A 24-year-old woman with a complex medical history including Ehlers-Danlos syndrome with hypermobility subtype, mast cell activation syndrome, eosinophilic esophagitis, and postural orthostatic tachycardia syndrome (POTS) presented to the emergency department (ED) for evaluation of menorrhagia, muscle cramps, and fatigue of 3 weeks’ duration. Her home medications included albuterol (90 μg/inhaler to be used every 6 hours as needed), cyanocobalamin (1000 μg daily), diphenhydramine (50 mg twice a day), epinephrine (0.3 mg/0.3 mL by auto-injector as needed), fexofenadine (180 mg twice a day), ketotifen (2 mg twice a day), and montelukast (10 mg daily at bedtime). Diagnostic evaluation at that time was notable for normocytic anemia with a hemoglobin level of 6.8 g/dL, mean corpuscular volume of 93.2 fL, hematocrit level of 22% (reference range, 35.5% to 44.9%), and platelet count of 217 × 109/L (reference range, 157 to 371 × 109/L), and the patient received a transfusion of 1 U of packed red blood cells. Prior to presentation, the patient’s baseline hemoglobin level ranged from 13 to 14 g/dL within the previous 12 months. Pelvic ultrasonography was performed and revealed no abnormalities. A regimen of 5-mg oral medroxyprogesterone once daily was prescribed, and the patient was discharged from the ED with outpatient follow-up scheduled. At her gynecology follow-up appointment, her menorrhagia was reported to have stopped.

The following month, she experienced recurrent menorrhagia that was characterized as menses requiring her to change her menses pad every 2 to 3 hours with use of up to 7 pads per day. Additionally, the patient also noted increased fatigue, new-onset bruising of her lower extremities, and mucosal bleeding provoked while brushing her teeth. These symptoms prompted her to return to the ED for further evaluation. In the ED, her temperature was 36.6 °C, heart rate was 126 beats/min, blood pressure was 93/65 mm Hg, and oxygen saturation was 96% while breathing room air. Her body mass index was 20.4 kg/m2.

Physical examination revealed a young woman in no acute distress. Examination of the head and neck revealed no lymphadenopathy, but there was gingivitis and ecchymoses of the soft palate. Auscultation of her chest was notable for a tachycardic heart rate without murmurs, and her lungs were clear bilaterally. Examination of her abdomen revealed mild diffuse tenderness without distention. Her skin examination was notable for petechiae of the lower extremities, mild nonpitting edema of the feet, prominent ecchymoses of the plantar surfaces of the feet, and pale appearance of the skin. Her neurologic assessment documented 5/5 strength of biceps and hip flexion; however, the patient was unable to ambulate due to weakness and pain while bearing weight. Tenderness to palpation was present on the plantar surfaces of both feet.

Initial laboratory studies revealed the following (reference ranges provided parenthetically): hemoglobin, 9.8 g/dL (11.6 to 15.0 g/dL); mean corpuscular volume, 85.7 fL (78.2 to 97.9 fL); platelet count, 168 × 109/L; elevated international normalized ratio of 1.6 (0.9 to 1.1); prolonged prothrombin time (PT) of 19.1 s (9.4 to 12.5 s); and partial thromboplastin time (PTT) of 24 s (25 to 37 s). A peripheral blood smear revealed 3 to 5 spherocytes per high-power field, 3 to 5 target cells per high-power field, and the presence of Döhle bodies. Iron studies revealed iron level of 48 μg/dL (35 to 145 μg/dL), suppressed total iron binding capacity of 234 μg/dL (250 to 400 μg/dL), and percent saturation of 21% (14% to 50%). Testing for hemolysis revealed the following: lactate dehydrogenase, 190 U/L (122 to 222 U/L); total bilirubin, 2.6 mg/dL (≤1.2 mg/dL); direct bilirubin, 0.4 mg/dL (0.0 to 0.3 mg/dL); and direct antiglobulin test (DAT), negative. The patient’s ferritin level was 113 μg/L (11 to 307 μg/L), reticulocyte count was 3.53%, and vitamin B12 level was 475 ng/L (180 to 914 ng/L).

Regarding the patient’s surgical history, she had previously undergone multiple spinal procedures as well as wisdom teeth extraction with no complications or excessive bleeding reported with any of the procedures. Prior to the patient’s hospitalization, she was being evaluated for numerous food intolerances previously attributed to mast cell activation syndrome. Despite negative results on skin prick testing for common allergies, the severity of her intolerances resulted in a progressively limited diet. For several months, the patient reported eating only oatmeal.1.Given this patient’s history and clinical presentation, which one of the following is the most likely explanation for her anemia and easy bruising?Hemolysis is an unlikely explanation for her presentation given her normal lactate dehydrogenase level, and negative DAT. Furthermore, with active bleeding noted on presentation, the more likely cause of her anemia was blood loss and not hemolysis. The patient had undergone multiple surgical procedures in the past without excessive bleeding, making an inherited coagulopathy less likely. Accidental rat poison ingestion can cause easy bruising as well anemia secondary to the bruising. It was recognized that the patient had multiple comorbidities contributing to her prolonged and progressive food aversion with risk of malnutrition, including mast cell activation syndrome and eosinophilic esophagitis. As the patient stated, her diet was limited to oatmeal and water, raising concern for nutritional deficiency as an explanation for her presenting symptoms. An acquired inhibitor coagulopathy was considered. However, the patient’s only risk factor was her sex. The most common acquired coagulation factor inhibitor is factor VIII, which would be associated with a prolongation of PTT. However, given the rarity of acquired coagulation factor inhibition and very minimal risk factors, it was less likely to explain her presentation. Given the patient’s very limited oral intake of primarily oatmeal, a nutritional deficiency was the most likely diagnosis in her case.2.Which one of the following is the most appropriate laboratory study that should be obtained for the assessment of the patient’s bleeding and anemia at this point?

Expanded DAT is unlikely to offer additional benefit in this clinical scenario given that the patient’s anemia is attributed to blood loss rather than hemolysis, based on presentation and laboratory results. The dilute Russell viper venom time test is a test used to assess for lupus anticoagulant, an antibody produced by the immune system more commonly associated with thrombosis than bleeding. A prothrombin mixing study uses equal volumes of patient and normal-pool plasma to evaluate whether a prolonged PT is due to a coagulation factor deficiency or factor inhibitor, making this test the most appropriate next step. While an elevated erythrocyte sedimentation rate could be a contributor to her anemia, as in the setting of anemia of inflammation, it would not explain the patient’s bleeding. Based on her previous surgical history without excessive bleeding, an inherited clotting disorder such as von Willebrand disease would be unlikely.

To assess for the possibility of a coagulation factor deficiency as a cause of the patient’s coagulopathy, she underwent a prothrombin mixing study, which revealed normalization of the PT. Vitamin K deficiency is the main cause of coagulation factor VII deficiency–associated prolonged PT that corrects on a mixing study. Concern for additional vitamin deficiencies prompted further testing, which revealed multiple nutrient deficiencies. Her vitamin C level was less than 0.1 mg/dL (0.4 to 2.0 mg/dL), vitamin K level was 0.04 ng/mL (0.10 to 2.20 ng/mL), vitamin A level was 5.7 μg/dL (32.5 to 78.0 μg/dL), folate level was 3 μg/L (≥4.0 μg/L), and vitamin E level was 4.6 mg/L (5.5 to 17.0 mg/L).3.Which one of the following comorbidities could be contributing to the patient’s bleeding?a.

Eosinophilic esophagitis–associated gastrointestinal hemorrhage

b.

POTS-associated cytopenias

c.

Mast cell activation syndrome and malnutrition from food aversion

d.

Ectopic pregnancy–associated blood loss

e.

Ehlers-Danlos syndrome and platelet dysfunction

Gastrointestinal hemorrhage is unlikely to be the cause of the patient’s bleeding because localized bleeding from the gastrointestinal tract was not identified on evaluation, and instead, she experienced a systemic coagulopathy with oropharyngeal, gynecologic, and cutaneous manifestations. While POTS is associated with many symptoms including dizziness, weakness, and fatigue, hemostatic abnormalities are not commonly reported with this condition. Her profound vitamin deficiencies, including both vitamin K and vitamin C, is most likely due to malnutrition. Given her multiple comorbidities, mast cell activation syndrome can be associated with gastrointestinal symptoms like nausea, cramping, abdominal pain, and diarrhea, which can be associated with decreased oral intake and impaired nutrient absorption. Consideration for a menstruating female who presents with vaginal bleeding and abdominal cramping should include pregnancy or ectopic pregnancy, but because the clinical scenario in our patient included more systemic evidence of coagulopathy including oral cavity and cutaneous symptoms, ectopic pregnancy appears less likely than nutritional deficits. Additionally, her pelvic ultrasonography did not reveal adnexal abnormality. Ehlers-Danlos syndrome can be associated with platelet function defects, qualitative disorders of adhesion, and activation or aggregation of platelets when contributing to hemostasis. However, Ehlers-Danlos syndrome is an inherited condition with known qualitative platelet defects. This disorder would most likely result in a lifelong coagulopathy and not a new coagulopathy developing over prior weeks.4.Based on this patient’s presentation, which one of the following is an additional important therapeutic intervention to consider for treatment and prevention of her underlying disease?a.

Psychiatric assessment for anxiety-associated oral intake

b.

Intravenous iron infusion

c.

Packed red blood cell transfusion

d.

Aminocaproic acid

e.

Hydroxychloroquine

In view of her complex and prolonged aversion to food leading to multiple nutritional deficiencies, the patient would most likely benefit from a psychiatric assessment of possible underlying comorbidities such as eating disordered anxiety attributed to prior experience with oral intake prompting symptoms. An iron infusion would not be warranted in a patient with suppressed total iron binding capacity. A packed red blood cell transfusion is not indicated in a patient with a hemoglobin level above 7 g/dL. Aminocaproic acid is a clot-stabilizing agent that can be given in acute diathesis. However, given that the patient’s primary deficiency is vitamin, it would not be the appropriate treatment. Hydroxychloroquine can be a treatment for a spectrum of rheumatologic conditions, none of which were diagnosed in this patient at the time of her presentation.5.If the patient’s primary medical problem remains untreated, which one of the following additional symptoms may develop?

Nutritional deficiency is not a reported risk factor for thrombosis. With her complex medical conditions, this patient is at risk for diarrhea (a symptom of POTS), eosinophilic strictures (a complication of eosinophilic esophagitis), and pneumothorax (a complication seen in patients with Ehlers-Danlos syndrome). Although these 3 conditions can be possible complications of her underlying medical issues, they are not the primary cause of her current presentation with coagulopathy related to nutritional deficiencies including vitamins K and C. Vitamin C deficiency can manifest as scurvy and can be associated with the physical examination findings of follicular hyperkeratosis and perifollicular hemorrhage.

The patient was considered to be symptomatic from vitamin C and vitamin K deficiency given her menorrhagia, gum bleeding, and petechiae and required treatment at this time. She was treated with vitamin C (1000 mg/d orally), vitamin D3 (5000 U daily), vitamin B12 (2000 μg daily), folic acid (1 mg), thiamine (500 mg in 5% dextrose with sodium chloride), and 3 days of intravenous vitamin K (1 mg in 0.9% normal saline) with transition to oral vitamin K (5 mg/d). Within 3 days of vitamin supplementation, her gum bleeding and menorrhagia resolved. The patient met with the psychiatry team and was discharged with a regimen of vitamin C (1000-mg tablet daily), vitamin D3 (5000 U/d), cyanocobalamin (1000-μg tablet daily), folic acid (1-mg tablet daily), thiamine (100-mg tablet daily), and vitamin K1 (5 mg/d). At follow-up in the hematology clinic 4 months later, her hemoglobin level had normalized and her bleeding had not recurred.

Discussion

Most vitamin deficiencies are rare in developed nations. This case illustrates the complex nature of our patient’s medical history including the diagnosis of Ehlers-Danlos syndrome and its contribution to bleeding. We will discuss the effects of vitamin deficiencies on bleeding as well as Ehlers-Danlos syndrome–associated platelet function defect.

Vitamin C deficiency was first mentioned in the time of Hippocrates, who wrote of soldiers suffering from gangrene of the gums that led to tooth loss and blood running from the nostrils. He termed the disease ileos ematitis.1

Maxfield L, Crane JS. Vitamin C deficiency. StatPearls website. Published July 2, 2020. PMID: 29630239.

Ascorbic acid (vitamin C) is a water-soluble vitamin consisting of the enolic form of an α-ketoalactone. Vitamin C is absorbed in the distal small intestine via transport that can absorb up to 180 mg/d.2Ronchetti I.P. Quaglino Jr., D. Bergamini G. Ascorbic acid and connective tissue. Levels usually start to deplete 4 to 12 weeks after decreased oral intake.3Fusaro M. Gallieni M. Rizzo M.A. et al.Vitamin K plasma levels determination in human health. Vitamin C has multiple roles, including assisting in fatty acid transport, collagen synthesis, neurotransmitter synthesis, prostaglandin metabolism, and nitric oxide synthesis. Its role in collagen synthesis is what predisposes an individual with vitamin C deficiency to experience increased bleeding. Ascorbic acid is an oxide donor necessary in the production of hydroxyproline, which is an essential component of collagen.5Shaikh H.G. Faisal M.S. Mewawalla P. Vitamin C deficiency: rare cause of severe anemia with hemolysis. Vitamin C deficiency is defined as serum concentration below 11.4 mg/dL. The rates of vitamin C deficiency vary geographically. In the United States rates are as low as 7.1%, and the highest rate is found in northern India with rates of 73.9%; however, this difference does not take into account that measuring vitamin C levels in some countries is more difficult to achieve.1

Maxfield L, Crane JS. Vitamin C deficiency. StatPearls website. Published July 2, 2020. PMID: 29630239.

Vitamin K is a key element in the coagulation pathway, and this fact has been harnessed to produce predictable anticoagulant effects through vitamin K antagonism pharmacotherapy. It indirectly affects clotting by serving as a cofactor for γ-glutamyl carboxylase, which leads to the formation of clotting factors including factors II, VII, IX, and X.3Fusaro M. Gallieni M. Rizzo M.A. et al.Vitamin K plasma levels determination in human health. Additionally, vitamin K is involved in the pathway to create proteins C, S, and Z, osteocalcin, and matrix Gla protein.6Zekavat O.R. Fathpour G. Haghpanah S. Dehghani S.J. Zekavat M. Shakibazad N. Acquired vitamin K deficiency as unusual cause of bleeding tendency in adults: a case report of a nonhospitalized student presenting with severe menorrhagia. It is estimated that in healthy adults, about 8% to 31% have vitamin K deficiency.3Fusaro M. Gallieni M. Rizzo M.A. et al.Vitamin K plasma levels determination in human health. There is usually a dietary component causing vitamin K–associated coagulopathy. For example, one case report described a female presenting with severe menorrhagia secondary to vitamin K deficiency in the context of poor diet consisting of energy drinks over a span of 6 months.7Callus C.A. Vella S. Ferry P. Our patient’s case was complicated with the diagnosis of Ehlers-Danlos syndrome, a group of genetic disorders of connective tissue. Ehlers-Danlos syndrome is caused by a mutation in collagen leading to fragility of capillaries and perivascular connective tissue that can contribute to bleeding. Type IV, vascular type, has the highest bleeding risk and arterial rupture can occur. A study examined a total of 38 patients with Ehlers-Danlos syndrome, both retrospectively and prospectively, and only 8% reported no history of bruising or bleeding.8Anstey A. Winter K.M.M. Van de Pette J. Pope F.M. Platelet and coagulation studies in Ehlers-Danlos syndrome. In this study, 18% of patients were found to have hematologic abnormalities on laboratory testing, including 8% with platelet release defect, 6% with factor XI deficiency, and 4% with factor XIII deficiency. One of our patient’s main symptoms was menorrhagia, which is a common concern in Ehlers-Danlos, with one report that 76% of women with a known diagnosis of hypermobile Ehlers-Danlos syndrome had menorrhagia.9Hugon-Rodin J. Lebègue G. Becourt S. Hamonet C. Gompel A. Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type Ehlers-Danlos syndrome: a cohort study. Up to 40% of patients with Ehlers-Danlos syndrome reported an abnormal bleeding severity score using the Bleeding Assessment Tool of the International Society on Thrombosis and Haemostasis, with 7% having prolonged PT and PTT and 90% of patients having platelet function abnormalities.

This case illustrates a complicated presentation with comorbidities in a patient presenting with new bleeding tendency and abnormal coagulation test results. Despite the fact that vitamin deficiencies are rare in the developed world, it is important to include in the differential diagnosis because vitamin supplementation can be an effective means to address current and future coagulopathy. Additionally, a diagnosis of Ehlers-Danlos syndrome can be associated with lifelong bleeding, particularly in the setting of surgical procedures, including qualitative platelet function defects.

Potential Competing Interests

The authors report no competing interests.

References

Maxfield L, Crane JS. Vitamin C deficiency. StatPearls website. Published July 2, 2020. PMID: 29630239.

Ronchetti I.P. Quaglino Jr., D. Bergamini G.

Ascorbic acid and connective tissue.

Subcell Biochem. 25: 249-264Fusaro M. Gallieni M. Rizzo M.A. et al.

Vitamin K plasma levels determination in human health.

Clin Chem Lab Med. 55: 789-799Jameson J.L. Fauci A.S. Kasper D.L. Hauser S.L. Longo D.L. Loscalzo J. Harrison's Principles of Internal Medicine. 20th ed. McGraw Hill, : 822-838Shaikh H.G. Faisal M.S. Mewawalla P.

Vitamin C deficiency: rare cause of severe anemia with hemolysis.

Int J Hematol. 109: 1-4Zekavat O.R. Fathpour G. Haghpanah S. Dehghani S.J. Zekavat M. Shakibazad N.

Acquired vitamin K deficiency as unusual cause of bleeding tendency in adults: a case report of a nonhospitalized student presenting with severe menorrhagia.

Case Rep Obstet Gynecol. 2017: 4239148Callus C.A. Vella S. Ferry P.

Scurvy is back.

Nutr Metab Insights. 11 ()Anstey A. Winter K.M.M. Van de Pette J. Pope F.M.

Platelet and coagulation studies in Ehlers-Danlos syndrome.

Br J Dermatol. 125: 155-163Hugon-Rodin J. Lebègue G. Becourt S. Hamonet C. Gompel A.

Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type Ehlers-Danlos syndrome: a cohort study.

Orphanet J Rare Dis. 11: 124Article InfoFootnotes

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Identification

DOI: https://doi.org/10.1016/j.mayocp.2022.01.032

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© 2022 Mayo Foundation for Medical Education and Research

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