120 Acquired Qualitative Platelet Disorders

Question 1

Hematologic disorders associated with abnormal platelet function

Answer 1

• Chronic myeloproliferative neoplasms
• Leukemias and myelodysplastic syndromes
• Dysproteinemias
• Acquired von Willebrand disease

Question 2

Systemic disorders associated with abnormal platelet function

Answer 2

• Uremia
• Antiplatelet antibodies
• Cardiopulmonary bypass
• Chronic liver disease
• Disseminated intravascular coagulation
• HIV Infection

Question 3

Irreversibly inactivates the enzyme cyclooxygenase (COX), also known as prostaglandin (PG) endoperoxide H synthase, by acetylating a serine residue at position 52

Answer 3

Aspirin

Question 4

Constitutively expressed by many tissues, including platelets, the gastric mucosa, and endothelial cells

Answer 4

COX-1

Platelets express only COX-1, whereas endothelial cells can express both COX-1 and COX-2

Present in the gastric mucosa, where its products protect the integrity of the gastric lining cells.

Question 5

Undetectable in most tissues, but its synthesis is rapidly induced in cells such as endothelial cells, fibroblasts, and monocytes by growth factors, cytokines, endotoxin, and hormones

Answer 5

COX-2

Platelets express only COX-1, whereas endothelial cells can express both COX-1 and COX-2

Question 6

Platelet product of COX-1–mediated PG synthesis; produces vasoconstriction and is a receptor-mediated agonist for platelet aggregation and secretion

Answer 6

Thromboxane A2 (TXA2)

Aspirin: prevents platelet synthesis of TXA2, thereby inhibiting platelet responses that depend on this substance

Question 7

Endothelial cell PG product; produces smooth muscle cell relaxation and vasodilation and increases the platelet content of cyclic adenosine monophosphate (AMP), thereby decreasing overall platelet reactivity.

Answer 7

Prostacyclin (PGI2)

Question 8

Platelet PG synthesis in an adult is nearly completely inhibited by this dose of Aspirin

Answer 8

Single 100-mg dose of aspirin or by 30 mg taken daily for 7–10 days

Question 9

TRUE OR FALSE

Aspirin irreversibly inhibit platelet and endothelial cell COX, they have lasting effect on PG synthesis by endothelial cells.

Answer 9

FALSE

Aspirin irreversibly inhibit platelet and endothelial cell COX, they have no lasting effect on PG synthesis by endothelial cells.

…because of the ability of these cells to synthesize additional COX unaffected by aspirin

Question 10

TRUE OR FALSE

Aspirin is one of the relatively few drugs that prolongs the bleeding time in humans and appears to do so by blocking aggregation rather than adhesion.

Answer 10

TRUE

Aspirin is one of the relatively few drugs that prolongs the bleeding time in humans and appears to do so by blocking aggregation rather than adhesion.

Question 11

Study that showed the significance of aspirin ingestion in general surgery

Although taking aspirin did not reduce the incidence of cardiovascular events, there was a small increase in hemorrhagic complications.

Answer 11

POISE-2 (perioperative ischemic evaluation) study

Thus, the clinician must thoroughly weigh the potential risks and benefits of discontinuing aspirin before noncardiac surgery.

Question 12

Has been effective in correcting a prolonged bleeding time caused by aspirin

Answer 12

Desmopressin (deamino D-arginine vasopressin [DDAVP])

Question 13

TRUE OR FALSE

Unlike aspirin, NSAIDs, such as ibuprofen, naproxen, diclofenac, sulindac, piroxicam, indomethacin, and sulfinpyrazone, reversibly inhibit COX enzymes.

Answer 13

TRUE

Unlike aspirin, NSAIDs, such as ibuprofen, naproxen, diclofenac, sulindac, piroxicam, indomethacin, and sulfinpyrazone, reversibly inhibit COX enzymes.

Can cause a transient prolongation of the bleeding time when given in therapeutic doses, this is usually not clinically significant

Question 14

Patients who require both NSAID and Aspirin should ingest aspirin at least ____ hours before the ingestion of traditional NSAIDs.

Answer 14

2 hours

Because ibuprofen, and probably other NSAIDs, binds to COX-1, blocking its acetylation by aspirin, coadministration of NSAIDs and aspirin may impair the irreversible, antithrombotic effects of aspirin on platelets.

Question 15

More specific for COX-2 versus COX-1; intended to reduce pain and inflammation with fewer gastric side effects than traditional NSAIDs

Answer 15

Coxibs (COX-2 Inhibitors)

COX-2 products such as PGE2 and PGI2 elicit an increased sense of pain and perpetuate the inflammatory process.

Question 16

Clinical trials revealed that coxib administration was associated with __________________ toxicity

Answer 16

Cardiovascular toxicity

(myocardial infarction [MI], stroke, edema, exacerbation of hypertension)

Partly because of inhibiting PGI2 synthesis

Clinical evidence suggests there is no excess cardiovascular risk from daily doses of celecoxib of 200 mg or less.

If indicated, analgesics such as acetaminophen, or sodium or choline salicylate, may be substituted for aspirin and NSAIDs, or alternative pain-relieving modalities (eg, nerve blocks) could be considered for treating musculoskeletal pain.

Question 17

Drugs that form the active metabolites that irreversibly inhibit the platelet P2Y12 ADP receptor

Answer 17

Thienopyridines

Ticlopidine, clopidogrel, and prasugrel

All three thienopyridines are prodrugs that depend on oxidation by cytochrome P450 (CYP) enzymes in the liver (ticlopidine and clopidogrel) or in liver and intestine (prasugrel)

When given at their usual oral doses, the effect of thienopyridines on platelet aggregation and the bleeding time can be seen within hours of the first dose but are not maximal for 4–6 days.

Question 18

CYP polymorphism that results in lower levels of active clopidogrel and ticlopidine metabolites

Answer 18

CYP2C19

Question 19

Thienopyridine whose metabolism and inhibition of platelet function are not affected by CYP2C19 polymorphisms

Answer 19

Prasugrel

Because the enzyme CYP3A is present in the intestine and can oxidize prasugrel to its pharmacologically active metabolite, intestinal metabolism may account for the rapid appearance and higher levels of the active metabolite in plasma after an oral dose.

Question 20

The clinical efficacy of prasugrel has been compared with clopidogrel in patients with acute coronary syndrome scheduled for percutaneous coronary intervention in this trial

Answer 20

Triton-TIMI 38 trial

Prasugrel had a significantly decreased incidence of ischemic events

However, major bleeding was also significantly increased

Question 21

Thienopyridine associated with potentially serious hematologic complications, including neutropenia (neutrophils <1200   109/L in 2.4% of individuals) and, less commonly, aplastic anemia and thrombocytopenia.

In addition, at least one in 5000 patients develops a thrombotic thrombocytopenic purpura (TTP)–like syndrome.

Answer 21

Ticlopidine

Clopidogrel may also be rarely associated with a TTP-like syndrome (1 in 270,000), although this rate is close to the TTP incidence in the general population.

Question 22

Are oral, reversible, nonthienopyridine P2Y12 receptor antagonists

Answer 22

Ticagrelor, cangrelor, and elinogrel

ADENOSINE DIPHOSPHATE RECEPTOR ANTAGONISTS

Because they are not prodrugs and do not require metabolic activation, the onset of their inhibitory activity is more rapid than that of the thienopyridines.

Question 23

A novel, and as yet unexplained, side effect of treatment with this class of the P2Y12 antagonists is the occurrence of

Answer 23

Dyspnea

Question 24

Clinical trials for Ticagrelor

Answer 24

(PLATO) trial: acute coronary syndrome were randomized to treatment with either ticagrelor or clopidogrel

(ATLANTIC) trial: administration of ticagrelor in the cath lab or in the ambulance for new ST elevation myocardial infarction to open the coronary artery

Thus, ticagrelor, like prasugrel, appears to be more efficacious than clopidogrel at preventing adverse cardiovascular events but with more hemorrhagic complications.

Question 25

Most potent physiologic platelet agonist

Answer 25

Thrombin

Question 26

The major platelet thrombin receptor

Three G protein–coupled thrombin receptors have been identified in humans (protease-activated receptors [PARs] 1, 3, and 4).

Answer 26

PAR-1

Human platelets express both PAR-1 and PAR-4

PAR-4 signaling appears to be unnecessary for platelet activation if PAR-1 signaling is intact.

Question 27

Thrombon receptor antagonists

Answer 27

Vorapaxar
Atopaxar

Question 28

A potent, selective, long-acting, oral PAR-1 inhibitor generated from the naturally occurring muscarinic receptor antagonist himbacine

Answer 28

Vorapaxar

Atopaxar, a second PAR-1 antagonist, is currently being evaluated in clinical trials.

Has a shorter half-life than vorapaxar, suggesting that potential bleeding complications might be easier to manage.

Question 29

Integrin αIIbβ3 receptor antagonists

Answer 29

Abciximab, eptifibatide, and tirofiban

Abciximab is a human-murine chimeric Fab fragment, eptifibatide is a cyclic heptapeptide based on the sequence Lys-Gly-Asp (KGD), and tirofiban is an Arg-Gly-Asp (RGD)-based peptidomimetic.

Efficacy in the management of patients with acute coronary syndromes, particularly in the setting of percutaneous coronary interventions (PCIs) in which iatrogenic artery wall injury occurs.

Question 30

Inherited integrin αIIbβ3 abnormality

Answer 30

Glanzmann thrombasthenia

Question 31

Clinical trials for Integrin αIIbβ3 receptor antagonists

Answer 31

Abciximab: EPIC, EPILOG
Tirofiban: PRISMPLUS
Eptifibatide: PURSUIT

Question 32

Can rapidly reverse the platelet function defect in patients receiving abciximab, presumably by decreasing the overall extent of integrin blockade

Answer 32

Platelet transfusions

These drugs have very short half-lives if renal and hepatic function are normal.

Question 32

The mechanism responsible for thrombocytopenia after the administration of Integrin αIIbβ3 receptor antagonists is uncertain but may be related to

Answer 32

Presence of preexisting antiintegrin αIIbβ3 antibodies

This recognize epitopes exposed by the antagonist or, in the case of abciximab, to murine sequences incorporated into the abciximab Fab fragment.

Question 33

Pyrimidopyrimidine derivative that inhibits platelet cyclic nucleotide phosphodiesterase, resulting in the intraplatelet accumulation of the inhibitory cyclic nucleotide cyclic AMP (cAMP)

Answer 33

Dipyridamole

In the European Stroke Prevention Study 2 (ESPS 2), dipyridamole was beneficial in preventing stroke and transient ischemic attack, but there was no difference in mortality between patients taking dipyridamole and placebo or among patients taking dipyridamole plus aspirin compared with either dipyridamole or aspirin alone.

Question 34

Stimulate platelet adenylyl cyclase, causing an increase in platelet cAMP and a decrease in platelet responsivenes

Cause a transient inhibition of platelet shape change, aggregation, and secretion

Answer 34

PGE1, PGI2, or stable PGI2 analogues

However, their clinical utility is limited by their short half-life and side effects that include peripheral vasodilation.

Question 35

A phosphodiesterase III inhibitor, has been approved in the United States for the treatment of peripheral vascular disease and may have utility in the prevention of cardiac stent occlusion

Answer 35

Cilostazol

Question 36

Inhibit platelet function in vitro, probably by activating guanylyl cyclase, thereby increasing cGMP

Answer 36

NO and organic nitrates such as nitroglycerin

Question 37

Mechanism of thrombocytopenia with Penicillins

Answer 37

• Reduce platelet aggregation and secretion, as well as ristocetin-induced platelet agglutination, they may affect both platelet adhesion and platelet activation
• Impair the interaction of agonists and von Willebrand factor (vWF) with the platelet membrane

Their effect on platelets is maximal after 1–3 days of administration and may remain for several days after the antibiotic has been stopped, suggesting that the effect of these antibiotics on platelets in vivo is irreversible.

The inhibitory effect of penicillin G on platelet function in vitro is potentiated by the presence of probenecid.

Bleeding attributable to antibiotic-induced platelet dysfunction is **uncommon and unpredictable. **

Question 38

Broad-spectrum antibiot:ics can also cause a bleeding diathesis attributable to

Answer 38

Killing of gut flora, resulting in vitamin K deficiency

Question 39

Antibiotic that may cause a mild prolongation of the bleeding time and impair platelet aggregation when blood levels of the drug are higher than 20 μM, as may occur in patients with renal insufficiency

Answer 39

Nitrofurantoin

Question 40

An antifungal agent, inhibits human and rabbit platelet COX in vitro and rabbit platelet COX after IV infusion

Answer 40

Miconazole

Question 41

The broad-spectrum protein tyrosine kinase inhibitor, impairs collagen-induced platelet activation in vitro and increases tail bleeding times in mice, perhaps explaining some bleeding episodes in patients with chronic myelogenous leukemia who have been treated with the drug

Answer 41

Dasatinib

Question 42

Several factors contribute to the hemostatic abnormalities in the MPNs:

Answer 42

• Increased whole-blood viscosity in polycythemia vera
• Intrinsic defects in platelet function
• Elevated platelet counts
• Leukocytosis may represent a risk factor for thrombosis in the MPNs

Question 43

Represents a potential major cause of bleeding in the chronic MPNs, is most frequently associated with extreme elevations of the platelet count (eg, ≥1000–1500 x109/L)

Answer 43

Acquired von Willebrand syndrome

The most frequently encountered functional abnormality is a decrease in platelet aggregation and granule secretion in response to epinephrine, ADP, or collagen.

The defect in epinephrine-induced aggregation often includes absence of the primary wave of aggregation, which is unusual in other conditions.

Question 44

A syndrome of redness and burning pain in the extremities

Answer 44

Erythromelalgia

Is strongly associated with essential thrombocythemia and polycythemia vera and is thought to be partly caused by arteriolar platelet thrombi, although it may also have vasculopathic and neuropathic components

Question 45

An imidazoquinoline derivative, is thought to decrease platelet counts by impairing megakaryocyte maturation.

Answer 45

Anagrelide

No effect on red and white cell counts and is not known to be leukemogenic

10% to 20% of patients experience neurologic, GI, and cardiac side effects, in particular fluid retention

Question 46

May temporarily improve hemostasis if the patient has an acquired storage pool defect or acquired von Willebrand syndrome

Answer 46

DDAVP infusion

Question 47

Useful in patients with essential thrombocythemia and thrombosis, particularly those with erythromelalgia or with digital or cerebrovascular ischemia

Answer 47

Low-dose aspirin (~80–100 mg/day)

Question 48

The most frequent cause of bleeding in patients with leukemia or a myelodysplastic syndrome is

Answer 48

Thrombocytopenia

Question 49

Effective treatment in individuals with acquired von Willebrand syndrome associated with lymphoproliferative disorder or,with an IgG MGUS

Answer 49

High-dose intravenous immunoglobulin (IVIG)

IVIG likely acts by delaying vWF clearance via reticuloendothelial cell blockade, although other mechanisms have been postulated

Question 50

The pathophysiology of acquired von Willebrand syndrome

Answer 50

Reduction in circulating vWF (and its associated factor VIII molecule), generally because of rapid vWF turnover in the circulation

In lymphoproliferative disorders, a specific, often nonneutralizing anti-vWF antibody is present, whereas in autoimmune disorders, anti-vWF antibodies are part of a generalized autoimmune response.

Increased adsorption of vWF by tumor cells: Wilms tumor, osteosarcoma
Increased adsorption of vWF by platelets : MPN
Increased vWF proteolysis: Aortic stenosis, ventricular assist devices
Decreased vWF production: Hypothyroidism

Question 51

Diagnostic evaluation of Acquired von Willebrand syndrome includes

Answer 51

Factor VIII activity, vWF antigen, ristocetin cofactor activity, and vWF multimer analysis

Question 52

Diagnostic evaluation of Acquired von Willebrand syndrome includesTreatment should be reserved for

Answer 52

Patients with active bleeding or those who are likely to bleed if left untreated

Infusions of DDAVP or factor VIII/vWF concentrates may be useful, although the rapid clearance of vWF may limit efficacy.

Treatment has included glucocorticoids or rituximab in patients with lupus and recombinant factor VIIa or high-dose IVIG.

Treatment of the underlying disease can be effective in some situations (eg, hypothyroidism with thyroid replacement, Gaucher disease with enzyme replacement therapy,and extreme thrombocytosis with cytoreduction.

Question 53

As with inherited von Willebrand disease, longstanding acquired von Willebrand syndrome can be associated with and complicated by

Answer 53

GI tract arteriovenous malformations

Question 54

GI bleeding is found in patients with severe aortic stenosis and is referred to as

Answer 54

Heyde syndrome

Question 55

The hemostatic defect in uremia has been attributed to

Answer 55

Defects in platelet function

Question 56

In uremic patients, successful treatment of anemia with red blood cell transfusion or recombinant human EPO results in partial or complete correction of primary hemostasis when the hematocrit is increased to ______% to _____%

Answer 56

27% to 32%

Question 56

A prominent factor in terminal kidney disease is

Answer 56

Renal failure–associated anemia

A lowered hematocrit ex vivo induces a defect in platelet adhesion that can be corrected by increasing the hematocrit to 30% or more.

Question 57

TRUE OR FALSE

Abnormal platelet aggregation is common in uremic patients, but by itself is not an indication for therapeutic intervention.

Answer 57

TRUE

Abnormal platelet aggregation is common in uremic patients, but by itself is not an indication for therapeutic intervention.

Question 58

The mainstay of therapy for uremic thrombocytopathy

Answer 58

Dialysis

Peritoneal dialysis and hemodialysis are equally effective.

If a patient undergoing dialysis bleeds, it may be worthwhile to increase the intensity of the dialysis.

Question 59

If dialysis is not effective, _______ is the treatment of choice for uremic bleeding, particularly if only a short-term effect is required.

Answer 59

DDAVP

Administered intravenously at 0.3 mcg/kg over 15– 30 minutes (maximum dose, 20 mcg), but it is also effective at this dose when given

Alternatively, the drug can be given intranasally.

Question 60

Most antiplatelet antibodies are directed against

Answer 60

Integrin αIIbβ3

But antibodies directed against GPIb/IX/V, integrin α2β1, and GPIV have been detected as well

Question 61

Platelet dysfunction should be suspected in any patient with ITP or SLE who has

Answer 61

Mucocutaneous bleeding with a platelet count that is not ordinarily associated with bleeding (eg, ≥~30   109/L)

The clinical spectrum of autoimmune platelet dysfunction may also include some individuals with “easy bruising” and a normal platelet count.

These patients may have ITP with “compensated thrombocytolysis” because a substantial proportion have circulating antiplatelet antibodies and large platelets.

Question 62

The most frequently reported abnormalities in antiplatelet antibodies

Answer 62

Absence of platelet aggregation in response to low concentrations of collagen
and
Absence of the second wave of aggregation in response to ADP or epinephrine

In fact, both ITP and SLE may be associated with an acquired form of storage pool disease manifested by a reduced platelet content of dense- and α-granule components.

Question 63

TRUE OR FALSE

Thrombocytopenia is a consistent feature of bypass surgery.

Answer 63

TRUE

Thrombocytopenia is a consistent feature of bypass surgery.

Typically, platelet counts begin to decrease to approximately 50% of presurgical levels within the first half hour after the initiation of bypass, but thrombocytopenia can occur within 5 minutes and often does not nadir for the first few days.

The major factor responsible for thrombocytopenia is hemodilution from priming the pump with colloid or crystalloid solutions, but it is often more profound than can be accounted for by hemodilution alone.

The severity of these abnormalities correlates with the duration of extracorporeal bypass,and they generally resolve within 2–24 hours