Annals of African Medicine
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Table of Contents
Year : 2022  |  Volume : 21  |  Issue : 3  |  Page : 291-295  

Dual arterial thrombosis: A diagnostic enigma

Department of Neurology, JSS Medical College, Mysore, Karnataka, India

Date of Submission13-Oct-2020
Date of Acceptance23-Mar-2021
Date of Web Publication26-Sep-2022

Correspondence Address:
Shasthara Paneyala
Department of Neurology, JSS Medical College, Mysore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aam.aam_96_20

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Cold agglutinin disease is a rare cause of arterial thrombosis leading to stroke, commonly encountered against a background of mycoplasma pneumonia infections. A 22-year-old patient presented with acute-onset left hemiplegia preceded by a short history of fever and cough. Magnetic resonance imaging (MRI) showed a right middle cerebral artery infarct. Serially repeated hemoglobin levels showed a progressive drop and peripheral smear showed evidence of hemolysis. Blood drawn for investigations would rapidly clot, suggesting a possibility of cold agglutinin-induced hemolysis. The patient was then worked up for all the possible causes of hemolytic anemia including secondary causes which were all negative except for significant immunoglobulin M mycoplasma levels with elevated cold antibody titers. The patient was then initiated on pulse steroids with azithromycin and doxycycline and hemoglobin levels stabilized. The patient also developed pulmonary thromboembolism which was managed with anticoagulation. The patient made a steady improvement, was discharged, and is on follow-up. Here, we present a unique case of mycoplasma associated cold agglutinin disease causing arterial thrombosis.

   Abstract in French 

La maladie à l'agglutinine froide est une cause rare de thrombose artérielle conduisant à un accident vasculaire cérébral, couramment rencontré dans un contexte d'infections à la pneumonie des mycoplasmes. Un patient de 22 ans a présenté une hémiplégie gauche aiguë précédée d'une courte histoire de fièvre et de toux. L'imagerie par résonance magnétique (IRM) a montré une infarctus de l'artère cérébrale moyenne droite. Les niveaux d'hémoglobine répétés en série ont montré une baisse progressive et le frottis périphérique a montré des preuves d'hémolyse. Le sang prélevé pour les investigations allait rapidement, suggérant une possibilité d'hémolyse induite par l'agglutinine froide. Le patient a ensuite été élaboré pour toutes les causes possibles de l'anémie hémolytique, y compris des causes secondaires qui étaient toutes négatives, sauf pour des niveaux d'immunoglobuline M de Mycoplasma significatifs avec des titres élevés d'anticorps froid. Le patient a ensuite été initié sur des stéroïdes d'impulsion avec de l'azithromycine et des niveaux de doxycycline et d'hémoglobine stabilisés. Le patient a également développé une thromboembolie pulmonaire qui a été gérée avec l'anticoagulation. Le patient a fait une amélioration constante, a été libéré et est sur le suivi. Ici, nous présentons un cas unique de maladie d'agglutinine à froid associée aux mycoplasmes provoquant une thrombose artérielle.
Mots-clés: Maladie d'agglutinine à froid, accident vasculaire cérébral, thrombose pulmonaire

Keywords: Cold agglutinin disease, ischemic stroke, pulmonary thrombosis

How to cite this article:
Paneyala S, Nemichandra S C, Sundaramurthy H, Colaco K V. Dual arterial thrombosis: A diagnostic enigma. Ann Afr Med 2022;21:291-5

How to cite this URL:
Paneyala S, Nemichandra S C, Sundaramurthy H, Colaco K V. Dual arterial thrombosis: A diagnostic enigma. Ann Afr Med [serial online] 2022 [cited 2023 Jun 6];21:291-5. Available from:

   Introduction Top

Mycoplasma pneumonia is known to cause hemolytic anemia.[1] Case reports of arterial thrombosis secondary to the hemolytic anemia have also been described.[2],[3],[4] However, occurrence of a stroke in this setting, though previously reported,[5] is a very rare phenomenon. The management of a stroke secondary to cold agglutinin disease differs greatly from a conventional stroke. This case report aims to highlight the unique process by which mycoplasma through cold agglutination causes vascular thrombosis and further more highlights the therapeutic implications of the same.

   Case Report Top

A 22-year-old female with no previously known comorbidities presented to the hospital with the history of left-sided weakness and slurring of speech for 1 day. The patient had been recently treated for symptoms of cough and fever lasting for 5 days and had been afebrile for 36 h before symptom onset. On clinical examination, the patient was noted to be drowsy and arousable and left-sided upper motor neuron type of facial palsy and left-sided hemiparesis were noted. MRI brain done revealed acute infarcts in the right fronto-parieto-temporal lobes, thalamus, caudate nucleus, and insular cortex with thrombosis of M2, M3, and M4 segments of right middle cerebral artery [Figure 1] and [Figure 2].
Figure 1: Diffusion-weighted imaging ADC magnetic resonance imaging images

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Figure 2: Time-of-flight magnetic resonance angiography images

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The patient was admitted to the intensive care unit (ICU) and initiated on antiplatelets and neuroprotectives. Baseline blood investigations including complete hemogram, renal function, and hepatic parameters were within normal limits except for mild hemolytic anemia. First-line workup for stroke in young was sent including tests for procoagulant factors. Included factors were antithrombin activity, protein C, protein S, factor V Leiden mutation, prothrombin gene mutation, and MTHFR mutation. Fasting lipid profile done was also normal. Chest X-ray showed left-sided mild pleural effusion. Pleural tap was done which showed lymphocytic pleocytosis with elevated protein levels. Broad-spectrum antibiotics with atypical coverage were started. Over the next 48 h, the patient remained neurologically stable; however, a gradual and steady drop in hemoglobin was noted. Repeat peripheral smear done revealed features of hemolytic anemia [Figure 3].
Figure 3: Peripheral smear

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To confirm, Coombs test was done which was also positive. The patient was initiated on pulse methyl prednisolone and hemoglobin levels were closely monitored.

On day 3 of hospital stay, the patient developed sudden tachypnea and tachycardia. Electrocardiogram and echocardiogram repeated only showed sinus tachycardia; however, D-dimer levels were found to be elevated. In view of suspicion of pulmonary thromboembolism (PTE), computed tomography pulmonary angiogram was done which showed evidence of thromboembolism in bilateral peripheral pulmonary arteries [Figure 4] and [Figure 5].
Figure 4: Computed tomography pulmonary angiogram

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Figure 5: Computed tomography pulmonary angio-axial

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Anticoagulation was then initiated. Venous Doppler of lower limbs was done which was normal, ruling out a peripheral cause of PTE.

A vexing problem encountered with this particular patient was rapid clotting of the blood drawn for the purpose of investigations. Due to this phenomenon, possibility of underlying cold agglutinin-induced hemolysis was thought of. Cold antibody titers sent were found to be elevated.

Workup was done for all other possible secondary causes of hemolytic anemia induced by cold agglutinins. ANA profile was negative. Quantitative G6PD levels were found to be normal (18.8 U/gHb). Lupus anticoagulant and antiphospholipid antibodies were negative ruling out catastrophic antiphospholipid antibody syndrome. To rule out paroxysmal nocturnal hemoglobinuria, CD55 and CD59 levels done were also normal. Cryoglobulins were also negative. In view of background history of fever, immunoglobulin M (IgM) mycoplasma levels were sent which were found to be significantly elevated. Hence, a diagnosis of mycoplasma pneumonia associated cold agglutinin-induced hemolytic anemia was made. The patient was given pulse steroid and atypical antibiotic coverage. During her ICU stay, care was taken to maintain the temperature as close to the ambient room temperature as possible.

The patient soon stabilized and was shifted back to the ward. The rest of her hospital stay was uneventful and the patient was discharged on oral steroids and anticoagulants. The patient has been on regular follow-up and is showing signs of neurological improvement with no recurrence of any thrombotic event.

   Discussion Top

Mycoplasma pneumoniae (MP) is a common cause of pneumonia in the environmental setting, responsible for nearly 40% of pneumonias in the pediatric age group.[1],[2] Infections affecting the pulmonary system vary in severity, with the majority of patients having only mild symptoms.[3],[4] Among the extrapulmonary manifestations of the disease, central nervous system (CNS) involvement is the most common, with studies reporting 1%–10% CNS involvement among hospitalized patients with MP infection.[5],[6] CNS involvements can cause a broad array of manifestations including meningoencephalitis, demyelinating pathologies such as optic neuritis and transverse myelitis, and rarely strokes.[6],[7] Due to the relative rarity of the association between stroke and MP infection, only case reports have been published so far. In addition to the immediate temporal association, a large prospective study noted that patients with MP followed up over 5 years had a higher incidence of stroke compared to matched controls.[8] Studies have thus shown that there is an overall increased risk of stroke in patients with MP infection both in the short-term period and on the long-term follow-up.[9],[10]

The underlying pathophysiology of thrombosis is mainly attributable to two primary factors: vasculitis and hypercoagulability induced by the infection.[5] In addition, direct invasion of the vascular endothelium by the offending pathogen, leading to the initiation of an inflammatory cascade mediated by pro-inflammatory chemokines, also plays a role.[11],[12] These events lead to the causation of local inflammation of the vessels, which can be isolated or occur in combination with a thrombus leading occlusion. This mechanism or vascular injury can occur in the absence of systemic prothrombotic state and thus be the sole cause for ensuing thrombotic complications. The etiology behind this systemic prothrombotic state has been researched extensively, and surface proteins of the pathogen have been implicated for the same.[13] Components of MP organisms have been shown to be responsible for the immunological reaction within the CNS.[11]

In our patient, considering two discrete arterial thrombotic events and rapid clotting of the blood as soon as it was drawn, a systemic hypercoagulable state induced by cold agglutinin caused by recent mycoplasma pneumonia infection is the likely mechanism. There are studies that have investigated the etiology behind the formation of these cold agglutinins. These studies have hypothesized that the offending pathogen induces a change in the structure of the antigen of the surface of the red blood cell, triggering formation of autoantibodies against it.[14] This leads to antibody-mediated hemolysis. The generation of hydrogen sulfide has been noted to be an additional contributory factor causing hemolysis.[15]

Research has also shown transitory anticardiolipin antibodies production in patients with MP infection.[16] However, in our patient, anticardiolipin antibodies were negative. In 2018, a review of patients with stroke in MP infections showed that the most commonly implicate artery was the middle cerebral,[17] similar to our patient. Almost, all the patients analyzed in that review were treated with antibiotics and overall neurological prognosis was good.

   Conclusion Top

In this particular case, a diagnosis of MP-related prothrombotic state was made by eliminating all the possible secondary causes for hemolytic anemia and establishing a temporal relationship between the recent infection, symptoms onset of weakness, and raised IgM mycoplasma titers. The rarity of this association makes this case report a unique one. An additional challenging aspect of this case was the rapid clotting of all blood samples drawn for investigations, necessitating elaborate measures to obtain laboratory results and requirement of maintaining ambient room temperature in the ICU setting. Knowledge of this clinical entity, especially in a context of stroke in young patients, is essential, and mycoplasma antibody levels must be done in all patients with evidence of hemolysis in the peripheral smear and arterial thrombosis. The rapid clinical response to steroids, good clinical outcomes with early treatment initiation, and the absence of future recurrences warrant prompt recognition of this disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Koskiniemi M. CNS manifestations associated with Mycoplasma pneumoniae infections: Summary of cases at the University of Helsinki and review. Clin Infect Dis 1993;17 Suppl 1:S52-7.  Back to cited text no. 1
Kolski H, Ford-Jones EL, Richardson S, Petric M, Nelson S, Jamieson F, et al. Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994-1995. Clin Infect Dis 1998;26:398-409.  Back to cited text no. 2
Waites KB, Katz B, Schelonka RL. Mycoplasmas and ureaplasmas as neonatal pathogens. Clin Microbiol Rev 2005;18:757-89.  Back to cited text no. 3
Sánchez-Vargas FM, Gómez-Duarte OG. Mycoplasma pneumonia – An emerging extra-pulmonary pathogen. Clin Microbiol Infect 2008;14:105-17.  Back to cited text no. 4
Tsiodras S, Kelesidis I, Kelesidis T, Stamboulis E, Giamarellou H. Central nervous system manifestations of Mycoplasma pneumoniae infections. J Infect 2005;51:343-54.  Back to cited text no. 5
Yiş U, Kurul SH, Cakmakçi H, Dirik E. Mycoplasma pneumoniae: Nervous system complications in childhood and review of the literature. Eur J Pediatr 2008;167:973-8.  Back to cited text no. 6
Kim GH, Seo WH, Je BK, Eun SH. Mycoplasma pneumoniae associated stroke in a 3-year-old girl. Korean J Pediatr 2013;56:411-5.  Back to cited text no. 7
Chiang CH, Huang CC, Chan WL, Chen YC, Chen TJ, Lin SJ, et al. Association between Mycoplasma pneumonia and increased risk of ischemic stroke: A nationwide study. Stroke 2011;42:2940-3.  Back to cited text no. 8
Higuchi ML, Sambiase N, Palomino S, Gutierrez P, Demarchi LM, Aiello VD, et al. Detection of Mycoplasma pneumoniae and Chlamydia pneumoniae in ruptured atherosclerotic plaques. Braz J Med Biol Res 2000;33:1023-6.  Back to cited text no. 9
Momiyama Y, Ohmori R, Taniguchi H, Nakamura H, Ohsuzu F. Association of Mycoplasma pneumoniae infection with coronary artery disease and its interaction with chlamydial infection. Atherosclerosis 2004;176:139-44.  Back to cited text no. 10
Launes J, Paetau A, Linnavuori K, Iivanaineu M. Direct invasion of the brain parenchyma by Mycoplasma pneumoniae. Acta Neurol Scand 1997;95:374.  Back to cited text no. 11
Atkinson TP, Balish MF, Waites KB. Epidemiology, clinical manifestations, pathogenesis and laboratory detection of Mycoplasma pneumoniae infections. FEMS Microbiol Rev 2008;32:956-73.  Back to cited text no. 12
Baseman JB, Reddy SP, Dallo SF. Interplay between mycoplasma surface proteins, airway cells, and the protean manifestations of mycoplasma-mediated human infections. Am J Respir Crit Care Med 1996;154:S137-44.  Back to cited text no. 13
Costea N, Yakulis VJ, Heller P. The mechanism of indction of cold agglutinins by Mycoplasma pneumoniae. J Immunol 1971;106:598-604.  Back to cited text no. 14
Großhennig S, Ischebeck T, Gibhardt J, Busse J, Feussner I, Stülke J. Hydrogen sulfide is a novel potential virulence factor of Mycoplasma pneumoniae: Characterization of the unusual cysteine desulfurase/desulfhydrase HapE. Mol Microbiol 2016;100:42-54.  Back to cited text no. 15
Espinosa G, Santos E, Cervera R, Piette JC, de la Red G, Gil V, et al. Adrenal involvement in the antiphospholipid syndrome: Clinical and immunologic characteristics of 86 patients. Medicine (Baltimore) 2003;82:106-18.  Back to cited text no. 16
Mélé N, Turc G. Stroke associated with recent Mycoplasma pneumoniae infection: A systematic review of clinical features and presumed pathophysiological mechanisms. Front Neurol 2018;9:1109.  Back to cited text no. 17


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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