Valproate induced thrombocytopenia, 발프로산과 혈소판감소증

Valproate induced thrombocytopenia

목적 : 방법론적 차이로 인해 발프로산(VPA) 유도 혈소판감소증의 빈도는 이전에 문헌에서 서로 상이했다. trough VPA level과 PLT 수의 관계를 평가하고 혈소판감소증에 대한 위험 인자를 평가하는 것을 목표로 한다.

방법 : refractory partial epilepsy 환자 & double‐blind & multicenter & concentration-response trial

⇒ the efficacy and safety of high versus low trough plasma VPA concentrations following administration of divalproex sodium as monotherapy

24주간의 시험 기간 동안의 trough VPA level과 PLT수 ⇒ 다양한 VPA 농도에서 혈소판감소증이 발생할 확률을 결정하기 위해 logistic regression analysis

결론 : 265명의 환자의 851개의 trough VPA level과 동반된 PLT 수를 분석하였다. 이 중 17.7%의 환자가 divalproex sodium에 노출된 후 적어도 한 번 혈소판감소증(PLT≤ 100,000/μL)을 경험하였다. trough VPA level과 PLT 수의 상당한 음의 관계가 관찰되었다. 여성에게서 혈소판감소증이 나타날 확률이 훨씬 더 높았다. 발병 확률은 여성의 경우 100 mcg/mL 이상, 남성의 경우 140 mcg/mL 이상에서 크게 증가하였다.

토의 : Our data strongly support a causal relationship between rising plasma VPA levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.

Concentration–response design trial that compared the safety and efficacy of high (80–150 μg/ml) and low (25–50 μg/ml) target trough plasma VPA concentrations in patients with complex partial seizures treated with DVPX as monotherapy.

Patients were randomly assigned in a 1:1 ratio at each center into the high (80–150 μg/ml) or low (25–50 μg/ml) target trough plasma VPA concentration groups.

• baseline phase : 8-12 wk
• double-blind experimental phase : 24 wk(첫 8 wk : dosage adjustment period + 뒤이은 16 wk : dosage maintenance period)

* dosage adjustment period 때 기존에 복용하던 항뇌전증약은 taper되고 valproate 치료가 시작되었다. target range의 최고점을 위해 점진적인 증량되었다.

Trough VPA level & PLT 수의 측정 : 마지막 VPA 투여 8-15시간 후 or 첫 투여 1시간 이내

Trough plasma VPA concentrations and platelet counts were determined from analysis of blood samples collected either 8–15 h after the last DVPX dose or less than 1 h after the first dose of the day (taken before noon).

	low target	high target
용량 during double‐blind phase	16.5 mg/kg/day	40.3 mg/kg/day

Linear regression of platelet counts versus trough VPA plasma levels with 95% confidence intervals. There was a significant negative correlation that best fitted the following formula: Expected platelet count = 297 – (1.03 * VPA trough level); (r =–0.61, p < 0.01).

Probability of developing a platelet count ≤100,000/μl at various trough plasma VPA levels for the whole group of patients (middle line) and for women and men analyzed separately.

발프로산 유도 혈소판감소증의 특징

출혈 합병증 유무에 상관없이 PLT 수 nadir의 유의미한 차이가 없었다.(t-test, p>0.1)

	with bleeding complication	without bleeding complication
average nadir platelet counts	60,000/μl (range 16,000–75,000/μl)	48,000/μl (range 26,000–74,000/μl)
baseline platelet count	241,000/μl (range 167,000–337,000/μl)	272,000/μl (range 157,000–380,000/μl)
the mean age	28.5 years (range 16–49)	38.4 years (range 20–57)

VPA induced thrombocytopenia 메커니즘

• VPA 유도 혈소판감소증의 메커니즘은 명확하지 않음
• dose‐dependent suppression of bone marrow production of platelets or peripheral platelet destruction due to the development of a platelet antibody brought about by VPA or one of its metabolites.
• Favoring the peripheral platelet destruction hypothesis, Barr et al. (1982) reported that 82% of cases of VPA‐induced thrombocytopenia were associated with an increased platelet‐related immunoglobulin level, and that the platelet count was inversely correlated to the concentration of platelet‐related immunoglobulin (Barr et al., 1982).
• It was suggested that the structural similarity between VPA and the fatty acid constituents of cell membranes may lead to an increased incidence of immune thrombocytolysis (Sandler et al., 1978; Morris et al., 1981).
• The reported finding of normal or slightly increased levels of megakaryocytes in bone marrow examination of patients with VPA‐induced thrombocytopenia is also consistent with increased peripheral platelet destruction (Neophytides et al., 1979).
• This hypothesis does not however adequately explain the rapid reversal of thrombocytopenia after reduction of VPA dosage (Delgado et al., 1994).
• Kishi et al. (1994) have shown that a high plasma VPA concentration is associated with in vivo and in vitro bone marrow suppression.
• While the VPA concentration‐dependent thrombocytopenia could be explained by the mechanism of bone marrow suppression, the rare occurrence of pancytopenia suggests that other mechanisms must be involved that renders the platelet cell lineage more vulnerable to VPA suppression or damage (Robinson et al., 1995; Oluboka et al., 2000).
• It is possible that both immune‐mediated peripheral destruction and VPA concentration‐dependent suppression of platelet precursors may be operating simultaneously.

reference;

1) Nasreddine, Wassim, and Ahmad Beydoun. "Valproate‐induced thrombocytopenia: a prospective monotherapy study." Epilepsia 49.3 (2008): 438-445.

2) 약학정보원