Therapeutic plasma exchange in the treatment of the hereditary thrombotic thrombocytopenic purpura

Summary

Therapeutic plasma exchange is the treatment of choice for thrombotic thrombocytopenic purpura (TTP). Patients chronically treated with plasma exchange are frequently exposed to a large number of single plasma donors units, however successfull clinical and laboratory improvement is generally achieved. Therapeutic plasma exchange significantly decreased mortality of this disease. Plasma treatment offers two possibilities – plasma infusion or plasma exchange and possibility of using different plasma types. Cryoprecipitate-poor plasma was introduced as better alternative to FFP, however studies presented later do not confirm the therapeutic benefit. Quarantine FFP is prevalently used for patients with TTP in Czech Republic; this type is tested frequently for negativity of human immunodeficiency virus, hepatitis B virus, hepatitis C virus and syphilis. In Czech Republic is not common a treatment with pathogen inactivated plasma: solvent detergent plasma, methylen-blue plasma, psoralen treated plasma or riboflavin treated plasma. Authors are looking for efficacy of different plasma types and present their own experience with plasma treatment in 7 patients with hereditary TTP. In 5 patients therapeutic plasma exchange with quarantine fresh frozen plasma is used. During each treatment 1,5 plasma volume is exchanged. 2 patients – teenagers are treated at the department of pediatrics with plasma infusion in regular 2 weeks intervals.

Key words:
TTP, therapeutic plasma exchange, quarantine fresh frozen plasma

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a serious life-threatening disorder characterized by classic pentad of signs: microangiopatic haemolytic anemia with schistocytes in peripheral blood smear, fever, thrombocytopenia, renal and neurologic dysfunction, nevertheless all these symptoms are fully presented only in a minority of patients (1). ADAMTS 13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, repeats13) protease deficiency is responsible for development of the condition. ADAMTS13 cleaves large multimers of von Willebrand factor; in order to prevent the spontaneous formation of platelet thrombi in the microcirculation. The absence or severely reduced plasma ADAMTS13 activity leads to the persistence of high molecular weight vWF multimers with ensuing platelet aggregation and thrombotic microangiopathy (2, 3). There are different presentations of TTP. Congenital TTP is very rare (2 – 3% patients) (4). It is caused by genetic mutations in the coresponding gene. In these patients plasma ADAMTS13 activity could be reduced to the extremely low values (3-5%) while about 10% of protease value is sufficient to multimers cleaving (5, 6). In acquired TTP ADAMTS13 is deficient due to autoantibody inhibitor. Before effective treatment with plasma therapy the outlook of TTP was extremely grave with mortality rates about 90% (7). Plasma exchange or plasma infusions replenish a deficient plasma metalloprotease that cleaves present vWF multimers and in this way induce disease remission. Repeated plasma exchange allows removal of the pathogenic substance and lowering the concentration of specific, tissue-directed antibodies and toxins (8).

Effectiveness of TTP treatment using various plasma products.

Quarantine fresh frozen plasma (FFP)

Quarantine FFP is produced from a single blood donor or is separated from a single donor via machine.  Within six hours is plasma unit (about 250ml) frozen solid in shock freezer at -30°C. Hereby are procoagulation factors preserved. After that plasma is stocked up to 36 months at  -25°C. During first six months of plasma stocking the plasma donors are re-tested for serological markers of HIV, HBV, HCV and syphilis. Screening for these markers are obligatory in Czech republic. This strategy helps to reduce the risk of the pathogen transmission in window period regarding the timing of seroconversion. Quarantine fresh frozen plasma is the most common applicated plasma product in Czech Republic.

Quarantine K-plasma.

Quarantine K-plasma is plasma depleted of cryoprecipitate (cryoprecipitate-poor plasma) prepared in blood establishments. Because of lower fibrinogen, factor VIII, factor XIII and lower large multimers level in K-plasma compared to FFP, it had led to assumption about preferency of K-plasma in TTP treatment (9). Indeed later was approved the significance of metalloprotease level for disease remission that is present in both aforementioned alternatives (10).

Patients with TTP usually require daily plasma exchange in which is replaced 1.0 to 1.5 plasma volumes (3000ml of plasma) with FFP or cryoprecipitate-poor plasma. The therapy continues until the platelet count normalizes and there is minimal hemolysis. Because of the large volume, the number of donor exposures, and prolonged duration of therapy, adverse reactions to plasma are common in the treatment of TTP.  There is a risk of disease transmission, TRALI and allergic complications from mild to serious forms (11,12).

Pathogen inactivated plasmaNowadays pathogen inactivated plasma means solvent-detergent treated plasma, methylen-blue treated plasma, and psoralen or riboflavin treated plasma.

Solvent-detergent treated plasma (SD-plasma)

Solvent-detergent treated plasma is a biopharmaceutical product prepared from pooled FFP (100-1600 donors per batch) with ABO compatibility. Solvent (tri-n-butyl phosphate) -detergent (Triton^® X-100) technology inactivates well lipid-enveloped viruses (HIV, HBV, HCV), but is less effective in inactivation of non-enveloped viruses like parvovirus B19 or HAV. Pooling of plasma units can lead to neutralization of antibodies and allergens in plasma and thus significantly decrease risk of TRALI and other serious adverse effects (13). European SD- plasma is predominantly produced by Octapharma (Octapharma, Switzerland) and is distributed as a medical product Octaplas (14). Number of clinical studies confirmed the benefit of Octaplas in treatment of patients with TTP (15,16).

Methylen-blue treated plasma (MB plasma)

Treatment of plasma with methylen blue, a fenothiazin dye, and subsequent visible light exposure generate superoxides (hydrogen peroxide and hydroxyl), which target nucleic acids of the virus (17,18). The System effectively inactivates lipid-enveloped viruses but is less effective in non-lipid enveloped viruses (19). Nevertheless, clinical efficicacy of MB plasma is lower than quarantine FFP (20).

Psoralen inactivated plasma (INTERCEPT)

Riboflavin inactivated plasma (MIRASOL^® PRT)

Both systems can be used for pathogen inactivation directly in blood establishments.

INTERCEPT Blood system, produced by Cerus (USA), for plasma uses the addition of a psoralen (amotosalen HCl, S-59) followed by illumination with UVA to inactivate pathogens (21, 22). This system is certificated also for platelets. Until now only one small clinical trial regarding the treatment of TTP was published (23).

MIRASOL^® PRT, produced by CaridianBCT, Inc. (USA), treatment utilizes exposure to light in the presence of riboflavin to introduce irreparable lessions to nucleic acids thereby inhibiting pathogen and WBC replication. At present the system is certificated only for platelets treatment. Plasma treatment is still under preclinical development (14).

Patients and results

There are 7 patients with rare congenital TTP are treated in Faculty Hospital Ostrava. Five adult patients undergo regular therapeutical plasma exchange using ComTec 204 separators (Fresenius GmbH, Germany), in intervals (3-7 weeks) derived from empirical experience; it means according to platelet count, which decrease under values that are innate to the patients in the long-term monitoring (the platelet count drop under these values is accompanied by rising level of lactate dehydrogenase). During single plasma exchange 1.5 plasma volumes is replaced with quarantine FFP. Before procedure antihistaminic drugs are administrated, and during the procedure is administrated bolus of corcticosteroids. Even though plasma-related allergic complications were reported. Three patients (no. 1, 2 and 4 see table 1) developed light to mediate allergic reaction as allergic exanthema on upper part of body and respiratory distress. Two of our patients (no. 3 and 6 see table 1) experienced serious generalized allergic reaction. Teenage patients no. 6 and 7 (see table 1) are regularly treated with by plasma infusion (in 2 weeks intervals) in dosage 10ml per kilogram. In one of them was reported serious allergic reaction. 

Discussion

Patients with rare congenital TTP are treated in Faculty Hospital of Ostrava. In all of these patients first symptoms has manifested in childhood; in four of them (1, 3, 5 and 6 see table 1) as relapsing haemolytic – uraemic syndrome. The patient number 2 was primarily diagnosed with idiopathic thrombocytopenic purpura (ITP) at two years of age, The patient number 4 experienced first attack at 13 years of age; the episode was diagnosed as ITP and anemia. Therapeutical plasma exchange is essential in TTP patients (24). Our patients respond to the treatment well, which is apparent from laboratory findings particularly by improvement of thrombocytopenia and parameters of hemolysis (lactate dehydrogenase level). However, plasma replacement has risk. There is as a possibility of pathogen transmission and complications including allergic reactions, volume shifts citrate toxicity and TRALI. However Octaplas is according to the references in foreign literature safer and more efficient. Availability of aforementioned plasma alternatives is challenging. Hence as results of several clinical trials presented the benefit of Octaplas as a substitution solution instead of quarantine FFP, we aim to use this biopharmaceutical product in treatment of selective group of patients with hereditary TTP in future.

Conclusions:

Quarantine fresh frozen plasma is reasonable and effective treatment in the therapy of patients with TTP. Availability of Octaplas, which is as presented in a number of foreign studies more safe and efficient, is in Czech Republic at pressent difficult and due to large volumes of replaced plasma also financial demanding.  

Abbrevations:

ADAMTS13   -          a disintegrin-like and metalloprotease with thrombospondin type 1 motif,  13    

FFP                 -          fresh frozen plasma

HAV               -          hepatitis A virus

HBV                -          hepatitis B virus

HCV               -          hepatitis C virus

HIV                 -          humann immunodeficiency  virus

ITP                  -          idipathic thrombocytopenic purpura

K – plazma      -          cryoprecipitate - poor plasma

MB                  -          methylen blue

PRT                 -         pathogen reduction technology

SD                   -          solvent – detergent

TPE                 -          therapeutic plasma exchange

TRALI             -          transfusion-related acute lung injury

TTP                 -          thrombotic thrombocytopenic purpura

vWF                -          von Willebrand factor