Hemofili A hastalarında kan grubu ile faktör VIII arasındaki farmakokinetik ilişki
Pharmacokinetic relation between blood antigen group and factor VIII i̇n hemophilia a patients
Yazar: ALI GIOVENTIKLI
Danışman: PROF. DR. MUHLİS CEM AR
İstanbul Üniversitesi-Cerrahpaşa / Cerrahpaşa Tıp Fakültesi / İç Hastalıkları Ana Bilim Dalı
Derece: Tıpta Uzmanlık, 2021
Konu: İç Hastalıkları = Internal diseases
Dizin: Faktör VIII = Factor VIII ; Farmakokinetik = Pharmacokinetics ; Hemofili = Hemophilia ; Hemofili A = Hemophilia A ; Hemofili A = Hemophilia A ; Kan grupları = Blood groups ; Von willebrand faktörü = Von willebrand factor

Özet:
AMAÇ
    	Hemofili A, FVIII'in eksikliğinden kaynaklanan düzenli faktör replasmanı gerektiren doğumsal hastalıktır. FVIII'in farmakokinetiği; yaş, kilo, VWF seviyeleriyle değişkenlik gösterir.
            Çalışmamız, ağır hemofili A (FVIII <% 2) hastalarında kan gruplarının tedavi amaçlı uygulanan eksojen FVIII'in yarı ömründeki etkisini incelemeyi hedeflemektedir.

GEREÇ VE YÖNTEM
     	Çalışmaya; FVIII düzeyi <% 2, inhibitörü olmayan, 13 0, 8 A, 6 B ve 2 AB grubundan  29 hasta alındı. Kan gruplarına göre " 0" ve " 0-dışı" olarak ayrıldı. 0. saatte, 3-4. saatte ve 24-32. saatte 3 kez FVIII, vWf-antijeni, vWf-RiCof seviyeleri ölçüldü. Bu verilerle hastaların yaşı, kilosu da myPKFiT™ 'e işlendi ve kişiye özel farmakokinetik veriler toplandı. 
İstatiksel analiz SPSS ver.22 ile yapıldı. Çalışma kolları değişkenleri, parametrenin türüne, dağılımına göre Bağımsız T testi ve Mann-Whitney-U testlerinden uygun olanı kullanılarak karşılaştırılmıştır. 

BULGULAR
             Hastalarda inhibitör yoktu ve hepsi erkekti. Popülasyonunun ortalama ağırlığı 78.17 kg'dı (grup 0:79,23 kg, grup 0-dışı:77,31 kg). FVIII'in ortalama yarı ömrü, "0-dışı" grubuyla karşılaştırıldığında "0" grubunda anlamlı düzeyde kısaydı (12.31 saate karşı 11.09 saat). Beklendiği üzere, 0.saatte  "0" grubu hastalarda "0-dışı" olanlara göre bazal vWf-antijeni düşüktü. Fark istatistiksel olarak anlamlı değildi. Aralarındaki ortalama vWf-Ricof seviyeleri benzerdi. 



SONUÇ
     	Çalışmamız, kan grubu "0" olan hemofili A hastalarında FVIII yarılanma ömrünün anlamlı düzeyde daha kısa olduğu kanıtlamaktadır. İstatiksel olarak anlamlı olmamasına rağmen aynı grupta daha düşük bazal vWf-antijen seviyeleri bulunmuştur. Bu durum kan grubu "0" olan hemofili A hastalarında FVIII konsantrelerinin yarı ömürlerinin daha kısa olduğunu açıklamaktadır. Bulgularımız genel olarak güncel literatür verileriyle örtüşmektedir.
ANAHTAR KELİMELER
Hemofili A, kan grubu, von Willebrand faktör,  farmakokinetik, yarı ömür

Abstract:
OBJECTIVE
    	 Haemophilia A is a congenital bleeding disorder caused by the deficiency of the clotting factor VIII (FVIII) requiring a life-long regular intravenous replacement of the missing factor (prophylactic treatment)  to prevent beleeding , mostly, into the joints.  Pharmacokinetics of FVIII concentrates including the half-lives differ from one individual to the other depending on various factors such as age, weight, co-existing prothrombotic mutations, von Willebrand Factor levels, etc. 
      	This study aims to investigate the impact of blood groups (O versus non-O) on the plasma half-life of exogenous FVIII in people with severe haemophilia A (FVIII <%2). 
MATERIALS AND METHOD
      	A total of 29 people with haemophilia A (PwH) with FVIII levels <%2 and no inhibitors followed at the Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Department of Internal Medicine, Division of Haematology  were included in the study. Blood groups O, A, B and AB were identified in 13, 8, 6, and 2 of the 29 patients, respectively. Patients were divided into 2 arms depending on their blood groups as "Group O" and Group Non-O" while comparing the pharmacokinetic data. FVIII, vWf-antigen, vWf-RiCof activity levels were measured immediately before (timepoint "0") and at 3-4 hours and 24-32 hours following intravenous administration of prophylactic FVIII dose in all of the recruited patients. Data on patient's age, weight, basal FVIII level, administered FVIII dose, and FVIII levels measured at above mentioned timepoints were entered into a software called myPKFiT™ to obtain FVIII pharmacokinetic data (clearance volume,  half-life, time to 1% trough level, etc). myPKFiT™ is a software developed by Takeda Pharmaceuticals Company which enables drawing pharmacokinetic plots of individual patients by using data on population pharmacokinetics via Bayesian approach. 
Statistical analysis was made with SPSS ver.22. Variables of the 2 study arms were compared using independent T test and Mann-Whitney-U tests whichever is appropriate depending on the type of the parameter (parametric vs non-parametric) and its distribution.

RESULTS
       	 All of the recruited patients had FVIII levels < 2% (3 patients between 1-2%, 26 patients <1%). None of the patients had inhibitors and all were male. Mean weight of the total study population was 78.17 kg (range: 48-100), this being 79.23 kg and 77.31 kg in Groups "O" and "Non-O", respectively. Mean prophylactic factor dose administered prior to factor level measurements was 1741.38 IU (22,27 IU/kg) for the total study population and  1653,85 IU (20.87 IU/kg) and 1812.50 IU (23.44 IU/kg) for patients with blood groups "O" and "Non-O", respectively. 
        	Mean plasma half-life of the exogenous FVIII was significantly shorter in the Group "O" when compared to Group "Non-O" (11.09 hrs vs. 12.31hrs). As expected, basal levels of vWf-antigen measured at timepoint 0 (prior to FVIII concentrate administration) were lower in patients with blood group "O" than those with blood group "Non-O". However, the difference was not statistically significant. Mean vWf-RiCof levels between two groups were found to be similar at predefined time points. 
CONCLUSION
Our results demonstrated that myPKFiT™ was a useful and reliable device for measuring pharmacokinetic properties of FVIII concentrates at individual level. We were able to show that in severe haemophilia A patients with blood group "O" the plasma half-life of exogenous FVIII was significantly shorter. Although statistically not significant we found lower levels of basal vWf-antigen in the same group indicating that this could be an explanation for the decreased half-life of FVIII concentrates in blood group "O" patients. These findings are basically in line with the current literature. Studies with higher number of patients are required to clarify the issue. 
KEY WORDS
Haemophilia A, blood group, von Willebrand factor, pharmacokinetics, half-life