Unmasking Hypercoagulability: Superior Sagittal Sinus Thrombosis Attributed to Pernicious Anemia in a Patient With Normal Hemoglobin Levels

Introduction

Pernicious anemia is an autoimmune condition that targets gastric parietal cells and intrinsic factor (IF), disrupting gastric absorption of vitamin B12 [1]. Anti-parietal-cell antibodies destroy the cells responsible for IF production, whereas anti-IF antibodies either block vitamin B12 from binding to IF or prevent absorption of the B12-IF complex in the terminal ileum [2].

Vitamin B12 deficiency leads to hyperhomocysteinemia because vitamin B12 is a cofactor for the enzyme methionine synthase, which converts homocysteine to methionine [1]. When this reaction is impaired, homocysteine accumulates, increasing the risk of thrombotic events [3–5].

Hyperhomocysteinemia promotes endothelial oxidative damage and dysfunction [6]. The proposed mechanism involves oxidative endothelial injury due to suppression of the vasodilator nitric oxide, increased levels of asymmetric dimethylarginine, and impaired methylation [6,7]. Consequently, vascular smooth muscle proliferation occurs, platelet activation and aggregation are promoted, and the normal procoagulant-anticoagulant balance is disrupted, favoring thrombosis [6,7].

Hypercoagulability refers to a pathological state characterized by an increased tendency for blood clotting, which can occur even in the absence of active bleeding and often leads to venous or arterial thrombosis [1]. Hypercoagulable disorders may be inherited (eg, Factor V Leiden, antithrombin III deficiency, protein C or S deficiency, or prothrombin G20210A mutation) or acquired (eg, antiphospholipid syndrome or malignancy) [6]. An uncommon etiology of dural venous thrombosis is hypercoagulability caused by vitamin B12 deficiency.

Thrombosis of the superior sagittal sinus is a cerebrovascular disorder characterized by clot formation within a dural venous sinus, which impedes normal cerebral venous drainage [1]. Under normal physiology, superficial (dural sinuses and cortical veins) and deep (straight sinus, internal cerebral veins, and vein of Galen) venous systems converge into the internal jugular veins, ensuring efficient venous outflow [1]. Obstruction can elevate intracranial pressure, causing cytotoxic and vasogenic edema and potentially parenchymal hemorrhage [1].

Analyses of risk factors for cerebral venous thrombosis indicate that most patients have at least 1 established risk factor, such as hormonal influences, infection, malignancy, or inherited thrombophilia; hyperhomocysteinemia is present in a small fraction of cases [8]. Previously reported cases of vitamin-B12-related cerebral venous thrombosis began with overt anemia, and hematologic abnormalities served as diagnostic clues to the underlying deficiency [9].

Here, we describe a patient who developed superior sagittal sinus thrombosis despite normal hemoglobin and hematocrit values, in the absence of other recognized risk factors. This atypical presentation emphasizes the need for further research concerning the prevalence and mechanisms of thrombotic events in patients with functional vitamin B12 deficiency, as well as studies that evaluate optimal screening strategies and treatment approaches to prevent thrombosis. It reinforces the perspective that clinicians should maintain a high index of suspicion for vitamin B12 deficiency in patients with unexplained thrombotic events, even when routine hematologic parameter levels are normal.

Case Report

A 52-year-old man with no significant medical history presented to the emergency department after experiencing a first-time seizure at home. The patient’s wife reported that she had been speaking with him and noticed intermittent confusion. He then developed generalized whole-body shaking with ocular retroversion. He collapsed to the floor, where the shaking persisted and was accompanied by foaming at the mouth. Emergency Medical Services personnel subsequently witnessed what appeared to be a generalized tonic-clonic seizure during transport to the hospital.

On arrival, the patient displayed acute encephalopathy and lethargy consistent with a postictal state, but he had no focal neurologic deficits. His pupils were equal, round, and reactive to light bilaterally. Extraocular movements were intact, and no nystagmus was present. There was no lower extremity edema, and peripheral pulses were palpable. Bilateral Homans’ sign results were negative. The remainder of the initial physical examination showed unremarkable findings.

The patient denied drug use and the use of any medications or supplements. He also reported no dietary restrictions; he maintained a normal, varied diet. Urinalysis confirmed that the patient tested negative for all substances except benzodiazepines, which had been administered en route to the hospital. He had no family history of malignancy or thrombosis.

An initial contrast-enhanced computed tomography (CT) scan of the brain revealed acute intraparenchymal hemorrhage in the right superior parietal lobe and thrombosis of the superior sagittal sinus (Figure 1). Subsequent brain magnetic resonance imaging demonstrated thrombosis of the superior posterior segment of the superior sagittal sinus (Figure 2). A heparin infusion was initiated. CT imaging of the chest, abdomen, and pelvis did not detect malignancy; scrotal ultrasound showed no evidence of testicular malignancy. Venous duplex ultrasonography of the upper and lower extremities incidentally revealed deep venous thrombosis in the right peroneal vein.

Extensive hypercoagulable studies were performed, focusing on antithrombin III, Factor V Leiden, prothrombin gene mutation, lupus anticoagulant, and beta-2 glycoprotein antibodies; all of these tests showed negative results. Protein C and protein S levels were within normal limits. Thromboelastography findings were unremarkable. Transthoracic echocardiography with Definity contrast and bubble study showed no evidence of intracardiac shunting.

Homocysteine levels were assessed, revealing an elevated level of 105.4 μmol/L (reference range, 5.5–16.2 μmol/L). The patient’s hemoglobin level was normal at 13.3 g/dL (reference range, 12.6–16.7 g/dL), with an increased mean corpuscular volume of 108.2 fL (reference range, 80–100 fL). Additional testing demonstrated a considerably elevated methylmalonic acid level of 3.20 nmol/mL (reference range, ≤0.40 nmol/mL). Folate levels were within the normal range at 13.4 ng/mL (reference range, >3.5 ng/mL).

White blood cell and platelet counts were within normal limits. His serum vitamin B12 level was below the lower limit of the laboratory’s measurable range (<148 pg/mL; reference range, 213–816 pg/mL). Peripheral blood smear findings, including moderate anisopoikilocytosis with macro-ovalocytes, were consistent with vitamin B12 deficiency.

The diagnosis of pernicious anemia was confirmed by the presence of anti-parietal-cell antibodies and IF-blocking antibodies; thus, the patient was treated with high-dose oral vitamin B12 during hospitalization.

Heparin treatment reached therapeutic levels according to anti-Xa monitoring on hospital day 3 and remained within range until discontinuation at discharge. Repeat head CT performed on hospital day 5 demonstrated stable intraparenchymal hemorrhage and cerebral venous sinus thrombosis.

The patient was discharged after a 5-day hospitalization on levetiracetam 1000 mg twice daily for seizure prophylaxis, apixaban 5 mg twice daily for anticoagulation, atorvastatin 40 mg, and cyanocobalamin 1000 μg/mL intramuscular injections administered once daily for 3 consecutive days to initiate vitamin B12 repletion.

The patient did not have an established primary care provider at discharge and was referred to a transitional primary care clinic for recently discharged patients. He missed his initial outpatient appointments but followed up with outpatient neurology 3 months after discharge. At that time, he reported no longer receiving vitamin B12 supplementation. The patient has not followed up with outpatient primary care and has been nonadherent with outpatient vitamin B12 supplementation.

Discussion

This case highlights an atypical presentation of pernicious anemia that manifested as dural venous thrombosis, emphasizing its potential role in hypercoagulability even in patients who present with normal hemoglobin levels.

Although most reported cases of vitamin-B12-related thrombosis have occurred in patients with pronounced megaloblastic anemia, the current case is distinct in that hemoglobin and hematocrit levels remained within normal limits; there were no dietary clues to suggest deficiency. A similar report described cerebral venous thrombosis associated with hyperhomocysteinemia secondary to vitamin B12 deficiency caused by autoimmune gastric pathology; however, the patient in that case presented with overt anemia [9]. Other documented cases have involved thrombotic events such as acute bilateral pulmonary embolism with severe megaloblastic anemia, as well as massive pulmonary embolism and deep vein thrombosis in the context of low hemoglobin and dietary vitamin B12 deficiency [10,11].

Collectively, these reports demonstrate that obvious hematologic abnormalities or dietary insufficiency often provide clear diagnostic clues to vitamin B12 deficiency. Early recognition was more difficult in our patient, who presented with normal hemoglobin levels and a regular, varied diet. Subtle findings, such as mild macrocytosis or anisopoikilocytosis, were the only indicators. Serum vitamin B12 and homocysteine measurements should be performed in patients with unexplained or unprovoked thrombosis to facilitate earlier diagnosis and treatment of vitamin B12 deficiency.

Hematologic changes often evolve gradually in cases of pernicious anemia. When anemia becomes evident, the deficiency may already be advanced. Prolonged vitamin B12 deficiency resulting from this autoimmune process ultimately leads to megaloblastic anemia because of impaired DNA synthesis in erythroid precursors. In the present case, the diagnosis was confirmed by the presence of IF-blocking and anti-parietal-cell antibodies, indicating that the vitamin B12 deficiency was secondary to autoimmune destruction of gastric parietal cells rather than a dietary cause.

Vitamin B12 deficiency is an uncommon but important cause of thrombosis [7]. A case-control study involving 326 patients with thrombosis and 351 controls revealed that vitamin B12 levels below 200 pmol/L were present in 17.2% of the patients with thrombosis, and levels below 150 pmol/L were noted in 8.6% [7] (for comparison, the level in our patient was <148 pg/mL, or approximately <109 pmol/L); however, the authors did not report the proportion of thrombosis cases attributable solely to vitamin B12 deficiency. These findings highlight the prevalence of low vitamin B12 levels among patients with thrombosis [7].

Pernicious anemia itself does not directly cause thrombosis but serves as an underlying autoimmune etiology of vitamin B12 deficiency, which can lead to hyperhomocysteinemia and increased thrombotic risk. Pernicious anemia detection is clinically important because lifelong vitamin B12 replacement addresses the root cause of hyperhomocysteinemia and reduces the risk of recurrence. However, anticoagulation remains essential to treat existing thrombosis in conjunction with vitamin B12 supplementation, which ameliorates the prothrombotic state linked to hyperhomocysteinemia. In support of this perspective, a case report described a patient with recurrent cerebral venous thrombosis secondary to hyperhomocysteinemia caused by pernicious anemia [12]. Vitamin B12 supplementation normalized homocysteine levels and prevented further thrombotic events, highlighting the clinical importance of early recognition and correction of vitamin B12 deficiency in reducing thrombotic risk [12].

Genetic testing for thrombophilia, including methylenetetrahydrofolate reductase (MTHFR) mutation analysis, was considered but not performed during hospitalization in our case. This testing is generally conducted in the outpatient setting. Unfortunately, the patient missed his scheduled outpatient follow-up visits and did not respond to attempts to reschedule.

In the present case, there was low clinical suspicion for meningitis given the absence of fever, neck stiffness, and photophobia, as well as the presence of a normal white blood cell count; these observations allowed the diagnostic workup to focus on other causes of encephalopathy and hypercoagulability.

Treatment of cerebral venous thrombosis secondary to vitamin B12 deficiency requires deficiency correction and anticoagulation [12]. In our case, high-dose oral vitamin B12 was selected over intramuscular therapy due to concurrent heparin use, allowing safe and effective repletion while minimizing bleeding risk. This approach also aligned with treatment goals of rapidly correcting vitamin B12 deficiency to prevent further thrombotic events. Timely supplementation, patient education regarding adherence, and regular monitoring of vitamin B12 and homocysteine levels are essential steps to prevent recurrence [12]. Comprehensive evaluation for other thrombophilic conditions helps guide long-term management and ensures accurate identification of the cause of thrombosis; coordinated treatment of the thrombotic event with anticoagulation and the underlying deficiency with vitamin B12 supplementation helps prevent recurrent thrombotic complications [12].

After his diagnosis, the patient immediately began receiving high-dose oral vitamin B12, an evidence-based alternative to intramuscular injections of vitamin B12 [13]. A randomized trial demonstrated that 2000 μg of oral vitamin B12 daily was not only effective but superior to intramuscular dosing in raising serum levels and improving neurologic symptoms among patients with pernicious anemia [13]. The study also showed that a daily dose of 1000 μg produced adequate vitamin B12 levels, supporting the efficacy of lower-dose oral supplementation in affected patients [13].

Additionally, intramuscular injections are avoided in patients receiving anticoagulation therapy due to the increased risk of hematoma formation at the injection site [14]. Therefore, intramuscular cyanocobalamin was contraindicated while our patient was receiving heparin infusion treatment, making oral vitamin B12 therapy the preferred option [14]. Pernicious anemia impairs oral vitamin B12 absorption due to IF deficiency, making intramuscular injections the standard therapy to ensure adequate absorption, particularly among patients with poor adherence or additional gastrointestinal disorders [15]. High-dose oral vitamin B12 can be effective for patients who cannot tolerate injections or when intramuscular therapy is contraindicated, although strict adherence is required to maintain adequate vitamin B12 levels [15].

The patient was discharged with a 3-day course of 1000 μg/mL intramuscular injections for repletion of the deficiency. Treatment of his condition was limited because continued supplementation is essential to maintain normal vitamin B12 levels. However, the patient did not attend his scheduled initial appointments and is no longer receiving vitamin B12 supplementation. His nonadherence is likely to impact long-term management.

During the patient’s hospitalization, heparin infusion was initiated for anticoagulation of the cerebral venous sinus thrombosis and the incidentally detected right peroneal deep venous thrombosis, despite the presence of intracranial hemorrhage. Anticoagulation aims to prevent thrombus propagation, facilitate recanalization, and reduce the risk of recurrence [16]. This approach is essential to limit thrombus extension, reopen occluded cerebral veins, and minimize complications such as deep vein thrombosis and pulmonary embolism in patients with an underlying thrombotic predisposition [16]. The results of 2 randomized controlled trials comparing anticoagulation with placebo – although not statistically significant – indicated more favorable outcomes with anticoagulation and demonstrated its safety, even among patients with cerebral hemorrhage [16]. Evidence from these trials, together with observational studies, suggests that anticoagulation is a safe and effective treatment for cerebral venous sinus thrombosis [16].

Vitamin-B12-deficiency-induced hyperhomocysteinemia can cause cerebral venous thrombosis, even in the absence of anemia or other recognized risk factors. When patients present with thrombosis in the absence of apparent triggering factors, an underlying prothrombotic condition should be suspected. Given the unremarkable personal and family histories of our patient, a comprehensive evaluation (eg, coagulation studies, cardiac assessment, and other investigations) was necessary to identify potential inherited or acquired causes of thrombosis. In the present case, severely low vitamin B12 levels, considerably elevated homocysteine, and positive anti-parietal-cell and IF antibodies guided the decision to initiate high-dose oral vitamin B12 supplementation in conjunction with anticoagulation, despite the presence of intracranial hemorrhage.

Conclusions

This case highlights the importance of thorough evaluation of thrombotic events with no obvious etiology, given that reversible factors such as vitamin B12 deficiency can be promptly addressed to improve outcomes and prevent recurrence. Clinicians should consider vitamin B12 deficiency in patients with unexplained thrombotic events regardless of hemoglobin level. Assessments of vitamin B12 and homocysteine may facilitate timely diagnosis and targeted therapy. Future research should explore the prevalence of functional vitamin B12 deficiency in patients with thrombosis, evaluate optimal supplementation strategies – including oral versus intramuscular therapy – and clarify the mechanisms by which hyperhomocysteinemia promotes thrombosis, thus informing both screening and management approaches.