Postscript

Hypersplenism is a common disorder characterized by an enlarged spleen which causes rapid and premature destruction of blood cells. The term is steeped in history and has undergone significant revisions in definition, mechanisms and differential diagnosis over time. Because of this rich history, we have organized this tutorial chronologically beginning with early papers published in the area and ending with current views on the topic and learning points. We have included TBP footnotes where appropriate.

Timeline in History

Year	Finding	Reference
1866	Gretsel first used the term splenic anemia for cases in which there was both splenomegaly and anemia, thus implying that the anemia was splenic in origin.	Gretsel. Ein Fall von Anaemia splenica bei einem Kinde, Berl. klin. Wschr. 3:212-14, 1866.
1882	Banti popularized the term splenic anemia; published his first description of the association between anemia and splenomegaly, and began a series of experiments demonstrating the pathogenic relationship between the enlarged spleen and the anemia.	Banti, G. Dell’ anemia splenica. Florence (Italy). Reprint from R. Istituto di Studi Superiori Pratici e di Perfezionamento in Firenze, 1882
1907	Chauffard’s was first to use the term hypersplenism, applying it to the role of the enlarged spleen in hereditary spherocytosis.	Chauffard, M. A’propos de la communication de M. Vaquez. Bull. Soc. med. Hop. Paris 24:1201-03, 1907.
1942	Extended the concept of hypersplenism beyond ITP and hemolytic anemia to include *splenic neutropenia*, characterized by a decrease in the number of circulating neutrophils, an enlarged spleen, and a bone marrow that gave evidence of being normal in its capacity to produce this type of cell. Also reported favorable response to splenectomy.	Wiseman and Doan, Ann Int Med 1942;16:1097
1946	The term splenic panhematopenia was reported by Doan and Wright.	Blood, I946, I, 10-26
1950	Dameshek reported that hypersplenism is a functional rather than an anatomical diagnosis.	Dameshek and Estren, M. Clin. North America, I950 34, 1271-1289.

1949

Hypersplenism = hyperfunctional spleen with respect to destruction of blood cells.
Hypersplenism has resulted in ever increasing indications for splenectomy.
Causes include:¹
- Chronic splenic neutropenia
- Acute splenic neutropenia
- Acute and chronic splenic panhematopenia
  - Congenital
  - Acquired²
- Familial hemolytic icterus³
- Idiopathic thrombopenic purpura ⁴
Functions of spleen:
- Destruction of blood cells:
  - The evidence that the spleen serves as the graveyard for blood cells seems convincing.⁵
  - This particular function becomes perverted in hypersplenism, resulting in depleted numbers of cells in the peripheral blood.⁶
  - Evidence includes:
    - Examination of the venous blood supply of the spleen shows a definite increase of bilirubin in the splenic vein as compared with the splenic artery.⁷
    - In diseases such as idiopathic thrombopenic purpura, examination of blood from the splenic vein shows a reduction in the number of thrombocytes as compared with the number in the splenic artery.⁸
- Storage of blood:
  - The spleen is a reservoir, the chief function of which is the storage of blood.
  - Even this function⁹ may become perverted at times, removing excessive numbers of cells from the vascular system and resulting in depleted cellular values¹⁰ throughout the peripheral blood.
  - This fact can be amply demonstrated with the epinephrine test, commonly employed in the diagnosis of hypersplenism:¹¹
    - Give the patient an injection of 0.5 to 1 cc. of 1: 1,000 epinephrine solution
    - Note:
      - Contraction of the spleen.¹²
      - Simultaneous rise in cellular values in the peripheral blood.
  - “It is possible that hypersplenism may be caused by a lack of epinephrine and, therefore, may be primarily a disease of the adrenal gland. It is impractical, however, to supply epinephrine in sufficient amounts through the process of injection; therefore, the best procedure is simply to remove the organ”.¹³
- Production of lymphocytes
Diagnosis of hypersplenism:
- Enlarged spleen
  - The single exception being found in some cases of essential thrombopenic purpura.¹⁴
  - Therefore, it is not entirely necessary that splenic enlargement be present before a diagnosis of hypersplenism can be established.
- Cytopenia(s)
- Demonstration that bone marrow production not impaired
- Demonstration of splenic overactivity by epinephrine test:

1951

There is now a considerable body of morphologic as well as other kinds of evidence to indicate that the spleen may indeed selectively retain abnormal red cells and accelerate their destruction.¹⁵
Functions of spleen:
- Depot function¹⁶
- Hematopoiesis:
  - During embryogenesis
  - In pathology
- Destruction of blood cells:
  - Spleen need not be itself “hypersplenic” for this to happen. For example:
    - If the erythrocytes of congenital hemolytic disease are transfused into an intact normal subject, they are found to have a short life span.¹⁷
    - In acquired hemolytic jaundice abnormal red cells doubtless also are sequestered and destroyed in the spleen.
- Resistance to infection

1952

In 1942 Wiseman and Doan described a syndrome termed primary splenic neutropenia and characterized by:
- A decrease in the number of circulating neutrophils¹⁸
- An enlarged spleen
- A bone marrow that “gave evidence of being normal in its capacity to produce this type of cell.”
It has gradually become apparent that this neutropenic deficit can involve the other formed elements of the blood either singly or in groups.¹⁹
Awareness of the existence of this syndrome is important because of:
- Its disabling potentialities
- Its threat to life itself
- The fact that a cure is so readily obtainable²⁰
Some relationship seems to exist between this syndrome, congenital hemolytic icterus, essential thrombocytopenic purpura, and possibly some of the other splenomegalies, the etiologies of which are so obscure.²¹
Functions of spleen:
- Destruction of red blood cells
- Blood storage
- Production of lymphocytes
Hypersplenism involves:
- Pathological increase in the destruction of blood cells:
  - Excessive phagocytosis of apparently normal hematologic cellular elements may result from:
    - Increased cellular destructive power of the spleen for any reason.
    - Loss of spleen’s normal selective action such that it becomes unable to distinguish between the normal formed elements of the blood and the abnormal.
  - It is possible for the spleen to destroy red cells, white cells, and platelets, the condition resulting being a true splenic panhematopenia.²²
  - In congenital hemolytic icterus²³ it is the red cell that is apparently singled out for destruction. In essential thrombocytopenia it is the blood platelet. In primary splenic neutropenia it is the white cell.
- Blood storage
The bone marrow attempts to compensate for the blood deficit. As a result, one is able to see in the bone marrow an excessive production of those cells or their progenitors, which are lacking in the peripheral circulation. One can thus see that a prerequisite for the diagnosis of hypersplenism is a hyperplastic bone marrow.
Diagnostic criteria:²⁴

Splenomegaly:
- Although in a great majority of the cases the spleen is clinically enlarged, there may be an occasional case where the enlargement is not of such a magnitude that it can be palpated. Also on occasion, as in essential thrombocytopenia purpura, the spleen is actually not enlarged to any great degree.²⁵
- Accordingly, while it is desirable to have an enlarged spleen to make this diagnosis, in the occasional case where this organ cannot be palpated the diagnosis of hypersplenism cannot be ruled out.
Cytopenias:
- Deficiencies may involve any one of the formed elements of the blood or a combination of them.
Splenectomy cures hypersplenism.

1955

“Over the years the association of one or another of the blood cytopenias with splenomegaly has been termed, correctly or incorrectly, hypersplenism.”
Banti popularized the term splenic anemia in a long series of publications beginning 1882 and continuing for about thirty years. He concluded that the spleen was the site of a “noxa,” which resulted in:
- A low-grade febrile disturbance
- A certain degree of anemia and leukopenia
- Eventually cirrhosis of the liver
Banti’s idea of a “noxa” originating in the spleen and terminating as cirrhosis of the liver was eventually largely discarded when it was found that cirrhosis of the liver was in all probability the initiating factor of the splenomegaly by way of portal hypertension and that the leukopenia was a later phenomenon.
Who first used the term hypersplenism is not accurately known, but it began to appear in Chauffard’s writings from I907.
Classification of hypersplenism:
- Selective vs total:²⁶
  - Selective – splenomegaly associated either with anemia or leukopenia, or thrombocytopenia
  - Total – combinations of these cytopenias²⁷
- Primary vs secondary:²⁸
  - Primary – primary disturbance of the spleen and of unknown origin.
  - Secondary – presence of splenomegaly due to some well-defined cause such as tuberculosis, sarcoid, etc.,
Mechanisms of hypersplenism:
- Doan and his group have concluded that the various types of cytopenias were due to selective sequestration of the various hematologic elements in the enlarged spleen and in their eventual phagocytosis.
- “Our own concept” is that the enlarged spleen has an indirect or humoral action upon the bone marrow, either by preventing the growth or maturation of the various cells, or else by blocking their delivery from the marrow to the blood.
What is not hypersplenism:
- Hereditary spherocytosis:²⁹
  - Red cells are trapped by the normal spleen, sequestered there, and ultimately destroyed.
  - Because the spleen is called upon to sequester and destroy more cells than is normal, it gradually becomes larger.
  - This is not hypersplenism in the sense of our definition but is simple splenomegaly occurring in response to an outside factor, in this instance, the presence of spherocytosis.
  - That hypersplenism is not a factor is indicated by the short survival time of the hereditary spherocytes when they are transfused into an individual having a normal spleen.
  - Conversely, when the spleen is removed from a patient with hereditary spherocytosis, the red cell life span becomes normal, and the anemia previously present becomes completely corrected.
  - Thus, in this disease, the fundamental disturbance is a defective red blood cell
- Acquired autoimmune hemolytic anemia:³⁰
  - Red cells are produced in normal fashion by the bone marrow. They appear in the circulation as entirely normal cells, but are then attacked by antibodies which have the capacity of fixing themselves on the patient’s own red blood cells
  - As the result of the antibody attack, the red blood cells become injured and thus spherocytic to greater or less degree; they are then trapped by the spleen, as in the case of the hereditary spherocyte, phagocyted, and ultimately removed.
  - Thus, their life span is distinctly shortened.
  - This is not hypersplenism in the sense that we consider it, but simply splenomegaly on the basis of extra work by that organ, both by reason of phagocytosis and perhaps also on the basis of excessive antibody production.
  - Here the fundamentally abnormal condition is the antibody productive mechanism and not a primary disturbance in the spleen.
- ITP³¹

1962

The word hypersplenism appeared in Paris early in the 20th Century, used first by Chauffard to describe the role of the spleen in hereditary spherocytosis.
In the 40 years from 1907 to 1947 the term was used less than a dozen times, and only with reference to anemia.
Hypersplenism today has a broader connotation of exaggerated or perverted splenic activity which may be directed against many parts of the blood and marrow.
This modern word hypersplenism did not achieve wide usage until 1947, after Dameshek and Estren had published a fascicle, “The Spleen and Hypersplenism”. Then the word and the concept immediately came into vogue, and a flood of publications began.
Mechanisms of hypersplenism:
- Two hypotheses:
  - Doan declared that hypersplenism results from sequestration and destruction of blood cells in the spleen.
  - Dameshek declared that hypersplenism results from inhibition of bone marrow by humoral factors from the spleen.
- At present, the preponderance of evidence favors splenic sequestration and lysis of blood elements as the mechanism of hypersplenic cytopenias.
The definition and diagnosis of hypersplenism are difficult because:
- We do not know with certainty how the spleen behaves toward the blood cells.
- We usually do not know for certain that hypersplenism is present until the spleen is remove.
Criteria for diagnosis of hypersplenism:
- Splenomegaly
- Blood cytopenia or cytopenias
- Hypercellular marrow
- Splenectomy results in correction of the cytopenia³²
Diseases that others have disqualified as hypersplenism:³³
- Hereditary spherocytosis (HS)
- Autoimmune hemolytic anemia (AIHA)
- Immune thrombocytopenia
For the purpose of this discussion, which is limited to hematologic aspects, hypersplenism is the detrimental increase of splenic activity. When a person is hematologically better off without his spleen he has hypersplenism.
Hypersplenic anemia:
- HbSS
- Congestive splenomegaly:
  - With or without cirrhosis.
  - Experimentally, it may result from ligation of the splenic vein.
  - The hemolytic process is promptly relieved by splenectomy.
  - Hypersplenic leukopenia and thrombocytopenia are often associated with the anemia of congestive splenomegaly; These cytopenias are cured by splenectomy.
- Splenic vein thrombosis
- Myelofibrosis
- Hereditary spherocytosis (HS):
  - HS hemolytic disease is the consequence of a normal splenic reaction to abnormal red cells; HS cells transfused into a normal recipient are promptly destroyed but normal cells have a normal life span in the HS patient.
  - And in both types of recipient the HS red cells survive normally after splenectomy, although the cellular abnormality is not corrected by the operation.
  - Premature destruction of HS red cells is specifically a splenic function which is neither shared by other organs nor taken over postsplenectomy.
  - Microscopic examination of the HS spleen reveals a characteristic congestion of the pulp cords.
  - It is believed that movement of the HS red cells through the spleen is impeded in the pulp cords and this delay or temporary sequestration results in injury to the cells
  - Although the spleen is large, the leukocytes and platelets in HS, so far as we know, are not affected by the hypersplenism.
- Thalassemia major
- Autoimmune hemolytic anemia (AIHA):
  - Because the spleen is a source of antibodies it has been suggested that the production of abnormal autoantibodies may be one basis for the hypersplenism in AHA.
Hypersplenic thrombocytopenia:
- ITP:
  - Because many cases respond to splenectomy, it is justified to conclude that ITP is a form of hypersplenism (whether humoral or sequestering), but at present it is not possible to identify the hypersplenic cases without performing splenectomy.
  - In the hypersplenic situation of ITP the collaboration of antibody and spleen is required to destroy the platelets.
- Secondary hypersplenic thrombocytopenia (non-autoimmune disease):
  - Lymphoma
  - Gaucher’s disease
  - Banti’s syndrome
  - Kala-azar
Hypersplenic leukopenia:
- Primary hypersplenic leukopenia:
  - Felty’s
- Secondary hypersplenic leukopenia (may be associated with anemia, thrombocytopenia or both):
  - Lymphoma
  - Banti’s syndrome
  - Gaucher disease
  - Sarcoidosis
  - Tb
  - Malaria
  - Kala-azar

1963

The term hypersplenism has become generally accepted to designate an abnormal hematological state brought about by overactivity of the spleen.
Essential clinical features include:
- Splenomegaly (usually)³⁴
- Peripheral blood cytopenias
- Normally cellular or hypercellular bone marrow
- Symptoms attending these abnormalities³⁵
Term hypersplenism:
- Introduced by Chauffard in 1907.
- Popularized by Dameshek in 1941, then by Doan in 1942.
Mechanisms of hypersplenism:
- Dameshek believes that the normal spleen exerts a mild inhibitory effect on the bone marrow’s hematopoietic activity through a hormonal influence and that, in hypersplenism, the inhibition becomes pathologically severe.
- Doan is credited with the theory that splenic hyperfunction is due mainly to sequestration and phagocytosis of blood cells in the spleen. Supported by observations that:
  - Immediate termination of a true hemoclastic crisis at the moment of ligation of the splenic pedicle.
  - In hypersplenism the blood cell counts are lower in the splenic vein than in the splenic artery.
Classification of hypersplenism:³⁶
- Primary – no known disease involves the spleen directly:
  - ITP
  - Congenital hemolytic anemia (HS)
  - Primary splenic neutropenia or pancytopenia
- Secondary – caused by or associated with another pathologic state (direct tissue involvement of the spleen by a disease process, or the functions of the spleen are altered to produce cytopenias):
  - Direct tissue involvement of the spleen:
    - Leukemia
    - Lymphoma
    - Sarcoidosis
    - Metastatic tumors
    - Infections
  - Diseases indirectly producing splenic hyperfunction:
    - Acquired hemolytic anemia
    - Felty’s syndrome
    - Von Gierke’s disease
    - Gaucher’s disease
    - Collagen diseases
    - Cirrhosis of the liver with congestive splenomegaly

1967

In the bewildering vocabulary of Medicine there is probably no expression – possibly excepting the term “autoimmunity” – that is used so often by so many for so few reasons, as the expression “hypersplenism.”
The following are the cardinal features of hypersplenism:
- Splenomegaly, regardless of cause
- A reduction in one or more cellular elements of the blood with hyperplasia of their respective marrow precursors
- Correction of the blood cytopenia by splenectomy
Mechanisms of hypersplenism:
- The “organ mysterii plenum” releases humors which suppress the release of new cells from the bone marrow; studies have not provided clear or reproducible evidence for hematosuppressive splenic humors
- Large spleens have an enhanced capacity for sequestering blood cells and that the hematological changes reflect an increased rate of cell turnover. Cells are trapped and destroyed.

1968

The term hypersplenism defies precise definition.
Describes a common problem involving patients with:
- Large spleens
- A morphologically normal bone marrow
- Any combination of anemia, thrombocytopenia, and leukopenia
- Return of peripheral counts to normal after splenectomy
As our knowledge has grown, certain syndromes (i.e., idiopathic thrombocytopenic purpura and acquired hemolytic anemia) that were part of the earlier debate have been eliminated from the hypersplenic category.³⁷
The anemia of hypersplenism is of two types:
- Hemolytic
- Dilutional
Leukopenia:
- Cell turnover data in hypersplenic leukopenia is scarce but suggests increased peripheral destruction of granulocytes.
Thrombocytopenia:
- In contrast to red cells and white cells, platelet lifespan has been normal or slightly shortened in hypersplenic ³⁸
- There is an extravascular splenic pool of platelets.
- The estimated size of this pool varies from one to five times the circulating mass.
- In congestive splenomegaly the splenic pool is four or five times the circulating pool with the total pool no different from normal.
- In hypersplenic thrombocytopenia there appears to be a shift of platelets from the intravascular to the splenic pool with the total mass remaining normal.

1973

It has long been said that we shall understand hypersplenism only when we understand “splenism.”³⁹
Banti:
- Published his first description of the association between anemia and splenomegaly in 1882.
- Began a series of experiments demonstrating the pathogenic relationship between the enlarged spleen and the anemia.
- described leukopenia in patients with enlarged spleens and noted that frequently these patients died with cirrhosis of the liver.
- Was the first to question the mechanism of splenic cytopenias, that is, whether the enlarged spleen reduces peripheral blood cell counts by destroying circulating blood cells or by releasing humoral factors which suppress production or release of the blood cells from the bone marrow.
- Encouraged experimentation with splenectomy in human diseases characterized by splenomegaly and blood cytopenia.
Opinions differ as to what categories of diseases should be included within the definition of hypersplenism.⁴⁰
It is useful to define hypersplenism in a functional sense, that is, as those conditions where it is known, either from clinical experience or by kinetic studies using radioactively labeled blood cells, that:
- The spleen is the major site of blood cell destruction.
- The peripheral blood cytopenia will be corrected by splenectomy.
Definition of hypersplenism:
- Anemia, leukopenia, thrombocytopenia, or a combination of these resulting from excessive, splenic sequestration or pooling of blood cells.
- Usually associated with clinical splenomegaly.⁴¹
- Always ameliorated by splenectomy.
Classification of hypersplenism:
- Resulting from splenic enlargement (congestion, infiltration, infection):
  - The only true hypersplenism⁴²
  - The only instance in which primary changes in the spleen or splenic circulation are solely responsible for excessive destruction of blood cells.
- Resulting from splenic sequestration as secondary response to the presence of damaged blood cells in the circulation:⁴³
  - Intrinsic defects of blood cells (hereditary spherocytosis, sickle cell anemia):
    - Splenic enlargement result of a primary abnormality of the blood cells themselves leading to abnormal sequestration and destruction of these cells by the spleen.
  - Autoimmune destruction of blood cells (autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura):
    - Splenic enlargement result of the interaction of blood cells with humoral factors, leading to abnormal sequestration and destruction of these cells by the spleen.
Some investigators do not include the latter two categories within the definition of hypersplenism because the spleen is performing its normal physiologic function.
Ever since the work of Banti in the latter part of the Nineteenth Century, there has been a great deal of interest in the mechanism of hypersplenism. There are at least two possible mechanisms:
- The spleen produces humoral factors which suppress production or release of blood cells from the bone marrow,
- The spleen causes cytopenias by excessive pooling, sequestration, or both, and ultimate destruction of the circulating blood cells.
  - Most clinical observations and experimental work support this second hypothesis:
    - The bone marrow of patients with hypersplenism usually shows hyperplasia of the precursors of the cells that are decreased in the peripheral blood.
    - kinetic studies using isotopically labeled blood cells demonstrating increased cell destruction with splenic sequestration, and a compensatory increase in production of the involved cell lines by the bone marrow.
    - Direct counts of blood cells from splenic artery and vein have demonstrated cell density gradients across the splenic circulation in experimental animals and in patients with hypersplenism.
    - The reduction in cell density observed in splenic venous blood can be directly attributed to splenic sequestration of these cells.
    - Hypersplenism can be induced in experimental animals by various methods, and it can be demonstrated that the resulting cytopenias are caused by splenic sequestration and destruction of the involved blood cells.
Anatomy of spleen:⁴⁴
- The red pulp of the spleen where these processes occur is composed of cords and sinuses.
- The surfaces of these structures are lined by phagocytic macrophages and reticuloendothelial cells.
- Circulating blood cells enter the splenic cords from the terminal arterioles, pass through fenestrations in the basement membrane between cord and sinus and then through narrow slits between sinus endothelial cells into the sinuses, from which they exit via the splenic veins.
- The cord-sinus interface provides a unique screen-like filtration system through which all blood cells must pass.
- Openings through the fenestrations and slits measure less than three microns in width, offering a major anatomic barrier to passage of blood cells through the cord-sinus circulation.
- Abnormal red blood cells, such as those in hereditary spherocytosis, sickle cell anemia, or Heinz body hemolytic anemias, have difficulty passing through these small openings and become trapped in the splenic red pulp.
- Once sequestered in the spleen, these trapped cells are exposed to metabolic conditions (hypoxia, hypoglycemia, acidosis) which further limit their survival. Ultimately, the cells are destroyed by splenic macrophages and reticuloendothelial cells.
- Splenic sequestration may be initiated by either primary splenic enlargement or by intrinsic or extrinsic defects in the blood cells themselves.
- Regardless of the triggering event, splenic sequestration results in ‘work hypertrophy‘ of the spleen, an increase in the functional reticuloendothelial tissue mass, further sequestration, and further splenic hypertrophy.
Classification:
- Hypersplenism resulting from splenic enlargement has traditionally been considered to be either primary or secondary. It is doubtful, however, whether true primary hypersplenism exists.⁴⁵
- In the absence of demonstrable histopathologic changes in the spleen and in the absence of portal hypertension, the cytopenias previously regarded as primary hypersplenism are likely the result of either intrinsic defects in the blood cells themselves or immune cytopenias in which antibody activity has not been clearly demonstrated.⁴⁶
Causes of hypersplenism:⁴⁷
- Most common:
  - Cirrhosis of the liver with portal hypertension and congestive splenomegaly (Banti’s syndrome)
  - Neoplastic diseases of the spleen:
    - Lymphomas and Hodgkin’s disease
    - Leukemias
    - Myeloproliferative disorders
- Other causes:
  - Acute infections:
    - Mononucleosis
    - Hepatitis
    - Subacute bacterial endocarditis
  - Chronic infections:
    - Tuberculosis
    - Malaria
    - Syphilis
    - Kala-azar
  - Sarcoidosis
  - Connective tissues disease
  - Gaucher disease

1974

Most now agree that the term hypersplenism encompasses various disorders in which blood cytopenia is associated with splenomegaly.
Cardinal features of the syndrome are:
- Splenomegaly, which may be of unknown etiology (primary), or secondary to some known stimulus for splenic growth.⁴⁸
- A reduction of one or more cellular elements of the blood leading to anaemia, leukopenia, thrombocytopenia, or any combination of these, associated with hyperplasia of the respective marrow precursors of the deficient cell type
- Correction of the blood cytopenia(s) by splenectomy
Banti indicated that two hypotheses could be formulated to explain the syndrome:
- That the spleen destroys large numbers of blood cells.
- That certain biochemical processes taking place in the spleen result in the development of metabolites which enter the circulation and have secondary effects on hematopoietic organs.
Some 60 years later the hematology literature still carried extensive debate and laboratory investigation which supported one or the other of these two possibilities:
- Dameshek concluded that the spleen releases humours which suppress the production or release of new blood cells from the marrow.
- Doan argued that large spleens have an enhanced capacity, for sequestering blood cells, thereby lowering the peripheral blood counts of these elements.
Most investigators now favour the view that hypersequestration is the predominant mechanism for blood cytopenia in hypersplenism. Evidence includes:
- Major decreases in the leucocyte and platelet count can be demonstrated across the splenic circulation of enlarged spleens by sampling splenic arterial and venous blood.
- After injection of 51 Cr-labelled red cells or platelets into patients with hypersplenism, inordinate and progressive accumulation of radioactivity over the surface projection of the enlarged spleen occurs indicating preferential trapping of these cells.
- A typical hypersplenic syndrome can be induced in animals by chronically injecting them with poorly metabolizable polymers such as methylcellulose. Storage of these substances in the reticuloendothelial cells of the spleen results in splenomegaly and concomitantly pancytopenia.
Congenital haemolytic diseases such as hereditary spherocytosis and thalassemia (work load regulates spleen growth):
- Splenic enlargement seems to progress and haemolysis progressively worsen.
- Spleen growth may be stimulated by an increase in its ‘work load’, in this case, the work of trapping and destroying abnormal red cells.
- Worsening spiral of haemolysis in many chronic haemolytic states may be caused by a progressive increase in functional reticuloendothelial tissue which the processing of effete red cells seems to stimulate.
- The enlarging spleen in thalassemia has been shown to continuously increase its capacity to destroy transfused red cells.
- Thus, although overgrowth of the spleen my be induced by sequestration of abnormal red cells in these conditions, levels of platelets and leucocytes may be frequently depressed as well.
The various blood cells are affected differently when sequestered in hyperplastic spleens:
- Red cells
  - 51Cr kinetic studies which indicate no significant pooling of red cells in normal spleen.
  - Generally red cell survival is shortened proportionately with increasing splenic size.
  - Hemolysis associated with splenomegaly is usually mild.
  - The combination of splenic red cell destruction and diminished marrow response (e.g., leukemia, myelofibrosis, chronic infection) may produce significant anaemia.
  - Expansion of plasma volume which accompanies splenomegaly f any cause further increases the apparent anemia of hypersplenism.
  - Vascular pooling in the spleen diminishes red cell survival was suggested by early experiment:
    - mature red cells require a constant supply of glucose to generate ATP for cation pumping and membrane maintenance.
    - ATP production is markedly inhibited at acidic pH.
    - Measurements of splenic pulp blood suggest that glucose concentration is roughly one third of that in normal plasma, and pH is strikingly lowered as well.
    - Recovery from metabolic deprivation in red cells may require minutes to hours in vitro. Thus, mildly damaged red cells which are returned by chance to the enlarged spleen shortly after previous release may become additionally damaged.
    - This repeated mild metabolic injury (or ‘conditioning’) caused by splenic pooling finally results in irreversible changes and phagocytic removal.
- Platelets:
  - About 30% of platelets are normally present in this organ.
  - Unlike detained red cells, platelets released from the excessive splenic pools of splenomegalic patients have been shown to survive normally.
  - The absence of injury to splenic-pooled platelets probably reflects their small size and ability to pass freely through the fenestrations between sinuses and cords while constantly bathed by fresh plasma.
  - With radioisotope measurements the sum of the platelets in the circulation and in the spleen in hypersplenic thrombocytopenia computes to a nearly-normal total platelet mass. Thus, the marrow output of platelets in hypersplenic states seems not to respond, or to respond suboptimally, to low concentrations of circulating platelets but to be regulated mainly by total platelet mass.
- White blood cells:
  - Mild leukopenia is common in patients with splenomegaly but generally does not cause clinical concern.
  - The mechanism for reduced white cell levels in splenomegaly is not as well elucidated as with the other cytopenias, but kinetic evidence using DF32P-labelled granulocytes also suggests the presence of large splenic pools of leukocytes in patients with hypersplenic granulocytopenia.

1988

Functions of the spleen:
- Phagocytosis of particular matter
- Immunological responses
- Blood pooling
Normal spleen pools:
- About 30% of the total body platelet mass:
  - Freely exchanging with the remaining fraction in the general circulation.
  - Pooled in the spleen are in dynamic equilibrium with circulating platelets and not permanently sequestered.
- About 3% of the total red cell mass:
  - 20-40 ml of erythrocytes.
  - These splenic erythrocytes are also in dynamic equilibrium with the circulating erythrocytes, making up an exchangeable red cell pool.
- The splenic kinetics of granulocytes is less well understood. However, in recent years rather convincing results have appeared as to the existence of a sizable exchangeable splenic granulocyte pool.
Mechanisms of cytopenias:
- Thrombocytopenia may be mediated by:
  - Increased reversible pooling of platelets in the enlarged spleen:
    - Pooling of platelets in an enlarged spleen accounts for the thrombocytopenia of the hypersplenic state.
    - The splenic platelet pool found to be proportional to spleen size.
  - Splenic phagocytosis and destruction of IgG-coated platelets.
- Anemia:
  - Increased reversible pooling of RBCs in the enlarged spleen:
    - Exchangeable splenic red cell pool increases with increasing spleen size.
    - About 50-60% of the total red cell mass can be retained in massively enlarged spleens.
    - Expansion of the plasma volume, which invariably follows splenic enlargement, contributes to a reduction in the value for venous hematocrit.
  - Destruction of RBCs:
    - Physiological destruction of erythrocytes takes place in the spleen.
    - Elimination of spherocytes, heat-damaged and antibody-coated erythrocytes.
- Leukopenia:
  - A positive relationship was also established between the size of the marginating granulocyte pool and splenomegaly, and there was a decrease in this pool following splenectomy.

2000

The term hypersplenism was first introduced by Chauffaud in 1907.
Hypersplenism is characterized by:
- Splenomegaly (the incidence of splenomegaly in cirrhosis varies from 36 to 92% in different series.)
- Significant reduction in one or more of the cellular elements of the blood in the presence of normocellular or hypercellular bone marrow.
The incidence of hypersplenism is variable. It has been described in between 11% and 55% of patients with cirrhosis and portal hypertension in different series.
There is a loose correlation between spleen size and the hematological features.
Mechanisms of cytopenias:
- Anemia:
  - Red cell survival is often shortened in chronic liver disease and the spleen is a major site of red cell destruction.
  - Structural and metabolic changes in the red cell membrane frequently contribute to haemolytic anaemia in cirrhosis.
  - Anaemia in liver disease may be compounded by reduced erythropoietin production.
- Thrombocytopenia:
  - Thrombocytopenia in cirrhosis is probably due to a combination of:
    - Platelet sequestration in the spleen
    - Impaired platelet production in the bone marrow
    - Impaired thrombopoietin production by a failing liver
    - Decreased platelet survival
  - Compared to normal controls, platelet survival time in the circulation is reduced from a mean of 8.4 to a mean of 5.7 days.
  - In normal subjects approximately 37% of platelets were sequestered in the spleen and 24% in the liver.
  - These figures changed to 71 and 14%, respectively, in patients with splenomegaly.

2005

The spleen is:
- The body’s largest filter of the blood.
- A unique lymphoid organ.
The organ is surrounded by a fibrous capsule of connective tissue.
The spleen is organized as a ‘tree’ of branching arterial vessels, in which the smaller arterioles end in a venous sinusoidal system.
The smaller branches of the arterial supply are sheathed by lymphoid tissue, which forms the white pulp of the spleen.
The smallest arterial branches traverse the marginal zone to form the venous system of the red pulp, which is named after the large, blood-filled sinuses.
Red pulp:
- The specialized structure of the venous system of the red pulp gives this area its unique capacity to filter the blood and remove old RBCs.
- Arterial blood arrives into cords in the red pulp, which consist of fibroblasts and reticular fibers and form an open blood system without an endothelial lining.
- Many macrophages are found in the cords.
- From the cords, the blood passes into the venous sinuses of the red pulp. These sinuses are lined by endothelium that has an unusual discontinuous structure. Stress fibers extend underneath the basal plasma membrane.
- The arrangement of the stress fibers, together with the parallel arrangement of the endothelial cells of the sinuses, forces the blood from the cords into the sinuses, through the slits that are formed by the stress fibers.
- This passage becomes difficult for ageing erythrocytes, which have stiffening membranes, such that they stick in the cords and are phagocytosed by the red-pulp macrophages that are located in the cords.
- Red pulp is also involved in:
  - Recycling iron
  - Producing antibodies

White pulp:
- The white pulp is organized as lymphoid sheaths, with T- and B-cell compartments, around the branching arterial vessels.
- The correct organization and maintenance of the white pulp is controlled by specific chemokines that attract T and B cells to their respective domains, thereby establishing specific zones within the white pulp.
Marginal zone:
- An important transit area for cells that are leaving the bloodstream and entering the white pulp.
- In addition to being a transit area, the marginal zone contains a large number of resident cells including:
  - Macrophages
  - B cells
  - Dendritic cells

2009

Hypersplenism is a syndrome comprising:
- Splenomegaly
- Anemia, leucopenia and/or thrombocytopenia
- Compensatory bone marrow hyperplasia
- Improvement after splenectomy (if performed)

2015

Hypersplenism is seen when the spleen sequesters formed elements of the blood leading to a fall in red blood cells, white blood cells (WBCs), platelets or any combination thereof.
The spleen is usually enlarged but the severity of the hypersplenism is not directly related to the size of the spleen or severity of portal hypertension.⁴⁹
Hypersplenism can be seen in a variety of conditions including:
- Infectious diseases such as malaria
- Infiltrative diseases
- Liver disease
Splenomegaly and hypersplenism are common in patients with cirrhosis.
Patients with cirrhosis and normal sized spleens may have cytopenias from other causes. For example:
- Thrombocytopenia may be caused by:
  - Antiplatelet antibodies
  - Toxic effects of alcohol
  - Bone marrow suppressive effects of hepatitis C virus (HCV)
  - Decreased thrombopoietin production
- Leukopenia may be caused by Bone marrow suppressive effects of hepatitis C virus (HCV)
- Anemia may be caused by:
  - Nutritional deficiencies
  - Abnormalities in the RBC’s cell membrane
  - GI tract bleeding

2018

The normal weight of the spleen in healthy adult humans ranges from 50 to 250 g (men: 80–200 g; women: 70–180 g) with a median weight of 150 g.
Normal human adult spleen size is defined by sonography by a length less than 13 cm and a thickness of 5 cm or less.
Spleen is divided into two distinct macroscopic compartments:
- Red pulp:
  - Consists of a microcirculatory structure of venous sinuses, reticular fibers and fibroblasts.
  - Cord-like projections of fibroblasts and fibrils of connective tissue known as the splenic cords or ‘Cords of Billroth’ infiltrate the red pulp.
  - The splenic cords act as a bottleneck for erythrocytes, only allowing highly deformable erythrocytes to navigate these passages.
  - Abnormal cells are engulfed and destroyed by splenic macrophages.
- White pulp:
  - the region directly surrounding the splenic arterioles is known as the periarteriolar lymphoid sheath (PALS).
  - The PALS contains T cells and facilitates their interaction with dendritic cells and passing B cells.
  - B cells reside in primary follicles that facilitate clonal proliferation upon B cell activation.
  - The white pulp is bordered by the marginal zone, a transit area that allows the migration of blood cells between the circulation and the white pulp.

Histology of normal mouse spleen highlights the distinct regions of the red pulp (most pink eosin stain) and the
white pulp (stained blue by hematoxylin). The connective tissue capsule can be observed surrounding the spleen.

Mechanisms of splenomegaly:
- Increased splenic function (work hypertrophy)
  - Results from excessive function of normal splenic activities.
  - Red cell sequestration (expansion of red pulp):
    - Splenic engorgement results from increased sequestration of abnormal erythrocytes from the circulation.
    - Erythrocytic diseases such as hereditary spherocytosis or sickle cell anemia, result in the splenic cords and venous sinuses becoming engorged with diseased cells leading to splenomegaly.
    - The reticuloendothelial system hypertrophies as a result, leading to splenomegaly as observed during splenic sequestration crisis in sickle cell disease.
  - Immune hyperplasia (expansion of the white pulp; follicular hyperplasia):
    - Chronic systemic infections such as malaria, measles, typhoid fever, and viral illnesses.
    - Immune mediated disorders such as ITP or RA.
- Infiltration:
  - Cancer:
    - Benign
    - Malignant, especially:
      - Lymphoma
      - Leukemia
      - Primary myelofibrosis
  - Metabolic conditions such as Gaucher’s disease (deficiency in glucocerebrosidase enzyme activity).
- Congestion:
  - Blockage of the blood flow through the splenic vasculature and pooling of blood in the red pulp.
  - This leads to dilated veins and sinuses; fibrosis of the red pulp; and hemosiderin-laden macrophages.
  - Occurs in cirrhosis and congestive heart failure.

2023

UpToDate

Definition: Hypersplenism refers to splenic pooling or sequestration of blood cells to a degree that causes one or more cytopenias:
- These might be associated with a known underlying condition or identified when a complete blood count (CBC) is performed for another reason.
- All of the normal splenic functions are thought to be accentuated in an enlarged spleen.
Clinical features of hypersplenism:
- Typically, the cytopenias are relatively mild and transfusions are rarely indicated.
- The spleen is often enlarged (splenomegaly) and congested with blood.
- However, hypersplenism and splenomegaly do not always coexist.
Causes of hypersplenism:
- Liver disease, especially cirrhosis with increased portal pressure.
- Portal or hepatic vein thrombosis with portal hypertension.
Treatment of hypersplenism:
- Supportive, with treatment of the underlying cause and avoidance of interventions that could further worsen hepatic or splenic function.
- For individuals with significant splenomegaly, avoiding high-impact activities and reducing the risk of falls may be indicated.
- Identify and treat other causes of cytopenias, which may include autoimmune destruction; deficiencies of iron, vitamin B12, or folate; or bone marrow abnormalities.
- Other interventions that may be appropriate in selected, clinically severe cases include:
  - Splenic artery embolization
  - Splenectomy
  - Thermal ablation using microwaves or focused ultrasound (experimental)

Learning Points

The spleen consists of red pulp and white pulp.

Most common definition of hypersplenism includes 4 criteria:
- Splenomegaly
- Cytopenia(s)
- Hyperplasia of the respective marrow precursors of the deficient cell type
- Correction of the blood cytopenia(s) by splenectomy
Caveats:
- Most but not all patients with hypersplenism have splenomegaly.⁵⁰
- There is no correlation between spleen size and degree of cytopenias.
- Hyperplasia of the respective marrow precursors may not occur if there is concomitant condition suppressing hematopoietic such as primary bone marrow process or nutritional deficiencies.
- There may be other factors contributing to cytopenias, e.g., reduced thrombopoietin levels in patients with cirrhosis.
- The diagnosis is made before splenectomy, and moreover patients rarely their spleen removed.
Any condition that leads to splenic sequestration +/- destruction of blood cells and secondary cytopenia(s) may cause hypersplenism:
- If there is an inherently defective blood cell (for example in hereditary spherocytosis or thalassemia), or if there are humoral factors affecting blood cells (for example in autoimmune hemolytic anemia of ITP), the removal of that cell type by the spleen and subsequent reduction in their circulating levels does not count as hypersplenism. It is only when the hyperactive (usually enlarged) spleen starts to indiscriminately pool +/- destroy additional blood cell types that hypersplenism emerges.
- Any cause of splenomegaly may in theory lead to hypersplenism by virtue of indiscriminate pooling/destruction of blood cells. It seems likely that those causes leading to work hypertrophy/expansion of the red pulp have a greater likelihood of causing hypersplenism than conditions associated with immune hyperplasia or infiltration since this is the region of the spleen where cells tend to pool.

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