Acquired Disorders of Platelet Function

A. Koneti Rao

Joel S. Bennett

Platelets are essential for normal hemostasis. Thus, defects in platelet function may lead to bleeding diatheses. Platelet function defects can be inherited or acquired, with the latter being far more common. Moreover, abnormalities are often observed in multiple facets of platelet function, including adhesion, aggregation, secretion, and procoagulant activity. Although it would be preferable to classify these disorders on the basis of specific biochemical or functional defects, this is often not possible because in many instances, the basis for the defective platelet function is poorly understood. In this chapter, acquired platelet function disorders are described in relation to the disease states in which the perturbed platelet function is observed (Table 66.1). In some disease states, such as the myeloproliferative disorders, intrinsically abnormal platelets are produced by the bone marrow. In others, platelet dysfunction results from the interaction of otherwise normal platelets with exogenous factors such as drugs, artificial surfaces, toxic metabolites, or antibodies. Acquired platelet dysfunction is a prominent feature of renal failure, liver failure, and cardiopulmonary bypass. The platelet dysfunction associated with these conditions is discussed specifically in Chapters 126, 127, and 129.

Bleeding due to acquired platelet dysfunction is usually mucocutaneous in nature. However, the impact of these disorders on clinical hemostasis is often unpredictable, and in some instances, perturbed platelet function can only be detected in the laboratory. When bleeding occurs, it is usually mild to moderate, although the potential for severe life-threatening bleeding exists. Acquired platelet function disorders can prolong the cutaneous bleeding time and perturb ex vivo measurements of platelet aggregation. For example, aspirin ingestion impairs platelet aggregation and secretion in response to weak agonists such as ADP and epinephrine in most individuals, but only prolongs the bleeding time in half of them.¹^,² Moreover, the correlation between bleeding time prolongation and clinical bleeding is weak. This also applies to other methods used to detect abnormal platelet function, including the platelet function analyzer (PFA), the VerifyNow rapid PFA, the Impact cone and plate(let) analyzer (CPA), and flow cytometry.

CHRONIC MYELOPROLIFERATIVE DISORDERS

Bleeding and thrombosis are frequent complications of the chronic myeloproliferative disorders such as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF).³^,⁴ Factors that contribute to these hemostatic abnormalities include the increased whole-blood viscosity present in PV, intrinsic defects in platelet function, elevated platelet counts, as well as leukocyte and/or endothelial dysfunction.

Clinical Features

Large retrospective analyses have indicated that the frequency of thrombosis consistently exceeds the frequency of hemorrhage in these disorders.⁵ Nonetheless, a wide range in the probability of major thromboses has been reported: 7.6% to 29.4% and 11.2% to 38.6% for newly diagnosed ET and PV, respectively.⁵ By contrast, bleeding has been reported in 3% to 18% of patients with ET and 3% to 8.1% of patients with PV.⁵ Most symptomatic patients experience either bleeding or thrombosis; however, some develop both complications during the course of their disease. Bleeding usually involves the skin or mucous membranes, but may also occur after surgery or trauma. Thrombosis can involve arteries, veins, and the microvasculature and may occur in unusual locations such as abdominal wall vessels or the hepatic, portal, and mesenteric circulations.⁶^,⁷^,⁸^,⁹ Indeed, fullblown or latent myeloproliferative disorders account for a substantial proportion of patients with the Budd-Chiari syndrome or portal vein thrombosis.⁶^,¹⁰^,¹¹^,¹² Individuals with ET may experience ischemia and necrosis of the fingers and toes due to digital artery thrombosis, microvascular occlusion in the coronary circulation, and transient neurologic symptoms due to cerebrovascular occlusion.¹³ Erythromelalgia, characterized by redness and burning pain in the extremities, is strongly associated with ET and PV and is thought to be due primarily to arteriolar platelet thrombi.¹⁴^,¹⁵ It is difficult to predict the risk of bleeding or thrombosis in an asymptomatic patient,¹⁶ but in a review of 891 patients with ET as defined by the World Health Organization criteria and followed for a median time of 6.2 years, 12% experienced arterial and venous thrombosis at a rate of 1.9% patient years.¹⁷ A similar thrombosis rate was observed in the UK MRC Primary Thrombocythemia 1 study that compared treatment of high-risk ET patients with hydroxyurea/aspirin versus anagrelide/aspirin.¹⁸ Predictors for arterial thrombosis in the former study were age >60 years, a history of thrombosis, cardiovascular risk factors, leukocytosis, and the presence of the JAK2 V617F mutation. This analysis is consistent with previous studies also showing that vascular complications are more likely to occur in patients older than 60, in patients with other risk factors for vascular disease, and when baseline leukocytosis is present.¹⁹^,²⁰^,²¹^,²²^,²³ By contrast, only male sex predicted venous thrombosis. Surprisingly, platelet counts >10⁶/µL were associated with a significantly lower risk of arterial thrombosis in both the JAK2 V617F-positive and -negative patient populations.

A major advance in understanding the pathogenesis of the myeloproliferative disorders was the identification of gainof-function mutations in the JAK2 or MPL genes in approximately 95% of patients with PV and approximately 50% to 60% of patients with ET and MV.²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰ While it is plausible that
gain-of-function mutations in the protein products of these genes might influence hemostatic mechanisms, including the activation state of platelets,³¹^,³²^,³³ their precise impact on platelet function and thrombotic risk remains unclear.⁵^,³⁴^,³⁵^,³⁶ For example, some studies concluded that the presence of the JAK2 V617F or a high JAK2 V617F allele burden³⁷^,³⁸ confers increased thrombotic risk in ET, but others have failed to show such an association.³⁹^,⁴⁰^,⁴¹^,⁴² It may be useful in the future if such correlative studies were to focus on the JAK2 V617F allele burden in platelets and granulocytes separately.⁴⁰^,⁴³

Table 66.1 Disorders associated with acquired defects in platelet function

Uremia
Myeloproliferative neoplasms
	Essential thrombocythemia
	Polycythemia vera
	Chronic myelogenous leukemia
	Primary Myelofibrosis
Acute leukemias and Myelodysplastic syndromes
Dysproteinemias
Cardiopulmonary bypass
Acquired von Willebrand Disease
Acquired Storage pool deficiency
Antiplatelet antibodies
Liver disease
Drugs and other agents

Abnormalities in Platelet Function and Biochemistry

Under the light or electron microscope, platelets from patients with these disorders may be larger or smaller than normal, may be abnormally shaped, and may exhibit a reduction in the number of storage granules.⁴⁴ In ET, platelet survival may be modestly reduced.⁴⁵ In addition, a number of diverse functional and biochemical abnormalities have been described. The most frequently encountered abnormality is a decrease in platelet aggregation and secretion in response to epinephrine, ADP, or collagen.⁴⁶ The defect in epinephrine-induced aggregation often includes absence of the primary wave of aggregation. This is not simply due to an elevated platelet count, because it is not encountered in reactive thrombocytosis.⁴⁷^,⁴⁸

The reduced platelet aggregation and secretion has also been associated with one or more of the following: decreased agonist-induced release of arachidonic acid from membrane phospholipids⁴⁹^,⁵⁰; reduced conversion of arachidonic acid to prostaglandin endoperoxides or lipoxygenase products⁵¹; reduced platelet responsiveness to thromboxane A2⁵²; deficiency of dense- or α-granules⁵³^,⁵⁴; deficiency of the integrin α₂β₁, resulting in variable changes in platelet responsiveness to collagen⁵⁵; and decreased numbers of α₂-adrenergic receptors.⁵⁶^,⁵⁷

Similarly, a reduction in platelet procoagulant activity has been reported in some patients,⁵⁸ as have specific platelet membrane abnormalities, including decreased expression and activation of the integrin α_IIbβ₃⁵⁹; decreased amounts of the glycoprotein Ib-V-IX complex, resulting in an acquired Bernard-Soulier syndrome⁶⁰; decreased numbers of prostaglandin PGD2 receptors⁶¹; increased numbers of FcγRIIa receptors⁶²; an increase in CD36 expression⁶³^,⁶⁴^,⁶⁵; and decreased expression of Mpl receptors.⁶⁶^,⁶⁷ By contrast, spontaneous platelet aggregation, as well as increased thromboxane biosynthesis, has been reported for platelets from patients with ET and PV.⁶⁸^,⁶⁹^,⁷⁰ It has also been reported that Src kinase in unstimulated PV and ET platelets is present in a preactivated state (i.e., the inhibitory residue Tyr527 is dephosphorylated perhaps due to constitutive activation of the phosphatase SHP-2), perhaps causing these platelets to be hypersensitive to agonist stimulation.⁷¹

It is important to recognize that none of these biochemical and functional abnormalities are unique to a particular myeloproliferative disorder, their relative frequencies vary widely in reported series, and none are predictive of either bleeding or thrombosis. Since these disorders represent clonal abnormalities of hematopoiesis, megakaryocytes likely acquire these abnormalities as they develop from a clone of abnormal progenitors.

Treatment

Therapy should be considered for symptomatic patients, for patients >60 years of age, and for individuals about to undergo surgery.²⁰^,²²^,³⁴^,⁷²^,⁷³ Treatment includes correction of polycythemia and maintenance of a normal red cell mass, which may be approximated by a hematocrit <45% in males and <42% in females,⁷⁴ as well as treatment of the underlying disorder.³⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸ Platelet count reduction to <400,000/mm³ in patients with thrombocytosis, either by plateletpheresis or by cytoreductive agents, has generally been considered to be the target value associated with clinical improvement.²¹^,⁴²^,⁷⁷^,⁷⁹

Effective cytoreductive agents include the ribonuclease reductase inhibitor hydroxyurea,⁸⁰ interferon-α, and anagrelide.²⁰^,⁷⁹^,⁸¹^,⁸² In a prospective, randomized trial of 114 “high-risk” individuals with ET who were either >60 years of age or had a previous history of thrombosis, hydroxyurea significantly reduced the incidence of new thrombosis from 24% to 3.6%.⁸⁰ Anagrelide, an imidazoquinazolin derivative, is thought to decrease platelet counts by specifically impairing megakaryocyte maturation.⁸³ Anagrelide has essentially no effect on red and white cell counts and is not known to be leukemogenic. Nevertheless, 10% to 20% of patients experience neurologic, gastrointestinal, and cardiac side effects, in particular fluid retention, often necessitating discontinuation of the drug.⁸²^,⁸⁴^,⁸⁵ When hydroxyurea and anagrelide were compared head-to-head in a randomized trial of 809 patients with ET, subjects in the anagrelide group showed an increased rate of arterial thrombosis, major bleeding, and transformation to MF compared to the group treated with hydroxyurea.¹⁸ Progression to MF despite treatment with anagrelide was also observed in a phase II study.⁸⁶ During an episode of acute bleeding in the chronic myeloproliferative disorders, 1-desamino-8-d-arginine vasopressin (DDAVP) infusion may temporarily improve hemostasis if the patient has an acquired storage pool defect or acquired von Willebrand disease (AvWD).⁵⁴^,⁸⁷

Low-dose aspirin (100 to 300 mg/d) may be useful in patients with ET and thrombosis, particularly those with erythromelalgia
or with digital or cerebrovascular ischemia.¹⁵^,³⁴^,⁷⁸^,⁸⁸^,⁸⁹ In a recent double-blind, placebo-controlled study of 518 patients with PV who were judged to have no contraindications to daily low-dose (100 mg) aspirin, subjects in the aspirin arm exhibited a reduced risk of nonfatal arterial and venous cardiovascular endpoints. While aspirin was well tolerated, there was no effect of aspirin on overall and cardiovascular mortality.⁹⁰ However, aspirin can exacerbate a bleeding tendency in patients with myeloproliferative disorders.²⁰^,⁹¹

ET and PV in pregnancy pose special challenges because of an apparent increased risk of unsuccessful pregnancy, thrombotic or bleeding complications, and potential teratogenicity of hydroxyurea.⁹² In ET, the risk of first-trimester miscarriages may be higher among women with the JAK2 V617F mutation.⁹³ Barbui and Finazzi⁹⁴ have recommended a risk-stratified approach to management in pregnancy in which high risk is defined as either previous major bleeding or thrombotic episodes, previous pregnancy complications, or a platelet count >1.5 million/µL. Low-risk individuals are maintained at a hematocrit <45% and receive aspirin, 100 mg/d during pregnancy and low molecular weight heparin, 4,000 U/d for 6 weeks after delivery. Interferon-α is considered rather than aspirin if there has been previous major bleeding or if platelets are >1.5 million/µL. In addition, high-risk patients are recommended to receive low molecular weight heparin throughout pregnancy. However, in a retrospective analysis of 122 consecutive pregnancies in 92 women with ET, the risk of spontaneous abortion was 2.5-fold higher than in a control population and aspirin did not affect the live birth rate, but treatment with interferon-α was associated with better outcomes.⁹⁵ Consistent with previous reports, the presence of the JAK2 V617F mutation was again found to be an adverse prognostic factor.

ACUTE LEUKEMIAS AND MYELODYSPLASTIC SYNDROMES

Thrombocytopenia is the major cause of bleeding in acute leukemias and myelodysplastic syndromes (MDS). However, bleeding complications may occur in patients with normal platelet counts because of platelet dysfunction. Acquired platelet defects have been reported in acute myelogenous leukemia, as well as in acute lymphoblastic and myelomonoblastic leukemias and hairy cell leukemia.⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹ The reported abnormalities in these patients include impaired platelet aggregation responses to ADP, epinephrine, and collagen and diminished nucleotide secretion, serotonin uptake and release, TXA₂ production, platelet PDGF and β-thromboglobulin levels, and platelet procoagulant activities. In patients with hairy cell leukemia, the platelet dysfunction appears to improve postsplenectomy.¹⁰²^,¹⁰³^,¹⁰⁴ Acquired forms of vWD¹⁰⁵ and Bernard-Soulier-like platelet defects have been described in hairy cell leukemia and juvenile MDS,⁶⁰ respectively. Decreased platelet aggregation in response to one or more agonists has been described in MDS.¹⁰⁶^,¹⁰⁷^,¹⁰⁸

In acute leukemias and MDSs, platelets may be large and morphologically abnormal, with a balloon-like appearance. Ultrastructural studies have shown decreased microtubules, reduced number and abnormal size of dense granules, and excessive membranous systems⁹⁷^,⁹⁸^,⁹⁹; megakaryocytes can have a dysplastic appearance.⁹⁷^,⁹⁸ Bleeding in acute leukemias and MDS usually responds to transfusion of platelets.

DYSPROTEINEMIAS

Bleeding in patients with dysproteinemias can result from multiple hemostatic abnormalities including platelet dysfunction, specific coagulation abnormalities, hyperviscosity, and amyloid deposition in vessel walls.¹⁰⁹^,¹¹⁰ Qualitative platelet defects occur in 33% of patients with IgA myeloma or Waldenstrom macroglobulinemia, 15% of patients with IgG multiple myeloma, and infrequently in monoclonal gammopathy of undetermined significance. Several coagulation abnormalities have been reported in patients with dysproteinemias including factor × deficiency related to amyloidosis,¹¹¹ circulating heparin-like anticoagulants,¹¹² and impaired fibrin polymerization.¹¹³ An acquired form of vWD has been described in some patients.¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷ Platelets express Fc receptors, and it has been proposed that paraprotein binding to these receptors interferes with normal platelet membrane functions. In rare cases, paraprotein binding to platelet GPIIIa inhibited platelet aggregation or binding to GPIb interfered with its interaction of von Willebrand factor (vWF).¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁸

ACQUIRED vON WILLEBRAND DISEASE

AvWD is a bleeding disorder that is often unrecognized. Most patients with AvWD are older (median age 62 years) and have no previous personal or family history of a bleeding diathesis. Disorders associated with AvWD in these patients are diverse¹¹⁹^,¹²⁰^,¹²¹; the major associations include lymphoproliferative or plasma cell proliferative disorders (50%), cardiac disease (20%), and myeloproliferative diseases (15%). AvWD has been reported in chronic lymphocytic leukemia, hairy cell leukemia, acute myeloid and lymphoblastic leukemias, and non-Hodgkin lymphoma. In patients with myeloproliferative diseases and in reactive thrombocytosis, there is a strong correlation between the plasma vWF abnormalities and elevated platelet counts.¹²²^,¹²³ AvWD has been observed in patients with autoimmune disorders, including systemic lupus erythematosus, scleroderma and mixed connective tissue disease, hypothyroidism, and the antiphospholipid antibody syndrome,¹¹⁹^,¹²⁰ and following administration of ciprofloxacin,¹²⁴ valproic acid,¹²⁵ griseofulvin,¹²⁶ and the plasma expander hydroxyethyl starch.¹²⁷^,¹²⁸ AvWD has been reported in patients with solid tumors, most notably Wilms tumor, but case reports have noted an association with others as well (adrenocortical, lung, and gastric carcinoma).¹¹⁹^,¹²⁹ Patients with severe aortic stenosis and congenital valvular heart disease may have excess bleeding (particularly gastrointestinal), and several reports have documented AvWD in these patients,¹³⁰^,¹³¹^,¹³²^,¹³³^,¹³⁴^,¹³⁵ as well as in patient with left ventricular assist devices (LVADs).¹³⁶^,¹³⁷^,¹³⁸ Vincentelli et al.¹³¹ studied 50 consecutive patients with aortic stenosis and found skin or mucosal bleeding in 21% of patients with severe aortic stenosis. Abnormal platelet function documented by the PFA-100, decreased vWF binding to collagen, and loss of the largest
vWF multimers, or a combination of these findings, has been reported in 67% to 92% of patients with severe aortic stenosis. These abnormalities were corrected following surgery.

AvWD arises from a variety of mechanisms.¹¹⁹^,¹²¹ Some patients (especially those with dysproteinemias or lymphoproliferative diseases) have antibodies directed against functional domains of vWF¹¹⁹^,¹²¹^,¹³² that the antibodies that inhibit ristocetin cofactor activity or interfere with platelet or collagen binding. In some patients, antibodies enhances vWF clearance. Increased shear stress-induced proteolysis of vWF can produce AvWD, especially in patients with severe aortic stenosis,¹³¹^,¹³³^,¹³⁴ congenital cardiac diseases,¹³⁰ and LVAD.¹³⁶^,¹³⁷^,¹³⁸ In some patients, cellular adsorption and removal of vWF by malignant or other cells is the responsible mechanism.¹¹⁹^,¹²¹ Nonimmunologic binding and precipitation of vWF has been noted following administration of hydroxyethyl starch.¹²⁷ Lastly, decreased vWF synthesis has been invoked in patients with hypothyroidism¹³⁹ and those receiving valproate.¹²⁵

Laboratory findings in AvWD have included various combinations of a prolonged bleeding time, decreased plasma levels of vWF antigen and ristocetin cofactor activity and decreased factor VIII levels; most important is a selective reduction in large vWF multimers. Plasma levels of activated vWF, representing GPIbα binding form of vWF, are decreased in severe aortic stenosis.¹³⁴ vWF propeptide levels have been found to be elevated.

Therapy

The goals of treatment are first to raise plasma vWF levels to treat or prevent bleeding and second to address the underlying associated condition.¹²¹ The first goal can be achieved by administration of DDAVP or factor VIII concentrates containing vWF.¹¹⁹^,¹²¹^,¹³² Cryoprecipitate is also effective, but is associated with the risk of transfusion-transmitted diseases. Recombinant factor VIIa has also been used to control bleeding in patients with AvWD.¹⁴⁰ Several reports have found intravenous immunoglobulin to be effective, including in patients with plasma cell dyscrasias.¹¹⁹^,¹²⁰^,¹³²^,¹⁴¹^,¹⁴² Other modalities include plasma exchange¹¹⁶ and extracorporeal immunoadsorption.¹⁴³

Treatment of the underlying disorder is an important component of managing patients with AvWD. In patients with elevated platelet counts due to myeloproliferative disorders, cytoreduction is effective in reversing the vWF abnormalities.¹²²^,¹⁴⁴ Remissions have occurred spontaneously or after therapy of the underlying disease, such as lymphoproliferative disease, Wilms tumor, multiple myeloma, hypothyroidism, chronic myelogenous leukemia (CML), or cardiac valve abnormalities.¹¹⁹^,¹³¹

ACQUIRED STORAGE POOL DISEASE

Inherited deficiency of the platelet-dense granule pool of ATP and ADP (storage pool deficiency, SPD) is associated with impaired platelet function and a bleeding diathesis (Chapter 65). Several patients have been reported in whom SPD appears to have been acquired as a result of in vivo activation and release of platelet-dense granule contents or the production of abnormal platelets by the bone marrow. The presence of antiplatelet antibodies has been associated with acquired SPD.¹⁴⁵^,¹⁴⁶ It has also been reported in patients with disseminated intravascular coagulation, hemolytic-uremic syndrome, renal transplant rejection, multiple congenital cavernous hemangiomas, myeloproliferative diseases, chronic granulocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia.⁵⁰^,⁹⁸^,¹⁴⁷^,¹⁴⁸^,¹⁴⁹^,¹⁵⁰^,¹⁵¹^,¹⁵² Depletion of platelet granule contents has also been reported in patients with severe valvular disease and with Dacron aortic grafts, in patients undergoing cardiopulmonary bypass, and in platelet concentrates stored for transfusion.¹⁵³^,¹⁵⁴^,¹⁵⁵^,¹⁵⁶

ANTIPLATELET ANTIBODIES AND PLATELET DYSFUNCTION

Antibody binding to platelets can lead to accelerated destruction, cell lysis, platelet aggregation and secretion, and expression of platelet procoagulant activity. Antibody binding can also impair platelet function by inhibiting platelet activation or by binding to surface glycoproteins. The overall impact may be thrombocytopenia and/or impaired platelet function, as noted in a wide range of autoimmune disorders, including primary immune thrombocytopenic purpura (ITP), collagen vascular diseases, and AIDS. In addition, these antibodies inhibit megakaryocytopoiesis and proplatelet formation.¹⁵⁷^,¹⁵⁸ Patients with ITP have decreased platelet survival with increased plateletassociated antibodies demonstrable in most patients. It has been generally considered that the circulating platelets in these patients are young and have enhanced function; for example, bleeding times have been reported to be disproportionately shortened in relation to the platelet counts in patients with ITP compared with those with regenerative thrombocytopenia.¹⁵⁹ However, the function of platelets in patients with ITP may also be impaired, even when platelet counts are adequate. In one study, defective in vitro platelet aggregation was observed in 9 of 11 patients with chronic ITP and normal platelet counts.¹⁶⁰ Serum globulin fractions from some of these patients were found to inhibit the aggregation responses of normal platelets to collagen and ADP. In another study, IgG and F(ab’)2 fragments from some ITP patients inhibited responses of normal platelets.¹⁶¹ Impaired platelet aggregation responses to agonists (ADP, epinephrine, and collagen) with and without prolonged bleeding times have been reported in ITP and in disorders such as systemic lupus erythematosus and Graves disease, diseases in which platelet-associated antibodies have been detected.¹⁴⁵^,¹⁴⁶^,¹⁶²^,¹⁶³^,¹⁶⁴^,¹⁶⁵^,¹⁶⁶^,¹⁶⁷^,¹⁶⁸

Multiple mechanisms have been reported that produce antibody-induced platelet dysfunction. In some patients, the antibodies are directed against specific platelet surface membrane glycoproteins (GPIb,¹⁶⁹^,¹⁷⁰ α_IIbβ₃,¹⁷¹^,¹⁷² GPIa-IIa,¹⁷³^,¹⁷⁴ and GPVI¹⁷⁵^,¹⁷⁶) or glycosphingolipids.¹⁷⁷^,¹⁷⁸ In others, antibody specifically blocked platelet aggregation induced by collagen through interaction with GPVI¹⁷⁵ or GPIa/IIa.¹⁷³^,¹⁷⁴ In one report, an anti-GPVI antibody induced selective clearance of the GPVI/FcR gamma chain complex from the platelet surface.¹⁷⁶ Antibodies against GPIb-IX and α_IIbβ₃ have been detected in 5% to 29% and 10% to 75% of ITP patients, respectively.¹⁶⁹^,¹⁷¹^,¹⁷⁹ Rarely, these antibodies induce acquired forms of the Bernard-Soulier syndrome and Glanzmann thrombasthenia. One study noted that the severity of thrombocytopenia was not related to the glycoprotein specificity of the autoantibody.¹⁸⁰ Most of the platelet antibodies in ITP have been IgG, with IgM and IgA occurring less frequently.¹⁸¹ Other functional defects in ITP platelets include impaired platelet arachidonate metabolism, as reflected by increased lipoxygenase activity and decreased cyclooxygenase (COX) products (TXA₂ and hydroxyheptadecatrienoic acid),¹⁶⁵ and deficiency of platelet granule contents.¹⁴⁵^,¹⁴⁶^,¹⁸²

Table 66.2 Drugs that affect platelet function

COX Inhibitors

Aspirin

Nonsteroidal anti-inflammatory agents (indomethacin, phenylbutazone, ibuprofen, sulfinpyrazone, sulindac, meclofenamic acid, naproxen, diflunisal, piroxicam, tolmetin, and zomepirac)

ADP Receptor Antagonists

Thienopyridines: ticlopidine, clopidogrel, and prasugrel

Ticagrelor

GPIIb-IIIa Antagonists

Abciximab, tirofiban, eptifibatide

Drugs that Increase Platelet Cyclic AMP or Cyclic GMP

Prostaglandin I₂ and analogs

Phosphodiesterase inhibitors (dipyridamole, cilostazol, caffeine, theophylline, and aminophylline)

Nitric Oxide and Nitric Oxide donors

Antimicrobials

Penicillins

Cephalosporins

Nitrofurantoin

Hydroxychloroquine

Miconazole

Cardiovascular Drugs

β-adrenergic blockers (propranolol)

Vasodilators (nitroprusside and nitroglycerin)

Diuretics (furosemide)

Calcium channel blockers

Quinidine

Angiotensin-converting enzyme inhibitors

Anticoagulants

Heparin

Thrombolytic Agents

Streptokinase, tissue plasminogen activator, urokinase

Psychotropics and Anesthetics

Tricyclic antidepressants (imipramine, amitriptyline, and nortriptyline)

Phenothiazines (chlorpromazine, promethazine, and trifluoperazine)

Selective serotonin release inhibitors (fluoxetine, paroxetine, etc.)

General anesthesia (halothane)

Chemotherapeutic Agents

Mithramycin

1,3-bis (2-chloroethyl)-1-nitrosurea

Daunorubicin

Dasatinib

Miscellaneous Agents

Dextrans and hydroxyethyl starch

Lipid-lowering agents (clofibrate and halofenate)

e-Aminocaproic acid

Antihistamines

Ethanol

Vitamin E

Radiographic contrast agents

Food items and food supplements (ω-3 fatty acids, vitamin E, chocolates, onions, garlic, ginger, cumin, turmeric [curcumin], clove, black tree fungus, and Ginkgo)

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