8.6.3 Platelets normalization

Platelets are anucleate corpuscles with a life span of 7-10 days. Produced in the marrow, they are eliminated by the reticuloendothelial system in spleen and liver. Platelets are closely dependent on red blood cells for their supply of thromboxane or prostaglandin precursor lipids and substrate for ADP metabolism [11]. In addition, marginalisation of platelets in blood stream by mass of erythrocytes that remain in the middle of the stream increases the chances of thrombocyte attachment to the vascular wall [17]. In severe anaemia, erythocyte transfusion therefore improves platelet function.

Platelet transfusion

One unit of platelets contains about 2 x 10¹¹ thrombocytes. In an adult, it increases the circulating level to a maximum of 20,000/mcL, often less. Most surgical procedures can be performed without difficulty with a thrombocyte count between 50,000/mcL and 75,000/mcL; only intracranial procedures require a value of > 100,000/mcL. Transfusion events and risks of viral or bacterial contamination are more frequent with platelet infusions (11‰) than with erythrocyte (3.5‰) or FFP (0.8‰) infusions [14]. The risk of TRALI (transfusion-related acute lung injury) is also higher: on average 1:2,000 for platelets, while it is 1:5,000 for packed red cells [16]. A febrile or hypotensive episode is common during infusion (see Chapter 28 Blood product risks). Mortality rate is 1:40,000 transfusions.

Platelet administration is only justified in haemorrhagic procedures performed in patients with either dysfunctional or insufficient thrombocytes: patients on uninterrupted antiplatelet therapy and patients with bone marrow failure or acute consumption. Indeed, platelet transfusion in general surgery is associated with an increased risk of stroke and arterial thrombosis (OR 1.55) and excess mortality (OR 2.40) [6]. The same association is found in cardiac surgery, with excess stroke (OR 2.56) and mortality (OR 4.76) in thrombo-transfused patients [15]. In neurology, platelet transfusion doubles the risk of death and complications after haemorrhagic stroke in patients previously on antiplatelets (OR 2.05) [3].On the other hand, normalising platelet function in patients on antiplatelets puts them at increased risk of vascular thrombosis, particularly in stents and endoprosthesis. It is therefore clear that prophylactic administration of thrombocytes is more dangerous than beneficial and is only recommended in cases of bone marrow failure or equivalent.

Under antiplatelet therapy with an irreversible agent (aspirin, clopidogrel, prasugrel), platelets are inhibited for their entire life span, but the substance is permanently bound to thrombocytes. As soon as equilibrium is reached between plasma and platelet receptors, thrombocyte aggregability is no longer dependent on the serum level of the agent. When the serum level decreases with elimination (12.5% after 3 half-lives), freshly circulated platelets or transfused platelets function normally, which is the case 12 hours after aspirin or prasugrel ingestion and 24 hours after clopidogrel ingestion, even though the patient's thrombocytes are still blocked for several days. The situation is different with reversible antiplatelet agents such as ticagrelor, because the substance is in constant equilibrium between plasma and receptors, whether the platelets are the patient's own or those from a transfusion (Figure 8.23). In this case, inhibition of aggregability is directly proportional to the serum level for all platelets, and the transfusion will only be effective after at least 3 half-lives, in this case beyond 36 hours. As ticagrelor has a high affinity and strong binding to ADP receptors, back-diffusion from platelets is slow, so the clinical effect tends to be extended beyond the theoretical pharmacokinetic time. Despite having a lower risk of spontaneous bleeding than clopidogrel or prasugrel, ticagrelor raises a serious problem when bleeding requires platelet transfusion, as this will be less effective for 2-3 days after the last dose [8]. An in vitro study has shown that addition of platelets to blood samples from patients on anti-platelet drugs suppresses the effect of aspirin, significantly reduces the effect of clopidogrel, but is less effective in reversing the effect of ticagrelor [5].

Figure 8.23: Antiplatelet agents (AP) and thrombocyte transfusion. A: Irreversible agents such as clopidogrel or prasugrel diffuse from the blood to the platelets and remain bound there while the serum level decreases according to the plasma half-life. The degree of platelet inhibition does not depend on the serum level of the substance. Transfused platelets encounter less circulating agent the longer the time since last administration: 50% after1 half-life, 25% after2 half-lives and 12.5% after3 half-lives; they function normally beyond 2-3 half-lives, while the patient's platelets remain permanently blocked. B: With reversible agents such as ticagrelor, a dynamic equilibrium is established between the blood, the patient's platelets and the transfused platelets; the substance is distributed according to concentration gradients. The degree of platelet inhibition depends directly on the serum level of the substance. Since ticagrelor is strongly bound to ADP receptors, back-diffusion to the plasma is slowed, but the substance can diffuse between platelets (cross-diffusion), which also impairs the function of transfused thrombocytes.

Transfusion of platelet concentrates during cardiac procedures should be restricted to the following conditions

• Thrombocytopenia < 50,000/mcL ;
• Platelet dysfunction proven by functional test (Multiplate™, VerifyNow™, etc);
• Hemorrhage on uninterrupted preoperative antiplatelet therapy;
• Hemorrhage not controlled by usual measures.

Thromboplegia

By blocking platelet aggregation induced by the action of preformed IgG antibodies on PF4-heparin complexes during ECC with a short-acting antiplatelet agent, the stimulation and consumption of thrombocytes by contact with foreign surfaces, which leads to postoperative thrombocytopenia and platelet dysfunction, should be avoided. This thromboplegia, or thromboanesthesia, is an option already used in patients with anti-heparin antibodies (see HIT). Several possibilities are considered.

• Heparin (usual dose) + prostacyclin (Iloprost^® ): increases intraplatelet cAMP and inhibits activation. Half-life 15-30 min. Infusion of 3-12 ng/kg/min (avg 7.6 ng/kg/min), HIPA (Heparin-induced platelet aggregation) assay for activation < 5%. The infusion is halved after protamine and reduced to one quarter on arrival in the ICU and stopped 1 hour later [10]. Disadvantages: iloprost causes hypotension (regulated by norepinephrine), and intraoperative HIPA tests are time consuming (30-40 minutes).
• Heparin (bolus 5,000 IU and infusion 1,000 IU/h) + tirofiban (Aggrastat^® ): blocker of the GP IIb/IIIa receptor of platelets, responsible for binding of platelets with fibrinogen (see Figures 8.12 and 8.13). Half-life: 2 hours. Bolus 0.4 mcg/kg, then infuse 0.15 mcg/kg/hour. Stop 1 hour before the end of the ECC [7].
• Cangrelor (Kengrexal^® ): a reversible direct P2Y receptor inhibitor₁₂ , marketed only for PCI and acute coronary syndrome. Half-life 9 minutes. Infusion 0.75 mcg/kg/min [1]. Interrupted 30 minutes before protamine. It blocks platelet activation induced by ECC and hypothermia, and reduces the complications associated with them in vitro and in vivo [9].

Desmopressin

Desmopressin (DDAVP: deamino-D-arginine vasopressin, Octostim^® , Minirin^® ) stimulates the production of factor VIII and von Willebrand factor by the endothelium; it increases their levels by 3 to 5 times and improves platelet adhesion to collagen. It is therapeutic in certain conditions with specific thrombocyte dysfunction (non-severe haemophilia A, congenital or acquired von Willebrand disease type I, uraemia, liver disease, severe aortic stenosis) (see Chapter 21, Haematological Diseases). Although responsiveness of platelets in vitro to various aggregation stimulants is markedly improved by DDAVP [13], reduction in bleeding is modest in clinical practice [18]. Desmopressin is useful in platelet dysfunction, reducing blood loss by 23% and transfusions by 25% during coronary revascularisation in ECC in patients receiving antiplatelet therapy; the rate of re-intervention for haemostasis is reduced (OR 0.39) [4,12]. Its dosage is 0.3 mcg/kg intravenously over 30 minutes (half-life 4-5 hours). Simultaneous administration of tranexamic acid is recommended as desmopressin also stimulates fibrinolysis.  

© CHASSOT PG, MARCUCCI Carlo, last update November 2019. 

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