AJTCCM VOL. 29 NO. 3 2023 139
CORRESPONDENCE: CASE
To the editor: rombotic disease may involve the arterial or venous
systems. Arterial thrombosis (AT) typically occurs through erosion
and rupture of an atherosclerotic plaque or via platelet-mediated
thrombi. Important drivers of AT include inammation, immune
activation and hyperlipidaemia.[1] Venous thrombosis is widely
accepted as a combination of stasis and hypercoagulability rather
than endothelial damage. Venous thrombi typically consist of brin
and red blood cells, unlike platelet-rich atherosclerotic plaques.[1]
Hyperhomocysteinaemia appears to traverse the arterial and
venous systems as a thrombotic risk factor. It is a documented
cause of AT and a theoretical risk factor for venous thrombosis.[2]
One important cause of raised homocysteine levels is vitamin B12
deciency.
We present a case of chronic pulmonary thromboembolic disease
(TED) in which, aer extensive investigation, it was postulated that
vitamin B12 deciency with resultant elevated homocysteine was
thecause.
A 40-year-old woman with a 1-year history of dyspnoea,
palpitations and bilateral lower limb oedema presented with
worsening dyspnoea, left-sided pleuritic chest pain, and an
intermittent cough that had been occurring for 1 week.
The patient had a significant past medical history of
thromboembolic disease. At the age of 19, she had experienced
a stroke, with the oral contraceptive being the only identiable
prothrombotic risk factor. A computed tomography pulmonary
angiogram (CTPA) 3 months before the current admission conrmed
the presence of chronic thromboembolic disease, and the patient
had therefore been initiated on warfarin treatment. However, the
initial work-up to identify an underlying prothrombotic risk factor
did not provide any enlightening results. On further questioning of
the patient, a seemingly unrelated history of repeated admissions
for symptomatic anaemia emerged. An incomplete work-up for the
underlying cause was noted, and treatment with intermittent ferrous
sulphate and oral folic acid was started.
Clinical examination at the current admission revealed that the
patient was pale with mild jaundice, grade 1 pedal oedema and an
oxygen saturation of 83% on room air. ere was no neurological
fall-out or evidence of lower limb deep-vein thrombosis.
The electrocardiogram (ECG) revealed sinus tachycardia and
right heart strain, and dilated pulmonary vessels were noted on
the chest radiograph (available as supplementary material online
at https://www.samedical.org/le/2066). A repeat CTPA (available
as supplementary material online at https://www.samedical.org/
le/2069) showed a worsening lling defect compared with the
previous image. Echocardiography conrmed a preserved ejection
fraction with right ventricular systolic pressures of 70 + 15 (85)
mmHg. A bubble test excluded a patent foramen ovale, and a Holter
ECG excluded a paroxysmal arrhythmia predisposing to thrombosis.
e laboratory work-up during the current admission (Table1)
revealed grade 2 macrocytic anaemia and grade 2 thrombocytopenia.
e international normalised ratio was within the therapeutic range
at visits prior to and at the current presentation. e vitamin B12
level was low with both positive antiparietal cell and anti-intrinsic
factor antibodies. e results of serum folate and iron studies were
normal. Gastroscopy showed atrophic gastritis. Further investigation
revealed an elevated homocysteine level, postulated as the possible
cause of the recurrent TED.
Biochemical work-up (Table1) also indicated the presence of non-
immune haemolysis. is was evidenced by low haptoglobin, raised
lactate dehydrogenase, unconjugated hyperbilirubinaemia and a
negative direct Coombs test. In addition, few schistocytes were seen
on the peripheral smear. In the context of vitamin B12 deciency,
ineective erythropoiesis with resultant intramedullary cell death
was the suspected cause of the haemolysis.
Intravenous vitamin B12, oral folate and ferrous sulphate were
instituted, resulting in an improvement of the peripheral counts, a
decrease in homocysteine levels and resolution of the haemolysis.
Warfarin was continued.
Infectious diseases and inherited thrombophilia were ruled
out. Vitamin B12 deficiency with hyperhomocysteinaemia was
presumed to have contributed to the patient’s history and subsequent
presentations.
Homocysteine is a non-proteinogenic α-amino acid. It is formed by
removing the terminal C methyl group from methionine. Although
similar to cysteine, it differs by the presence of an additional
methylene bridge. In the body, it can be recycled into methionine or
converted into cysteine with the assistance of B vitamins.
Hyperhomocysteinaemia is well documented in AT, but its role
in venous thromboembolism is controversial.[2] The proposed
mechanisms are modified factor V activity, increased tissue
factor expression, diminished anticoagulant processes, disrupted
fibrinolysis, vascular and endothelial injury, enhanced platelet
reactivity and increased thrombin generation.[3] There has
previously been interest in hyperhomocysteinaemia as a risk factor
for thrombosis, but it lost favour over the past decade because
several studies failed to demonstrate a signicant association.[4,5] A
further confounder in the literature is that treatment of vitamin B12
deciency and the subsequent reduction in homocysteine levels are
not associated with a reduction in thrombosis risk.[6]
Vitamin B12 deciency is frequently a result of pernicious anaemia.
Our case conrmed this by the presence of antiparietal cell and anti-
intrinsic factor antibodies. In addition, our patient’s signicant and
recurrent history of both arterial and venous TED is postulated to
be due to hyperhomocysteinaemia secondary to pernicious anaemia.
e delay in diagnosis of the vitamin B12 deciency and ad hoc
folic acid supplementation may have resulted in an intermittent
lowering of the homocysteine level, thereby altering the risk of
thrombosis. e homocysteine-lowering properties of folic acid have
been documented in the literature.[7]
A rare presentation of vitamin B12 deficiency with hyper-
homocysteinaemia is that of pseudomicroangiopathy. is entity
is characterised by schistocytes, with biochemical evidence
Vitamin B12 deciency presenting with pulmonary embolism:
Anunusual presentation
140 AJTCCM VOL. 29 NO. 3 2023
CORRESPONDENCE: CASE
of haemolysis. The most common mechanism of schistocyte
development is marked anisopoikilocytosis secondary to ineective
erythropoiesis. It is also proposed that hyperhomocysteinaemia
has the potential to induce endothelial damage, driving red cell
fragmentation.[8]
is case highlights the importance of considering rarer causes
of TED in patients with young-onset and recurrent thrombosis. In
cases of hyperhomocysteinaemia, a vitamin B12 deciency should
be sought, and lifelong replacement therapy should be instituted to
prevent recurrence of TED.
In conclusion, in patients with young-onset and recurrent TED of
unexplained aetiology, hyperhomocysteinaemia secondary to vitamin
B12 deciency should be considered a possible cause.
L W Ndaba, MB ChB, FCP (SA), Dip Int Med (SA), Dip HIV (SA),
PG Dip Renal Med (UK)
Registrar, Department of Internal Medicine, Faculty of Health
Sciences, University of the Witwatersrand, Johannesburg, South Africa
ndabalw@gmail.com
S A van Blydenstein, MB BCh, DCH, MMed (Int Med), FCP (SA),
Cert Pulm (SA)
Department of Internal Medicine, Chris Hani Baragwanath Academic
Hospital, Johannesburg, South Africa
K E Hodkinson, MB BCh, MMed (Haem), FCPath (Haem)
Department of Molecular Medicine and Haematology, Faculty of
Health Sciences, University of the Witwatersrand and National Health
Laboratory Service, Johannesburg, South Africa
1. L W Ndaba, MB ChB, FCP (SA), Dip Int Med (SA), Dip HIV (SA), PG Dip Renal Med
(UK) ORCID for author Ndaba: https://orcid.org/0000-0002-2605-8134
2. Registrar, Department of Internal Medicine, Faculty of Health Sciences, University of
the Witwatersrand, Johannesburg, South Africa ndabalw@gmail.com
3. S A van Blydenstein, MB BCh, DCH, MMed (Int Med), FCP (SA), Cert Pulm (SA)
Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital,
Johannesburg, South Africa
4. K E Hodkinson, MB BCh, MMed (Haem), FCPath (Haem) Department of
Molecular Medicine and Haematology, Faculty of Health Sciences, University of the
Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa
5. Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous
and arterial thrombosis. Blood Transfus 2011;9(2):120-138. https://doi.
org/10.2450/2010.0066-10
6. Ekim M, Ekim H, Yilmaz YK, Kulah B, Polat MF, Gocmen AY. Study on relationships
among deep vein thrombosis, homocysteine & related B group vitamins. Pak J Med
Sci 2015;31(2):398-402. https://doi.org/10.12669/pjms.312.6049
7. Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: From basic science
to clinical evidence. romb Haemost 2005;94(5):907-915. https://doi.org/10.1160/
TH05-05-0313
8. Marcucci R, Gori AM, Abbate R. Hyperhomocysteinemia: Cause or effect of
disease? Blood 2005;105(8):3382-3383; author reply 3-4. https://doi.org/10.1182/
blood-2004-12-4610
9. Fay WP. Homocysteine and thrombosis: Guilt by association? Blood 2012;119(13):2977-
2978. https://doi.org/10.1182/blood-2012-01-401513
10. Ray JG, Kearon C, Yi Q, Sheridan P, Lonn E; Heart Outcomes Prevention Evaluation I.
Homocysteine-lowering therapy and risk for venous thromboembolism: A randomized
trial. Ann Intern Med 2007;146(11):761-767. https://doi.org/10.7326/0003-4819-146-
11-200706050-00157
11. Homocysteine Lowering Trialists’ Collaboration. Dose-dependent eects of folic acid
on blood concentrations of homocysteine: A meta-analysis of the randomised trials.
Am J Clin Nutr 2005;82(4):806-812. https://doi.org/10.1093/ajcn/82.4.806
12. Ventura P, Panini R, Tremosini S, Salvioli G. A role for homocysteine increase in
haemolysis of megaloblastic anaemias due to vitamin B(12) and folate deciency:
Results from an in vitro experience. Biochim Biophys Acta 2004;1739(1):33-42.
https://doi.org/10.1016/j.bbadis.2004.08.005
Submitted 7 September 2022. Accepted 27 January 2023. Published 19 September 2023.
Afr J Thoracic Crit Care Med 2023;29(3):e285.
https://doi.org/10.7196/AJTCCM.2023.v29i3.285
Table1. Complete patient work-up*
Coagulopathy screen
Protein C (55 - 123 IU/dL) 66
Protein S (70 - 130 IU/dL) 74
Factor V Leiden mutation Negative
Prothrombin 20210A mutation Negative
Autoimmune screen
Intrinsic factor antibodies Positive
Antiparietal cell antibodies Positive
Anti-Sm antibodies Negative
Anti-ribonucleoprotein antibodies Negative
Anti-Sjögren’s syndrome antigen, A and B Negative
Anticardiolipin antibody Negative
Lupus anticoagulant Negative
Rheumatoid factor (<20 IU/mL) <10
Full blood count
Haemoglobin (13.4 - 17.5 g/dL) 8.2
Mean cell volume (83.1 - 101.6 fL) 105.1
White cell count (3.92 - 10.40 × 109/L) 4.29
Neutrophils (1.6 - 8.3 × 109/L) 2
Platelet count (171 - 388 × 109/L) 85
Liver function tests
Total bilirubin (5 - 21 µmol/L) 57
Direct bilirubin (0 - 3 µmol/L) 7
Coagulation
D-dimer (0.0 - 0.25 mg/L) 1.65
Anaemia work-up
Vitamin B12 (141 - 489 pmol/L) 37
Serum folate (8.8 - 60.8 nmol/L) 30
Haptoglobin (0.30 - 2.0 g/L) 0.01
Iron (9.0 - 30.4 µmol/L) 7.7
Transferrin (2.5 - 3.8 g/L) 2.22
Transferrin saturation (15 - 50%) 14
Ferritin (15 - 150 µg/L) 65
Reticulocyte production index 0.4
Other
Homocysteine (5.1 - 15.4 µmol/L) 20.1
Direct Coombs Negative
Lactate dehydrogenase (100 - 190 U/L) >2 500
HIV Negative
*e values in parentheses are the normal laboratory values.
