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Thrombozytenkonzentrat

"This article describes my approach to PLT transfusion or use of pharmacologic agents in such clinical scenarios based solely on personal experience and very limited published data." Ravi Sarode (1)

(Patho)physiology (1): platelets (PLT) play an important primary hemostatic function. They are 1 to 2 mm in size with a life span of 8 to 10 days. During normal laminar blood flow in intact blood vessels, red blood cells (RBC) are present in the center followed by white blood cells (WBCs), PLTs, and plasma toward the periphery in contact with endothelium. Upon endothelial
injury, turbulence in the laminar blood flow generates eddy currents that bring PLTs in contact with the damaged or altered endothelium, and PLTs are activated. PLTs change their shape from discoid to spherical through rearrangement of their cytoskeleton. Von Willebrand factor (VWF) present on subendothelial collagen tethers PLTs to the injury site via the glycoprotein (GP) Ib receptor. Biochemical reactions occurring within PLTs through cyclooxygenase-1 (COX-1) and thromboxane synthetase pathways generate thromboxane A2 (TXA2) via various prostaglandin intermediates. TXA2 is one of the most potent PLT aggregants; it causes vasoconstriction and induces further secretion of the contents of both alpha and dense granules of PLTs. The granules’ contents include adenosine diphosphate (ADP), adenosine triphosphate, serotonin, Ca2+, and VWF, which promote PLT aggregation at the site of injury. GPIIb/IIIa receptors undergo a conformational change leading to interaction mainly with fibrinogen and, to a lesser extent, VWF causing PLT aggregation. During this process other agonists released or generated at the site of injury (ADP, collagen, thrombin, etc.) also activate more PLTs, ultimately leading to the formation of a fibrin-PLT thrombus at the site of injury. The normal endothelium is coated with prostacyclin (PGI2) that is also synthesized through the COX-1 pathway. Prostacyclin has the exact opposite effect of TXA2, that is, it inhibits PLT aggregation and secretion and causes vasodilatation.

Variants (1):
  • COX-1-inhibitors (aspirin+nonsteroidal anti-inflammatory drugs): ASA is immediately absorbed after ingestion, and its effect can be seen within 15 to 30 minutes. It acts on circulating PLTs by irreversibly binding to COX-1 in portal circulation during its transport from the GI tract to the liver. Once metabolized in the liver, the ASA metabolite is inactive and has no anti-PLT effect. High doses of ASA (>350 mg) can escape liver metabolism by bypassing the liver. It may then affect endothelial COX-1 and COX-2, leading to inhibition of prostacyclin synthesis and thus resulting in diminished anti-PLT effect.
  • ADP receptor (P2Y12) inhibitors: The thienopyridine group of drugs are prodrugs and must be metabolized via cytochrome P450 into active compounds that are responsible for their action on the ADP receptor P2Y12. Their inhibiting effect on the receptor is dose dependent. By blocking the P2Y12 receptors, these drugs inhibit the ADP-induced breakdown of intra-PLT cAMP, resulting in decreased PLT function. The action of these thienopyridines is irreversible due to tight biding of metabolite to the P2Y12 receptor; no free metabolite is detected in patients’ plasmas.
  • GPIIb/IIIa inhibitors (fibrinogen receptor antagonists): the final stage of PLT activation involves a conformational change in GPIIb/IIIa receptors allowing fibrinogen to attach to these receptors and to cross-link adjacent PLTs, thereby leading to PLT aggregation.
  • Miscellaneous group: dipyridamole and cilostazol inhibit the 2,3-phosphodiesterase enzyme, thereby elevating PLT cAMP content that inhibits ADP-induced aggregation. These are considered to be weak APA. A combination drug that contains ASA and dipyridamole is a very effective anti-PLT therapeutic agent. Similarly, fish oil and several herbs, including gingko biloba and ginseng, are also known to cause global PLT inhibition.
Treatment (1):
  • COX-1-inhibitors:
    • Marrow releases approximately 10% of PLTs daily. Discontinuation of ASA for 2 days in a patient with a PLT count of 250 G/L will result in production of approximately 50 G/L functionally normal PLTs and, therefore, have near normal hemostatic function of PLTs. If the patient requires urgent surgery (other than neurosurgery) and is on a standard dose of ASA (81-325 mg per day), then no prophylactic PLT transfusion is recommended. In fact, discontinuing ASA in patients with coronary artery disease or cerebrovascular accidents may pose thrombotic risk. If the patient requires urgent neurosurgery (or an eye surgery), transfusion of 1 unit of PLTs is recommended a few hours before surgery.
    • Nonsteroidal anti-inflammatory drugs (NSAIDs) bind to COX-1 reversibly for only 6 to 8 hours and, accordingly, are not considered APAs. However, NSAID ingestion several hours before ASA renders ASA ineffective, as COX-1 receptors are temporarily occupied by the NSAID that prevents ASA binding. Patients on high doses of NSAID for rheumatism or chronic pain should discontinue the drug 12 hours before elective surgery. There is no need for transfusion of PLTs for urgent surgery in patients who have ingested NSAIDs.
  • ADP receptor (P2Y12) inhibitors:
    • Discontinuation of P2Y12 inhibitors 5 to 7 days before surgery is consequently recommended due to increased risk of perioperative bleeding. If the patient requires urgent surgery or spinal anesthesia or presents with significant bleeding (e.g., gastrointestinal, posttraumatic, etc., but not bruises, petechiae), I recommend a transfusion of one dose of PLTs. If the patient requires neurosurgery or eye surgery or presents with an ICH, I recommend a transfusion of two doses of PLTs because these patients probably require around 100 G/L functional PLTs. The reversal strategy for prasugrel should be similar to clopidogrel. Ticlopidine reversal is also managed similarly to that of clopidogrel. Ticlopidine is known to cause idiopathic TTP due to formation of an autoantibody against ADAMTS13.24 These patients may present with purpuras and some mucosal bleeding. However, such patients should be urgently treated with plasma exchange rather than PLT transfusion.
  • GPIIb/IIIa inhibitors (fibrinogen receptor antagonists):
    • Upon discontinuation of abciximab, PLT function reverses to normal within 24 to 48 hours. In the case of coronary intervention, if the patient bleeds excessively after heparin has been reversed adequately with protamine sulfate, I recommend one dose of PLT transfusion. Sometimes a higher dose of protamine sulfate is given (1.2 mg/100 units of unfractionated heparin) with the intention of neutralizing 100% of unfractionated heparin (rather than 80%). This may result in the presence of free protamine sulfate in plasma, which acts as a weak anticoagulant by interfering with PLT and fibrinogen function. Accordingly, it is prudent to rule out protamine sulfate overdose as a cause of bleeding postcoronary interventions and possibly may be detected by thromboelastography.
    • Abciximab is known to cause transient pseudothrombocytopenia in approximately 2% to 3% of patients, with mild to moderate reduction in the PLT counts. There is, however, no increased risk of bleeding as PLT counts improve despite continued therapy. However, 1% to 2% of patients may develop true thrombocytopenia, which is attributed to presence of preformed antibodies directed against murine IgG. These patients, unlike pseudothrombocytopenic patients, generally develop severe thrombocytopenia and can exhibit an increased bleeding tendency. If there is mild to moderate thrombocytopenia (PLT count >50 G/L) and the patient is not bleeding, I do not recommend PLT transfusion to correct PLT count. If the patient has a true thrombocytopenia (PLT count <20 G/L) or the patient is bleeding (after ruling out heparin overdose as a cause of bleeding), I would recommend transfusion of one dose of PLTs.
    • Upon discontinuation of eptifibatide, the PLT function reverts to normal within 2 to 4 hours. Rarely, it can also cause thrombocytopenia lasting for several days. Rarely, moderate to severe thrombocytopenia with bleeding has been described, in which case PLT transfusion is indicated.Due to the short half-life of the drug the transfused PLTs are not affected by these inhibitors.
    • Once tirofiban is discontinued, the PLT function returns to normal within 4 to 6 hours. Rarely, moderate to severe thrombocytopenia with bleeding has been described, in which case PLT transfusion is indicated.Due to the short half-life of the drug the transfused PLTs are not affected by these inhibitors.
  • Miscellaneous group:
    • ASA + dipyridamole: for urgent surgery I do not recommend prophylactic transfusion. However, if the patient requires urgent neurosurgery or eye surgery or presents with intracranial hemorrhage, I recommend transfusion of one dose of PLTs.
    • Cilostazol and fish oil: patients generally do not have excessive bleeding during surgery; prophylactic PLT transfusion is not indicated.
  • COX -1-inhibitors + ADP receptor inhibitors: for patients requiring urgent surgery or presenting with bleeding, I recommend transfusion of one dose of PLTs. For those patients requiring urgent neurosurgery or eye surgery or presenting with ICH, I recommend transfusing two doses of PLTs.
  • Alternative to PLT transfusion:
    • Desmopressin (DDAVP) is often used nonspecifically to treat PLT dysfunction, especially in uremia and cardiac surgery. DDAVP is known to stimulate release of stored VWF from endothelium, especially the ultralarge multimers, which are known to be functionally superior to other forms of multimers, thereby indirectly improving PLT function. The dose of DDAVP is 0.3 mg/kg by slow intravenous infusion. The DDAVP can be administered every 12 hours for a maximum of six doses; thereafter, it is ineffective due to development of tachyphylaxis.
    • Although the exact dose of rFVIIa is not titrated for such a condition, a modest dose of 10 to 15 mg/kg may be used. If there is no response to this dose, it may be increased to 30 mg/kg. Higher doses may pose a thrombotic risk to the patients with hypercoagulable state for which they are on anti-PLT drugs.
References:
  1. How do I transfuse platelets (PLTs) to reverse anti-PLT drug effect? Transfusion. 2012;52:695-701: periop.