Incidence of Infectious and Noninfectious Side Effects in Hemophilia Patients in the New German Federal States during Treatment with Cryoprecipitate

In the 1970s and 1980s treatment of hemophilia in the former German Democratic Republic (GDR) with factors (F) VIII:C and FIX concentrates involved almost exclusively cryoprecipitates and PPSB. These agents were prepared by local blood transfusion services. They were relatively well-suited for use during minor operations and in cases of mild to moderate bleeding as well as for prophylaxis.

Problems with these low-purity products were encountered when there was severe bleeding or major surgery that required very high levels of FVIII:C or FIX. There were also problems because of the occasional lack of availability of such preparations.

Treatment with cryoprecipitates and PPSB is associated with both infectious and noninfectious side effects.[1] Cryoprecipitate, in the form of a small-pool concentrate, was first obtained only as one transfusion unit from two donors. It had a specific activity of 0.20 to 0.35 U FVIII:C/mg protein. The average FVIII:C content in a so-called transfusion unit was 130 to 150 U FVIII:C, but this fluctuated widely because of the different levels of FVIII:C in individual donors. In order to reduce this variability, the Leipzig transfusion service pooled up to 10 donors in the 1980s. Sometimes a so-called middle-pool concentrate, prepared from a pool of 30 to 50 donors and supplied with a defined FVIII:C content, was also available.

Acute side effects are generally rarer the higher the degree of purification a plasma preparation undergoes or the lower its protein content. In our patients, acute side effects were quite common after administration of cryoprecipitate. Table [1] shows that over the period 1976 to 1990 acute side effects occurred after 0.97% of administrations; in other words, there was about 1 adverse reaction in every 100 administrations. Over this time period, 32 of 42 patients exhibited at least one reaction. The acute side effects we observed included shivering, urticaria, headache, and signs of incipient circulatory failure and acute gastrointestinal symptoms that could occur with or without fever. We observed 142 reactions with fever and 29 without; in 72 cases fever was the only symptom seen, and in 48 cases there was a rapid onset of fever with shivering. All other reactions were (Table [1]) much less common. The exact cause of these reactions could not be identified in each individual case. A test for human leukocyte antigen (HLA) antibodies in 5 of these patients, who had had reactions more than once, was negative.

If one looks at the onset of acute side effects encountered in the different individual types of concentrate, it turns out that there was one reaction to 103 administrations of standard cryoprecipitate and to 22 administrations of the so-called middle-pool concentrate (see earlier), in which more plasma donors were involved. Only very rarely did we see reactions with the imported concentrates, the ``intermediate purity concentrates,'' in fact, only once in 9779 administrations (Table [2]).

It is worth noting that when cryoprecipitate was given prophylactically at home there were never any reports of side effects, although the patients or parents were asked to report them. One reason for this could be that fever reactions in hospital are recorded more carefully, but a more important factor seems to be that at home generally only one cryoprecipitate was administered. In contrast, under inpatient conditions in the hospital, significantly larger amounts were given because of the bleeding involved. Each patient being treated at home was equipped with cortisone preparations in case of side effects. According to the reports we received, the parents never used these preparations. None of the acute side effects that we saw in hospital resulted in any permanent harm to the patients.

Unfortunately, in addition to the acute noninfectious side effects, blood and plasma preparations also gave rise to infections.[2] [3] [4] [5] [6] Nevertheless, we were able to confirm that the cryoprecipitates used by us in the 1980s protected our patients from HIV infection.[5] However, protection from HIV infection was not achieved by inactivation of the virus or by other technical means but was a consequence of the prevailing epidemiology at that time. Because in the GDR the population groups who were blood donors were almost totally excluded from traveling, spread of HIV was limited to a few isolated cases. As far as we know, none of the hemophiliacs of the GDR treated with cryoprecipitate alone became infected; the only exceptions were 4 or 5 patients who additionally received imported highly concentrated preparations because of a need for emergency surgery.

Because, as already mentioned, the preparations used were not virus inactivated, other viral infections could not be prevented, in spite of the small pool size. In two series of experiments, we found that in 1986 to 1987 and 1991 to 1992 there was a very low rate of cytomegalovirus (CMV) infection (Table [3]).

Testing for Epstein-Barr virus (EBV) antibodies gave different results. Here, testing showed that the rate for the spread of infection in 1986 to 1987, probably caused by a very insensitive test, was very low, whereas in 1991 to 1992, 25 of 28 patients tested positive for antibodies.

For 1992 to 1993, 2 years after introduction of the large-pool concentrate, the spread of infection with parvovirus B19 was investigated; the incidence of this is known to be high during childhood in the population at large. Nevertheless, it is significant that 21 of 23 patients (91%) undergoing regular substitution had antibodies; however, of 15 patients receiving occasional substitution, with mild or moderate clotting problems, the corresponding figure was only 10 (67%) (Fig. [1]).

A major problem for hemophiliacs is the spread of hepatitis infections.[3] [4] [5] [6] It is generally held that hepatitis A is relatively rarely transmitted by plasma preparations. In 1992, 6 of our 40 patients tested positive. Of these, 1 patient was infected in association with the administration of an SD-inactivated preparation; another became ill independently of administration of plasma concentrate. Hepatitis A virus (HAV) antibodies were detected in 4 patients, although they had no history of hepatitis A infection.

Antibody screening was performed before we started vaccinating hemophiliac children against hepatitis B in 1988 to 1989. Of 39 patients, 18 had antibodies and 2 were carriers of hepatitis B surface (HBs) antigen. All 4 patients with mild hemophilia tested negative. In the cases of severe and moderately severe hemophiliacs, there was a clear relationship between the rate of infection and age as well as, indirectly, the number of substitutions (Fig. [2]). Of those patients over 12 years of age, more than 80% were antibody-positive, and all of those over 15 years of age were positive. Today, because vaccination is available, hepatitis B infections are not a major problem for young children with hemophilia.

In the case of hepatitis C infections, the rate of infection was as high as that for hepatitis B before introduction of vaccination.[4] Up to 7 years of age, very few infections occurred. Because only 2 of 22 patients in the group up to 7 years of age were hepatitis C virus (HCV)-positive, this clearly shows that the use of minipool concentrates was of great benefit when the number of administrations remained relatively small. Of those patients who were given preparations significantly more often, in other words, the 8 to 16 year olds, 19 of 26 were HCV-positive (Fig. [3]). At the end of the 1980s, we were able to use Beriate HS^℗ as a study product and in this way gave a virus-inactivated preparation to 4 previously untreated patients with severe and moderately severe hemophilia A.

Seen in perspective, the cryoprecipitate prepared using the minipool procedure at a time when virus inactivation was not generally performed was of great benefit to patients as far as infection was concerned. It prevented HIV infections because of the specific prevailing epidemiological circumstances. Hepatitis infections were generally relatively rare in younger patients as well as in older patients who were not treated frequently.

For a long time now, virus-inactivated preparations have been used routinely, so this evaluation can be regarded as being of historic interest. Today, one can be confident of avoiding viral infections by using the current preparations, the only exception being transmission of parvovirus.

REFERENCES

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