Pancytopenia and TTP-like picture secondary to pernicious anaemia

Abstract

A 21-year-old man presented to the emergency department with generalised weakness, weight loss and decreased appetite for few weeks. He had evidence of severe pancytopenia and haemolysis. His peripheral smear with many schistocytes was suspicious for thrombotic thrombocytopenic purpura (TTP). He was supported with blood transfusions and daily plasmapheresis. His platelet counts worsened despite 4 days of therapy. Bone marrow biopsy was significant for hypercellular bone marrow with megaloblastic changes. Further workup revealed normal ADAMTS13 level, low vitamin B₁₂, positive intrinsic factor antibodies and high methylmalonic acid. Diagnosis of pernicious anaemia was established and he was started on daily treatment with intramuscular vitamin B₁₂ which subsequently improved his symptoms and haematological parameters. This report highlights the importance of checking vitamin B₁₂ level in patients presenting with pancytopenia and TTP-like picture before making a diagnosis of TTP.

Background

Thrombotic thrombocytopenic purpura (TTP) secondary to vitamin B₁₂ deficiency, also known as pseudo-TTP, is an uncommon manifestation, accounting for about 2.5% of all patients with TTP.¹

Pernicious anaemia (PA) is the most common cause above all, about 68% (28/41) according to the literature review in 2018 (intrinsic factor antibody was not available in many patients).^{2 3} In most of these cases, pancytopenia is not common.³ Pancytopenia with pseudo-TTP can be secondary to a series of different underlying diseases notably myelodysplastic syndrome, drug-induced TTP and connective tissue disease.^4–7 In cases with pseudo-TTP and pancytopenia secondary to PA, simple vitamin B₁₂ supplementation will completely reverse the symptoms with good prognosis. Herein, we report an unusual case of pseudo-TTP and pancytopenia caused by PA where his haematological parameters improved with vitamin B₁₂ replacements rather than plasmapheresis. Thus, we like to present this case for clinician in the future to consider checking vitamin B₁₂ level in patients presenting with pancytopenia and TTP-like picture.

Case presentation

A 21-year-old recently immigrated Haitian man with unspecified anaemia presented to the hospital with 3 weeks of generalised weakness and vomiting with decreased appetite. He also admitted to a 4.5 kg weight loss within the last 6 months. Home medications included ranitidine for intermittent gastric pain and ferrous sulfate for anaemia. The patient was noted to have grey hair on physical examination including scleral icterus and mild decrease in sensation in bilateral lower extremities. Otherwise, vital signs and physical examination were unremarkable.

Investigations

Initial laboratory studies were significant for severe pancytopenia with haemoglobin 40 g/L; haematocrit 12%; mean corpuscular volume (MCV) 95.8 fL, platelet count 47×10⁹/L; white cell count (WCC) 1.8×10⁹/L; differentials: absolute neutrophil count (ANC) 0.7×10⁹/L, absolute lymphocyte count (ALC) 0.9×10⁹/L and reticulocyte count 1.5%. Total bilirubin was elevated at 2.3 mg/dL and direct bilirubin was 0.6 mg/dL. Serum lactate dehydrogenase (LDH) was elevated at 4300 U/L and haptoglobin <15 mg/dL. International normalized ratio (INR) 1.25 (normal <2), prothrombin time (PT) 14 (normal 12–14), fibrinogen was 360 mg/dL (normal 200–400 mg/dL) on admission. Peripheral smear was significant for numerous schistocytes and anisocytosis (figure 1).

Figure 1.

Peripheral smear from initial presentation in this patient.

TTP was suspected due to the presence of schistocytes on the blood smear along with thrombocytopenia and an elevated LDH.

Daily plasmapheresis was initiated for possible TTP. However, he had no clinical response after four sessions, and platelet count worsened to 33×10⁹/L despite plasmapheresis.

Bone marrow biopsy was performed, aspirate revealed hypercellular bone marrow with prominent erythroid hyperplasia and megaloblastic changes (figure 2). Cytogenetic analysis did not reveal any abnormalities. Next-generation sequencing analysis did not show any mutations. Anti-nuclear antibody (ANA) panel, double-stranded DNA (dsDNA) antibody, HIV, hepatitis panel, parvovirus and urine toxicology results were negative. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif) activity was found to be 71%. Following further evaluation, vitamin B₁₂ was 159 pg/mL (normal 190–950 pg/mL), serum folate was 14 ng/mL (normal 2.76–20.00 ng/mL), methylmalonic acid was 5400 nmol/L (normal 87–318 nmol/L, antiparietal antibodies were high (56.6 U) and intrinsic factor antibodies were positive, thus confirming the diagnosis of PA.

Figure 2.

Bone marrow biopsy: (A) low power view and (B) high power view. Bone marrow showed marked hypercellularity, and megaloblastic changes with marked increase in megaloblastic cells, showing nuclear enlargement, noticeable nucleoli increased nuclear cytoplastic ratio and almost no iron seen with iron stain.

Differential diagnosis

Our patient presented with anaemia, thrombocytopenia, elevated LDH, indirect bilirubinemia and schistocytes in the blood smear suggesting microangiopathic haemolytic anaemia suspicious for TTP. But he also had associated neutropenia in addition to anaemia and thrombocytopenia. Usually TTP does not present as pancytopenia. Before the result of vitamin B₁₂ level became known, the initial differential diagnoses besides TTP were focused on the differential diagnoses related to a combination of pancytopenia and TTP-like picture which commonly included myelodysplasia (MDS), connective tissue diseases and drug-induced TTP. There have been five cases which report the association of MDS with TTP.^{4 8–13} MDS, mostly affects the elderly, but there have been cases in young adults like our case. Hence, for further evaluation, a bone marrow biopsy was performed, which showed hypercellular bone marrow and megaloblastic changes and absence of cytogenetic abnormalities such as del(5q), trisomy 8, monosomy 7, der(11q), der(12 p) and so on.¹⁴ Connective tissue diseases, especially systemic lupus erythematosus, have been associated with TTP. The incidence of patients with systemic lupus erythematosus (SLE) presented as TTP is about 2%⁷ and these patients will respond well to the combination of the treatment of plasmapheresis and corticosteroids.¹⁵ Our patient’s ANA, rheumatoid factor and dsDNA antibody were negative, making the diagnosis of SLE less likely. With the prevalence of recreational drug use in the USA, there is no doubt to consider the impact of possible illicit drug use, especially in young adults. There were six cases reporting cocaine-induced microangiopathic hemolytic anemia (MAHA) mimicking TTP with the laboratory evidence of haemolysis and the presence of schistocytes on the peripheral blood smear.^{16 17} Our patient did not have any history of recreational drug use and also had a negative urine toxicology, thereby ruling out cocaine-induced MAHA.

Treatment

Patient was started on daily treatment with intramuscular vitamin B₁₂ which led to symptomatic and haematologic improvement. Plasmapheresis was discontinued. At discharge, patient was symptom free with haemoglobin 9.3 g/dL and platelet count 231×10⁹/L. He was recommended to continue daily intramuscular B₁₂ for a week, followed by monthly treatments.

Outcome and follow-up

After a month, the patient was followed up in haematology clinic. He felt energetic and did not have any significant symptoms. His complete blood count (CBC) was normalised and his smear did not reveal any schistocytes. He was advised to maintain on vitamin B₁₂ treatment life long and follow-up every 6–8 weeks.

Discussion

Pseudothrombotic microangiopathy (or pseudo-TTP) has been documented as a rare clinical manifestation induced by vitamin B₁₂ deficiency. It is named due to the symptoms being very similar to TTP but it does not respond to plasmapheresis, the typical treatment for TTP.

On literature review from 1990 to 2019, there were several cases of TTP caused by PA. Selection of 37 studies representing total of 47 patients was reviewed.^18–54 Among these patients, 31 patients had confirmed diagnosis of PA with positive intrinsic factor antibody according to the diagnostic criteria of PA.^26–54 From these 31 patients, 13 patients of PA presented as TTP and pancytopenia,^44–54 including our patient and summarised in table 1. In the series (n=14), the median age was 47.5 (range: 21–72) with 5/14 (35.7%) being women. Biochemical and haematologic results are presented in table 1. All 14 patients (including our patient) had pancytopenia. Heamolytic anaemia was severe (median 5.35 g/dL) while thrombocytopenia was moderate with median platelet count of 54×10⁹/L and MCV≥100 fL, which was seen in 7/14 patients (50%). Vitamin B₁₂ was checked in all 14 patients and were all <190 pg/mL. Folate level was checked in 13 patients and most were in normal range. Only one case had slightly decreased levels and was given folate supplement while correcting vitamin B₁₂ deficiency. The median level of methylmalonic acid and homocysteine was 70 and six times higher than normal range, respectively. LDH was significantly elevated in all 14 patients, 8 cases (61.5%) even higher than 2500 U/L. Haptoglobin in 11 patients was lower than usual or undetectable. ADAMTS13 activity was only checked in five patients, and all were normal.

Table 1.

Review of case reports of the clinical features of PA presenting as TTP and pancytopenia

Category criteria		Proportion criteria	Percentage
Fever		1/14	7.1
Jaundice		5/14	35.7
Neurological symptoms		5/14	35.7
Glossitis		1/14	7.1
Leucocytopenia (WCC <4×109/L)		14/14	100
Anaemia (Hb <12 g/dL)		14/14	100
	↑MCV (fL ≥100)	7/14	50
	Schistocytes (yes)	14/14	100
	↓Retic (<0.5%)	0/11	0
	↓cRetic (<2%)	11/11	100
	↓RPI (<3.0%)	11/11	100
Thrombocytopenia (Plt <1 50 000 mm3)		14/14	100
↑LDH (LDH >2500 U/L)		8/13	61.5
↑Total bilirubin (Tbili >1.2 mg/dL)		9/10	90
↑Unconjugated bilirubin (Ubili >0.9 mg/dL)		7/8	87.5
↓Vitamin B12 (B12 <190 pg/mL)		14/14	100
↑Methylmalonic acid (MMA >0.4 μmol/L)		8/8	100
↑Homocysteine (HC >15 µmol/L)		5/5	100
Intrinsic factor antibody +		14/14	100
Parietal cell antibody +		6/7	85.7
Chronic atrophic gastritis		8/8	100
↓ADAMTS13 activity level		0/5	0
Plasmapheresis		5/14	35.7

Hb, haemoglobin; LDH, lactate dehydrogenase; PA, pernicious anaemia; Plt, platelet; RPI, reticulocyte production index; TTP, thrombotic thrombocytopenic purpura; WCC, white cell count.

Based on these findings, we could make a conclusion that features of elevated MCV (>100 fL, 50%), LDH (>2500 U/L, 61.5%), hyperbilirubinemia (87.5%) in patients with severe cytopenia with TTP like picture, a diagnosis of PA with pseudo-TTP should be considered (table 1). Noel et al²⁵ had compared seven patients with PA with pseudo-TTP to six patients with TTP and proposed that high LDH, high platelet count, lower reticulocytes, absence of renal failure and neutropenia favour the diagnosis of PA with associated pseudo-TTP. Our patient with LDH 4500 IU/mL, corrected reticulocyte count of 0.8% (normal 0.5%–1.5%), platelet count of 35 000/mm³ and absolute neutrophil count of 1000/mm³, meets the criteria with Noel et al for consideration of PA. Most patients with TTP have high LDH, low reticulocytes count and low platelet count but rarely have neutropenia (six patients in Noel series had WCCs over 5000/mm³). We further calculated the incidence of severe pancytopenia in PA with TTP-like picture which was around 45% (13 patients out of 31). Therefore, we emphasise that a diagnosis of PA should be strongly considered when patients present with TTP-like picture and severe neutropenia.

Our patient with MCV within the normal range (95.8 fL), not typically seen in patients with PA (usually >100 fL), likely is secondary to a concomitant iron deficiency, which was confirmed by endoscopic examination showing chronic gastritis after admission. Parvoviral aetiology was ruled out with the initial presentation of poor appetite and weakness and with associated pancytopenia. Underlying PA can also present with severe anaemia and gastrointestinal (GI) symptoms. In the absence of fever and lymphocytosis, viral aetiology or Ebstein Barr Virus (EBV) or cytomegalovirus (CMV) infection is unlikely.

The TTP-like manifestation of vitamin B₁₂ deficiency is the result of ineffective erythropoiesis and hyperhomocysteinemia due to dysfunction of methionine synthase and methylmalonyl-coenzyme A (CoA) mutase where vitamin B₁₂ is the cofactor.⁵⁵ Hyperhomocysteinemia causes coagulation activation and endothelial dysfunction, which could result in the presence of TTP-like picture with the presence of schistocytes and haemolytic anaemia.^{27 56} Other conditions causing TTP-like manifestations in the setting of pancytopenia include myelodysplastic syndrome and drug-induced TTP.

In conclusion, an awareness of a combination of pancytopenia and TTP-like picture could be secondary to PA and recognition of this combination could spare patients from unnecessary and expensive plasma exchange therapy.

Learning points.

• Patients with vitamin B₁₂ deficiency can manifest with a wide variety of symptoms including thrombotic thrombocytopenic purpura (TTP)-like picture.

• When pancytopenia and TTP-like picture showed up at the same time, vitamin B₁₂ level is worthy to check and may avoid invasive test and treatment in the early diagnosis phase.

• Elevated MCV (>100 fL), highly elevated lactate dehydrogenase (>2500 U/L) and hyperbilirubinemia are hints to check vitamin B₁₂.

• TTP-like picture caused by vitamin B₁₂ deficiency should highly suspect pernicious anaemia in further investigation of the cause of anaemia.

• In cases with pseudo-TTP and pancytopenia secondary to pernicious anaemia, simple vitamin B₁₂ supplementation will completely reverse the symptoms with good prognosis.