CHAPTER 14: Platelet Disorders

Platelets assume an important role in a wide variety of disease states. Morbidity related to platelet dysfunction is generally due to bleeding, but occasionally thrombosis is dominant. As summarized in Table 14-1, bleeding can occur if the platelet count is too low or if there is a qualitative defect in platelet function. In patients with platelet disorders, bleeding is usually superficial and localized to skin and mucous membranes, a phenomenon known as purpura. Petechiae are small, 2-to-5 mm, red or purple macules (spots) that appear most often in the distal lower extremities (Fig. 14-1A) but also on the conjunctiva and palate. Small petechiae often merge to form larger lesions. Very large, purpuric lesions are called ecchymoses (Fig. 14-1B). In contrast to telangiectasia, petechiae and ecchymoses do not blanch under pressure. Mucosal purpura is generally associated with severe thrombocytopenia and may be a harbinger of complications such as gastrointestinal bleeding or even brain hemorrhage. In contrast to the superficial bleeding seen in patients with thrombocytopenia and qualitative platelet disorders, defects in the soluble coagulation factors, such as hemophilia (Table 14-1), typically present with deep bleeding, such as hemarthroses.

In a clear and informative parallel to anemia, thrombocytopenia can be due either to decreased platelet production or enhanced platelet destruction. The life span of normal platelets in the circulation is about 7 to 9 days. Therefore, if the bone marrow stops producing platelets, it takes nearly a week before severe thrombocytopenia develops. In contrast, an acute immune or consumptive process that suddenly and drastically curtails platelet survival can produce severe thrombocytopenia within hours.

DECREASED PRODUCTION

Damage or suppression of pluripotent hematopoietic stem cells may result in not only thrombocytopenia but also anemia and leukopenia (pancytopenia) accompanied by marrow aplasia. Aplastic anemia and other causes of pancytopenia are covered in Chapter 4. Transient thrombocytopenia due to marrow aplasia and decreased platelet production predictably follows certain forms of chemotherapy or radiation therapy for cancer. Other drugs selectively inhibit platelet production. Occasionally, patients with severe alcoholism will present with thrombocytopenia that appears to be due to a toxic effect of ethanol on megakaryocytes. In most cases, the platelets gradually return to baseline levels following cessation of therapy or drinking. Somewhat less often, decreased platelet production is due to a primary bone marrow disorder such as acute leukemia or a myelodysplastic syndrome. Less severe thrombocytopenia can be due to megaloblastic anemia or to invasion of the bone marrow by tumors such as lymphoma or carcinoma.

The administration of thrombopoietin (Tpo) or Tpo-mimetic agents is seldom effective in the treatment of severe thrombocytopenia due to impaired platelet production. This may be due to the fact that endogenous plasma Tpo levels are already markedly elevated in these patients, owing to very low numbers of megakaryocytes in the bone marrow as well as platelets in the periphery. (See Chapter 2 for information on the regulation of platelet production by endogenous Tpo.) Because the platelet life span is usually normal in these patients, platelet transfusions produce a significant and beneficial rise in the platelet count unless or until the patient develops alloimmunization. In contrast, platelet transfusions are much less effective in patients in whom thrombocytopenia is due to enhanced destruction.

SEQUESTRATION

As explained in Chapter 1, the spleen in normal individuals contains (sequesters) about a third of the body's platelets. Patients who have splenomegaly due to a wide range of disorders (Chapter 1, Table 1-4) have a higher proportion of their platelets entrapped along with white and red blood cells. A significant reduction in one or more of the peripheral blood counts by splenic sequestration is called hypersplenism.

Patients with hypersplenism generally have platelet counts of 50,000 to 120,000/mm³. Thus, the degree of thrombocytopenia is almost never low enough to pose a risk of hemorrhage. Accordingly, splenectomy is not indicated for correction of the platelet count. However, some patients may have neutropenia that is sufficiently severe to warrant splenectomy.

INCREASED CONSUMPTION/DESTRUCTION

Severe thrombocytopenia is commonly caused by rapid destruction of platelets, most often due either to immune clearance or to consumption in conditions associated with intravascular thrombosis. In either case, the bone marrow produces increased numbers of platelets that have a short survival in the circulation. Because platelets normally become smaller as they age in vivo, the few platelets that are seen in blood films of patients with thrombocytopenia due to increased destruction tend to be larger than average.

IMMUNE THROMBOCYTOPENIA

Immunologic recognition followed by destruction of platelets is a relatively common cause of severe thrombocytopenia in individuals of all age groups. Most of these individuals come to medical attention because they develop purpura—hence the designation immune thrombocytopenic purpura (ITP). In children, the peak incidence is about 5 years of age. These previously healthy children typically develop a sudden onset of petechiae or ecchymoses within a few days or weeks following an infectious illness, usually viral. In the majority of these patients, the thrombocytopenia and purpura resolve within 6 months regardless of whether they have received therapy. Adults with ITP have a strikingly different clinical presentation and course. In these patients, the onset is insidious and seldom accompanied by a viral prodrome. The illness is chronic and, when severe, requires meticulous and often complex management. In both children and adults, if ITP is the primary diagnosis, patients normally have no symptoms or physical findings except for purpura. The spleen and lymph nodes are not enlarged. Some women also experience menorrhagia. Gastrointestinal bleeding is much less common. Rarely patients with ITP sustain cerebral hemorrhage.

PATHOGENESIS

There is overwhelming circumstantial evidence that in ITP platelets are destroyed by autoantibodies directed against platelet antigens. In early (less regulated) days of clinical research, it was noted that the intravenous administration of plasma from a patient with ITP to a normal volunteer resulted in the development of acute and severe thrombocytopenia and purpura. These studies led to the hypothesis that ITP patients had circulating autoantibodies directed against "public" antigens displayed on the surface of platelets in all individuals. These antibody-coated platelets are rapidly cleared by the interaction of the Fcγ receptor on tissue macrophages with the Fc (constant) portion of the immunoglobulin.

The primary public antigen targeted for immune attack in ITP is GPIIb/IIIa, which, as explained in Chapter 13, undergoes a conformational change during platelet activation and is the site of fibrinogen cross-linking. As shown in Figure 14-2, once the antibody-coated platelet is recognized and engulfed by the macrophage, GPIIb/IIIa as well as other platelet membrane proteins are degraded. These peptide antigens are then coupled with HLA class 2 molecules and displayed on the macrophage cell surface. This antigen-presenting complex interacts with the T-cell receptor on CD4 helper lymphocytes, inducing proliferation and recruitment of antigen-specific B-cell clones, which also proliferate and produce high levels of antibody against not only GPIIb/IIIa but also GPIb/IX and other platelet antigens.

The rapid destruction of platelets by resident macrophages results in Tpo-mediated stimulation of megakaryocyte production in the bone marrow. Thus, patients with ITP usually have increased numbers of marrow megakaryocytes (Fig. 14-3). Indeed, as a general rule, the level of platelet production parallels the number of megakaryocytes in the bone marrow. In this respect, the pathophysiology of ITP closely parallels that of immune hemolytic anemia (Chapter 11). In both disorders, the enhanced destruction of the blood cell in the peripheral circulation is accompanied by a compensatory hyperplasia of the respective precursors in the bone marrow. However, the plasma levels of the critical cytokines differ in the two disorders. In immune hemolytic anemia, as in nearly all other types of anemia, plasma erythropoietin levels are markedly elevated, in response to hypoxic stress (Chapter 1). In contrast, in ITP, plasma Tpo levels are generally normal or modestly elevated, owing to the clearance of this cytokine by hyperplastic marrow megakaryocytes.

DIAGNOSIS

Most often, immune thrombocytopenia arises spontaneously in otherwise healthy individuals with no underlying illness. The sudden development of purpura in an asymptomatic patient with normal hemoglobin level, white blood cell count, and differential count is very likely to be ITP. However, even in this setting the possibility of associated disorders should be investigated and ruled out. Immune thrombocytopenia is encountered in a substantial minority of patients with lymphoma and human immunodeficiency virus (HIV) infection, sometimes when these illnesses are at a preclinical stage. In other cases, the association with an underlying condition is obvious, such as immune thrombocytopenia seen in patients with acute mononucleosis, in those who have undergone bone marrow transplantation, and in those with systemic lupus erythematosus. Occasionally, drugs can cause immune-mediated destruction of platelets. The classic example is the antiarrhythmic agent quinidine, a drug that is now seldom used. Much more often the anticoagulant heparin (Chapter 13) is associated with immune thrombocytopenia. The drop in platelet count caused by heparin is generally modest, but affected patients are paradoxically at high risk of developing life-threatening venous and arterial thrombosis (see Chapter 17).

Other than a complete blood count, no other laboratory test is essential in making the diagnosis of ITP. However, it is prudent to check a baseline coagulation profile to rule out disseminated intravascular coagulation and to obtain screening tests for lupus and infection with HIV and Epstein-Barr virus. Unfortunately, no serological test for detecting antibody coating of platelets is nearly as reliable as the Coombs test for detecting antibody-coated red cells. As mentioned earlier, the presence of large platelets in the peripheral blood smear suggests that the thrombocytopenia is due to a decrease in platelet life span. If doubt persists, a bone marrow examination will provide more definitive evidence as to whether the thrombocytopenia is due to impaired production or increased destruction.

TREATMENT

As mentioned earlier, most children with ITP remit spontaneously and therefore do not require treatment. In contrast, adult patients require treatment if the thrombocytopenia poses a significant risk of bleeding (platelet count <50,000/mm³). The treatment strategy for ITP closely parallels that of immune hemolytic anemia (Chapter 11). Administration of high doses of corticosteroids reliably results in a boost in the platelet count within the first week, and with continued treatment, the platelet count often reaches normal levels. Steroid therapy appears to suppress both the clearance of the antibody-coated platelets and the production of anti-platelet autoantibodies. Most patients relapse during or following the withdrawal of steroids. Alternative therapy is required in patients who either fail to respond to steroids or require prolonged treatment in order to maintain platelet counts in a safe range (>50,000/mm³). Currently, the recommended second-line therapy is rituximab, a monoclonal antibody directed against the CD20 surface antigen on B lymphocytes. If this treatment is not effective, splenectomy offers a good chance of prolonged remission. It should be noted that this is true even though splenomegaly is not a feature of ITP. Recent clinical trials have shown that Tpo-mimetic drugs are effective in patients with refractory ITP, but it is too early to know whether this treatment will become part of standard care. Patients with extremely low platelet counts and those being prepared for surgery generally respond promptly, albeit transiently, to the intravenous (IV) administration of high doses of immunoglobulin; the mechanism of this response is not known.

DISSEMINATED INTRAVASCULAR COAGULATION

Disseminated intravascular coagulation is a relatively common cause of thrombocytopenia due to enhanced platelet destruction. This often catastrophic complication is encountered in patients with a wide range of severe illnesses including sepsis, obstetrical emergencies, trauma, and cancer. In contrast to ITP, the coagulation profile is markedly abnormal. Rapid platelet consumption is secondary to inappropriate triggering of the coagulation cascade. This topic is covered in detail in Chapter 16.

In thrombotic thrombocytopenic purpura (TTP), a relatively uncommon but sometimes life-threatening disorder, patients present with acute onset of hemolytic anemia and thrombocytopenia, sometimes preceded by viral-infection-like symptoms of fatigue, malaise, and fever. A substantial fraction of patients have central nervous system manifestations, such as seizures, coma, hemiplegia, and dementia. These findings may progress, but more often are transient or recurrent. A smaller number of patients have modest or moderate impairment of renal function. The anemia is often severe and accompanied by laboratory abnormalities stemming from acute hemolysis, including increased reticulocyte counts and elevated levels of serum lactate dehydrogenase and nonconjugated bilirubin. Occasionally, the intravascular hemolysis results in hemoglobinuria. The blood film (Fig. 14-5) reveals striking abnormalities of red cell shape, such as small fragments (schistocytes), helmet cells, and triangular cells, along with occasional nucleated red cells and marked thrombocytopenia. Importantly, the coagulation profile, assessed by partial thromboplastin time and prothrombin times, is normal, thereby distinguishing TTP from disseminated intravascular coagulation (Chapter 16). Thus TTP is a pentad of five features, summarized in the sidebar. The first two, thrombocytopenia and microangiopathic hemolysis, are major criteria required for diagnosis.

PATHOGENESIS

Pathologic examination of tissues from patients with TTP has revealed the presence of small platelet thrombi studding the endothelium of arterioles and capillaries. These thrombi contain abundant von Willebrand factor (vWF) and relatively little fibrin. The only plasma abnormality is the presence of unusually high molecular weight multimers of vWF in the plasma, shown in Chapter 15, Figure 15-3. Taken together, these observations suggest that these abnormally large vWF multimers act like extra-sticky molecular glue, tethering platelets to the endothelial surface (Fig. 14-4). Very rare families have been encountered with chronic relapsing TTP. These individuals have an inherited deficiency of the protease ADAMTS13, which cleaves extra-large vWF into normal size multimers. In those with sporadic acquired TTP, a large majority of patients have inhibitory antibodies directed against ADAMTS13. These convergent insights have elucidated the molecular pathogenesis of this complex and formerly puzzling disease.

TREATMENT

Until 20 years ago, TTP was usually fatal. However, a decade prior to uncovering the role of ADAMTS13 in TTP, clinicians empirically discovered that plasma exchange is a remarkably effective therapy that can dramatically reverse the neurologic manifestations and reduce mortality in TTP. Elucidation of the importance of antibody inhibition of ADAMTS13 now provides a satisfying rationale for plasma exchange, which serves to both decrease the inhibitory antibody titer and to supply normal-sized vWF multimers.

Young children can develop acute microangiopathic hemolysis and thrombocytopenia accompanied by oliguria, proteinuria, and uremia, often following a diarrheal illness. In contrast to complications of TTP, neurologic complications are rarely encountered. This constellation of findings is designated hemolytic uremic syndrome (HUS). The anemia and thrombocytopenia are less severe than those seen in TTP, but the renal impairment is more severe. HUS is the most common cause of acute renal failure in young children. About 50% of cases are caused by an enteropathic strain of Escherichia coli (O157:H7), which releases a Shiga-like toxin. It is not understood how this toxin induces hemolysis and thrombocytopenia; damage to endothelial cells is suspected to incite the process. Supportive care is the mainstay of therapy. Children with enteropathic HUS have normal plasma levels of ADAMTS13 protease and do not benefit from plasma exchange.

Children with atypical (non-diarrheal) HUS commonly have a mutation in one of three proteins involved in the regulation of the complement cascade: factor H, membrane cofactor protein, or factor I. These patients have a more severe clinical course. About half require chronic dialysis therapy for renal failure.

In adults, there is a continuous spectrum between HUS and TTP. Measurement of plasma ADAMTS13 protease levels has not proven useful in predicting which patients respond to plasma exchange. Patients who have undergone bone marrow transplantation sometimes develop thrombotic microangiopathy with features overlapping those of TTP and HUS.

If platelet function is abnormal, bleeding may occur despite a normal or even high platelet count. Acquired qualitative platelet defects are very common; well-defined inherited defects are very rare, although uncharacterized hereditary thrombocytopathies are not uncommon.

ACQUIRED

Drugs may interfere with the biosynthesis of prostaglandins not only in platelets but also in endothelial cells. By far the most common offender is aspirin. As shown in Figure 14-6, aspirin inhibits cyclooxygenase, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins PGG2 and PGH2. Platelets and endothelial cells are affected differently by this inhibition. In the platelet, aspirin suppresses the level of thromboxane A₂. Thromboxane A₂ is released from platelets during activation, thus leading to activation of other platelets, and aspirin interferes with this process. In the endothelial cell, aspirin suppresses the formation of prostaglandin I₂, which is a vasodilator and protects the vessel from thrombus formation. Patients who take conventional doses of aspirin for relief from pain and/or inflammation are at risk of bleeding by virtue of impairment of platelet activation. Aspirin also has been shown to be effective in the prevention of arterial thrombosis (see Chapter 17). There is evidence that low doses (baby aspirin) lessen the risk of bleeding but are sufficient to have an anti-platelet effect. Furthermore, with low doses of aspirin, endothelial cells maintain production of anti-thrombotic prostaglandin I₂.

In addition to aspirin, a wide range of other non-steroidal anti-inflammatory drugs (NSAIDs) also lower platelet levels of thromboxane A₂ and therefore enhance the risk of bleeding. For this reason, patients are warned not to take these drugs prior to elective surgery. Moreover, aspirin and NSAIDs pose a much higher risk of significant hemorrhage in patients with underlying bleeding disorders such as hemophilia or von Willebrand disease and are thus contraindicated.

Patients with uremia also have impaired platelet function that can lead to serious bleeding, particularly in the gastrointestinal tract. The mechanism underlying this defect is unknown. Platelet function improves after uremic patients undergo dialysis therapy.

Patients with primary bone marrow disorders commonly have qualitative platelet defects superimposed on abnormalities in the platelet count. Those with myelodysplastic syndromes (Chapter 20) often have thrombocytopenia. Even when their platelet counts are normal, their bleeding times are often prolonged, and they are at an increased risk of clinical bleeding. In contrast, patients with myeloproliferative disorders (Chapter 20) usually have elevated platelet counts but, nevertheless, often have prolonged bleeding times. These patients are highly prone to developing either bleeding or thrombosis. Platelet aggregation studies are frequently abnormal in these patients, but the results have not been helpful in predicting either bleeding or thrombosis.

INHERITED

Rare families have been encountered with bleeding disorders owing to defective platelet receptor function. Molecular genetic studies have revealed the precise defect in several of these familial platelet disorders. This information, although not useful to the practicing physician, has provided invaluable insights into key proteins involved in platelet function as well as a clearer understanding of platelet aggregation tests.

Figure 14-7 shows platelet aggregation profiles that are particularly informative. As mentioned in Chapter 13, the binding of GPIIb/IIIa to divalent fibrinogen is required for the formation of crosslinks that lead to the aggregation of platelets in plasma. Patients with Glanzmann thrombasthenia have a bleeding syndrome owing to the inheritance of a defect in either the gene for GPIIb or GPIIIa. As a result, their platelets lack docking sites for fibrinogen binding. Even though agonists such as adenosine diphosphate, arachidonic acid, epinephrine, and collagen can activate their platelets, aggregation fails to occur due to the absence of fibrinogen cross-linking. The only agonist that triggers crosslinking of Glanzmann platelets is ristocetin, which "conditions" vWF to bind to platelet GPIb/IX, thereby providing an alternative, nonphysiologic mechanism for platelet agglutination.

Note that the opposite pertains in patients with Bernard-Soulier syndrome. These individuals have defective GPIb/IX, due to mutations in the gene encoding this receptor. Therefore, their platelets aggregate normally in response to adenosine diphosphate, arachidonic acid, epinephrine, and collagen but do not aggregate or agglutinate in the presence of ristocetin.

Abnormal platelet aggregation due to a storage pool defect is also shown in Figure 14-7. Families have been described with abnormalities either in the structure of the dense or alpha granules or in the ability to release granule contents during activation. Both types of defects lead to impairment of the "second wave" of aggregation that normally arises from the release of adenosine diphosphate from platelet granules. When a population of platelets is exposed to low concentrations of agonists, only a minor fraction is activated initially (the first wave). However, adenosine diphosphate released from these early responders activates additional platelets, starting a second wave of aggregation that eventually involves the whole population. In platelets with a release defect, this amplification loop fails, and much higher doses of agonists may be required to achieve full platelet activation. This is illustrated in Figure 14-7, in which a platelet population with a storage pool defect responds partially to a low dose of arachidonic acid but aggregates fully when exposed to a high dose. Of course by far the most common cause of insensitivity to low doses of agonists and absence of a second wave is drug-induced (eg, aspirin) inhibition of thromboxane A₂ synthesis.