Several new agents have recently been developed or been applied to the treatment of ITP. There were

initially several studies with rituximab, which is a chimeric humanized monoclonal antibody directing

CD20 against B cells.59–61 It was primarily developed to treat lymphoma but it has been used in

autoimmune disorders and has been tried in phase 2 studies for chronic splenectomy failure ITP.

Response rates have been somewhat sporadic between 25% and 50%. Two new drugs binding the

thrombopoietin receptor on megakaryocytes have recently been approved for second-line treatment of

chronic ITP: the recombinant peptide romiplostim and eltrombopag, a thrombopoeitin nonpeptide

mimetic.62 Again, it was realized that there is decreased thrombopoietin production for the degree of

thrombocytopenia seen in ITP. Romiplostim, which is a fusion protein agonist for thrombopoietin

receptor administered by subcutaneous injection, led to response rates of 49% versus 2% for placebo

with an overall clinical response rate of 83%.48,63 An oral nonpeptide thrombopoietin receptor agonist,

eltrombopag, showed response rates of 79% versus 28% in a placebo controlled trial.64 Several other

newer agents including AKR-501 (thrombopoietin nonpeptide mimetic), and fostamatinib disodium, a

spleen tyrosine kinase inhibitor are under clinical investigation.62 The role of these and other agents in

the armamentaria against treatment of ITP will only likely increase in scope in the future. Future

studies will define the role of these new compounds and may decrease the incidence and need for

splenectomy.

Thrombotic Thrombocytopenia Purpura

Thrombotic thrombocytopenia purpura, or Moschcowitz syndrome, is a poorly understood much more

virulent syndrome than ITP in which thrombocytopenic purpura is only one manifestation. This disease

is characterized by widespread occlusion of arterials and capillaries by hyalin membranes that are

composed of a combination of platelets and fibrinogen. The classic pentad of symptoms reflects various

organ injuries with this microvascular process. This includes thrombocytopenic purpura, with

microvascular disease in the skin, neurologic manifestations due to microvascular disease in the central

nervous system, renal failure or hematuria due to microvascular disease in the kidney, microvascular

hemolytic anemia due to destruction of red cells traveling to damaged small vessels, and fever. The

precise etiology is unknown but may be related to an autoimmune response to small vessel endothelial

cell antigen.

Table 73-8 Results From 135 Combined Case Series Evaluating Splenectomy for

ITP

The therapeutic options for this disease include administration of fresh frozen plasma and/or

plasmapheresis, high-dose corticosteroids, and antiplatelet drugs.65 The benefits seen with

plasmapheresis would indicate that there is a toxic substance that is contributing to the etiology of this

disorder circulating in the plasma, whereas the benefit of administration of fresh frozen plasma would

indicate lack of some necessary substance that has yet to be identified. High-dose corticosteroids also

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lead to some benefit. Aspirin and dipyridamole block platelet agglutination. A combination of these

therapies now leads to a significant improvement of symptoms in 70% of patients. For patients failing

to respond or patients who relapse, a splenectomy has been performed with some success.66,67 The

majority of the long-term survivors with thrombotic thombocytopenic purpura (TTP) have undergone

splenectomy, implying that this organ has some major role in the pathophysiology of this disease.68 The

precise mechanism of splenic contribution is unclear. Mortality rates in the past have been as high as

90% to 95% for this disorder but are improving with aggressive treatment plans and a better

understanding and diagnosis of this disorder.

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia or acquired hemolytic anemia results from antibodies produced to red

cell membrane proteins that lead to red cell destruction. This disease is more common in women than in

men with the ratio of 2:1, and it typically presents after the age of 50 years. Patients present with acute

symptoms consisting of anemia, jaundice, and occasional fever. The spleen is enlarged in approximately

half of the patients. Laboratory diagnosis shows a positive direct Coomb test indicating antibody coating

the erythrocytes. There is also significant reticulocytosis and increased indirect bilirubin in the serum.

The disease is considered to be either idiopathic in 40% to 50% of the cases in which no identified

drug or infectious cause is identified or secondary to infection or drug. Of the secondary cases, the most

common infections are mycoplasmal pneumonia, viral infections, infectious mononucleosis, and AIDS,

and it can also occur with neoplastic diseases such as leukemia and lymphoma. The major drugs that

cause secondary autoimmune hemolytic anemia are penicillin, quinidine, hydralazine, and methyldopa.

A second way that autoimmune hemolytic anemia is categorized is by either cold antibodies or warm

antibodies. Warm antibodies are predominantly IgG, whereas cold antibodies are predominantly IgM.

This distinction is quite important when considering splenectomy as a treatment. The spleen contains

macrophages that bind the Fc portion of IgG. For this reason, in patients with warm antibody hemolytic

anemia, the spleen is the primary source of destruction of the red cells by the red pulp macrophages.

However, since the spleen does not contain receptors to bind IgM or the cold antibodies, there is no

destruction of the red cells in this form of hemolytic anemia. Rather, IgM either causes complement

fixation with destruction of red cells in the liver predominantly, or there is agglutination of red cells in

peripheral circulation such as the distal extremities leading to peripheral red cell destruction with

clinical manifestations similar to Raynaud phenomenon. Splenectomy for patients with cold antibody or

IgM hemolytic anemia is not effective.

The treatment of autoimmune hemolytic anemia initially consists of supportive therapy such as blood

transfusions. For patients who have disease secondary to an acute infection such as a mycoplasm

pneumonia, the disease may be self-limited. For drug-induced hemolytic anemia, the offending agent is

removed as quickly as possible. The initial form of treatment is typically high-dose corticosteroids that

cause a beneficial response in 75% of the patients. If patients again have drug-induced disease and the

offending agent is removed or the acute infection resolves, this may lead to long-term resolution. In

idiopathic autoimmune hemolytic anemia, only 25% of patients have sustained remission from steroid

use. In patients who have relapse after steroid therapy or who are ineligible for steroid therapy and

have warm antibodies, a splenectomy has a high likelihood of benefit. Eighty percent of patients show a

good response in correcting the anemia by splenectomy.69 This is felt to be almost certainly related to

removal of the site of destruction of the erythrocytes but also may be due to a decrease in production of

source of antibodies.

Autoimmune Neutropenia (Felty Syndrome)

Approximately 1% of patients with chronic rheumatoid arthritis will develop splenomegaly and

neutropenia. This triad of rheumatoid arthritis, neutropenia, and splenomegaly is known as Felty

syndrome.70 High levels of IgG have been identified on the surface of neutrophils with evidence of

increased production of granulocytes in the bone marrow. Pathologic analysis of spleens removed in

patients with Felty syndrome show a significant but proportional increase in the white pulp of the

spleen as opposed to other conditions of splenomegaly.71 Microscopically, there is evidence of excess

accumulation of neutrophils in both the T cell zone and the white pulp, as well as the cords and sinuses

of the red pulp.

Patients with this disease will have recurrent infections due to neutropenia as well as dysfunction of

the available neutrophils that are coated with antineutrophil IgG. Recurrent infections, as well as

chronic leg ulcers, are the predominant symptoms. Symptomatic patients should undergo splenectomy

and the vast majority of patients will have resolution of their neutropenia within 2 to 3 days.72 Even

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patients who do not have a significant increase in neutrophil count should get some benefit because of

improved neutrophil function.73

Hereditary Spherocytosis

Hereditary spherocytosis, also known as congenital hemolytic jaundice or familial hemolytic anemia, is

an autosomal dominant disease that is the most common of the congenital hemolytic anemias affecting

1 in 5,000 individuals.74 There are a variety of genetic defects in this syndrome that primarily affect

spectrin and ankyrin that alter the binding of the cytoskeleton to the erythrocyte cellular membrane

causing decreased cellular plasticity with membrane loss.75 The normal shape of the erythrocyte is

changed from the biconcave disc into a sphere and the decreased membrane-to-volume cell ratio causes

a lack of deformability that impacts the passage of erythrocytes through channels of the splenic red

pulp. Because of this delay in cell transit, there is ATP deprivation resulting in increased cellular

destruction. The condition is more frequent in Caucasians and in African Americans and is usually noted

in the childhood or adolescent ages. Since it is an autosomal dominant inheritance, patients may be

screened and diagnosed at quite an early age.

The diagnosis is primarily made by evaluation of the red cell smear showing a large number of

spherocytes. Spherocytes may also appear during autoimmune hemolytic anemias but in hereditary

spherocytosis the Coombs test is negative and an osmotic fragility test may be performed which is

diagnostic. Also, contributing to the diagnosis is a positive family history.

Patients with hereditary spherocytosis have mild to moderate anemia, splenomegaly, and jaundice.

The patients may have intermittent flares of disease that cause significant increased rates of hemolysis

causing jaundice. Between 30% and 60% of patients have been reported to have pigmented gallstones

due to the breakdown of hemoglobin.74

The treatment for hereditary spherocytosis is splenectomy that is indicated in virtually all patients.76

This treatment does not remove the spherocytes but it relieves all symptoms.77 The major question

involving management of these patients is the timing of splenectomy. Because of the increased

incidence of overwhelming postsplenectomy sepsis in very young children, it is usually recommended

that patients wait until after the age of at least 4 if not 6 years prior to splenectomy. For younger

patients who are very symptomatic and require splenectomy, partial splenectomies have been reported

to be beneficial in relieving the abdominal symptoms as well as the anemia and may be a useful

alternative procedure until patients reach an age in which total splenectomy is safer.78 Patients with

partial splenectomies had regrowth of tissue but with short term did not have recurrent anemia.69

Patients should be assessed at the time of scheduling a splenectomy for the presence of gallstones and a

laparoscopic cholecystectomy should be performed if stones are identified.

Hereditary Elliptocytosis

Hereditary elliptocytosis is a disease that is related to hereditary spherocytosis although not as severe.

For patients who are symptomatic, virtually all of the same comments regarding pathophysiology and

treatment can be made about hereditary elliptocytosis as for hereditary spherocytosis. This disease is

also inherited in an autosomal dominant pattern and the defect is felt to be present in spectrin. The

predominant abnormality changes spectrin such that it exists as a dimer instead of tetramer that is the

normal structure. This change leads to an alteration in membrane plasticity that creates cells that are

more elliptically shaped instead of a biconcave disc.

The signs and symptoms caused in this disease are much more mild than hereditary spherocytosis in

that only 10% of patients have clinical manifestations of anemia, splenomegaly, and in some cases

jaundice. The treatment recommendation for symptomatic patients is splenectomy again, which may be

performed with laparoscopic techniques and also cholecystectomy if gallstones are present.

Hereditary Nonspherocytic Hemolytic Anemia

There is a heterogeneous group of rare hemolytic anemias caused by inherited defects primarily

enzymes involved in glycolysis. It is felt that these genetic defects may decrease cellular energy

production leading to increased red cell destruction as these cells pass through the relatively hypoxic

environment of the red pulp of the spleen. The most common subtypes in this group of hemolytic

anemias are pyruvate kinase deficiency and glucose 6-phosphate dehydrogenase (G6PD) deficiency.

Patients present with anemia, jaundice, increased reticulocytes, and possibly cholelithiasis. The

diagnosis can be facilitated in that the shape of the cell does not show typically spherocytes and there is

normal osmotic fragility.

The primary treatment for these diseases is blood transfusion. In G6PD deficiency, splenectomy is not

2002