IU
s
MEDIE E TYD RIF 21 Julic 1979 Since the diagnosis of lP' ha eldom been madebefore death, therapy ha not been adequately evaluated. teroid alone or teroids in combination with azathio-prine and y lopho phamide have been tried with ome suc e ."" Regression of coronary after aneurysm in an infant with polyarteritis nodosa after treatment ha been reported.H
I hould like to than Professor A. Olinsky, Department of Paediatrics. niver ity of the Orange Free tate. for help and ad ice. a well a Professor G. F. Rohm and hi staff. Department of AnatOmical Pathology. niversity of the Orange Free wte. for performing [he autOpsy and reporting on [he histOlogical findings.
REFERE 'CES
I. Landing, B. H. and Lar on, E. J. (1977): Pediatrics, 59, 6-1. 1. Rob«ts. F. B. and Fetterman, G. H. (1963): J. Pediat., 63, -19. 3. Kato, H., Koike, " Yamamolo, M. et al. (1975): Ibid., 86, 92.
~. Benyo, R. B. and P«rin, E. V. (I 6 ): Amer. J. Dis. Cbild .. 5.
:!:~;S::;ki,
T., Kosaki, F., Okawa, .et al.(197~):
Pediatrics, 54,171.0. Becker, A. E. (1 76): Lancet, I, 64.
7 Ahlslr5m. H., Lundstrom, T., Mortensson. W et al. (1977): Acta
paediat. scand., 66. 193.
Caner, R. F., Haynes, M. E. and Monon, J. (19761: Lancet. 2, 125~. ~. Zenter, G. and Menahem, S. (1973): Au t. paed,at. J., 9, 35. 10. Fujiwara, H. and Hama hima, Y. (197): Pediatrics, 61, 100. 11. Melam, H. and Patter on, R., (1971): Amer. J. Di. Child., 121, ~24.
12. Magilavy, D. B.. Petty, R. F .. Cas,idy, J. T. er al. (1977): J. Pediat.. 91. r.
13. Reimold, E. W .. Weinberg, A. G., Fink, C. W. er al. (1976): Amer.
J. Di . Child., 130. 534.
14. Glanz, ., Bittner, J., Berman, M. A. er al. (1976): ew Engl. J. Med., 294, 939.
Inactivated Proplex for the lIaemophiliac \vith Inhibitors
A Case Report
P. B. HESSELl G
S
MMARY
Inactivated prothrombin complex (Proplex) with a King-don time between 100 and 138 seconds effected func-tional recovery and adequate haemostasis in a haemo-philiac with inhibitors of the high-responder type at comparatively low cost, and with no adverse effects. Home treatment was successful.
Liver function remained normal during treatment. Statistically significant changes occurred in the pro-thrombin time (PT), fibrinogen levels and the thrombin time after each infusion, No evidence of diffuse intra-vascular coagulation (Die) was ever detected, The in-hibitor level decreased from 10 to 2 Bethesda units, and the radio-immunoassay (AlA) for Australia antigen re-mained negative,
S . .-llt. met!. J.. 56. 108 119 9).
The development of inhibitors or antibodies to human factor VB I in 5 - 21", of patients with severe haemophilia A who receive repeated transfusions of blood or plasma derivatives containing factor VIll' constitutes a major hazard.
Personal experience (unpublished uata) with bovine factor
vm.
which stopped bleeding in a haemophiliac of the high-responder type who bled profusely after syno-vectomy de pite ma sive infusions of human factor VIII.Department of Paediatrics, Tygerberg Hospital, Parowvallei,
ep
P. B. HE ELf lG. '<l.B. CH.B., '<l.'<'ED. (PAED.)Date received: 4 December 1978.
proved [hat it might be life-saving. Another similar patient was treated successfully with inactivated prothrombm complex (Proplex). The clinical detail of this patient are presented, and the implications of the treatment are discussed.
CASE REPORT
A 5-year-old haemophiliac with inhibitors of the high· responder type (a patient whose antibody titre increase after each antigeni stimulation, or whose antibody titre persists for a long time in the absence of transfusion. i .:alled a high-responder haemophiliac) had developed re-peated spontaneous haemarthroses of the left knee as 0-ciated with severe pain and progressive severe impair-ment of function since May 1978.'
Conservative therapy consisting of immobiLization and high doses of human factor III plus E-aminocaproic acid proved ineffective. B Augu t J97 the patient had developed chronic pain, and the knee was fixed at 1200 ftexion deformity.
Investigations at this stage showed a moderate inhibitor level of 10 Bethesda unit. (A titre of more than 20 Belhesda units is considered to be a high antibody titre'.) Antithrombin 1\1 activit. was 95°" and results of radio-immunoassay (R lA) for Australia antigen were negative.
An infusion of 0 Ikg 'inactivated' prothrombin com-plex (Procom-plex: Hyland). with a Kingdon time varying be-[ween 100 and 138 seconds, depending on the batch used. wa given intravenously on 55 different occa ions, at I - 3-day intervals between 25 Augu t and 13 December.
Since 11 October the child's mother has administered the Proplex at home. Weekly administration by the mother
21 JlIl\ Iq l/ ,,\ \ II 0 I l .\I
J
U l It~ A I Ill\} at the haemalOlog~ cllmc "n ur"d proper upervl'lOn andalllJ\\ed continuou monitoring of change m the patient' dOlling profile. The haemarthro e re olved. Phy iotherap~
given after ea 'h Proplex admini-tration ha aided reco er}. and the 'nee joint i fun'tional and ha full exten ion. DUring thi period of treatment ' minor haemorrhage developed in the right ankle. right forearm. right knee. left thigh. nd from the no e. single do e of Prople ,'0 kg re ulted in re olution of the haematoma within 36 hour in all but the right ankk· haemorrhage. which re olved after :I daily admini tration of Proplex.
The mother remarked on th quick relief of pam after the infu ion. hoar e oice or light abdominal cramp developed within minute of the infu ion of Prople on 4 occasion. but these minor 3ide-eflects disappeared when the infu ion wa given over 20 in tead of 10 minute,.
TABLE I. LIVER FUNCTION TESTS Oat!' ro ro
....
....
00 ~ 00....
a ~ 0'"
0 (") Protein (g/l) 77 69 80 77 Albumin (g/l) 38 44 49 44Aspartate transaminase (U/I) 58 71 57 62
Alanine transaminase (U/I) 38 28
Lactic dehydrogenase (U/I) 271 331 238 260 Alkaline phosphatase (U/I) 216 199 223 178
Globulin (g/l) 39 25 31 33
Total bilirubin (/' mol/l) 5 6 7 4
Direct bilirubin (IImol/l) 1 3 2 2
LI er tunctlon te t~ (. 1 ( rechOlcon) ha\ e rem med negati e (Table I)
rhe inhibitor level dedmed to 2 Bethe da units on 10
OClOb r. [he RI for u tralia antigen wa, till negatl e rhe panial thrombopla tin time (p 11) wa mea ured be· fore and JU t after infu ion of Prople . u 109 the General Diagno'tic Platelin piu' a'tivalOr kit. Ihe PI remained honened 4 hour fter Infu ion. a mea-ured on 3 occa· ion. Fibnnog n le el were mea ured befor and after in u ion with the Hyland QlIIk-Pal- I fibrinogen test. mall de rea e occurred on each occa3ion ..[ he thrombin time increa ed after ea h infu ion. Paired I ,tati tical ana-l} i pro ed the-e hange to be Ignifi ant (Table Ill.
Fibrinog n degradation product m a ured \\ ilh the rhrombo-Wellcote t and monomers l11ea~ured with the ethanol gelation le t \\ere alwa) ab-ent before and after Proplex infu ion. Ihe Kingdon lime 1'1r each hatch of Prnplex \\a~ ,upplied h) the manufacturer.
DlSCl)
~10
Ier~ high do e vI gl} cme-preclpltated factor III gl en a a bolus every 12 hour or III the form of a C'lIltmllllU Infu ion may be effective in topping bleedll1g III patient' with inhibitor of the low -re ponder t) pe or a 10\\' IIlhibitor titre. Thi therap) ma} he inefleclive In patient, with high-re ponder type inhibitor, or In pallent, \\Ilh a high-inhibitor titre. It i re erved for eriou, blecdlllg and i meffective in t he treatment (It lh pall nt \\ ilh IIlhi bltor \\ ho i bemg Crippled b) repeated JOint bleeding. fhe exorbllant co,!. lhe po.,.,ihill\~ ot an anamne,lIC 11'>1: In factor 111 inhibitors_ the po ,ihle induction of haemo lytic anaemia. and a high ri k of hepallli are Ilther un-favllurable a~pcct of Ihi therapy.
TABLE 11. CHANGES IN THE CLOniNG PROFILE WITH PAl RED t STATISTICAL ANALYSIS
P Fibrinogen (s) (mg/dl) De e Befor!' Before Af er 25. 8.1978 85,5 67.5 64 28. 8.1978 75.5 60.5 64 1. 9.1978 75,0 60.5 61 250 215 8. 9.1978 66.5 56,S 15. 9.1978 72,S 55,5 4.10.1978 72,0 50,0 345 280 11.10.1978 79,0 61.5 300 225 18.10.1978 92.0 57,0 25.10.1978 55.0 33.0 350 300 1.11.1978 65.5 57,0 420 365 8.11.1978 57,0 55.5 375 340 15.11.1978 65.5 62.0 320 270 22.11.1978 61,0 52,0 29.11.1978 64,0 56,5 270 230 13.12.1978 68.0 45,0 250 230 Mean 70,27 55,33 320 272,78 SO 10,13 8,18 58,36 53,74 t 6,66 8,44 df 14 8 P ... 0.001 '-0.001 Thrombm Ime (s) 13.8 14,4 10.2 11.2 12,9 13.5 13,4 13,5 11.4 12,1 11.3 12.0 11.3 12.8 13,9 14.8 12,7 12.9 12,32 13.02 1.31 1,16 5,02 8 /0,01 Klngdon time of Proplex (s) 100 100 100 100 100 124 124 124 124 124 138 138 138 138 138
110
SA
MEDIE E TYD KRIF 21 Julie 1979 Immunosuppre ive agent, e.g. azathioprine. corricote-roids and cyclophosphamide u ed alone or in combination with large doses of factor VIII, have been used with limited success in patients with low titres of inhibitors.' Animal factor VIII (bovine or porcine) may be life-saving in emergencies. However, allergic reactions 7 - 10 days later, thrombocytopenia and a higher risk of inducing inhibitor formation than that attached to human fa tor VIIL limit the u e of this material.'
In 1972, Fekete el aI' reported the use of Autofactor
IX in the management of patients with inhibitors. Other reports of the use of activated prothrombin complex con-centrates (PCC), such as Autofactor IX and Proplex,' Autofactor IX: Konyne'" and Feiba" followed. on-acti-vated PCC was also found to be effective and safe for the haemophiliac with inhibitor using Proplex"'" and Prothrombinex.13
Achievement of haemostasis and restoration of function have been reported after the use of very high doses of human factor VIII and PCC over a prolonged period. Inhibitors disappeared."
The mechanism whereby PCC bypasses factor VIII inhibitors is uncertain, and is ascribed by some authors to the presence of factors Xa or lXa."·" The platelets in the starting plasma from which PCC is manufactured are related to the difference in clot-promoting activity of various PCCs."· ,. There is evidence that activated PCCs enhance platelet coagulant activity by in~reasing the activity of platelet factor X activator.""
Thrombotic episode and disseminated intravascular
0-agulation have been well documented following infusion of PCC in patients with Christmas disease or liver disease, and after operation in these patients, but these compli-cations have not been documented in the patient with inhibitors to factor VlII.~l'"
A Kingdon time assay is performed in order to detect the presence of thrombogenic materials in PCCs." The Kingdon time process is insensitive to the presence of catalytically inactive, pro-enzyme forms of the clotting factors which occur in plasma. but does react with shortened clotting times to the presence of traces of the enzymatically active forms of the clotting factors such as thrombin, and factors Xa, lXa and XIa. on-activated human plasma has a Kingdon clotting time in excess of 200 seconds. F. Th. Lenich (personal communication) re-commends a Kingdon time of less than 150 seconds if an 'inactivated' PCC (one containing a small amount of enzymatically active clotting factors) is used.
A rise in inhibitor titre has been reported with Immuno AG'" and Feiba.lO
The development of resistance to Feiba
with a concomitant rise in antithrombin III and anti-factor Xa ha been recorded."
Hepatitis may follow infusions with both PCC or glycine-precipitated human factor VU],
CO CL 810
T'Inactivated' Proplex with a Kingdon time of between 100 and 13 seconds effected functional recovery and adequate haemostasis in a haemophiliac with inhibitors of the high-responder type at comparatively low cost, and with no adverse effects. Home treatment was successful. The safe use of this product requires normal antithrombin III activity. normal liver function. infusion immediately after reconstitution over a period not shorter than 20 minutes. and knowledge of the degree of activation of the PCC, as expressed in Kingdon time. Serial estimations of liver function and the clotting profile hould be performed and therapy discontinued if evidence of liver dysfunction or disseminated intravascular coagulation is found.
REFERENCES
I. AlIain. J. P. and Frommel. D. (1976): Blood. 47, 973.
2. Blatl. P. M .. White. G. C .. McMillan. C. W. ec al. (1977): Thrombos. Haemostas .. 38. 514.
3. Nilsson. I. M. and Hedner. U. (I 76): Seand. J. Haem.!.. 16, 369. 4. RizZ3. C. R. (1976): Clin. Hemal. N. Amer.. 5. 111.
5. Fekete, L F., HoIst, S. T .. Petoom. F. et al. (1972): Abstract 295. 14th lnternational Congress of Hematology, Sao Paulo.
6. Kurczynski, E. M. and Penner. J. A. (1974): New Engl. J. Med., 291, 164.
7. Sonoda, T .. Solomon, A .. Krauss. S. et al. (1976): Blood. 47, 9 3. 8. Abildgaard, C. F .. BrittOn. M. and Harrison. B. S. (1976): J. Pedial..
88, 200.
9. De Witl. R. T. and Feinstein, D. J. (1977): Arch. intern. Med., 137, 1211.
10. Preston, F. E.. Dinsdale. H. C. W .. Sutcliffe. D. J. ec al. (1977):
Thrombos. Res.. 11, 643.
11. Keliy, P. and Penner. J. A. (1976): J. Amer. med. Ass.. 236, 2061. 12. Yolken. R. H. and Hil2artner. N. W. (197 ): Amer. J. Dis. Child ..
132, 291.
-13. Price. D. A., d'Souza, S. and Ekert, H. (1977): Ausl. N. Z. J. Med .. 7. 286.
14. Brackmann, H. H .. Euel. F .. Hofmann, P. ec al. (1977): Thrombos. H"mostas .. 38. 369.
15. Blatl. P. M .. Lundblad. R. L .. Kingdon. H. S. el al. (1974): Ann. intern. Med .. 81, 766.
16. El6di, S. (1977): Blood. 50, 961.
17. White. G. C. 11. Roberls. H. R .. Kingdon. H. S. ec al. (1977): Ibid., 50, 962.
I . King. J. B. and Fiugerald. L D. (191'): Paper presented at the XIVth Congress of the International Society of Blood Transfusion (Xth Congress of the World Federation of Hemophili.). Helsinki. Finland.
19. Hedner. U .. Nilsson. I. M. and Bergentz. S. E. (1976): Thrombos. Haemostas., 35, 3 6.
20. Vennylen, J., Schetz, J., Sermeraro. N. ec al. (1978): Bril. J. Haemat., 38, 235.
21. Trianlaphylloooulos. D. C. (1972): Amer. J. clin. Path .. 57, 603. 22. Kasper. C. K. (973): 'ew Eng!. J. Med .. 289. 160.
23. Davey, R. J .. Shashaty, G. G. and Rath. C. E. (1976): Amer. J. Med., 60, 719.
24. Aledon. L. M. (1977): Seand. J. Haemat.. supp!. 30. p. 40. 25. Kingdon, H. S.. Lundblad. R. L.. Veltkamp. J. 1. ec al. (1975):
Thrombos. Diathes. haemorrh. (Stutt2.). 33. 617.
26. Mannucci, P. M .. Bader, R. and Ruggeri. 1. M. (1976): Lancet.
1, 41.
