Haemorrhage Associated with Thrombocytopenia in Megaloblastic Anaemia

Smith, Mary D.; Smith, D. A.; Fletcher, Margaret J.

doi:10.1136/bmj.1.5283.982

Cited by 29 publications

(13 citation statements)

References 2 publications

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“…However, histologic examination failed to detect deep intracerebral hemorrhages in PCFT Ϫ/Ϫ brain sections. Hemorrhages associated with thrombocytopenia may develop in patients with megaloblastic anemia, 35 and this clinical manifestation of folate deficiency is recapitulated in the PCFT knockout model.…”

Section: Discussionmentioning

confidence: 99%

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Salojin

Cabrera²,

Sun

et al. 2011

Blood

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IntroductionFolate is an essential cosubstrate of many biochemical reactions, such as the de novo synthesis of purines and pyrimidines, methionine, and deoxythymidylate monophosphate. 1,2 Mammals cannot synthesize folate; therefore, inadequate dietary supply or folate malabsorption results in defective DNA synthesis. One of the first manifestations of a folate deficiency is in the rapidly proliferating cells of the hematopoietic system, leading to pancytopenia and anemia of the megaloblastic type. Patients with megaloblastic anemia demonstrate ineffective erythropoiesis by harboring large immature red blood cell (RBC) precursors that fail to survive to the postmitotic, terminal stages, undergoing premature apoptosis. 2 Three mammalian folate transporter systems have been described to date in a variety of tissues: (1) the bidirectional reduced folate carrier 1 (RFC1), also known as SLC19A1, 3,4 (2) the glycosyl-phosphatidylinositol-anchored folate receptors (FOLR1, FOLR2, and FOLR4) and one secreted receptor in humans without a mouse homolog (FOLR3), 5 and (3) the human proton coupled folate transporter (PCFT). 6-8 The RFC1 transporter is expressed ubiquitously, including the brush-border membrane of epithelial cells in the small intestine. 9 Although RFC1 is necessary for folate transport in erythroid cells, its involvement in intestinal folate uptake has not been confirmed. 6 Inactivation of RFC1 in mice by homologous recombination led to either embryonic lethality or defective erythropoiesis in pups born to mothers who were supplemented with 1 mg daily subcutaneous doses of folic acid. 10,11 Because this transporter functions at a neutral pH optimum whereas the majority of intestinal folate transport occurs in an acidic luminal milieu, RFC1 is an unlikely candidate for an intestinal folate transporter. 7 The role of FOLR1 in folate absorption and transport has also been demonstrated, where a 60% to 70% reduction was observed in plasma folate of FOLR1 Ϫ/Ϫ mice fed low folate and normal chow. 12 FOLR1 also regulates folate homeostasis via endocytotic mechanisms during embryonic development, and mice rendered null for this receptor display severe morphogenetic abnormalities and die in utero unless provided supraphysiologic concentrations of either folinic acid or 5-methyltetrahydrofolate. 5,13 The PCFT transporter is highly expressed in tissues involved in folate and heme transport, including the duodenum and liver. 6,14 Initially, PCFT was identified as a low-affinity, pHindependent heme transporter 14 and then later described to function as a low pH-dependent folate transporter in intestinal cells. 6 The latter role of the transporter was confirmed by the identification of loss-of-function mutations in the human PCFT gene in persons diagnosed with hereditary folate malabsorption syndrome. 6 Studies have also indicated that PCFT facilitates folate transport during folate receptor-mediated endocytosis, where FOLR1 binds folate, and its export into the cytosol is driven by PCFT activity as the vesicle undergoes en...

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Section: Discussionmentioning

confidence: 99%

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Salojin

Cabrera²,

Sun

et al. 2011

Blood

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“…It has been proposed that the tran sient thrombocytosis may lead to throm boembolic complications. Thus, in each of two materials of 9 and 21 patients with PA, four thrombotic episodes occurred following therapy with vitamin B,2 [5,9]. In our ma terial, 1 patient with thrombocytosis devel oped a deep venous thrombosis in the left leg.…”

Section: Discussionmentioning

confidence: 87%

Platelet Dysfunction in Patients with Vitamin B<sub>12</sub> Deficiency

Ingeberg

Stoffersen

1979

Acta Haematol

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10 cases of pernicious anaemia are reported in which 6 had abnormal aggregation with epinephrine, 3 with fibrinogen, 2 with ADP, and 2 with ristocetin. 5 patients had thrombocytopenia and 3 of these had a prolongation of the bleeding time. These abnormalities were normalized after vitamin B₁₂ treatment. After treatment, platelet size changed toward a smaller diameter, but platelet size, however, was not significantly different from the normal platelet size distribution.

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“…Bleeding diathesis in the form of hematemesis was seen in two patients and melena in three patients in their series. In another series from the UK, Smith et al [6] reported nine cases of hemorrhagic emergencies attributable to megaloblastic anemia. Hematemesis and melena were the presenting symptoms in three cases in their series.…”

Section: Discussionmentioning

confidence: 97%

Hemorrhagic manifestation of megaloblastic anemia: report of two cases and literature review

Masoodi

Kakar

Byotra

et al. 2011

Blood Coagulation &Amp; Fibrinolysis

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Megaloblastic anemia is not uncommon in developing countries. Its presentation as thrombocytopenia and hemorrhagic manifestation are, however, rare. We describe the clinical scenario in two young patients who presented to the emergency room of Sir Ganga Ram Hospital, a tertiary care center in New Delhi, India, with pancytopenia and bleeding diathesis. Both patients improved after B12 supplementation. Reports of two cases and a brief review is presented.

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Haemorrhage Associated with Thrombocytopenia in Megaloblastic Anaemia

Cited by 29 publications

References 2 publications

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Platelet Dysfunction in Patients with Vitamin B<sub>12</sub> Deficiency

Hemorrhagic manifestation of megaloblastic anemia: report of two cases and literature review

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