120 Acquired Qualitative Platelet Disorders Flashcards
Hematologic disorders associated with abnormal platelet function
- Chronic myeloproliferative neoplasms
- Leukemias and myelodysplastic syndromes
- Dysproteinemias
- Acquired von Willebrand disease
Systemic disorders associated with abnormal platelet function
- Uremia
- Antiplatelet antibodies
- Cardiopulmonary bypass
- Chronic liver disease
- Disseminated intravascular coagulation
- HIV Infection
Irreversibly inactivates the enzyme cyclooxygenase (COX), also known as prostaglandin (PG) endoperoxide H synthase, by acetylating a serine residue at position 52
Aspirin
Constitutively expressed by many tissues, including platelets, the gastric mucosa, and endothelial cells
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.
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
COX-2
Platelets express only COX-1, whereas endothelial cells can express both COX-1 and COX-2
Platelet product of COX-1–mediated PG synthesis; produces vasoconstriction and is a receptor-mediated agonist for platelet aggregation and secretion
Thromboxane A2 (TXA2)
Aspirin: prevents platelet synthesis of TXA2, thereby inhibiting platelet responses that depend on this substance
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.
Prostacyclin (PGI2)
Platelet PG synthesis in an adult is nearly completely inhibited by this dose of Aspirin
Single 100-mg dose of aspirin or by 30 mg taken daily for 7–10 days
TRUE OR FALSE
Aspirin irreversibly inhibit platelet and endothelial cell COX, they have lasting effect on PG synthesis by endothelial cells.
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
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.
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.
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.
POISE-2 (perioperative ischemic evaluation) study
Thus, the clinician must thoroughly weigh the potential risks and benefits of discontinuing aspirin before noncardiac surgery.
Has been effective in correcting a prolonged bleeding time caused by aspirin
Desmopressin (deamino D-arginine vasopressin [DDAVP])
TRUE OR FALSE
Unlike aspirin, NSAIDs, such as ibuprofen, naproxen, diclofenac, sulindac, piroxicam, indomethacin, and sulfinpyrazone, reversibly inhibit COX enzymes.
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
Patients who require both NSAID and Aspirin should ingest aspirin at least ____ hours before the ingestion of traditional NSAIDs.
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.
More specific for COX-2 versus COX-1; intended to reduce pain and inflammation with fewer gastric side effects than traditional NSAIDs
Coxibs (COX-2 Inhibitors)
COX-2 products such as PGE2 and PGI2 elicit an increased sense of pain and perpetuate the inflammatory process.
Clinical trials revealed that coxib administration was associated with __________________ toxicity
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.
Drugs that form the active metabolites that irreversibly inhibit the platelet P2Y12 ADP receptor
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.
CYP polymorphism that results in lower levels of active clopidogrel and ticlopidine metabolites
CYP2C19
Thienopyridine whose metabolism and inhibition of platelet function are not affected by CYP2C19 polymorphisms
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.
The clinical efficacy of prasugrel has been compared with clopidogrel in patients with acute coronary syndrome scheduled for percutaneous coronary intervention in this trial
Triton-TIMI 38 trial
Prasugrel had a significantly decreased incidence of ischemic events
However, major bleeding was also significantly increased
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.
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.
Are oral, reversible, nonthienopyridine P2Y12 receptor antagonists
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.
A novel, and as yet unexplained, side effect of treatment with this class of the P2Y12 antagonists is the occurrence of
Dyspnea
Clinical trials for Ticagrelor
(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.
Most potent physiologic platelet agonist
Thrombin
The major platelet thrombin receptor
Three G protein–coupled thrombin receptors have been identified in humans (protease-activated receptors [PARs] 1, 3, and 4).
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.
Thrombin receptor antagonists
Vorapaxar
Atopaxar
A potent, selective, long-acting, oral PAR-1 inhibitor generated from the naturally occurring muscarinic receptor antagonist himbacine
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.
Integrin αIIbβ3 receptor antagonists
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.
Inherited integrin αIIbβ3 abnormality
Glanzmann thrombasthenia
Clinical trials for Integrin αIIbβ3 receptor antagonists
Abciximab: EPIC, EPILOG
Tirofiban: PRISMPLUS
Eptifibatide: PURSUIT
Can rapidly reverse the platelet function defect in patients receiving abciximab, presumably by decreasing the overall extent of integrin blockade
Platelet transfusions
These drugs have very short half-lives if renal and hepatic function are normal.
The mechanism responsible for thrombocytopenia after the administration of Integrin αIIbβ3 receptor antagonists is uncertain but may be related to
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.
Pyrimidopyrimidine derivative that inhibits platelet cyclic nucleotide phosphodiesterase, resulting in the intraplatelet accumulation of the inhibitory cyclic nucleotide cyclic AMP (cAMP)
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.
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
PGE1, PGI2, or stable PGI2 analogues
However, their clinical utility is limited by their short half-life and side effects that include peripheral vasodilation.
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
Cilostazol
Inhibit platelet function in vitro, probably by activating guanylyl cyclase, thereby increasing cGMP
NO and organic nitrates such as nitroglycerin
Mechanism of thrombocytopenia with Penicillins
- 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.
Broad-spectrum antibiotics can also cause a bleeding diathesis attributable to
Killing of gut flora, resulting in vitamin K deficiency
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
Nitrofurantoin
An antifungal agent, inhibits human and rabbit platelet COX in vitro and rabbit platelet COX after IV infusion
Miconazole
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
Dasatinib
Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor efficacious in a wide variety of lymphoid malignanies is associated with hemorrhagic complications in up to half of patients, with significant hemorrhagic toxicity in 5%.
Several factors contribute to the hemostatic abnormalities in the MPNs:
- 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
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)
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.
A syndrome of redness and burning pain in the extremities
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
An imidazoquinoline derivative, is thought to decrease platelet counts by impairing megakaryocyte maturation.
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
May temporarily improve hemostasis if the patient has an acquired storage pool defect or acquired von Willebrand syndrome
DDAVP infusion
Useful in patients with essential thrombocythemia and thrombosis, particularly those with erythromelalgia or with digital or cerebrovascular ischemia
Low-dose aspirin (~80–100 mg/day)
The most frequent cause of bleeding in patients with leukemia or a myelodysplastic syndrome is
Thrombocytopenia
Hairy cell leukemia is a lymphoproliferative disease in which platelet dysfunction may rarely complicate the clinical picture; bleeding is usually caused by thrombocytopenia rather than platelet dysfunction.
Effective treatment in individuals with acquired von Willebrand syndrome associated with lymphoproliferative disorder or,with an IgG MGUS
High-dose intravenous immunoglobulin (IVIG)
IVIG likely acts by delaying vWF clearance via reticuloendothelial cell blockade, although other mechanisms have been postulated
The pathophysiology of acquired von Willebrand syndrome
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
Diagnostic evaluation of Acquired von Willebrand syndrome includes
Factor VIII activity, vWF antigen, ristocetin cofactor activity, and vWF multimer analysis
Diagnostic evaluation of Acquired von Willebrand syndrome includesTreatment should be reserved for
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.
As with inherited von Willebrand disease, longstanding acquired von Willebrand syndrome can be associated with and complicated by
GI tract arteriovenous malformations
Acquired von Willebrand syndrome
GI bleeding is found in patients with severe aortic stenosis and is referred to as
Heyde syndrome
The hemostatic defect in uremia has been attributed to
Defects in platelet function
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 _____%
27% to 32%
A prominent factor in terminal kidney disease is
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.
TRUE OR FALSE
Abnormal platelet aggregation is common in uremic patients, but by itself is not an indication for therapeutic intervention.
TRUE
Abnormal platelet aggregation is common in uremic patients, but by itself is not an indication for therapeutic intervention.
The mainstay of therapy for uremic thrombocytopathy
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.
If dialysis is not effective, _______ is the treatment of choice for uremic bleeding, particularly if only a short-term effect is required.
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.
Most antiplatelet antibodies are directed against
Integrin αIIbβ3
But antibodies directed against GPIb/IX/V, integrin α2β1, and GPIV have been detected as well
Platelet dysfunction should be suspected in any patient with ITP or SLE who has
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.
The most frequently reported abnormalities in antiplatelet antibodies
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.
TRUE OR FALSE
Thrombocytopenia is a consistent feature of bypass surgery.
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
The most important determinant of blood loss after cardiopulmonary surgery
The surgical procedure itself
