Splenomegaly: Difference between revisions

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! colspan="2" align="center" style="background:#DCDCDC;" |[[Lymphoma]]<ref name="pmid25131182">{{cite journal |vauthors=Ishibashi N, Maebayashi T, Aizawa T, Sakaguchi M, Abe O, Saito T, Tanaka Y |title=Myelosuppression toxicity of palliative splenic irradiation in myelofibrosis and malignant lymphoma |journal=Hematology |volume=20 |issue=4 |pages=203–7 |date=May 2015 |pmid=25131182 |doi=10.1179/1607845414Y.0000000192 |url=}}</ref>
! colspan="2" align="center" style="background:#DCDCDC;" |[[Lymphoma]]<ref name="pmid25131182">{{cite journal |vauthors=Ishibashi N, Maebayashi T, Aizawa T, Sakaguchi M, Abe O, Saito T, Tanaka Y |title=Myelosuppression toxicity of palliative splenic irradiation in myelofibrosis and malignant lymphoma |journal=Hematology |volume=20 |issue=4 |pages=203–7 |date=May 2015 |pmid=25131182 |doi=10.1179/1607845414Y.0000000192 |url=}}</ref>
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Unknown
* Mutation
* Infection
| align="center" style="background:#F5F5F5;" |Any
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Epstein–Barr virus
* Positive family history
* Smoking
* HIV
* Autoimmune diseases
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |–
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Lymphadenopathy
* Itching
* Night sweats
* Anorexia
* Respiratory distress or dyspnea
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |High ferritin
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Different histopathological features based on types and stages
* Reed–Sternberg cell
* Malignant cells
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Peritoneal lymphomatosis on CT scan
| align="center" style="background:#F5F5F5;" |Lymph node biopsy
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Primary immune disorder
| align="center" style="background:#F5F5F5;" |
* Post-transplant
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
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|-
|-
! colspan="2" align="center" style="background:#DCDCDC;" |[[Leukemia]]<ref name="pmid26614896">{{cite journal |vauthors=Quest GR, Johnston JB |title=Clinical features and diagnosis of hairy cell leukemia |journal=Best Pract Res Clin Haematol |volume=28 |issue=4 |pages=180–92 |date=December 2015 |pmid=26614896 |doi=10.1016/j.beha.2015.10.017 |url=}}</ref>
! colspan="2" align="center" style="background:#DCDCDC;" |[[Leukemia]]<ref name="pmid26614896">{{cite journal |vauthors=Quest GR, Johnston JB |title=Clinical features and diagnosis of hairy cell leukemia |journal=Best Pract Res Clin Haematol |volume=28 |issue=4 |pages=180–92 |date=December 2015 |pmid=26614896 |doi=10.1016/j.beha.2015.10.017 |url=}}</ref>
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Unknown
* Mutation
* [[Bone marrow]]<nowiki/>infiltration
* Ineffective [[hematopoiesis]]
* Immune mediated
| align="center" style="background:#F5F5F5;" |Elderly, male>female
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* History of hematological disorder
* History of [[chemotherapy]] and[[ionizing radiation]]
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* [[Pallor]]
* [[Chloroma|Leukemia cutis]]
* [[Bruising]]
* [[Petechia|Petechiae]]
* [[Ecchymosis]]
* [[Fatigue]]
* Bone [[tenderness]]
* Early satiety
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |High ferritin
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Leukemic blasts
* Leukoerythroblastic features
* Giant [[Platelet|platelets]]
| align="center" style="background:#F5F5F5;" |NA
| align="center" style="background:#F5F5F5;" |[[Bone marrow examination]] + clinical manifestation
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* [[Infection|Infections]] of variable severity
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* [[Nerve palsy|Cranial nerve palsy]]
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|-
|-
! colspan="2" align="center" style="background:#DCDCDC;" |[[Polycythemia vera|Polycythemia Vera]]<ref name="pmid23281576">{{cite journal |vauthors=Chou YS, Gau JP, Yu YB, Pai JT, Hsiao LT, Liu JH, Hong YC, Liu CY, Yang CF, Chen PM, Chiou TJ, Tzeng CH |title=Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk factors for hemorrhage |journal=Eur. J. Haematol. |volume=90 |issue=3 |pages=228–36 |date=March 2013 |pmid=23281576 |doi=10.1111/ejh.12064 |url=}}</ref>
! colspan="2" align="center" style="background:#DCDCDC;" |[[Polycythemia vera|Polycythemia Vera]]<ref name="pmid23281576">{{cite journal |vauthors=Chou YS, Gau JP, Yu YB, Pai JT, Hsiao LT, Liu JH, Hong YC, Liu CY, Yang CF, Chen PM, Chiou TJ, Tzeng CH |title=Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk factors for hemorrhage |journal=Eur. J. Haematol. |volume=90 |issue=3 |pages=228–36 |date=March 2013 |pmid=23281576 |doi=10.1111/ejh.12064 |url=}}</ref>
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Autonomous [[erythrocyte]]<nowiki/>production
* [[JAK2]]<nowiki/>mutation
| align="center" style="background:#F5F5F5;" |Mean age >60 years old
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Positive family history
| align="center" style="background:#F5F5F5;" |–
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |–
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |–
| align="center" style="background:#F5F5F5;" |–
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Erythromelagia
* Chest pain
* Stroke-like symptoms
* Pruritis
* Dizziness
* Visual disturbance
* Facial plethora
* Painful erythema
* Lymphadenopathy
| align="center" style="background:#F5F5F5;" |Nl to ↑
| align="center" style="background:#F5F5F5;" |↑ RBC mass
| align="center" style="background:#F5F5F5;" |Nl to ↑
| align="center" style="background:#F5F5F5;" |High ferritin
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Elevated normochromic, normocytic [[Red blood cell|RBCs]]
* [[Thrombocytosis]]
* Rarely immature cells
* Leukoerythroblastic picture
| align="center" style="background:#F5F5F5;" |NA
| align="center" style="background:#F5F5F5;" |WHO criteria for PV
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* [[Stroke]]
| align="center" style="background:#F5F5F5;" |
* [[Venous thrombosis]]
| align="center" style="background:#F5F5F5;" |
* [[Myelofibrosis]]
| align="center" style="background:#F5F5F5;" |
* [[Acute leukemia]]
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|-
|-
! colspan="2" align="center" style="background:#DCDCDC;" |[[Multiple myeloma]]<ref name="pmid3400674">{{cite journal |vauthors=Grieco A, Manna R, Mancini R, Gambassi G |title=Massive hepatomegaly following splenectomy for myeloid metaplasia |journal=Am. J. Med. |volume=84 |issue=4 |pages=797 |date=April 1988 |pmid=3400674 |doi= |url=}}</ref>
! colspan="2" align="center" style="background:#DCDCDC;" |[[Multiple myeloma]]<ref name="pmid3400674">{{cite journal |vauthors=Grieco A, Manna R, Mancini R, Gambassi G |title=Massive hepatomegaly following splenectomy for myeloid metaplasia |journal=Am. J. Med. |volume=84 |issue=4 |pages=797 |date=April 1988 |pmid=3400674 |doi= |url=}}</ref>
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Unknown
* Mutation
* Infection
| align="center" style="background:#F5F5F5;" |Any, more in adults
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Exposure to chemicals
* [[Radiation therapy|Radiation]]
* Pre-existent blood disorders
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |+
| align="center" style="background:#F5F5F5;" |–
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Lymphadenopathy
* Itching
* Night sweats
* Anorexia
* Dyspnea
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |High ferritin
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Hemoglobinuria
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* Blast cells
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |Bone marrow examination
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
* [[Tumor lysis syndrome]]
| align="center" style="background:#F5F5F5;" |
* [[Infection]]
| align="center" style="background:#F5F5F5;" |
* [[CNS]] involvement
| align="center" style="background:#F5F5F5;" |
* [[Disseminated intravascular coagulation|DIC]]
| align="center" style="background:#F5F5F5;" |
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|-
|-
! colspan="2" align="center" style="background:#DCDCDC;" |[[Essential thrombocytosis|Essential thrombocythemia]]<ref name="pmid25611051">{{cite journal |vauthors=Tefferi A, Barbui T |title=Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management |journal=Am. J. Hematol. |volume=90 |issue=2 |pages=162–73 |date=February 2015 |pmid=25611051 |doi=10.1002/ajh.23895 |url=}}</ref>
! colspan="2" align="center" style="background:#DCDCDC;" |[[Essential thrombocytosis|Essential thrombocythemia]]<ref name="pmid25611051">{{cite journal |vauthors=Tefferi A, Barbui T |title=Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management |journal=Am. J. Hematol. |volume=90 |issue=2 |pages=162–73 |date=February 2015 |pmid=25611051 |doi=10.1002/ajh.23895 |url=}}</ref>
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! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Fever
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Fever
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Fatigue
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Fatigue
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Weight loss
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Weight
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Abdominal pain
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Abdominal pain
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Bleeding
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Bleeding

Revision as of 18:37, 29 September 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Gichoya Judy Wawira [2], Moi University School of Medicine

Synonyms and keywords: Spleen enlargement; enlarged spleen; spleen swelling

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Splenomegaly from Other Diseases

Category Disease Etiology Clinical manifestations Para−clinical findings Gold standard Associated findings
Demography History Symptoms Signs Lab Findings Imaging
Fever Fatigue Weight Abdominal pain Bleeding BP JVP Jaundice Ascites Other CBC Iron LFT PT/PTT BUN/Cr UA Histopathology
WBC Hb Plt
Congestive Cirrhosis[1]
  • Infection
  • Alcohol
  • Autoimmune
 Any, more in elderly – + ↑↓ + + ↓ Nl + +
  • Spider angiomata
  • Palmar erythema
  • Weakness
 ↓ ↓ ↓ Nl ↑ ↑ ↑ Dark urine
  • Pancytopenia
  • Regenerating nodules of hepatocytes
  • Fibrosis
  • Deposition of connective tissue between these nodules
  • Small and nodular liver on ultrasound
  • Fibrosis on liver scan
 Liver biopsy
  • Hepatic encephalopathy
  • Gynecomastia
  • Hypogonadism
  • Esophageal varices
  • Caput medusa
  • Dupuytren's contracture
Heart failure[2]
  • Coronary artery disease
  • HTN
 Elderly
  • Smoking
  • Sedentary lifestyle
  • Obstructive sleep apnea
 – + ↑↓ – – ↑ ↑ ± +
  • Dyspnea
  • Weakness
  • Chest pain
  • Heart murmur
 ↓ ↓ ↑ Nl ↑ ↑ ↑ Nl NA
  • Normal or low ejection fraction on echocardiography
  • Cardiomegaly on chest xray
 Echocardiography
  • Pulmonary edema
  • Hyponatremia
  • Elevated BNP
Thrombosis of portal, hepatic, or splenic veins[3]
  • Thrombosis
 Any
  • Inflammation
  • Infection
  • Cirrhosis
  • Cancer
 + + ↑ + + ↓ Nl ± +
  • Weakness
  • Hematemesis
  • Melena
 ↓ ↓ ↓ Nl ↑ ↑ ↑ Dark urine NA
  • Reduced or absent blood flow on doppler ultrasonography
 Doppler ultrasonography
  • Portal hypertension
  • Esophageal varices
Malignancy Lymphoma[4]
  • Unknown
  • Mutation
  • Infection
 Any
  • Epstein–Barr virus
  • Positive family history
  • Smoking
  • HIV
  • Autoimmune diseases
 + + ↓ + + Nl Nl + –
  • Lymphadenopathy
  • Itching
  • Night sweats
  • Anorexia
  • Respiratory distress or dyspnea
 ↓ ↓ ↓ High ferritin ↑ ↑ ↑ Nl
  • Different histopathological features based on types and stages
  • Reed–Sternberg cell
  • Malignant cells
  • Peritoneal lymphomatosis on CT scan
 Lymph node biopsy
  • Primary immune disorder
  • Post-transplant
Leukemia[5]
  • Unknown
  • Mutation
 Elderly, male>female + + ↓ + + Nl Nl ± + ↓ ↓ ↓ High ferritin ↑ ↑ ↑ Nl
  • Leukemic blasts
  • Leukoerythroblastic features
  • Giant platelets
 NA Bone marrow examination + clinical manifestation
Polycythemia Vera[6] Mean age >60 years old
  • Positive family history
 – + Nl + – Nl Nl – –
  • Erythromelagia
  • Chest pain
  • Stroke-like symptoms
  • Pruritis
  • Dizziness
  • Visual disturbance
  • Facial plethora
  • Painful erythema
  • Lymphadenopathy
 Nl to ↑ ↑ RBC mass Nl to ↑ High ferritin Nl Nl Nl Nl
  • Elevated normochromic, normocytic RBCs
  • Thrombocytosis
  • Rarely immature cells
  • Leukoerythroblastic picture
 NA WHO criteria for PV
Multiple myeloma[7]
  • Unknown
  • Mutation
  • Infection
 Any, more in adults
  • Exposure to chemicals
  • Radiation
  • Pre-existent blood disorders
 + + ↓ + + Nl Nl + –
  • Lymphadenopathy
  • Itching
  • Night sweats
  • Anorexia
  • Dyspnea
 ↓ ↓ ↓ High ferritin Nl ↑ ↑
  • Hemoglobinuria
  • Blast cells
 Bone marrow examination
Essential thrombocythemia[8]
Primary myelofibrosis[9]
Primary splenic tumors[10]
Metastatic solid tumors[11]
Category Disease Etiology Demography History Fever Fatigue Weight Abdominal pain Bleeding BP JVP Jaundice Ascites Other WBC Hb Plt Iron LFT PT/PTT BUN/Cr UA Histopathology Imaging Gold standard Associated findings
Infection Viral Hepatitis
Infectious mononucleosis
Cytomegalovirus
Bacterial Salmonella
Brucella
Tuberculosis
Parasitic Malaria
Schistosomiasis
Toxoplasmosis
Kala-azar Visceral leishmaniasis
Infective endocarditis
Fungal
Inflammation Sarcoidosis
Serum sickness
Systemic lupus erythematosus
Felty syndrome
Category Disease Etiology Demography History Fever Fatigue Weight loss Abdominal pain Bleeding BP JVP Jaundice Ascites Other WBC Hb Plt Iron LFT PT/PTT BUN/Cr UA Histopathology Imaging Gold standard Associated findings
Infiltrative Gaucher disease[12]
Niemann-Pick disease
Amyloidosis
Langerhans cell histiocytosis
Hemophagocytic lymphohistiocytosis
Rosai-Dorfman disease
Hematologic (hypersplenic) states Hemolytic anemia
Sickle cell disease
Granulocyte colony-stimulating factor

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications, and Prognosis

Diagnosis

Treatment

Case Studies

Case #1

Related Chapters

References

  1. ↑ Wu Z, Zhou J, Pankaj P, Peng B (December 2012). "Laparoscopic and open splenectomy for splenomegaly secondary to liver cirrhosis: an evaluation of immunity". Surg Endosc. 26 (12): 3557–64. doi:10.1007/s00464-012-2366-5. PMID 22710653.
  2. ↑ Gedela M, Khan M, Jonsson O (September 2015). "Heart Failure". S D Med. 68 (9): 403–5, 407–9. PMID 26489162.
  3. ↑ Ferri PM, Ferreira AR, Fagundes ED, Liu SM, Roquete ML, Penna FJ (2012). "Portal vein thrombosis in children and adolescents: 20 years experience of a pediatric hepatology reference center". Arq Gastroenterol. 49 (1): 69–76. PMID 22481689.
  4. ↑ Ishibashi N, Maebayashi T, Aizawa T, Sakaguchi M, Abe O, Saito T, Tanaka Y (May 2015). "Myelosuppression toxicity of palliative splenic irradiation in myelofibrosis and malignant lymphoma". Hematology. 20 (4): 203–7. doi:10.1179/1607845414Y.0000000192. PMID 25131182.
  5. ↑ Quest GR, Johnston JB (December 2015). "Clinical features and diagnosis of hairy cell leukemia". Best Pract Res Clin Haematol. 28 (4): 180–92. doi:10.1016/j.beha.2015.10.017. PMID 26614896.
  6. ↑ Chou YS, Gau JP, Yu YB, Pai JT, Hsiao LT, Liu JH, Hong YC, Liu CY, Yang CF, Chen PM, Chiou TJ, Tzeng CH (March 2013). "Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk factors for hemorrhage". Eur. J. Haematol. 90 (3): 228–36. doi:10.1111/ejh.12064. PMID 23281576.
  7. ↑ Grieco A, Manna R, Mancini R, Gambassi G (April 1988). "Massive hepatomegaly following splenectomy for myeloid metaplasia". Am. J. Med. 84 (4): 797. PMID 3400674.
  8. ↑ Tefferi A, Barbui T (February 2015). "Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management". Am. J. Hematol. 90 (2): 162–73. doi:10.1002/ajh.23895. PMID 25611051.
  9. ↑ Cervantes F, Martinez-Trillos A (May 2013). "Myelofibrosis: an update on current pharmacotherapy and future directions". Expert Opin Pharmacother. 14 (7): 873–84. doi:10.1517/14656566.2013.783019. PMID 23514013.
  10. ↑ Adachi K, Ui M, Nojima H, Takada Y, Enatsu K (August 2011). "Isolated splenic peliosis presenting with giant splenomegaly and severe coagulopathy". Am. J. Surg. 202 (2): e17–9. doi:10.1016/j.amjsurg.2010.10.002. PMID 21810495.
  11. ↑ Huprikar NA, Kurtz MT, Mount CA (October 2013). "Massive splenomegaly and lymphopenia: a unique case of obstructive shock". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-201643. PMC 3822246. PMID 24172780.
  12. ↑ Ayto R, Hughes DA (2013). "Gaucher disease and myeloma". Crit Rev Oncog. 18 (3): 247–68. PMID 23510067.
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