These recommandations are based on the Guide Lines for Therapeutic Haemapheresis of the German Society for Blood Transfusion and Immunohaematology. They were developed from a special committee consisting of Drs. Löliger (Hamburg), Mansouri Taleghani (Würzburg), Ullrich (Regensburg) and Wiesneth (Ulm). The committee was chaired from Prof. Dr. Dr. h.c. Borberg.

These guide lines do not claim to be perfect, especially as they date back to 1998. Their purpose is to stimulate the developments of European guide lines, thus suggestions for further improvement, updates and also linguistic corrections are welcome.
Any member of the ESFH is invited to contribute.

Please send your suggestions to Prof. H. Borberg, German Haemapheresis Centre, Maarweg 165, 50825 Köln-Braunsfeld, Fax: +49 221 95423595 Phone:+49 221 95423595. Email: med@dhzcologne.de"

Please note, this text contains forms to download.
If you do not have the Acrobat Reader, you can download it directly and free from the website:www.adobe.com

 

RECOMMENDATIONS FOR
THERAPEUTIC HAEMAPHERESIS

(State: november 24^th, 1998)

1. Aims

These recommendations, based on the work of a special committee are supposed to serve as guidelines for therapeutic haemapheresis. After acceptance from the board of the German Society for Blood Transfusion and Immunohaematology (Deutsche Gesellschaft für Bluttransfusion und Immunhämatologie, DGTI) the guidelines may be used as part of the Guidelines for Transfusion Medicine of the Federal Physicians Board (Bundesärztekammer). These recommendations are partly supported from other already published recommendations and related German laws.

Literature

Richtlinien zur Blutgruppenbestimmung und Bluttransfusion (Hämotherapie). Aufgestellt vom wissenschaftlichen Beirat der Bundesärztekammer und vom Paul-Ehrlich-Institut. Überarbeitete Fassung 1996.
Deutscher Ärzteverlag, Köln.

Durchführung apparativer Hämapheresen zur Gewinnung von Blutbestandteilkonserven. Empfehlungen der Hämapheresekommission der Deutschen Gesellschaft für Transfusionsmedizin und Immunhämatologie.
Infusionsther Transfusionsmed 21 (1994): 222-231

Empfehlungen zur Durchführung von Plasmaaustauschbehandlungen. Empfehlungen der Hämapheresekommission der Deutschen Gesellschaft für Transfusionsmedizin und Immunhämatologie.
Infusionsther Transfusionsmed 22, 1 (1995): 51-63

Medizinproduktegesetz (MPG) vom 02.08.1994

BGB 1 I, 1994, pp 1963 ff

2. Definition

Therapeutic haemapheresis is understood as the selective separation of blood with the corresponding apheresis equipment and the selective removal of blood components for treatment purposes. The nomenclature used is summarised in enclosure 1.

3. Procedures for Haemapheresis Treatment

3.1 ACCESS TO THE CIRCULATION

The normal access to the circulation uses peripheral veins. This approach is based on the lower rate of complications using a peripheral venous access and the exclusion of serious complications. Also, the application of blood (cell) separators permits relatively high plasma flow rates even at rather low whole blood flow rates. An artificial access to the circulation (e.g. venous-arterial, subclavian catheter with high diameter, shunt) is acceptable only if extremely poor venous situations exist or in rare exempt situations due to the special problems of the patient or his disease.

3.2. CYTAPHERESIS TREATMENTS

Cytapheresis treatments are performed with continuous or discontinuous flow blood (cell) separators. The anticoagulation can be performed with citrate, heparin or a combination of heparin and citrate. For leukocyte apheresis the additional application of sedimenting agents such as Hydroxyethyl starch 10%, molecular weight 250.000 - 500.000 are recommended.

3.3. PLASMA SEPARATIONS

3.3.1 Primary separation

The separation of cells from plasma for plasma therapy (plasma separation, primary plasma separation) can be performed with blood (cell) separators and hollow fiber modules. Separation systems procuring platelet poor plasma (max. concentration 15.000 platelets / µl) are to be preferred against those providing for higher platelet numbers in the separated plasma. The anticoagulation can be performed using citrate, heparin of a combination of heparin and citrate. The control of the separation is usually performed automatically by special electronic control programs which among other variables take the relation of the hematocrit and the flow rates into account. In addition to these automatic control processes the possibility of a manual control for the adaptation to the individual therapeutic needs of the patient or to eliminate defects of the control systems must be available.

3.3.2 Differential separation

The separated plasma can be substituted against albumin, plasma extending solution, human plasma (plasma exchange, therapeutic plasmapheresis). It may also if cell free or with a very low cell content be used for secondary separation or plasma differential separation respectively (e.g. precipitation, secondary filtration or ad-absorption therapy respectively). The secondary separation of the plasma may be unspecific, selective or specific.

3.3.2.1 Precipitation

Plasma differential precipitation is exclusively applied for the elimination of high molecular weight plasma proteins such as LDL-cholesterol. Plasma after being separated from a hollow fiber module will be acidified and heparin is added. The precipitated plasma components are separated from a second hollow fiber module. The heparin excess is removed from an adsorption column from the plasma. The neutralised plasma is after dialysis and ultrafiltration returned with the cells.

3.3.2.2 Filtration

Plasma primary separation therapy is performed with centrifugal separators or, if the venous situation permits it, with hollow fiber modules. The secondary separation is always performed with a hollow fiber module adapting the pore size of the hollow fibers to the aim of the treatment.

3.3.2.3 Adsorption

Plasma primary separation should be performed in centrifugal devices, however, filtration techniques can also be applied. For the secondary separation of plasma, unspecific adsorption, hydrophobic interaction chromatography and specific affinity chromatography are available.

4. Responsibility

4.1 RESPONSIBILITY OF THE PHYSICIAN IN CHARGE

Haemapheresis treatments demand a sufficient experience with extracorporeal systems especially with blood (cell) separators. Know-how and experience can be considered as sufficient if the physician in charge of these treatments can demonstrate a proven and finished specialisation in transfusion medicine (Facharzt für Transfusionsmedizin), an appropriate partial specialisation in transfusion medicine (Teilgebietsbezeichnung), or af specialisation in nephrology or an appropriate combination of both specialisations.

The treating haemapheresis physician is responsible for the safety of the separation system and the patient. Prior to the initiation of the treatment he has to check on the safety of the technical system. He decides on the type and way of the therapeutical approach and the way the treatment is performed. The extent of the treatment and the appropriate safety measures should be documented prior to the initiation of the treatment. The treatment protocol of the operator should be signed from the physician in charge after the treatment was terminated (see enclosures).

4.2 RESPONSIBILITY OF THE OPERATOR

The operator is responsible for the preparation of the separation system, the surveillance of the technical system applied and the care of the patient during the treatment. The course of the treatment has to be documented in a written protocol. It is the task of the operator to set up the protocol and to sign it. The protocol should contain the following parameters:

• the prescription of the physician for the details of the treatment
• initiation and termination of the treatment
• regular control of blood pressure and pulse
• technical irregularities
• extent of the processed whole blood- and plasma volumes including the corresponding flow rates.
• anticoagulation
• data defining the type, the volume and the documentation of charges of the applied plasma exchange solutions or plasma differential separation systems
• undesired events or side effects if occurred
• volume balance or if necessary patient's weight prior and after treatment
• laboratory parameters prior and after the therapy
• drugs applied
• signature of the operator and the treating physician
• enclosures if necessary.

5. Prerequisites of room and equipment

Apheresis treatments should be performed within a hospital or correspondingly within an area which permits easy and quick access for an emergency team unless a physician sufficiently trained in emergency medicine is present.

For the details of the emergency equipment the German Guidelines for Plasma Donation are referred to. It has to be pointed out that the technical equipment embraces a monitor for the control of pulse and ECG for each treatment place.

The extent of the treatment room is 20% beyond that determined for donor plasmapheresis (1). The increased demand for treatment space is based on the additional necessary technical equipment and accordingly to the additional space necessary for the safety of the patient in case of emergency. If apheresis treatments are performed with the same equipment as used for the preparation of haemotherapeutics according to the German pharmaceutical law (Arzneimittel-gesetz), the option of separating patients and donors in different rooms should be considered.

Treatments must be performed using one-way systems unless otherwise legal permission is available.

References

1. Richtlinien zur Blutgruppenbestimmung und Bluttransfusion (Hämotherapie). Aufgestellt vom wissenschaftlichen Beirat der Bundesärztekammer und vom Paul-Ehrlich-Institut. Überarbeitete Fassung 1996.
   Deutscher Ärzteverlag, Köln.

6. Preparation and Performance of Haemapheresis Treatments

6.1 EXAMINATION OF THE PATIENT PRIOR TO THE TREATMENT

The haemapheresis physicians performs a physical examination of the patient prior to the first treatment, ideally one day prior to the treatment.. A written consent is necessary for each treatment (treatment series) (Form 1).

The establishment of a risk profile prior to the first treatment is prerequisite. The risk profile embraces all questions regarding the underlying disease as well as other diseases or a pregnancy, a physical examination and a corresponding laboratory status (Form 2).

If after termination of the first treatment series subsequent treatments are necessary a repetition of the physical examination and an interim history are necessary. It is left to the discretion of the responsible physician to extend the examinations according to the disease treated.(Form 3a)

The examination prior to the first treatment has to determine which access to the circulation should be used. The risks of an artificial access to the circulation should consider the total situation of the patient, the prognosis of the disease and the anticipated flow problems etc. and should not exceed the expected benefit of a haemapheresis treatment. (Form 3b)

Click here to download forms 1 to 3b.

6.2. PATIENT'S CONSENT

The consent of the patient refers to all treatment criteria. In detail:

• general treatment risks such as increased sensitivity against infections, an elevated bleeding risk due to anticoagulation,
• decrease of blood pressure, shock,
• risks of the application of plasma exchange fluids such as protein incompatibilities, transmission of viral diseases,
• technical risks such as haemolysis, air embolism.

Patient's consent has to be obtained in a written form and must be also given orally.

6.3 SELECTION OF THE TECHNICAL EQUIPMENT

The physician in charge of the haemapheresis treatment is obliged to select the best suited technical system. Only technical systems of the second and third generation admitted according to the national or European admittance standards are permitted to be used.

6.4 PREPARATION OF THE SEPARATION SYSTEMS

The operator prepares the separation systems. The preparation is associated with a high responsibility. A second, competent person examines the separation systems for completeness and technical safety of the preparation using a special check list (enclosure 4).

6.5 PERFORMANCE

If a treatment is performed the foreseeable risk according to chapter 6.1 is taken into consideration. Special emphasis is layed on the platelet replacement if a patient with thrombocytopenia is treated. It is recommended to take a platelet substitution into consideration if the platelet count is >30.000 thrombocytes/µl.

Haemapheresis treatments performed are determined from the special characteristics of the disease, the treatment technology and the patient. Special aspects are described in the appropriate chapters.

Each treatment has to be documented. Suggestions for appropriate controls are presented in the enclosures 4, 5 and 6.

Click here to download forms 4 to 5.

7. Indications for haemapheresis treatments

The indication is mainly drawn from the clinical symptoms. One differs between approved, debatable and uncertain indications.

7.1 CYTAPHERESIS TREATMENTS

7.1.1 General

Acute or subacute cytapheresis treatments are indicated for hypercytosis and advanced parasitaemia associated with disturbed organ function due to the underlying disease. In special situations also a hypercytosis with simultaneously compromised organ function (such as an accumulation of uric acid with eminent nephropathia due to chemotherapy in patients with extreme leucocytosis) may need therapeutic intervention. The pathophysiological basis of rheological alterations is partly determined from the number of cells, partly from membrane rigidity of certain cell types (2, 5, 6). The formation of cell aggregates and a potential resistance against deformation leads to alterations and disturbances of the capillary perfusion with a subsequent collaps of organ perfusion followed by an insufficient provision of necessary substrates (e.g. hypoxia) and insufficient removal of metabolic substances (e.g. hyperacidity). The advantage of cytapheresis treatments is considered to the due to the rapid effect on the microcirculation (mainly within a few hours), which can be obtained with a normalisation or a considerable numerical decrease of cells in the circulating blood. The number of cells demanding an intervention of cytapheresis depends on the type of the disease and is different from one individual to the other.

Intermediate or long term cytapheresis treatments are indicated for the support of blood diseases or situations characterised from an insufficient drug therapy or a clear contraindication against standard therapies.

Blood (cell) separators with continuous or discontinues blood flow may be used (1, 6). Whereas the tolerability of the therapeutic, apparative apheresis of adults depends on the general physical state, size and weight have to be taken into special consideration for children. Children with a weight of less than 20 kg can hardly be treated with blood (cell) separators. If apheresis treatments are necessary, exchange transfusion should be preferred as the challenge due to the lower volume is less (3, 4). From 30 kg body weight on cytapheresis using centrifugal systems may be used, however, the technical system, especially if a corresponding anaemia is present, should be primed with erythrocytes to assure that a minimal haematocrit of 0.30 in the blood of the children can be maintained.

It is a apparent that an artificial access to the circulation must be used more frequently in children as compared to adults.

References
1. Burgstaler,E.A., A.A.Pineda
Therapeutic cytapheresis: Continuous flow versus intermittent flow apheresis systems.
J Clin Apheresis 9, 4 (1994): 205 - 209

2. Galacki,D.M.

An overview of therapeutic apheresis in pediatrics.

J Clin Apheresis 12 (1997): 1-3

3. Girard,J., P.J.Tremisi, A.Kassir, T.Moullin, D.Rigal, G.Souillet

Apheresis tolerance and acceptability in the child weighing 30kg or less, with the exception of infants.

Transf Clin Biol 3, 5 (1996): 297-304

4. Kevy,S.V., M.Fosburg,

Therapeutic apheresis in childhood.

J Clin Apheresis 5, 2 (1990): 87-90

5. Klose,H.J., S.Kelson, G.Janka, K.Schwarzbach, R.Haas, K.Betke
Microrheological aspects in extreme leukocytotic acute childhood leukemia
Bibltheca haemat 47 (1981): 258 - 263
6. Preston,F.E., R.J.Sokol, J.S.Lilleyman, D.A.Winfield, E.K.Slackburn
Cellular hyperviscosity as a cause of neurological symptoms in leukaemia.
Brit med J 1 (1978): 476 - 478
7. Schmid-Schönbein,H., J.v.Gosen, L.Heinrich, H.J.Klose, E.Volger
A counter-rotating rheoscope chamber for the study of the microrheology of blood cell
aggregation by microscopic observation and microphotometry.
Microvasc Res 6 (1973): 366 - 376
8. Steeper,T.A., J.A.Smith, J.McCullough
Therapeutic cytapheresis using the Fenwal CS 3000 blood cell separator
Vox Sang 48, 4 (1985): 193 - 200

9. Strauss,R.A., E.S.Gloster, J.A.McCallister, J.F.Jimenez, R.W.Neuberg, D.H.Berry
Acute cytoreduction techniques in the early treatment of hyperleucocytosis associated with
childhood hematologic malignancies
Med Ped Oncol 13 (1985): 436 - 351

 

7.1.2 Erythrocytapheresis

Therapeutic erythrocytapheresis is indicated if a remarkable damage of the erythrocytes is related to an eminent organ failure (e.g. of the kidneys), which occurs for instance in acute crises of sickle anaemia and in severe courses of malaria parasitosis with more than 30 % infected erythrocytes. In cases of polycythaemia vera with considerable hyperviscosity (including the threat of clinically overt iron overload), in transfusion dependent sickle cell anaemias or in special cases of thalassaemia apheresis treatment should mainly be taken into consideration instead of blood letting. Erythroblystosis of the newborn is no indication for centrifugal cytapheresis. Erythroblastosis following severe transfusion accident may also be an indication for erythrocyte exchange.

Sickle cell anaemia

An acute crises of sickle cell anaemia may lead to considerable and self intensifying alterations of the microcirculation. This is followed from a lysis of defective erythrocytes in the terminal capillary perfusion in system and to a diminished oxygen supply of tissues. A timely erythrocyte exchange is thus indicated to reduce the percentage of defective erythrocytes to less than 30 % and thus to prevent a multiorgan failure (1, 3, 5, 7, 9). If necessary apheresis has to performed on several successive days. In cases of chronic substitution dependent anaemias exchange apheresis replacing simple transfusions may be indicated to prevent an iron overload and suppress the formation of defective erythrocytes. It may also serve as a replacement or as a complementary treatment with iron-chelate forming medication.

Polycythaemia vera

Depletion apheresis may be indicated in cases with hyperviscosity syndrome due to polycythaemia to diminish the number of erythrocytes in an efficient and long lasting way and also to reduce the formation of young erythrocytes (neocytes) (4, 7, 10). If apheresis is performed rather than a normal blood letting therapy this needsto be specially justified.

Thalassaemia

Extended substitution dependent anaemia may justify an erythrocyte exchange as described for sickle cell anaemia rather than normal transfusion therapy or chelate medication.

Malaria

In severe courses of malaria tropica with extended erythrocyte infection of erythrocytes (>30%) or with early organ failure, exchange apheresis may be indicated. The treatment aims at the reduction of parasites and at the damaging consequences of a parasite induced erythrocyte lysis with damage of the capillary membranes and subsequent edema formation. Due to the early damage of the border between blood and tissues, apheresis has to take an accurate fluid balance into account to avoid edema formation.

Babesiosis

Following splenectomy the infection with the protozoon babesia microti may lead to acute severe courses which may be an indication for exchange apheresis to reduce the number of protozoa (2, 8).

Filariose

Infection with microfilarii may lead to considerable parasitaemia of up to 3.000 filarii/ml blood with an initial lack of clinical symptoms. If in such patients due to an increasing helminthosis a chemotherapy is necessary, the sudden immobilisation of the microfilarii may lead to life threatening failures of the microcirculation and to hyperergic reactions with organ failure and severe affections of the central nervous system. A temporary reduction of the parasites prior to chemotherapy may be achieved with a protozoon-/leucocyte- depletion (12).

References

1. Bhattacharyya,N., A.S.Wayne, S.V.Kevy, R.C.Shamberger

Perioperative management for cholecystectomy in sickle cell disease.

J Pediatr Surg 28, 1 (1993 Jan): 72-5

2. Cahill,K.M., J.L.Benach, L.M.Reich, E.Bilmes, J.H.Zins, F.P.Siegel, S.Hochweis

Red cell exchange treatment of babesiosis in a splenectomized patient.

Transfusion 21, 2 (1981 Mar-Apr): 193-8

3. Campbell,L.C., G.von Burton, R.F.Holcombe

Transfusion therapy in sickle cell disease patients: methods and acute indications.

J La Stat Med Soc 154, 12 (1993 Dec): 515-21

4. Centurioni,R., P.Leoni, M.Candela, M.Cristina-Refe, A.Stella-Strusi, L.Fabietti, G.Danieli

Neocytoapheresis in the treatment of polycythemia vera.

Recenti Prog Med. 87, 4 (1996 Apr): 161-3

5. Koshy,M., D.Chisum, L.Burd, A.olina, H.How

Management of sickle cell anemia and pregnancy.

J Clin Apheresis 6, 4 (1991): 230-233

6. Lercari,G., G.Paganini, L.Malfanti, D.Rolla, A.M.Machi, F.Rizzo, G.Cannella, M.Valbonesi

Apheresis for severe malaria complicated by cerebral malaria, acute respiratory

distress syndrome, acute renal failure and disseminated intravascular coagulation.

J Clin Apheresis 7, 2 (1992): 93-96

7. Liersch,T., K.Vehmeyer, U.Kaboth

Large volume, isovolemic erythrocytapheresis in the treatment of polycythemia vera. Effect of massive iron

depletion on proliferation behavior of erythroid precursor cells (BFU-E).

Med Klin 90, 7 (1995): 390-397

 

8. Machtinger,L., S.R.Telford, C.Inducil, E.Klapper, S.H.Pepkowitz, D.Goldfinger

Treatment of babesiosis by red blood cell exchange in an HIV-positive

splenectomized patient.

J Clin Apheresis 8, 2 (1993): 78-81

9. Pisciotto,P., T.Kiraly, R.M.Kakaiya, L.Rink, H.A.Pearson

Clinical trial of young red blood cells prepared by apheresis.

Ann Clin Lab Sci 16, 6 (1986): 473-478

10. Wedzicha,J.A., A.C.Newland, D.W.Empey

Apheresis procedures in polycythemia.

Br Med J Clin Res Ed 289, 6451 (1984): 1072

11. Wong,R.D., A.R.Murthy, G.E.Mathisen, N.Glover, P.J.Thornton

Treatment of severe falciparum malaria during pregnancy with quinidine and

exchange transfusion.

Am J Med 92, 5 (1992 May): 561-2

12. Myulle,L., H.Taelman, R.Moldenhauer, R.v.Brabant, M.Peetermanns

Usefulness of apheresis to extract microfilariosis in management of loiasis

Brit med J Clin Res Ed 287, 6391 (1983): 519-520

7.1.3. Leukocytapheresis

Hyperleukocytosis in patients with acute and chronic leukaemia is the most frequent indication for acute cytapheresis treatment as hyperleukocytosis leads quite frequently to failures of organ perfusion though the corresponding anaemia compensates for the negative changes of the rheology up to some extent. Accordingly anaemia must be corrected after, never prior to cytapheresis treatment as otherwise a life threatening hyperviscosity may occur (1, 3). As the deformability of leukocytes appears to be less than that of erythrocytes (2, 4), this may add to the disadvantageous viscosity alteration due to the high leukokrit. The relation of the leukokrit to the volume of the single leukocytes explains among other reasons why in cases of myelocytic leukaemia (as compared to lymphocytic leukaemia) a much lower number of cells suffices to induce organ perfusion syndromes. In lymphocytic leukaemia the number of cells may be permitted to be twice as much (e.g. < 300.000/µl) as compared to myelocytic leukaemias (4).

The reduction of organ perfusion finally leading to leucostasis may impair the function of the central nervous system (headache, stupor, delirium, intracranial bleeding), of the eyes (problems of visual acuity, papillary edema, retinal bleeding), the kidneys (increase of kreatinin and urea until an appearingly necessary dialysis) and the lung (dyspnoe, tachypnoe) as well as other organs (e.g. priapism).

Another indication may be due to nephropathy developing in cases of hyperleukocytosis with an increasing concentration of urea after an acute destruction of cells following chemotherapy.

References
1. Ablin,A.R.
Managing the problem of hyperleukocytosis in acute leukemia.
Am J Pediatric Hematol. Oncol 6, 3 (1984): 287 - 290
2. Dintenfass,L.
Viscosity of the packed red and white blood cells.
Exp Molec Pathol 41 (1965): 597 - 599
3. Harris,A.L.
Leukostasis associated with blood transfusion
Brit Med J I (1978): 1169 - 1171
4. Lichtman,MA., J.M.Rowe
Hyperleukocytic leukemias: Rheological, clinical and therapeutic considerations
Blood 60, 2 (1982): 279 - 283

Acute Leukaemia

If a number of 100.000 - 150.000 cells/µl persists, a cell depletion may be indicated. According to the age of the patient, the mass of neoplastic cells and the organ involvement (e.g. splenomegaly) a cytapheresis treatment may reduce the number of cells in the peripheral blood within 3-4 hours about 25-70 %. If necessary, several treatments are indicated. Thrombo-cytopenias <30.000/µl may need substitution.

The prognosis is the worse, the higher the number of cells in the circulation is (2), however, if combined with an appropriate chemotherapy it may be improved in spite of high initial cell counts (3). Leukaemias with increased bleeding tendency (FAB M3) may especially benefit from the reduction of leukaemic cells. It should be pointed out that cytapheresis treatment must not neglect standard supportive therapies such as hydratisation, alkalisation of the urine, allopurinol medication and induction chemotherapy.

Potential side effects of the treatments are the drop of blood pressure due to hypovolaemia, hypervolaemia, hypocalcaemia, bleeding and transfusion reactions if the priming is performed with erythrocytes. An extremely rare side effect of the treatment was described as fragmentation of leukocytes during apheresis with subsequent, disseminated intravascular coagulopathy leading to death (9).

In patients with acute leukaemia the following indications were reported: Symptoms of the central nervous system (4), eminent or acute kidney failure (5, 8), venous thrombosis of the kidneys (7), pulmonal leukostasis (6), priapism (1).

References
1. Becker,H.C., H.Pralle, W.Weidner
Therapy of priapism in high counting myeloid leukemia - a combined oncological-urological approach
Urol Int 40 (1985): 284 - 286
2. Bunin,N.J., P.Ching-Hon
Differing complicationsof hyperleukocytosis in children with acute lymphoblastic or acute non-lymphoblastic
leukemia.
J Clin Oncol. 3,12 (1985): 1590 - 1595
3. Eguiguren,J.M., M.J.Schell, W.M.Crist, K.Kunkel, G.K.Rivera
Complications and outcome in childhood acute lymphoblastic leukemia with hyperleucocytosis.
Blood 79, 4 (1992): 871 - 875
4. Eisenstaedt,E.S., E.M.Berkmann
Rapid cytoreduction in acute leukaemia. Management of cerebral leukostasis by cell apheresis
Transfusion 18 (1978): 113 - 115
5. Despax,R., J.M.Dueymes, J.P.Pourrat, J.J.Conte, J.M.Bachaud, B.Launais, J.Pris, J.P.Calot, J.Ducos
Leucémie myélomonocytaire aiguë avec hyperleucotytose
Nouv Press Med 11,52 (1982): 3860
6. Lester,Th.J., J.W.Johnson, J.Cuttner
Pulmonary leukostasis as the single worst prognostic factor in patients with acute myelocytic leukemia
and hyperleukocytosis.
Am J Med 79 (1985): 43 - 48
7. Murray,J.C., S.R.Dorfman, M.L.Brandt, Z.A.Dreyer
Renal venous thrombosis complicating acute myeloid leukemia with hyperleukocytosis
J Pediatr Hematol Oncol 18, 3 (1996): 327 - 330
8. Rigal,D., H.Briand, A.Kassir, N.Philippe, G.Souillet, E.Hartemann
Cytaphérèse d'urgence chez quatre enfants atteints de leucémie aiguë hyperleucocytaire.
Ann Pédiat 30, 1 (1983): 25 - 30
9. VanRybroek,J.J., J.D.olson, C.P.Burns
White cell fragmentation after therapeutic leucapheresis for acute leucemia
Transfusion 27,4 (1987): 353 - 355

Chronic Leukaemias

According to our current knowledge leukocytapheresis treatment in patients with chronic leukaemia is considered as a symptomatic acute measurement. It is indicated as a long term treatment only if very clear contraindications against a standard therapy with drugs exists or if such drug therapy is insufficient.

Leukocytapheresis may lead to changes of the proliferation kinetics and the biochemical properties of leukaemic cells. Thus an activation of the cell cycle leading to an increase of cells in the S-phase or to a more frequent transfer of cells from the G0- into the G1-phase is reported (8, 14). These observations support the opinion that leukocytapheresis may exert a positive influence on to the efficacy of the subsequent pharmacotherapy especially if S-phase specific cytostatics are being applied.

Chronic myelocytic Leukaemia (CML)

Leukocytapheresis in these patients is indicated if symptoms which can be correlated with rheological alterations of the (micro-) circulation occur (leucostasis syndrome, s. also 7.1.3) (9,5). Such symptoms of an extreme leucocytosis (hyperleucocytosis) may occur as prodromi of serious complications such as cerebral ischaemia, central vein thrombosis or myocardial infarction. Therefore cell depletion therapy may be indicated as an urgent prophylactic measure. The number of leukocytes leading to a significantly elevated risk of a leucostase syndrome differs considerably in these patients and depends on multiple causes such as age and additional diseases and is generally above 100 000/µl (11,15).

The following indications for the treatment of CML with leukocytapheresis were reported: acute cochleovestibular symptoms (19), papillary oedema (16), priapism (18), pulmonary failure (7,13), pregnancy (complementary or as an alternative to chemotherapy) (2,3,4) retinopathy associated with hyperleucocytosis (12,6).

Chronic lymphatic Leukaemia (CLL)

Generally the indications as described for CML hold also true in analogy for patients with CLL, however, due to the already described different rheological effects of numerical expansion of lymphatic or myeolocytic cells, the rheologically dependent complications in patients with CLL may be expected at much higher cell numbers and are thus less frequent as compared to patients with CML. The number of leukocytes exceeds generally 200 000/µl, however, there is now definition of a border line cell number (1). In patients with CLL leukocytapheresis is also considered as a possibility to reduce the number of tumor cells (10).

In patients with CLL the following indications were reported: hyperviscosity syndrome (17), priapism (17).

 

References:

1. Baer,M.R., R.S.Stein, E.N.Dessypris

Chronic lymphocytic leukemia with hyperleukocytosis. The hyperviscosity syndrome.

Cancer 56,12 (1985): 2865-2869

2. Broccia,G., P.Casula, M.Andria

Chronic myelocytic leukemia in pregnancy: report of a case treated with leukapheresis.

Tumori 70,4 (1984): 371 - 374

3. Fitzgerald,D., J.M.Rowe, J.Heal

Leukapheresis for control of chronic myelogenous leukemia during pregnancy.

Am J Hematol 22,2 (1986): 213 -218

4. Fitzgerald,J.M., S.R.McCann

The combination of hydroxyurea and leukapheresis in the treatment of chronic myeolid leukaemia in pregnancy.

Clin. Lab. Haematol 15, 1 (1993); 63-65

5. Helmke,B.P., S.N.Bremner, B.W.Zwiefach, R.Skalak, G.W.Schmid-Schönbein

Mechanisms for increased blood flow resistance due to leukocytes.

Am J Physiol 273,6Pt2 (1997): H2884 - 2890

6. Jackson,N., S.C.Reddy, M.Hishamuddin, H.C.Low

Retinal findings in adult leukaemia: correlation with leukocytosis.

Clin Lab Haematol 18,2 (1996): 105 - 109

7. Karp,D.D., J.R.Beck, C.J.Jr.Cornell

Chronic granulocytic leukemia with respiratory distress. Efficacy of emergency leukapheresis.

Arch Intern Med 141,10 (1981): 1353 - 1354

8. Kotelnikov,V.M., V.V.Kasatkina, S.M.Dultsina, T.G.Sarytcheva, N.N.Kalinin, L.G.Kovaleva, A.M.Poljanskaja,

V.G.Isajev, N.D.Khoroshko, N.G.Lishmanova, et al.

Effects of cytapheresis on cell cycle distribution of peripheral blood and bone marrow cells in some hematolo-

gical malignancies.

Leuk. Res 11,4 (1987): 397 - 403

9. Lichtman,M.A., J.M.Rowe

Hyperleukocytotic leukemias: rheological, clinical, and therapeutic considerations.

Blood 60,2 (1982): 279 - 283

10. Marti,G.E., T.Folks, D.L.Longo, H.Klein

Therapeutic cytapheresis in chronic lymphocytic leukemia.

J Clin Apheresis 1,4 (1983): 243 -248

11. McLeod,B.C., R.G.Strauss, D.Ciavarella, R.O.Gilcher, D.O.Kasprisin, D.D.Kiprov, H.G.Klein

Management of hematological disorders.

J Clin Apheresis 8 (1993): 211 - 230

12. Mehta,A.B., J.M.Goldman, E.Kohner

Hyperleukocytotic retinopathy in chronic granulocytic leukaemia: the role of intensive leukapheresis.

Br J Haematol 56,4 (1984): 661 - 667

13. Moxey-Mims,M.M., N.L.Luban, G.H.Bock, E.J.Ruley, K.M.Preston

Relief of respiratory distress with leukapheresis in a child with chronic myelocytic leukemia.

J Clin Apheresis 4,1 (1988): 47 - 49

14. Powell,B.L., B.W.Gregory, J.K.Evans, J.C.White, E.S.Lyerly, H.M.Chorley, G.B.Russel, R.L.Capizzi

Leukapheresis induced changes in cell cycle distribution and nucleoside transporters in patients with untreated acute myeolid leukemia.

Leukemia 5,12 (1991): 1037 - 1042

15. Rowe,J.M., M.A.Lichtman

Hyperleukocytosis and leukostasis: common features of childhood chronic myelogenous leukemia.

Blood 63,5 (1984): 1230-1234

16. Stirling,M.L., A.C.Parker, A.J.Keller, S.J.Urbaniak

Leukapheresis for papilloedema in chronic granulocytic leukaemia.

Br Med J 10,2 (1977): 676-677

17. Strobel,E., J.Howe, U.Bäcker, G.Ernst, M.Mempel

Therapeutic lymphapheresis in leukostasis-induced priapism.

Dtsch Med Wochenschr. 112, 51-52 (1987): 1984 - 1985

18. Suri,R., J.M.Goldman, D.Catovsky, S.A.Johnson, E.Wiltshaw, D.A.Galton

Priapism complicating chronic granulocytic leukemia.

Am J Hematol 9,3 (1980): 295 - 299

19. Woldag,K., A.Schwarzer

Chronic myeloid leukemia - a rare cause of layrinth apoplexy.

Laryngorhinootologie 75,4 (1996): 247 - 249

 

7.1.4 Photopheresis

Photophoresis is associated with the extracorporeal activation of photodynamic substances in leukocytes. The treatment is performed in 3 steps: application of a photoactivating substance (e.g. Psoralen, as 8-Methoxypsoralen, 8-MOP), the separation of autologous leukocytes and the subsequent exposition to UV light (UV-A). Photopheresis is generally used in 2 different modifi-cations. The original procedure uses the oral application of Psoralen, a subsequent leukocyt-apheresis with a discontinuous blood cell separator, a direct, consecutive transfer of the separated leukocytes into a UV-A irradiation system with continuous return into the patient. Later on the procedure was modified in a way that patient leukocytes are collected from any blood cell separator whether continuous or discontinuous, the subsequent addition of Psoralen, the irradiation with UV-A light afterwards. The irradiated cell concentrate was finally retransfused.

The mechanism of action is not yet clear. However, the binding of the Psoralen to the DNA appears to essential. It is currently under investigation whether a binding to other biomacro-molecules such as lipids of cell membranes and proteins play a role.

An admitted indication is so far only the cutaneous T-cell lymphoma (mycosis fungoides). As it was assumed that the treatment is effective due to a specific suppressive reaction against pathogenic T-cell clones, a considerable number of other indications were taken into conside-ration. They embrace the following indications under debate: Atopia, arthritis (psoriatic arthritis, chronic lyme-arthritis, acute rheumatoid arthritis), diabetes type I, chronic erosive lichen planus, lupus erythaematosis, pemphigus vulgaris, sickle cell anaemia, scleroderma, host-versus-graft and graft-versus-host reaction. It is under investigation whether any of these indications will be able to collect sufficient evidence for its efficacy.

Photoallergy was described as side effect.

References:

1. Andreu,G, A.Leon, F.Heshmati, M.Tot, L. Laroche, C.J. Menkes, J. Baudelot

Extracorporeal Photochemotherapy: Evaluation of two Techniques and Use in Connective Tissue Disorders

Transfus Science 15 (1994): 443-454

2. Constanzo-Nordin,M.R., E.A.Hubbell, E.J.O'Sullivan, M.R.Johnson, G.M.Mullen, A.L.Heroux, W.G.Kao,

B.M.McManus, R.Pifarre, J.A.Robinson

Photopheresis versus Corticosteroids in the Therapy of Heart Transplant Rejection

Circulation 86 (1992) Suppl.2 II: 242-250

3. Dall'Amico, G.Zacchello

Treatment of graft-versus-host disease with photopheresis.

Transplantation 65,9 (1998): 1283-1284

4. Edelson,R.L., C.Berger, F.Gasparro, B.Jegasothy, P.Heald, B.Wintroub, E.Vonderheid, R.Knobler, K.Wolf,

G.Plewig, G.McKiernan, E.Christiansen, M.Oster, H.Honigsmann, H.Wilford, E.Kokoschka, T.Rehle, M.Perez,

G.Stingel, L.Laroche

Treatment of cutaneous T-cell-lymphoma by extracorporeal photochemotherapy.

N Engl J Med 316, 6 (1987): 297-303

5. Rook,A.H., J.T.Wolfe

Role of extracorporeal photopheresis in the treatment of cutaneous T-cell-lymphoma, autoimmune disease, and

allograft rejection. A review

J Clin Apheresis 9, 1 (1994): 28-30

6. Ullrich,H., W.Stolz, S.Barlage, K.J.Lackner, G.Rothe, G.Schmitz

Clinical and Flow Cytometric Outcome of Improved Photopheresis Method in Dermatologic Patients

Beitr Infusions Ther - Transfusion Med 34 (1997): 256-264

7. van Iperen,H.P., G.M.Beijersbergen van Henegouwen

Clinical and mechanistic aspects of photopheresis.

J Photochem Photobiol B: Biology 39 (1997): 99-109

8. van Iperen,H.P., G.M.Beijersbergen van Henegouwen

Photopheresis; the risk of photoallergy.

J Photochem Photobiol B 34, 2-3 (1996): 225-228

 

7.1.5 Blood stem cell apheresis

As stem cell apheresis will be taken care of a special commissions, the report of these commissions (e.g. Infusionsther Transfusionsmed 1998, 25: 325-335) is referred to.

7.1.6 Thrombocytapheresis

Thrombocytosis

Thrombocytosis is considered to be a reactive increase of platelets with an increase of mega-karyocytes and simultaneously a decrease of the megakaryocyte volume, occurring simultaneously with other diseases e.g. chronic inflammations or tumors or following surgical procedures such as splenectomy.

Apheresis therapy is only indicated if in immobilised patients with advanced arteriosclerosis the number of 1 million platelets per µl persists or if thromboembolic complications occur (3,5,6,7,9).

Thrombocythaemias

Thrombocythaemias are autonomous diseases of the myeloproliferative disease group (essential thrombocythaemia, polycythaemia vera, chronic myelocytic leukaemia) with clonal proliferation of a stem cell. The number of megakaryocytes as well as their volume are elevated. Half of the patients suffer of thromboembolic, less frequently from haemorrhagic complications or of both complications simultaneously (1,2,8).

It appears reasonable to reduce the increased number of platelets until a successful drug therapy is effective if the number of platelets increases beyond 1 million per µl. The treatment is indicated in symptomatic patients with acral pains or cerebrovascular microcirculation problems, angina pectoris, pulmonary embolism and perfusion problems of the gastrointestinal system.

Performance

If the treatment is well tolerated, 30-70% of the platelets should be eliminated per treatment. If the first treatment appears to be without success or if a rebound can be observed, the apheresis treatment can be repeated as it appears to be necessary. If more frequent or long lasting apheresis treatments cannot be avoided a sufficient substitution of electrolytes (Ca, K, Mg) an fluid volume has to be taken in consideration (4).

References

1. Adami,R.

Therapeutic thrombocythapheresis: a review of 132 pateints.

Int J Artif Organs 1993; 16 suppl 5: 183-4

2. Adamson,J.W.

Wither the platelet?

N E J M 1988; 318(20): 1331-1332

3. Fabris,E., M.Belloni, A.Casonato, M.Randi, G.Ongaro, A.Girolami

Improvement of platelet aggregation abnormalities in thrombocytosis after thrombocytopheresis.

Folia Haematol. Leipzig 1981; 108(6): 853-862

4. Organizational guidelines for therapeutic apheresis facilities.

J Clin Apheresis 1996; 11: 42-45

5. Schafer,A.

Bleeding and throbosis in myeloproliferation

Blood 1984 Jul; 64(1): 1-12

 

6. Silvergleid,A.

Applications and limitations of hemapheresis

Ann Rev Med 1983(34): 69-89

7. Strauss,R.G.

Mechanisms of adverse effects during hemapheresis

J Clin Apheresis 1996; 11(3): 160-4

8. Ullrich,H., Y.Waxenberger, M.Michels, K.V.Toyka, D.Wiebecke

Rationale for therapeutic hemapheresis. Current Advances in Therapeutic Plasmapheresis

(Yamamoto,A., H.J.Gurland, Ed.), p. 55-68, 1995, Churchill Livingstone, Tokyo

9. Urbaniak,S.J., A.Robinson,

ABC of transfusion. Therapeutic Apheresis.

BMJ 1990 Mar 10; 30(6725): 662-5.

 

7.2 PLASMASEPARATION THERAPIES

7.2.1 Plasma exchange

7.2.1.1 Indications and preparations

The indications may be seen from appendixes I and II

The preparations are essentially the same as those mentioned under 6, whereas some specialities may be taken into consideration.

1. Patient examination (s. 6.1)

The first examination of the patient should also be used to explain the treatment technology, the extent of the treatment and potential risks. A written consent is necessary prior to each treatment series (appendix 7).

The risk evaluation deserves special consideration. Thus the history does not only serve the search for risks due to the underlying disease but also for other diseases (or for a pregnancy). A physical examination and a laboratory status (s. chapter 6) consisting of a blood cell status, liver associated serum enzymes, electrolytes, urea (creatinin), blood glucose, coagulation (fibrinogen, antithrombin III) immunoglobulines and serum electrophoresis must be added. Furthermore a blood group determination and the exclusion of lues, hepatitis and AIDS appear to be necessary.

Furthermore an ECG and if necessary a thorax y-ray should be provided for. The data of other examinations may if not older than 1 week be included (appendix 8, 9a, 9b). The examinations including an interim history is necessary to be performed for any further treatment series. It is left to the discretion of the physician to add further, specially disease associated examinations.

It is also necessary to determine the access to the circulation prior to the treatment. The risk of catheter complications should not exceed the anticipated advantage of the plasma exchange therapy referring mainly to the total situation of the patient, the prognosis of the disease, the anticipated blood flow problems ect.

b) Informed consent (s. chapter 6.2)

 

Appendix I

---

Accepted Indications for Plasma Exchange Therapy

1. Para- und dysproteinaemias

(in case of existent hyperviscosity syndrome or as borderline therapy to prevent hyperviscosity syndroms)
MacroglobuliaemiaWaldenström
Benign hypergammaglobulinaemia Waldenström
Multiple myelom
Cryomacroglobulinaemia

2. Immune diseases

Goodpasture's syndrome
Myasthenia gravis
Haemophilia with antibody
Acute polyneuritis Guillain-Barré
Pemphigus vulgaris
Thrombotic, thrombocytopenic purpura (Moschcowitz)
Autoimmune uveitis

3. Endogenous Intoxications

Early thyroid storm (beginning cardiac symptoms)

4. Exogenous Intoxications

All intoxications with protein bound toxins

5. Metabolic diseases

(if alternatively, more selective procedures are not available)
familiar hypercholesterinaemia
Heredopathia atactica polyneuritiformis (Refsum)
(Diabetic) hypertriglyceridaemia with acute pancreatitis

---

Appendix II

---

Indications for Plasma Exchange under debate

1. Immune diseases
   
   

   1. Antibody mediated diseases

   Idiopathic thrombocytopenia
   RH-Immunisation
   Autoimmune haemolytic anaemia
   Antibody mediated transplant rejection

   2. Immune complex mediated diseases

   Rapid progressive glomerulonephritis
   Lupus erythematosus disseminatus
   Panarteriitis nodosa
   Allergic angiitis
   Wegener's granulomatosis
   3. Diseases with debatable immune pathogenesis

   Chronic polyneuritis Guillain-Barré
   Raynaud's syndrome
   Acute polyarthritis
   Haemolytic uraemic syndrome

2. Endogenous intoxikations

Early thyroid storm without cardiac symptoms
Acute liver failure

3. Other

Disseminated intravasal coagulation in septicaemia
Severe courses of malaria

---

c) Selection of technical equipment

The selection of the technical equipment is determined from the haemapheresis physician in charge of the treatment. Only officially admitted equipment of the I. and II. generation providing for cell poor plasma should be used. Also flat sheet membrane systems or hollow fiber plasma-seperators can be applied if they provide for a minimal whole blood flow rate of 70 cc/min without haemolysis. Systems, which for technical reasons, contain more than 15.000 platelets per µl plasma or those leading to haemolysis if a peripheral veno-venous blood flow is established or systems providing for less than 20 cc/min plasma flow cannot be recommended.

d) Preparation of the equipment (s. chapter 6.4)

 

7.2.1.2 Treatment process

a) Access to the circulation

The extracorporeal circulation in haemapheresis is generally established from one cubital or ante-cubital vein to the other. A central venous access being by far more risky should be avoided. It may be chosen if no sufficient blood flow (generally at least 40 cc/min) can be achieved if a peripheral veno-venous access is used. If such poor venous conditions exist a central-venous catheter should permit a blood flow rate of at least 60 cc/min. Shaldon-catheters or alternatively Broviac-catheters in paediatric patients are recommended as they are considered to be sufficiently stabile and do not kink. If a central venous catheter is used the risk of the catheter complication must not be higher as the anticipated advantage.

b) Selection of plasma exchange fluids

Generally 5% human albumin can be recommended as plasma exchange fluid. Fresh frozen quarantaine plasma may be reluctantly used as it is associated with a higher rate and more dangerous side effects. Fresh frozen quarantaine plasma is indicated for the treatment of thrombotic-thrombocytopenic purpura (Moschkowitz syndrome), the haemolytic-uraemic syndrome and exogenous as well as endogenous intoxications. Fresh frozen quarantaine plasma may also be recommended if, following a plasma exchange with human albumin or protein free substitution solutions, a potential risk associated decrease of coagulation factors occurred and must be corrected. Human albumin or fresh frozen plasma must be applied in accordance with the regional or national safety regulations and nowadays the guide lines of the European Union if already existent.

Protein free solutions may be applied to some extent for the treatment of hyperproteinaemias, hyperviscosity syndromes and for rheological therapies. If dextran is applied, a test injection of Hapten-Dextran (Promit) taking the instructions of the national safety commissions on undesired side effects of artificial colloidal volume replacement into account. If protein free solutions are used for substitution the consequences of a protein loss and the more rapid elimination of colloidal plasma exchange fluids from the circulation as compared to protein containing plasma substitution fluids have to be taken into a count prior to the therapy.

 

7.2.1.3 Extent of the single treatment

The extent of each treatment is determined from 2 criteria: The desired or necessary decrease of pathogenic or undesired substrates to be eliminated and the loss of normal plasma proteins. Whereas the decrease of the pathogenic or undesired substrates is a target criterium and should be maximal, the loss of normal plasma constituents is undesired. It is reasonable and corresponds to general experience that fibrinogen may be used as marker protein as the determination is relatively simple and fast, corresponds to the extent of the decrease of the substrate to be eliminated if fibrinogen free substitution fluids are used and as a potential indicator of the changes in the coagulation system. A laboratory value of less than 70 mg/dl (according to the procedure of Claus) should normally not be exceeded. This correlates the exchange volume for the majority of the indications (except for intoxications) to a plasma exchange volume of 150 - 180%. The exchange volume must be considerably higher if intoxications from protein bound toxin must be treated. This indication permits the use of fresh frozen quarantaine plasma especially at the second half or the end of the treatment.

The predictive, mathematical determination of the treatment volume should be preferred against the empirical procedure, however if possible it should be correlated with ad hoc measurements of the substrate to be eliminated (s. chapter 7.2.2.5).

 

7.2.1.4 Sequence and frequency of the treatments

The frequency of and the time interval between plasma exchange therapies is determined from the distribution kinetics and the synthesis rate (production kinetics) or the increase of the material to be eliminated. It is desirable to precisely define these parameters using laboratory determina-tions and mathematical prediction parameters (s. chapter 7.2.2.5). If this is not possible one should attempt to come as close as possible to the desired state. It appears to be useful to decrease the substrate to be eliminated as quickly as possible to the lowest level which is quite often obtained after 3 plasma exchange therapies and to maintain the lowest possible titer either with plasma exchange at short intervals (e.g. every second day) and/or the additional synthesis inhibiting drug therapy if necessary by synchronising plasma exchange in combination with drug therapy.

 

7.2.1.5 Additional application of drugs

The additional drug therapy is supposed either to increase the elimination of pathogenic substrates (for instance in intoxications) or to inhibit the synthesis of undesired or pathogenic substrates respectively (e.g. immunosuppressive drugs in patients with autoimmune diseases or HMG-CoA-Reductase inhibitors in patients with familial hypercholesterinaemia). The use of such medications should always be taken into consideration when the risk of synthesis stimulation of the pathogenic or undesired substrate exists.

If the initial titers of AT III and an increased risk of thromboembolism exists, a substitution of AT IIII during a treatment cycle may be necessary.

 

7.2.1.6 Termination of the treatment series

Treatment series will be terminated if either the condition of the patient is improved in a way that conventional therapy suffices for further treatment or if the underlying theoretical consideration permits the conclusion that the pathogenic substrate is more or less completely eliminated (considering production and distribution kinetics) or if no further efficacy of the treatment can be anticipated.

 

7.2.1.7 Treatment report

For the physician subsequently in charge of the patients a treatment report with the following details needs to be set up:

• Diagnosis
• Technique of plasma separation
• Kind and extent of the anticoagulation
• Exchange volume (absolute value in liters and percentage of the patient plasma volume)
• Exchange fluid
• Tolerance
• Laboratory values
• If necessary further treatment recommendations.

If patients are hospitalised the treatment report should accompany the patient during the transportation.

 

7.2.1.8 Laboratory controls

Prior to and after each treatment both disease specific examinations (if possible) an general laboratory examinations should be performed, especially:

• Electrolytes (Sodium, Potassium, Calcium, Chloride)
• Total protein
• Coagulation parameters (partial Thromboplastin time , Prothrombin time, e.g. Quick,
• Fibrinogen, Antithrombin III)
• Blood count (Erythrocytes, Haemoglobin, Haematocrit, Leukocytes, Platelets)
• Urea and/or Kreatinin.

 

7.2.1.9 Safety recommendation

To optimise the treatment safety the following recommendations should be taken into account:

1. Prior to the treatment a risk evaluation considering also all earlier diseases
2. The treatments should be performed applying a ECG-Monitor and regular blood pressure controls.
2. Patients at risk should be treated under intensive care unit conditions.
3. The physician in charge after the treatment should specially in hospitalised patients obtain immediately all essential treatment informations.
4. Anticoagulated (heparinised) outpatients should carry a written note on the anticoagula-tion applied, the telephone number of the treating institution and if applicable an ampoule of protamin.
5. Only the treating physician is permitted to dismiss the patient.

 

References

1. Medizinproduktegesetz (MPG) vom 02.08.1994

BGB 1 I, 1994, pp 1963 ff

PLASMADIFFERENTIAL SEPARATION

7.2.2.1 General Indications

The indication for the application of plasma differential separation therapies is closely related to the general problems of plasma exchange therapy.

Plasma exchange can be associated with the following difficulties.

1. If frozen plasma is chosen as plasma exchange fluid the transfer of virus mediated diseases and prions can not completely excluded. Whereas the transfer of virus transmittable diseases is hardly possible due to the increase of safety promoting measures (long term storage, sterilisation), the possibility (though rather limited) of a transfer of prions and other pathogenic factors is under debate. Also problems of availability may occur. Delays may occur due to transportation problems or, if simultaneously several patients are treated, difficulties due to the demand for substitution fluid may occur. Finally, fresh frozen plasma is associated with an increased rate of side effects.
2. If human albumin or comparably products or protein free solutions such as Hydroxyethyl starch are used for plasma exchange the extent for the single treatment can be limited due to the loss of protein (hypoproteinaemia, hypalmuminaemia, hypofibrinogenaemia etc.). These undesired effects may be increased if treatments need to be repeated at short intervals or at long term applications and may lead to inefficient treatments and/or undesired side effects such as protein depletions with hypovolaemia. However, it has to be pointed out that the application of selective differential filtration does not completely exclude such undesired effects, though they are by far not as frequent. Such problems do not occur if specific adsorption can be applied.
3. The economy of plasma exchange may be debatable.

Long term treatments such as LDL-Apheresis are best suited for plasma differential separation therapies.

7.2.2.2 Methods and special indications

The selection of one of the three technical procedures as listed in chapter 3.3 is related to the clinical treatment aim, the extent of the selectivity or specificity desired and to the economical considerations (1,2). All technologies can be considered to be save.

The differential precipitation with heparin is mainly used as an LDL-Elimination procedure. Due to it's selective character and the associated additional elimination of high molecular plasma proteins it is also suited for extracorporeal heamorheotherapy (5).

Originally differential filtration was applied in relation to the pore sizes of the individual secondary filter mainly for the treatment of hyperviscosity syndromes and LDL-Elimination. Though this technology leads due to it's selective character to a considerable loss of HDL-Cholesterol simultaneously with the LDL-Elimination it is of advantage for extracorporeal haemorheotherapy. Rheohaemapheresis is the most advanced extracorporeal rheotherapy. Further indications are under development.

Adsorption technologies may be unspecific such as activated charcoal perfusion, selective e.g. immunoadsorption or specific such as LDL-Apheresis. Depending on the extent of the plasma substrate to be eliminated and the adsorber costs the different adsorbers are applied as single device systems, sequentially or in a repetitive cycling manner.

Activated charcoal perfusion is indicated for the treatment of non dialyzable intoxications (4,9). According to the amount of toxin to be eliminate several adsorbing devices have to be used sequentially. Whole blood perfusion may be related to an excessive platelet loss (though rare nowadays) which can be avoided if plasma perfusion is applied. Repetitive cycling is applied with secondary separation devices.

Immunoadsoption is characterised from different ligands such as aminoacids (Tryptophan, Phenylalanin), protein A or polyclonal anti-immunoglobulin antibodies as ligands and differ in their elimination spectrum (9,9, 0). Adsorption devices using aminoacids as ligands are characterised from a relative wide adsorption spectrum for plasma proteins. This limits the extent of the single treatment mainly due to the elimination of fibrinogen comparable to the precipitation technology or the filtration technique. Alternatively such devices are suited for extracorporeal haemorheotherapy. Adsorption using protein A or anti-immunoglobulin-ligands are more selective for the elimination of immunoglobulins. Thus in spite of the repetitive application there are no technical volume limitations due to protein losses.

Selective whole blood perfusion of mainly LDL-cholesterol has some technical advantages as compared to plasma perfusion, however, as a single device technique the capacity of the treatment technology is limited.

The immunoadsorption of LDL (the original LDL-Apheresis) is the only procedure specific for the elimination of Apoprotein-B bound cholesterol. The ligand is generally a polyclonal antibody against Apoprotein-B. Due to the repetitive cycling during each treatment the procedure has the highest capacity for LDL-Elimination. The adsorption devices are reused (3,6).

 

7.2.2.3 Informed consent, selection and preparation of the devices

The preparations relate closely to those as described under 6 and 7.2.1.1, however, the system specific variations as provides for from the manufacturers has to be taken into consideration.

 

7.2.2.4 Treatments

a.) Access to the circulation: s. chapter 7.2.1.2 a

b.) The anticoagulation is performed with heparin, citrate or a heparin-citrate mixture.

 

7.2.2.5 Extent of the single treatment: s. chapter 7.2.1.3

 

7.2.2.6 Sequence and frequency of treatments: s. chapter 7.2.1.4

The term plasma exchange should correspondingly be replaced from the term plasma differential separation.

7.2.2.7 Additional application of drug therapy: s.chapter 7.2.1.5

 

7.2.2.8 End of a treatment series: s.chapter 7.2.1.6

7.2.2.9 Treatment report

At the end of the treatment a treatment report should be transferred to the physician subsequently in charge of the patient including the following date:

• Diagnosis
• Technique of primary and secondary plasmaseparation applied
• Kind and extent of the anticoagulation
• Processed plasma volume (total value in liter and per cent of the patient plasma
  volume)
• Tolerance (side effects)
• Laboratory values
• If applicable, further treatment recommendations.

Hospitalised patients should be accompanied from the treatment report for the physician subsequently in charge of the patient.

7.2.3 Laboratory control: s. chapter 7.2.1.8

7.2.3.1 Safety recommendation: s.chapter 7.2.1.9

References:

1. Borberg,H., R. Brunner, A. Gaczkowski, M. Michel, T. Schreiner, M. Tauchert
The role of rheology in haemapheresis.
Therapeutic Apheresis 5, 2 (2001): 128- - 233

2. Brunner,R., R.A.Widder, R.A.Fischer, P.Walter, K.U.Bartz-Schmidt, K.Heimann, H.Borberg
Clinical efficacy of extracorporeal treatment using plasma exchange, selective adsorption and membrane

differential filtration in maculopathy, retinal vein occlusion and uveal effusion syndrome.
Transfus Sci 17, 4 (1996): 493 - 498

3. Borberg,H.
Fifteen years of experience with LDL-apheresis
Jpn J Apheresis 16, 1 (1997): 56 - 62

4. Corby,D.G., W.J.Decker
Management of acute poisoning with activated charcoal.
Pediatrics 54, 3 (1974): 324 - 329

5. Schuff-Werner,P., E.Schutz, W.C.Seyde, T.Eisenhauer, G.Janning, V.W.Armstrong, D.Seidel
Improved haemorheology associated with a reduction in plasma fibrinogen and LDL in patients being treated by

heparin-induced extracorporeal LDL precipitation.
Eur J Invest 19, 1 (1989): 30 - 37

6. Stoffel,W., H.Borberg, V.Greve
Application of specific extracorporeal removal of low density lipoprotein in familial hypercholesterolaemia.
Lancet II (1981): 1005 - 1007

7. Sueoka,A.
Present status of apheresis technologies: Part 1 membrane plasma separators.
Therapeutic Apheresis 1, 1 (1997): 42 - 48

8. Sueoka,A.
Present status of apheresis technologies: Part 3 adsorbents.
Therapeutic Apheresis 1, 3 (1997): 271 - 283

9. Webb,D.
Charcoal haemoperfusion in drug intoxication.
Br J Hosp Med 49,7 (1993): 493 - 496

10. Yatzidis,H., G.Yulis, P.Digenis
Early clinical trial with sorbents.
Kidney Int Suppl (1976): 215 - 217

 

Appendix

Recommandations for the Nomenclature

Protocol recommandations for special apheresis indications

 

---

RECOMMANDATIONS FOR THE NOMENCLATURE

---

Cytapheresis
= selective removal of cells from the circulating blood

Therapeutic cytapheresis
= selective removal of cells from the circulating blood for treatment purposes

Erythrocytapheresis = selective removal of erythrocytes from the circulating blood

Therapeutic erythrocytapheresis (erythrocyte depletion)
= Depletion or exchange of erythrocytes of the peripheral blood for treatment purposes

Leukocytapheresis
= selective removal of leukocytes from the circulating blood

Therapeutic leukocytapheresis (leukocyte depletion)
= selective depletion of leukocytes from the circulating blood for treatment purposes

Granulocytapheresis
= selective removal of granulocytes from the circulating blood

Therapeutic granulocytapheresis
= Depletion of granulocytes from the circulating blood for treatment purposes

Lymphocytapheresis
= selective removal of lymphocytes from the circulating blood

Therapeutic lymphocytapheresis
= Depletion of lymphocytes from the circulating blood for treatment purposes

Monocytapheresis
= selective removal of monocytes from the circulating blood

Therapeutic monocytapheresis
= Depletion of monocytes from the circulating blood for treatment purposes

Blood stem cell apheresis
= selective removal of peripheral blood stem cells (haematopoetic precursor cells of the circulating blood, peripheral blood stem cells (PBSC) of the circulating blood.

Thrombocytapheresis
= selective removal of thrombocytes from the circulating blood

Therapeutic thrombocytapheresis
= Depletion of thrombocytes from the circulating blood for treatment purposes

Plasmapheresis
= Plasma donation

Plasmaseparation
= selective separation of plasma from the circulating blood

Plasma separation therapy
= separation of plasma from the circulating blood for treatment purposes with or without substitution

Therapeutic plasmapheresis (plasmaexchange)
= selective separation of plasma from the circulation blood with corresponding substitution

Plasma differential therapy
= differential separation of components from the separated plasma

Plasma differential precipitation
= selective separation of components of separated plasma using precipitation

Plasma differential filtration (cascade filtration, double filtration)
= differential separation of plasma components using filtration

Plasma differential adsorption
= differential separation of plasma components using adsorption

Immunoadsorption
= differential separation of plasma components from the separated plasma by immunological means

LDL-Apheresis
= specific elimination of Apolipoprotein B containing particles using therapeutic affinitic chromatography

Extracorporeal haemorheotherapy (Rheohaemapheresis)
= differential separation of high molecular weight plasma proteins or of blood cells for an optimation of haemorheology

Whole blood perfusion
= Elimination of plasmatic or cellular blood components from the circulation blood using whole blood perfusion

 

 

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PROTOCOL RECOMMANDATIONS FOR SPECIAL APHERESIS INDICATION

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1. Erythrocytapheresis treatment

1.1 Informed consent: s. form 1

1.2 Diagnosis of risk factors: s. form 2

1.3 Physical examination: s. form 3a

1.4 Treatment protocol I: s. appendix (Form 4a)

1.5 Treatment protocol II: s. appendix (Form 5a)

1.6 Treatment protocol III: s. appendix (Form 6a)

Click here to download forms 1 to 3b.
Click here to download forms 4a to 6a.

2. Leukocytapheresis Treatment (including Photopheresis)

2.1 Informed consent: s. form 1

2.2 Diagnosis of risk factors: s. form 2

2.3 Physical examination: s. form 3a

2.4 Treatment protocol I: s. appendix (Form 4b)

2.5 Treatment protocol II: s. appendix (Form 5b)

2.6 Treatment protocol III: s. appendix (Form 6b)

2.7 Accompanying form for photophoresis products s. appendix (Form)

Click here to download forms 4b to 6b.

3. Blood stem cell apheresis

3.1 Evaluation form of the German Stem Cell Apheresis Committee Click here to download Evaluation form.

4. Thrombocythapheresis Treatment

4.1 Informed consent: s. form 1

4.2 Diagnosis of risk factors: s. form 2

4.3 Physical examination: s. form 3a

4.4 Treatment protocol I: s. appendix (Form4c)

4.5 Treatment protocol II: s. appendix (Form 5c)

4.6 Treatment protocol III: s. appendix (Form 6c)

Click here to download forms 4c to 6c.

5. Plasmaexchange Treatment

5.1 Informed consent: s. form 7

5.2 Diagnosis of risk factors: s. form 8

5.3 Physical examination: s. form 9a

5.4 Subsequent treatment cycles s. form 9b

Click here to download forms 7 to 9b.

5.5 Treatment protocol I s. appendix (Form 4d)

5.6 Treatment protocol II s. appendix (Form 5d)

5.7 Treatment protocol III s. appendix (Form 6d)

Click here to download forms 4d to 6d.