Decreased production of platelets

Generalized diseases of bone marrow

••Aplastic anemia: congenital and acquired (see Table 13-7 )

••Marrow infiltration: leukemia, disseminated cancer

Selective impairment of platelet production

••Drug-induced: alcohol, thiazides, cytotoxic drugs

••Infections: measles, human immunodeficiency virus (HIV)

Ineffective megakaryopoiesis

••Megaloblastic anemia

••Myelodysplastic syndromes

Decreased platelet survival

Immunologic destruction

••Autoimmune: idiopathic thrombocytopenic purpura, systemic lupus erythematosus

••Isoimmune: post-transfusion and neonatal

••Drug-associated: quinidine, heparin, sulfa compounds

••Infections: infectious mononucleosis, HIV infection, cytomegalovirus

Nonimmunologic destruction

••Disseminated intravascular coagulation

••Thrombotic thrombocytopenic purpura

••Giant hemangiomas

••Microangiopathic hemolytic anemias

Sequestration

Hypersplenism

Dilutional

Immune Thrombocytopenic Purpura (ITP)

ITP can occur in the setting of a variety of conditions and exposures (secondary ITP) or in the absence of any known risk factors (primary or idiopathic ITP). There are two clinical

subtypes of primary ITP, acute and chronic; both are autoimmune disorders in which platelet destruction results from the formation of antiplatelet autoantibodies. We first discuss the more

common chronic form of primary ITP; acute ITP, a self-limited disease of children, is discussed later.

Immunologically mediated destruction of platelets (immune thrombocytopenia) occurs in many different settings, including systemic lupus erythematosus, acquired immunodeficiency

syndrome (AIDS), after viral infections, and as a complication of drug therapy. These secondary forms of immune thrombocytopenia can sometimes mimic the idiopathic autoimmune

variety, and hence the diagnosis of this disorder should be made only after exclusion of other known causes of thrombocytopenia. Particularly important in this regard is systemic lupus

erythematosus, a multisystem autoimmune disease ( Chapter 6 ) that can present with thrombocytopenia.

Pathogenesis.

Chronic ITP is caused by the formation of autoantibodies against platelet membrane glycoproteins, most often IIb-IIIa or Ib-IX.[53] Antibodies reactive with these membrane glycoproteins

can be demonstrated in the plasma as well as bound to the platelet surface (platelet-associated immunoglobulins) in approximately 80% of patients. In the overwhelming majority of cases,

the antiplatelet antibodies are of the IgG class.

The mechanism of platelet destruction is similar to that seen in autoimmune hemolytic anemias. Opsonized platelets are rendered susceptible to phagocytosis by the cells of the

mononuclear phagocyte system. About 75% to 80% of patients are remarkably improved after splenectomy, indicating that the spleen is the major site of removal of sensitized platelets.

Since it is also an important site of autoantibody synthesis, the beneficial effects of splenectomy may in part derive from removal of the source of autoantibodies. Although destruction of

sensitized platelets is the major mechanism responsible for thrombocytopenia, there is some evidence that megakaryocytes may be damaged by autoantibodies, leading to impairment of

platelet production. In most cases, however, megakaryocyte injury is not significant enough to deplete their numbers.

Morphology.

The principal morphologic lesions of thrombocytopenic purpura are found in the spleen and bone marrow but they are not diagnostic. Secondary changes related to the bleeding diathesis

may be found in any tissue or structure in the body.

The spleen is normal in size. On histologic examination, there is congestion of the sinusoids and hyperactivity and enlargement of the splenic follicles, manifested by the formation of

prominent germinal centers. In many instances, scattered megakaryocytes are found within the sinuses and sinusoidal walls. This may represent a very mild form of extramedullary

hematopoiesis driven by elevated levels of thrombopoietin. These splenic findings are not sufficiently distinctive to be considered diagnostic.

Bone marrow reveals a modestly increased number of megakaryocytes. Some are apparently immature, with large, nonlobulated, single nuclei. These findings are not specific for

autoimmune thrombocytopenic purpura but merely reflect accelerated thrombopoiesis, being found in most forms of thrombocytopenia resulting from increased platelet destruction. The

importance of bone marrow examination is to rule out thrombocytopenias resulting from bone marrow failure. A decrease in the number of megakaryocytes argues against the diagnosis of

ITP. The secondary changes relate to the hemorrhages that are dispersed throughout the body.

Clinical Features.

Chronic ITP occurs most commonly in adult women younger than age 40 years. The female-to-male ratio is 3:1. This disorder is often insidious in onset and is characterized by bleeding

into the skin and mucosal surfaces. Cutaneous bleeding is seen in the form of pinpoint hemorrhages (petechiae), especially prominent in the dependent areas where the capillary pressure is

higher. Petechiae can become confluent, giving rise to ecchymoses. Often there is a history of easy bruising, nosebleeds, bleeding from the gums, and hemorrhages into soft tissues from

relatively minor trauma. The disease may manifest first with melena, hematuria, or excessive menstrual flow. Subarachnoid hemorrhage and intracerebral hemorrhage are serious

consequences of thrombocytopenic purpura but, fortunately, are rare in treated patients. Splenomegaly and lymphadenopathy are uncommon in primary ITP, and their presence should lead

one to consider other possible diagnoses.

The clinical signs and symptoms associated with ITP are not specific for this condition but rather reflective of thrombocytopenia. Destruction of platelets as the cause of thrombocytopenia

is supported by the findings of a low platelet count and normal or increased megakaryocytes in the bone marrow. Accelerated thrombopoiesis often leads to the formation of abnormally

large platelets (megathrombocytes), detected easily in a blood smear. The bleeding time is prolonged, but PT and PTT are normal. Tests for platelet autoantibodies are not widely available.

Therefore, a diagnosis of ITP should be made only after other causes of platelet deficiencies, such as those listed in Table 13-9 , have been ruled out.

Almost all patients respond to immunosuppressive doses of glucocorticoids, but many eventually relapse and come to splenectomy. Most maintain safe platelet counts postsplenectomy and

require no further therapy. A significant minority, however, have refractory forms of ITP that can be very difficult to treat. Various immunosuppressive approaches may be effective in

such patients.

Date: 2016-04-22; view: 678