adherence to vitamin K antagonists treatment along with frequent INR testing.
	(5) In single or double positive non-“high risk” antiphospholipid antibody syndrome patients who have been on direct oral anticoagulants with good adherence for several months for a first episode of venous thromboembolism, we recommend a discussion with the patient of options including perceived risks and uncertainties, in the spirit of shared decision-making and review of whether continued treatment with a direct oral anticoagulant is appropriate.
	(6) In single- or double-positive non-“high-risk” antiphospholipid antibody syndrome patients with a single prior venous thromboembolism requiring standard-intensity vitamin K antagonists, with allergy or intolerance to vitamin K antagonists or erratic INRs despite patient adherence, we suggest that alternative vitamin K antagonists, if available, should be considered prior to consideration of a direct oral anticoagulant.
Adapted from (169).

British Society for Haematology Guidelines on Investigation and Management of Antiphospholipid syndrome:

	(1) For anticoagulation for treatment and secondary prophylaxis of arterial thrombosis in patients with antiphospholipid antibody syndrome, we recommend vitamin K antagonists (VKAs) and do not recommend direct oral anticoagulants (grade 1B).
	(2) We recommend against the initiation of direct oral anticoagulants for treatment or secondary prophylaxis in patients with venous thrombosis and known triple positive antiphospholipid antibody syndrome (grade 1B). For patients with triple positive antiphospholipid antibody syndrome who are currently on a direct oral anticoagulant, we recommend switching from the direct oral anticoagulant to a vitamin K antagonist after discussion with patients regarding the available evidence. For those patients who do not wish to switch, we recommend continuation of the direct oral anticoagulant over no anticoagulation (grade 1B).
	(3) For patients with non-triple positive antiphospholipid syndrome and venous thrombosis: - There is insufficient evidence to make strong recommendations in this group of patients. We suggest against the initiation of direct oral anticoagulants for treatment or secondary prophylaxis in patients with venous thrombosis and known non-triple positive antiphospholipid antibody syndrome (grade 2C). - Patients who are already on a direct oral anticoagulant may continue or switch to a vitamin K antagonist after discussion with the patient taking into account their clinical history, treatment adherence and previous experience. For those patients who do not wish to switch, we recommend continuation of the direct oral anticoagulant over no anticoagulation (grade 2C).
Adapted from (07).

European League Against Rheumatism (EULAR) recommendations for the management of antiphospholipid syndrome in adults (150):

	(1) In patients with definite antiphospholipid syndrome and first arterial thrombosis: A. Treatment with vitamin K antagonists (VKAs) is recommended over treatment with low-dose aspirin only (level of evidence 2b/grade of recommendation C).
	(2) Treatment with vitamin K antagonists with international normalized ratio 2-3 or international normalized ratio 3-4 is recommended, considering the individual’s risk of bleeding and recurrent thrombosis (1b/B). Treatment with vitamin K antagonists with international normalized ratio 2-3 plus low-dose aspirin may also be considered (4/C).
	(3) Rivaroxaban should not be used in patients with triple antiphospholipid antibody positivity and arterial events (1b/B). Based on the current evidence, we do not recommend use of direct oral anticoagulants in patients with definite antiphospholipid syndrome and arterial events due to the high risk of recurrent thrombosis (5/D).
	(4) In patients with recurrent arterial thrombosis despite adequate treatment with vitamin K antagonists, after evaluating for other potential causes, an increase of international normalized ratio target to 3-4, addition of low-dose aspirin, or switch to low molecular weight heparin can be considered (4-5/D).

16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends:

	(1) Direct oral anticoagulants should be avoided in antiphospholipid antibody syndrome patients with arterial thrombosis. For these patients, first-line therapy should be a vitamin K antagonist.
	(2) Direct oral anticoagulants should be avoided in thrombotic antiphospholipid antibody syndrome patients with small vessel thrombosis or aPL-related cardiac valvular disease. The first-line anticoagulant option should be a vitamin K antagonist.
	(3) For patients found to have single- or double-positive aPL following a first episode of venous thromboembolism (in the acute setting or later in their course), we suggest that continuation of the direct oral anticoagulant may be considered, while awaiting confirmation of persistence of aPL, based on testing after at least 12 weeks, and thereafter. Discussion with the patient and shared decision making regarding the perceived risks, benefits, and the uncertainties of choice of anticoagulant should be undertaken. Testing for ab2GPI to distinguish patients with double rather than triple aPL-positivity should be performed if a direct oral anticoagulant is considered.
	(4) For triple aPL-positive antiphospholipid antibody syndrome patients, if started on a direct oral anticoagulant upon initial presentation with a first episode of venous thromboembolism, and upon considering limitations of testing (especially as it pertains to assessment for the presence of LA), we recommend that therapy be switched to warfarin or an alternative vitamin K antagonist. If the patient declines, then the direct oral anticoagulant may be continued, with clinical surveillance. It is suggested that surveillance could include MRI brain imaging to identify ischemic lesions, which, if present, merit consideration of a switch to alternative anticoagulation, with the first option a vitamin K antagonist.
	(5) Direct oral anticoagulants should not be used in antiphospholipid antibody syndrome patients with recurrent thrombosis while on standard-intensity vitamin K antagonist. Other treatment options may include an increased target INR range, standard treatment dose low-molecular-weight heparin (LMWH), fondaparinux if vitamin K antagonist/low molecular weight heparin are not suitable, or the addition of antiplatelet therapy.
	(6) There is insufficient evidence to make strong recommendations about the use of low-dose aspirin for secondary prevention following a first antiphospholipid antibody syndrome-associated arterial thrombosis. Low-dose aspirin may be considered, in combination with standard-intensity vitamin K antagonist (target INR 2.5, range 2.0 to 3.0), in antiphospholipid antibody syndrome patients with a first arterial thrombosis, with an alternative option high-intensity vitamin K antagonist.
	(7) Low-dose aspirin may be considered, in combination with anticoagulation, in antiphospholipid antibody syndrome patients who develop recurrent arterial or venous thrombosis while on standard intensity vitamin K antagonist.
Adapted from (29).

Regarding the above recommendations about consideration of high-intensity vitamin K antagonist, it is important to note that in two prospective, randomized, controlled trials and in a 2020 Cochrane review, high-intensity warfarin with goal INR greater than 3.0 did not significantly reduce risk of recurrent thrombosis in comparison to standard intensity warfarin (goal INR 2 to 3), but was associated with an increased risk of hemorrhage (33; 55; 10).

Other thrombophilias

Data on the treatment and prevention of arterial ischemic stroke in the setting of other inherited or acquired thrombophilias (without history of deep venous thrombosis) are limited. American Heart Association/American Stroke Association 2021 guidelines recommend that a hypercoagulable state can be suspected in younger patients with cryptogenic stroke, self or family history of unprovoked thrombosis, history of spontaneous abortion, or signs and symptoms of hypercoagulability.

American heart Association/American Stroke Association guidelines are as follows, and decision about using treatment-dose anticoagulation should be made on a case-by-case basis in collaboration with hematology (89):

(1) In patients with ischemic stroke or transient ischemic attack of unknown source despite thorough diagnostic evaluation and no other thrombotic history, who are found to have prothrombin 20210A mutation, activated protein C resistance, elevated factor VIII levels, or deficiencies of protein C, protein S, or antithrombin III, antiplatelet therapy is reasonable to reduce the risk of recurrent stroke or transient ischemic attack (Class IIb, of recommendation 2a/Level of evidence C-limited data) (Class IIb, Level of evidence C).

Myeloproliferative disorders

For patients with arterial ischemic stroke or cerebral venous thrombosis associated with a myeloproliferative disorder (eg, JAK2 polycythemia vera or essential thrombocytosis, etc.), consultation with a hematologist and multidisciplinary management is advised. For arterial ischemic stroke, antiplatelet therapy is generally the first-line antithrombotic treatment unless other cardiovascular risk factors warrant anticoagulation whereas in cerebral venous thrombosis, anticoagulation is indicated. Cytoreductive therapy (eg, hydroxyurea) or additional treatments such as phlebotomy and use of JAK2 inhibitors may also be indicated (147).

SARS-CoV-2 (COVID-19)

Currently, there are no evidence-based guidelines to specifically address the management of arterial ischemic stroke in patients with COVID-19 infection. It is reasonable to evaluate for evidence of coagulopathy by checking prothrombin time, fibrinogen, D-dimer, and platelet count. Although cryptogenic stroke was more common in patients with COVID-19 infection in a case-control study, presumably due to the additional risk of coagulopathy (167), a thorough stroke work-up to evaluate conventional causes such as large artery atherosclerosis and cardioembolism is still warranted. Management should be tailored to the suspected stroke mechanism. When COVID-19 coagulopathy is the primary suspected mechanism of stroke, consultation with hematology and one’s institutional guidelines regarding antithrombotic management is advised. Ongoing research into the benefits versus risks of more intense antithrombotic regimens including full-dose anticoagulation for COVID-19 is important, as patients with COVID-19 are at risk of not only ischemic stroke but also primary intracerebral hemorrhage and hemorrhagic transformation of ischemic stroke, which may be exacerbated by anticoagulation (43).

Cerebral venous thrombosis

Initial management. American Heart Association/American Stroke Association guidelines for the management of cerebral venous thrombosis (142):

(1) For patients with cerebral venous thrombosis, initial anticoagulation with adjusted-dose unfractionated heparin or weight-based low molecular weight heparin in full anticoagulant doses is reasonable, followed by vitamin K antagonists, regardless of the presence of intracerebral hemorrhage (Class IIa, Level of Evidence B).

The reader is also encouraged to refer to the American Heart Association/American Stroke Association (AHA/ASA) guidelines and the report from the Society for Neurointerventional Surgery “Current endovascular strategies for cerebral venous thrombosis” for further discussion of management options in patients with clinical deterioration despite anticoagulation (142; 97).

The European Stroke Organization guidelines for the diagnosis and treatment of cerebral venous thrombosis recommend treating adult patients with acute cerebral venous thrombosis with anticoagulation, with low molecular weight heparin preferred over unfractionated heparin (51).

Direct oral anticoagulants. In 2019, RESPECT-CVT, the first randomized prospective trial of a direct oral anticoagulant for treatment of cerebral venous thrombosis, was published (54). RESPECT-CVT randomized 120 patients to either dabigatran 150 mg twice daily or warfarin (at 5-15 days after start of parenteral anticoagulation for initial management). At 6 months follow up, there was no significant difference in recurrent venous thromboembolism (none in both groups), major bleeding (one intestinal in dabigatran group, two intracranial in warfarin group), or rate of recanalization, suggesting that dabigatran is as safe and effective as warfarin for treatment of cerebral venous thrombosis. Other case reports and small series of cerebral venous thrombosis patients successfully treated with direct oral anticoagulants including apixaban, dabigatran, and rivaroxaban have been published.

A systematic review and metaanalysis of cerebral venous thrombosis patients treated with a direct oral anticoagulant or warfarin found that direct oral anticoagulants had a comparable risk of recurrent venous thromboembolism, major hemorrhage, intracranial hemorrhage, death, and complete venous recanalization when compared to warfarin (166). Finally, the ACTION-CVT study, a multicenter international retrospective study including of 845 cerebral venous thrombosis patients showed that direct oral anticoagulants were associated with similar risks of recurrent venous thrombosis, death, and rate of partial/complete recanalization, but a lower risk of major hemorrhage (166). This retrospective data suggest that direct oral anticoagulants are an appropriate treatment option for cerebral venous thrombosis, and further prospective randomized trials are indicated.

Duration of treatment. The American Heart Association/American Stroke Association guidelines for the management of cerebral venous thrombosis make recommendations for duration of anticoagulation (142). As these guidelines were published prior to any data regarding the use of direct oral anticoagulants, they refer only to warfarin; however, it is reasonable to also apply these guidelines to patients using direct oral anticoagulants:

	(1) In patients with a provoked cerebral venous thrombosis (associated with a transient risk factor), vitamin K antagonists may be continued for 3 to 6 months, with a target INR of 2.0 to 3.0 (Class IIb, Level of Evidence C).
	(2) In patients with unprovoked cerebral venous thrombosis, vitamin K antagonists’ may be continued for 6 to 12 months, with a target INR of 2.0 to 3.0 (Class IIb, Level of Evidence C).
	(3) For patients with recurrent cerebral venous thrombosis, venous thromboembolism after cerebral venous thrombosis, or first cerebral venous thrombosis with severe thrombophilia (ie, homozygous prothrombin G20210A gene mutation, homozygous factor V Leiden, deficiencies of protein C, protein S, or antithrombin III), combined thrombophilia defects, or antiphospholipid syndrome, indefinite anticoagulation may be considered with a target INR of 2.0 to 3.0 (Class IIb, Level of Evidence C).
	(4) Patients with associated infection or seizures should be treated accordingly with antibiotics or antiepileptic medications. Hematology consultation should be considered.

The European Stroke Organization guidelines recommend a time-limited course of anticoagulation between 3 to 12 months in patients without a medical condition associated with a high recurrence risk. In patients with an associated prothrombotic condition with high thrombotic risk, duration of anticoagulation should follow the recommendations for prevention of venous thromboembolism for that condition (51).

AHA/ASA 2014 secondary prevention guidelines advise to consider indefinite antiplatelet therapy after termination of anticoagulation for cerebral venous thrombosis, but acknowledge that there are no data to support this (87). Data from trials using direct oral anticoagulants either at full or reduced dose for extended treatment of venous thromboembolism in patients for whom there was equipoise about need for continued anticoagulation showed a significant reduction in recurrent venous thromboembolism with apixaban in comparison to placebo (01) and with rivaroxaban in comparison to aspirin (162), without an increase in bleeding. Although these studies did not specifically address cerebral venous thrombosis, they provide some information about the safety and efficacy of extended treatment with direct oral anticoagulants for venous thromboembolism prophylaxis. Whether there is benefit to long-term use of reduced dose direct oral anticoagulants in patients without an established indication for long-term anticoagulation (for example, unprovoked cerebral venous thrombosis in patients with negative thrombophilia testing) is unknown.

Special considerations

Pediatric arterial ischemic stroke and cerebral venous thrombosis. For the most current evidence-based guidelines for the diagnosis and management of pediatric ischemic stroke and cerebral venous thrombosis, including cerebrovascular disease due to hypercoagulable states, the reader is advised to refer to the “Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association” issued in 2019 by the American Heart Association/American Stroke Association (50).

Pregnancy

Pregnancy and the puerperium are associated with increased thrombotic risk due to pregnancy-related changes in the coagulation system, such as decreased protein S levels, increased vitamin-K-dependent clotting factors, and increased platelet aggregation. Antiphospholipid antibody syndrome is associated with recurrent first or second trimester fetal loss (152), and studies suggest that women with genetic thrombophilia have an increased risk of pregnancy complications (93). Because oral anticoagulants are teratogenic, hypercoagulable patients are typically treated with heparinoids rather than warfarin for cerebral venous thrombosis and with heparinoids or antiplatelets for ischemic stroke during pregnancy.

Ischemic stroke. American Heart Association/American Stroke Association 2014 “Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack” specifically addressed pregnancy-related stroke (87):

(1) In the presence of a high risk condition that would require anticoagulation outside of pregnancy, the following options are reasonable:
	(a) Low molecular weight heparin (LMWH) twice daily throughout pregnancy, with dose adjusted to achieve the low molecular weight heparin manufacturer’s recommended peak anti-Xa activity 4 hours after injection or,
	(b) Adjusted-dose UFH throughout pregnancy, administered subcutaneously every 12 hours in doses adjusted to keep the midinterval activated partial thromboplastin time at least twice control or to maintain an anti-Xa heparin level of 0.35 to 0.70 U/mL or,
	(c) UFH or low molecular weight heparin (as above) until the 13th week, followed by substitution of a VKA until close to delivery, when UFH or LMWH is resumed (Class IIa; Level of evidence C)
	(d) For pregnant women receiving adjusted-dose LMWH therapy for a high risk condition that would require anticoagulation outside of pregnancy, and when delivery is planned, it is reasonable to discontinue LMWH ≥ 24 hours before induction of labor or Cesarean section (Class IIa; Level of evidence C)
(2) In the presence of a low risk situation in which antiplatelet therapy would be the treatment recommendation outside of pregnancy:
	(a) UFH or LMWH, or no treatment may be considered during the first trimester of pregnancy depending on the clinical situation (Class IIb; Level of evidence C)
	(b) In the presence of a low risk situation in which antiplatelet therapy would be the treatment recommendation outside of pregnancy, low-dose aspirin (50-150 mg/d) is reasonable after the first trimester of pregnancy (Class IIa; Level of evidence B)

Consultation with hematology and maternal-fetal medicine specialists is advised to select the appropriate antithrombotic regimen for pregnant or breastfeeding patients, including eligibility for aspirin during the first trimester of pregnancy.

The reader is also referred to the “Canadian Stroke Best Practice Consensus Statement: Secondary Stroke Prevention During Pregnancy” and “Canadian Stroke Best Practice Consensus Statement: Acute Stroke Management during pregnancy” for guidelines from the Heart and Stroke Foundation Canadian Stroke Best Practice Advisory Committees (94; 148).

Cerebral venous thrombosis. The following are excerpts from the American Heart Association/American Stroke Association guidelines on the management of cerebral venous thrombosis in pregnancy (142):

	(1) For women with cerebral venous thrombosis 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 INR of 2.0 to 3.0 should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) (Class I, Level of Evidence C).
	(2) For women with a history of cerebral venous thrombosis, prophylaxis with LMWH during future pregnancies and the postpartum period is probably recommended (Class IIa, Level of Evidence C).

The European Stroke Organization guidelines for cerebral venous thrombosis also endorse low molecular weight heparin during pregnancy and the puerperium for patients with acute cerebral venous thrombosis, and prophylaxis with prophylactic dose low molecular weight heparin during pregnancy and the puerperium in subsequent pregnancies if there is no contraindication to anticoagulation nor an indication for therapeutic dose anticoagulation (51).

Anesthesia

A hypercoagulable state does not necessitate special considerations for anesthesia other than recognition of an increased risk of postsurgical thromboembolic complications and an increased risk of surgical bleeding in patients treated with anticoagulants. Spinal anesthesia should be avoided in patients receiving anticoagulants.