FROM THE DEPARTMENT OF ANAESTHESIOLOGY AND THE DEPARTMENT OF IMMUNOLOGY AND TRANSFUSION MEDICINE, NORDLAND CENTRAL HOSPITAL, BODØ. INSTITUTE OF MEDICAL BIOLOGY, DEPARTMENT OF BIOCHEMISTRY UNIVERSITY OF TROMSØ

HEREDITARY ANGIOEDEMA

by Erik Waage Nielsen

Nordland Central Hospital 1995

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Olav H. Hauge

FROM THE DEPARTMENT OF ANAESTHESIOLOGY AND THE DEPARTMENT OF IMMUNOLOGY AND TRANSFUSION MEDICINE,

NORDLAND CENTRAL HOSPITAL, BODØ. INSTITUTE OF MEDICAL BIOLOGY, DEPARTMENT OF BIOCHEMISTRY UNIVERSITY OF TROMSØ

HEREDITARY ANGIOEDEMA

by Erik Waage Nielsen

Nordland Central Hospital 1995

Erik Waage Nielsen Department of Anaesthesiology Nordland Central Hospital and University of Tromsø, Norway Bodø, 1995

ISBN

tilegnet Frank Henry Waage

Contents

Acknowledgements .................................................................................... 6 List of Papers .............................................................................................. 7 Abbreviations ............................................................................................. 8 Introduction Hereditary angioedema..... ................ .................................................9 Plasma cascade systems with emphasis on the role of C1inhibitor ............................................................................................. 15 • Complement system ................................................................... 16 • Kallikrein-kinin system ................................................................. 18 • Coagulation ................................................................................. 21 • Fibrinolysis .................................................................................. 23 Role of C1-inhibitor in the cascade systems; a summary ................ 25 Purpose of the study Background ...................................................................................... 27 Aim ................................................................................................... 27 Summaries of Findings Paper I .............................................................................................. 28 Paper II ............................................................................................. 28 Paper III ............................................................................................ 29 Paper IV ........................................................................................... 29 Paper V ............................................................................................ 29 Paper VI ........................................................................................... 30

Discussion Clinical aspects ................................................................................ 31 Functional assay of C1-inhibitor ....................................................... 35 Cascade activation ........................................................................... 37 Applicability of HAE-studies to edema in non-HAE patients..........................................................................................40 Conclusions ...................................................................................... 41

References ...........................................................................................43-59

Papers I - VI

6 Hereditary angioedema

Acknowledgements This work was carried out at the Department of Anesthesiology and at the Department of Immunology and Transfusion Medicine, Nordland Central Hospital, at the Institute of Pharmacy, University of Oslo, and at the Institute of Community Medicine and at the Institute of Medical Biology, University of Tromsø, during the years 1991-1995. I wish to express my gratitude to Jan Holt, with the Department of Pediatrics, who stimulated my interest in this field when we together discovered the fascinating features of this genetic disease on-duty. Special thanks to Lars Vorland for taking the initiative of bringing the University personnel in Tromsø together to help prepare the way for this thesis. Meeting with the University and the University Hospital of Tromsø represented by Per Arne Andresen, Lisbeth Tranebjærg and Bjørn Straume has been very challenging. Bjarne Østerud and Jan Ole Olsen spent 24 labour-intensive hours at my hospital and virtually transformed the bloodbank to a research laboratory for one experimental study. Thanks to them.The study has been supported by grants from the University of Tromsø and «Medisinsk Forskning i Nordland». I am in debt to Harald Thidemann Johansen at the Department of Pharmacy, who very early became interested in this project. I have benfitted from his expertise, enjoyed his support and friendship. I also extend my thanks to Nils Ove Hoem, for patiently guiding me through the use of helpful computer programs, as did my friend Jan Foss. Adam Babinski, Tove Sigstad Karlsrud and Øygunn Gaudesen have also provided interesting results from the laboratory. The unfailing support of my colleagues at the Department of Anaesthesiology has made it possible for me to complete these studies, and they also participated on one paper, as they helped me collect blood from placentas at any hour, day or night. A special thanks to the head of my Department, Sven William Nissen, for creating an atmosphere of encouragement. His concern for practical issues has been fundamental to my work. I have also greatly appreciated Erling Saltrøe’s reflections and the support from the Administration of my hospital and from the Computer Department. I am sincerely grateful to my supervisor Tom Eirik Mollnes, whose brilliant ideas, impressive thoroughness, ever lasting optimism, daily presence and warm support has brought this work forth. It has been a privilege to work with him. Fortunately, new projects are already emerging from this collaboration. I have deeply appreciated our conversations during world wide travels on our way to complement meetings, as I have enjoyed his toasted cheese-sandwiches, usually served at our very late hours Colloquiums. Most of all I appreciate his friendship. Bente Falang Hoaas, Grethe Bergseth and Tone Reitstad have performed excellent laboratory work. The support from my wife Trine, and my children Gunnar, Sofie and Espen has been invaluable. Thank you for your patience.

List of Papers

This thesis is based on the following papers, referred to by Roman numerals in the text. Paper I Nielsen EW, Gran JT, Straume B, Mellbye OJ, Johansen HT, Mollnes TE. Hereditary angioedema. New clinical observations and autoimmune screening, complement and kallikrein-kinin analyses. J Int Med. 1996; 239: 119-30.

Paper II Nielsen EW, Johansen HT, Straume B, Mollnes TE. Effect of time, temperature and additives on a functional assay of C1 inhibitor. J Immunol Methods 1994; 173: 245-51.

Paper III Nielsen EW, Johansen HT, Holt J, Mollnes TE. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr Res 1994; 35:184-7.

Paper IV Nielsen EW, Johansen HT, Gaudesen Ø, Østerud B, Olsen JO, Høgåsen K, Hack CE, Mollnes TE. C3 is activated in hereditary angioedema and C1/C1inhibitor complexes rise during physical stress in untreated patients. Sc J Immunol. 1995; 42: 679-85.

Paper V Nielsen EW, Morrissey J, Olsen JO, Østerud B. Factor VIIa in patients with C1inhibitor deficiency. Thromb. Haemost. 1995; 74: 1103-6.

Paper VI Nielsen EW, Johansen HT, Høgåsen K, Wuillemin W, Hack CE, Mollnes TE. Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. . Sc J Immunol. In press.

8 Hereditary angioedema

Abbreviations

α-2-M

alpha-2-macroglobulin

AT

Antithrombin

BK

Bradykinin

CPA

Cold promoted activation (of FVII)

C1r

Cormplement factor 1, subcomponent r

C1s

Cormplement factor 1, subcomponent s

C1-INH

C1-inhibitor

iC1-INH

proteolytic degraded C1-inhibitor

HAE

Hereditary angioedema

FVII

Factor VII

FVIIa

Activated factor VII

FIX

Factor IX

FXI

Factor XI

FXII

Factor XII

HK

High molecular weight kininogen

kD

kiloDaltons

PAGE

Polyacrylamide gel electrophoresis

PK

Prekallikrein

tPA

Tissue plasminogen activator

rt-PA

recombinant tissue-type plasminogen activator

TCC

Terminal complement complex (SC5b-9)

UK

Urokinase

9

Introduction

Hereditary angioedema Quincke first described and named angioneurotic edema (1), the striking influence of mental stress on the disorder led to the term neurotic which now is abandoned as the genetic cause is known. Nathaniel Hawthorne was apparently familiar with this disorder for in his 'House of the Seven Gables' (2), he describes the Pyncheon family with members who gurgled in the throat and chest when excited and who would sometimes die this way, ever since a curse to choke on blood had been placed on one of their ancestors. The following passages could indicate that Hawthorne recognised that a hereditary disease, not a curse, was responsible for the deaths: «This mode of death has been an idiosyncrasy with his family, for generations past» and «the curse,.. had become a part of the Pyncheon inheritance» (3). Persons with hereditary angiodema are victims of recurrent bouts of edema which may occur in nearly every part of the body (Fig. 1 - 3). Attacks typically last for 2 to 5 days. The disease has been reviewed in several papers (4-11). Fig. 1.Attack of HAE with moderate swelling of the right arm and hand

Skin Swellings most often involves the deep skin of extremities, genitals or face. In certain cases the swellings migrate around the body. Mottling, serpiginous or circular red rings may herald attacks. The rash bear some resemblance to urticaria, but do not itch (12). The swellings are non-pitting, non-pruritic and usually not painful. The edematous transformation of the face may occasionally be so severe as to frighten relatives.

Gastro-intestinal tract The most incapacitating symptoms stem from the edematous expansion of the gut wall which can be seen on ultrasound or when these patients erroneously have undergone laparotomy (13-16). The most frequent morbid outcome of C1-INH associated angioedema could in fact be unnecessary abdominal surgery (17-19). The crampy

10 Hereditary angioedema

abdominal pain and often profuse vomiting confine the patients to bed. The extravasation of fluid into the peritoneum manifest as ascites or, when entering the gut lumen, as watery diarrhea (8,20-25). HAE patients frequently suffer from ulcer or heartburn (14,26-28).

Airways Nasal obstruction and sinusitis are experienced by some (14,29,30). Laryngeal edema may progress to complete airway obstruction (4,31,32). The incidence of sudden death due to suffocation has been reported as high as 54% in some affected kindred, while 20-30% are more often cited (4,8). Pleural effusions and pulmonary edema have been observed (11,31,33-36).

Fig. 2. Attack of HAE involving face and oral cavity. Girl from the county of Nordland .

Uro-gentital tract Although infrequently reported, attacks of HAE may be accompanied by dysuria, hematuria, inability of passing urine and spasmodic pain in the urinary tract (6,37-39). Women with HAE frequently have polycystic ovaries in the presence of high beta-endorphin concentrations (40). Sexual intercourse can provoke edema of the genitals (33), a 15cm scrotal edema has been noticed (14) and vaginal delivery may precipitate attacks (41) or edema of the vaginal wall may lead to a difficult parturition (42).

Brain Serious attacks of cerebral edema and circulatory disturbances are rare, but may cause transitory ischemic attacks and fatal cases are described (8,31,33,43-46).

Hereditary angioedema

11

Circulatory system Dispersion of fluid into tissues during attacks is usually mild, but may occasionally bring about severe hemoconcentration. Fainting and symptoms of hypovolemia often succeed (15). Some patients reportedly suffered from hematocrit values of 75% (47).

Autoimmune diseases Numerous case reports and a few larger investigations link hereditary angioedema with autoimmune diseases. Glomerulonephritis and lupus like disorders are most frequently reported, while Sjögren’s syndrome, inflammatory bowel disease, thyroiditis, systemic lupus erythematosus, aortitis and rheumatoid arthritis are more rarely encountered (46,48-58). C1-INH plays an important role in regulating nonspecific complement activation, but has only limited effect on immune complex-induced C1 activation or when C1 is activator-bound (59-61). An overabundance of spontaneous C1 autoactivation, due to low C1-INH levels, underlies the abnormal activation of complement via the classical pathway seen in HAE patients (62). It is assumed that this consumption may expose HAE patients to an increased risk of immune-complex disease, as seen in patients genetically deficient of C2 and C4 (11,63,64). Explanations of a decreased solubility of immune complexes are given (65), as the classical pathway of complement has a pivotal role in keeping antigenantibody complexes small and soluble. The end result is the covalent binding of C3b to the antigen-antibody lattice, which not only keep these immune complexes soluble, but permits binding to complement receptor 1 (CR1) for removal from the circulation (66). Other studies did not show increased levels of circulating immune complexes and argue for other mechanisms (67). However, the largest clinical study on HAE ever published failed to demonstrate a significantly higher prevalence of biochemical markers of autoimmune disease in HAE (11).

Inciting events Many individuals with HAE will respond to mental stress by having an attack, and this is allegedly why Quincke more than a 100 years ago designated the disease as angioneurotic (1). The intake of estrogen containing pills regularly worsen symptoms (68-71). Ear nose and throat surgery, particularly dental extractions, or infections often initiate local swellings and at times life-threatening obstructions of the upper airway (39,72-80). Sustained pressure from shoes, clothes or repetitive

12 Hereditary angioedema

thumps often so mild as to be unnoted by unaffected persons, may also initiate attacks. The type of provocative events which cause attacks, however, is highly variable from patient to patient (81), and even within the same patient (6,11). Very often, there is no clue as to the cause of the attack.

Genetics The disease is inherited as an autosomal dominant trait. The C1-INH gene is localised on chromosome 11 (82). Heterozygous patients have one normal and one mutated allele, homozygous patients have not been reported. Two types of HAE has been described, both types have reduced levels of functional C1-INH stemming from only one normal allele. In type I HAE the mutant allele produces no C1-INH protein or one that is not detected by conventional antigenic methods, but in type II, a dysfunctional C1-INH protein from the mutant allele can be detected antigenically. Newly, sensitive methods have detected minor amounts of a defective C1-INH protein from the sick allele also in some type I HAE patients, defying the conventional classification of C1 inhibitor deficiencies as type I or type II (83,84). C1-INH values are generally lower than the 50% expected from a heterozygous condition, typically 10-30%. Explanations have been given of a negative feedback from the sick allele on the normal, thereby lowering the production (85). A more likely explanation is an increased consumption of C1-INH in HAE patients, caused by a continous activation of proteases. An original C1-INH content of 50% is probably too low to keep control of the cascades (86,87).

Pathophysiology During attacks, endothelial cells in postcapillary venules contract which allow fluid and plasma proteins to leak between them (88). The mediators of these events are not fully determined. Bradykinin, liberated from high molecular kininogen by the unopposed enzymes kallikrein and factor XII is important, as C1-INH is the major inhibitor of these proteases (89-91). The theory of a kinin like molecule from C2 by plasmin is now attenuated (92,93). C4a probably plays a subordinate role (94).

Diagnosis

Hereditary angioedema

13

The disease has often been misinterpreted by clinicians (14,95-98). A 46 year old man underwent 3 laparotomies, an appendicectomy, a cholecystectomy, partial resection of the terminal ileum, a Noble’s plication (to prevent intestinal adherences), and insertion of a Baker’s tube (a long tube to prevent small bowel obstruction) and 15 years of treatment with steroids, before receiving the diagnose HAE. On two occasions a psychiatric opinion had been obtained and electroconvulsive treatment given (18). Symptoms of recurrent swellings and crampy abdominal pain lasting for days rather than hours, with serum samples showing reduced C1-INH function or antigen, often below 20%, accompanied by low C4 values are hallmarks of hereditary angioedema. A suggestive family history obtained after thorough examinations on the characteristic symptoms with Fig.3. Endoscopic photo of edematous gastric similar biochemical findings folds during attack of HAE, the first ever published. The diagnosis was not known at the time. Man should follow in most cases. from the county of Nordland. Conversely, a finding of C1INH values compatible with HAE in only one single person, should raise suspicion of dealing with in vitro artefacts or acquired angioedema. In vitro artefacts can be due to cold promoted activation in test tubes, in which kallikrein, weakly inhibited by C1-INH at low temperatures, may cleave several plasma proteins including C1-INH (99-104). This will give false low functional C1-INH values. Acquired angioedema is not genetically transmitted, but rather caused by extensive complement activation as in B-cell lymphoma and some other conditions, in which both C1 and C1-INH are consumed. Autoantibodies against C1-INH can also produce acquired angioedema, which clinically can be indistinguishable from HAE (105-122) .

Treatment

14 Hereditary angioedema

Tranexamic acid has some effect in alleviating symptoms of HAE (13,123-125), but danazol has proven more effective (126-134). By intermittent and low-dosage use in periods with frequent attacks, side effects of this attenuated androgen can be avoided or minimised. Androgens augments the production of C1-INH from the normal allele (135). Acute therapy should address an edematous airway, and intravenous infusion of at least 1000 Units of virus inactivated C1-INH concentrate is successful in stopping airway swelling, usually within ½ h (69,128,136). The use of antihistamines, corticosteroids and adrenaline during an attack is generally not helpful (8,14,31,137,138).

15

Plasma cascade systems with emphasis on the role of C1-inhibitor The plasma cascade systems consist of proteins in the complement, kallikrein-kinin, coagulation and fibrinolytic systems which each have specialised functions. Cascade mechanisms include

(+=amplify, - = inhibition)

• Autoactivation or activation by an external initiator • Sequential activation by limited proteolytic cleavage or build-up of macromolecular complexes (+). • One activated molecule activates several molecules at the next step yielding an exponential amplification (+). • Amplification of the response by positive feedback (+). • Use of binding/helper proteins to bring reactants together (+). • Spontaneous or accelerated decay (-). • Destruction of activated proteins by further proteolytic cleavage (-). • Inhibition of activated proteases by inhibitor-complex formation (-). Cascade mechanisms are illustrated in Fig. 4

Cascade principles P=Proenzyme E=Enzyme

Biological effects

Inhibition E3

External activator

P1

E 1

Autoactivation

E2

P3

P2 P2

E3 E3 P3

E2

Amplification Fig. 4.

P3

P3 E3

16

Cascade systems

Complement system The complement system was first described around the turn of the century as a cytolytic mechanism responsible for lysing bacteria or erythrocytes sensitised with antibody. The term complement was used since the cytolytic principle complemented the action of the antibody. Today more than 30 proteins are known to participate in the complement system. More than half are inhibitory proteins, which indicates the potency of this system. A full blown activation of complement is highly detrimental to the host and can occur in conditions where one or several inhibitory proteins are lacking (139). One example is the very recent discovery of a porcine factor H deficiency causing lethal glomerulonephritis (140,141), for which human analogues exists (142,143).

A summary of the complement cascade Classical pathway

Alternative pathway Inflammation

C1 C4

Biologically active split products

C2

Factor B

C3 C5

Terminal pathway C6

SC5b-9

C7

C8

TCC

C9

Membrane damage Inflammation C5b-9(m)

Fig. 5

The complement system acts to lyse susceptible cells, to opsonize and to promote phagocytosis of target particles, and to solubilize immunecomplexes. Activation generates peptides, e.g. the anaphylatoxins, that mediate features of the inflammatory response by attracting neutrophils, releasing histamine, increasing capillary leakage and contracting smooth muscle. Complement is thus activated in autoimmune conditions, infections, trauma or when foreign materials like prostheses or a cardiopulmonary by-pass are introduced into the circulation or tissues (144). Activation is achieved by two independent routes with partially overlapping functions (145): the classical pathway, triggered mainly by immunoglobulins, and the alternative pathway, essentially initiated by cell membrane components. Both of them promote the

17

Cascade systems

generation of an enzyme-complex (C3 convertase) able to cleave the pivotal protein of the complement system, C3, thus initiating the common terminal pathway with the formation of a terminal complement complex (TCC) with inflammatory and lytic properties (144). (Fig. 6).

Membrane damage by complement Physical pore

Lysis

Calcium influx Cell stimulation Inflammation Fig. 6

The dichotomy of the early part of the complement system has recently been exploited therapeutically, as e.g. when infusing large doses of C1-INH concentrate to prevent acute rejection of transplanted organs or to hinder the complement mediated damage of ischemic heart muscle cells during reperfusion, as these events are mainly mediated through the classical pathway (146,147). The selective blocking of the classical pathway, leaves untouched the alternative pathway and the rest of the complement system, which are then capable of handling infection.

18

Cascade systems

Kallikrein-kinin system The plasma proteins involved in the kallikrein-kinin system are the proenzymes prekallikrein, factor XII (FXII or Hagemann factor), and the non-enzymatic co-factor high molecular weight kininogen (HK) (Fig. 7).

Fig. 7. The conversion of zymogen to enzyme are represented by arrows. Complexed HK is depicted as a circle. Names in italic and the fork like symbol depicts inhibition. A shaded area is drawn to portray the activating surface.

FXII autoactivates in the presence of negatively charged macromolecules like proteoglycans. Activated factor XII (FXIIa) then converts prekallikrein to kallikrein, which in turn digest HK to release bradykinin. Bradykinin binds to receptors on nearby endothelial cells which liberates vasoactive prostaglandins or nitric oxide, resulting in e.g. vasodilatation and increased capillary permeability. Bradykinin is also a potent inducer of uterine smooth muscle contractions in rodents and primates (148). Bradykinin is composed of nine amino acids and is extremely potent. Its half-life is just a few seconds, which makes a reliable direct detection in plasma samples difficult and indicates a primary local role of this peptide (149). However, when HK liberates bradykinin, a cleaved form of HK is formed which migrates differently in electrophoresis. It can thus be visualised on immunoblots.

Cascade systems

19

Fig. 8.

This indirect detection of bradykinin release has been applied in this thesis (150). As bradykinin participate in inflammation a variety of clinical conditions are likely to be modulated by the kallikrein kinin system. In some of these, however, bradykinin seem to have a more important role, as e.g. in the invasive growth of tumors (151) and bacterial spread (14th International Symposium on Kinins, Denver, CO, 1995 = «KININ 95», C60), in asthma (152,153), in mediating the effects of snake poison (154) (KININ 95, C43), in the regulation of bloodpressure (155-157) and blood-glucose (158-160), in acute pancreatitis (161), in septic states (162-166), in the edema of the brain (167-170) and in the capillary leakage following cardiopulmonary bypass (171176) (KININ 95, C20). Angiotensin converting enzyme (ACE) has a major role in degrading bradykinin. Thus, the actions of this enzyme go far beyond liberating angiotensin II from angiotensin I. Its very wide distribution in the body and its activity in vitro in fact indicate involvement in the metabolism of several biologically active peptides, among whom bradykinin seems to be pivotal (177). The importance of the kallikrein-kinin system and bradykinin in pathophysiology is accordingly demonstrated by the expanding role of ACE-inhibitors (178). The blood pressure-lowering

20

Cascade systems

and cardioprotective actions of ACE-inhibitors were formerly thought to be based solely on a reduction in vascular angiotensin II formation. However, since ACE also degrades bradykinin, it is now recognised that the local accumulation of this peptide represents an important mechanism by which ACE-inhibitors reduce blood-pressure and heartfailure (179-183), increase glucose uptake (184,185), sometimes even causing hypoglycemia (186,187), have cardioprotective effects in coronary ischemia-reperfusion injuries (188) and delay the development of various nephropathies and diabetic organ failure (189-191). Although their C1-INH concentration is normal, a small but significant proportion of patients treated with ACE-inhibitors suffer from symptoms resembling acute attacks of hereditary angioedema, including life threatening upper-airway edema and edema of the gastro-intestinal tract (192-197). This complication may be much more common than has been thought (198). It is believed that excessive regional amounts of bradykinin mediates these adverse effects as well (199). All these events are in keeping with the vital role bradykinin has in the body. Apart from liberating bradykinin from HK, kallikrein has also direct inflammatory functions by stimulating neutrophils (200). Plasma kallikrein is mainly inhibited by C1-INH and alpha-2-macroglobulin (7,201,202). Tissue kallikrein, the other form of kallikrein, has such a low concentration in the body, with the exception of glandular organs, that its role in mediating cutaneous or mucosal edema is believed to be minor. C1-INH is an inefficient inhibitor of tissue kallikrein, which makes its contribution in HAE less interesting. In addition to being the bradykinin-donor, HK also inhibits cystein proteases, has antiadhesive and anti-platelet roles (203,204), and has recently been shown to bind to the complement C1q receptor on endothelial cells (KININ 95, L03), which is yet another example of the links between the cascade systems. The former belief of kallikrein, HK, or FXII as participants of the so called contact system of coagulation is now abandoned (se below). Quite contrary, it has been shown that these factors promotes mild fibrinolysis (156,205-208) and several find the term «contact system of inflammation» as more appropriate (KININ 95).

Cascade systems

21

Coagulation Clotting involves plasma, platelets and components in the vessel wall. Platelets act as vehicles to concentrate and enhance coagulation on the damaged vessel. Up until some years ago, coagulation was divided into the intrinsic pathway initiated by factor XII, and the extrinsic- or tissuefactor pathway. This concept has changed (Fig. 9). A deficiency of prekallikrein, FXII or HK does not result in a bleeding disorder. In fact, persons with FXII deficiency often suffer from thromboembolic disease, and the inclusion of FXII assays in routine thrombophilia screening has recently been encouraged (205). For this reason activation of blood coagulation via the contact activation system is now believed to be an in vitro artefact, further supported by a series of recent clinical and experimental observations (156,207,209,210). The early discovery by Bjarne Østerud of a direct activation of FIX by tissue factor and FVIIa also attenuated the theory of two separate activation pathways (211). It now appears that tissue factor, which is a protein lipid complex in the vessel wall, and FVII play a major role in both the initiating as well as the propagation of normal coagulation (212,213). Lately, a reciprocal activation of FVII, by FIX and to a lesser degree FX has been proposed (214).

Fig. 9. The main pathways of the current concept of the coagulation system

However, patients lacking FXI, the remaining factor of the four contact system factors mentioned above, variably have a bleeding tendency. The recent observation of thrombin as an important activator of FXI, led to the suggestion that under certain conditions FXIa is needed for the maintenance of normal hemostasis (208). In this context, it is of some interest that the former belief of alpha-1-antitrypsin as the main inhibitor

22

Cascade systems

of FXI has recently been challenged. It was found that the majority of FXIa added to plasma formed complexes with C1-INH (215,216). It has also been recognised that the activation of protein C by thrombin, when thrombin is bound to endothelial cells, is a powerful anticoagulant event, leading to cleavage of FV and FVIII. Protein S is cofactor for protein C, but can probably also inactivate FXa directly (217). Protein S is bound to C4BP, which also binds the split product C4b of the complement system, but only on distinct chains. It is believed that these bindings are independent of each other (218). HAE patients have a continuous breakdown of C4 and, theoretically, would be expected to load the C4BP with increased amounts of C4b correspondingly. Interestingly, case reports of functional protein S deficiency in HAE have recently been published, although the mechanism is unexplained (219,220). Coagulative mechanisms of special interest in HAE patients are included in Fig. 10.

Fig. 10. The coagulation system with particular emphasis on reactions of possible importance in HAE. This includes the protein C/S system with C4b binding protein which also binds protein S, and a possible direct activation of FVII by the unopposed FXIIa. Names in italic and the fork like symbol depicts inhibition.

C1-INH can be secreted from platelets and also expressed on their activated membranes. The cell membrane expression of C1 INH may be important to modulate the activity of the proteases of the complement and kallikrein kinin systems in the local inflammatory response (221). How platelets function in HAE is an interesting issue (222,223), and remains to be thoroughly explored.

Cascade systems

23

FXIIa may activate FVII directly, but this pathway is probably of minor importance in normals. However, since FXIIa is inhibited by C1-INH, this pathway could be of some significance in HAE patients.

Fibrinolysis The fibrinolytic system interacts to regulate fibrin deposition and removal during healing. Plasmin is the key effector enzyme to fulfil this task (Fig. 11). Plasmin is derived from plasminogen, and is a highly unspecific protease, able to split several other plasma components. Fortunately, plasmin is mainly generated in the fibrin clot and cells are able to balance the secretion of activators and inhibitors so as to ensure a localised plasminogen activation. Circulating plasmin is rapidly inhibited by alpha-2-antiplasmin.

Fig. 11. The fibrinolytic system. Inhibitors and substances with inhibitory effects are shown in italics with a fork like symbol. The effect of streptokinase, when exogenously added, is also included. u-PA= urokinase type plasminogen activator. t-PA= tissue plasminogen activator. rt-PA = recombinantly produced PA. PAI-1= plasminogen activator inhibitor 1. AT=antithrombin. FDP= fibrinogen degradation products.

Even though C1-INH is a weak inhibitor of plasmin (224), plasmin/C1INH complexes or inactive C1-INH could be formed in extreme situations (225,226). Fibrinolysis is increased in HAE during attacks or in remission (227-229). Since plasminogen is present in the highest concentration of all the C1-INH inhibitable enzymes, activation of plasminogen could theoretically consume substantial amounts of C1INH (230). Such a situation is created during infusion of streptokinase, although opposing data as concerns the exhausting of C1-INH have been found (231-233). Plasmin can also activate C1s directly (234).

24

Cascade systems

Streptokinase also activates the classical complement pathway (234,235), which can be an additional mechanism by which the C1-INH pool decline. Moreover, plasmin enhances the production of bradykinin from HK (236), a process already enhanced in HAE patients. Tissue plasminogen activator (t-PA), normally inhibited by PAI-1, may during infusion of recombinant t-PA likewise overwhelm PAI and bind to C1-INH (237,238). About 8 % of the infused dose of recombinant t-PA (alteplase) was shown to be inhibited by C1- inhibitor at peak level (239). The concentration of C1-INH in plasma is normally more than 1000 fold higher than the peak t-PA level during therapeutical thrombolysis with rt-PA, but may diminish during a continuous infusion of t-PA over longer periods. According to the facts mentioned above, thrombolytic therapy with either streptokinase or rt-PA could represent a threat to patients with a marginal C1-INH pool.

Cascade systems

25

Role of C1-inhibitor in the cascade systems; a summary It is increasingly recognised that the historically and didactically motivated division of proteolytic plasma components into four cascade systems; complement, kallikrein-kinin, coagulation and fibrinolysis does not reflect the dynamic interplay in the body (232,240-242). Patients lacking C1-INH further illustrates the close relationship between the cascades, the advantage of a broad view on the cascades, and finally, the pivotal role of this inhibitor.

Fig. 12. The blocking of proteases by normal amounts of C1-inhibitor. Abbreviations, see Fig. 13.

In the event of limited C1-INH an extensive activation take place.

Fig. 13. Limited amounts of C1-inhibitor permits extensive activation across traditional cascade divisions. Kal = kallikrein. T-PA = tissue type plasminogen activator. Plmg = plasminogen. BK = bradykinin. HK = high molecular weight kininogen. PK = prekallikrein.

26

Cascade systems

As a result of low C1-INH, complement factors in the early classical complement pathway are cleaved. This may cause autoimmune disease, affect the function of C4BP and thereby possibly the Protein C/S system of coagulation. The activation of the kallikrein-kinin system yields bradykinin leading to enhanced capillary permeability and contraction of smooth muscle. Fibrinolysis is enhanced. By the administration of tranexamic acid, which restricts the effects of plasminogen and plasmin, patients with C1-INH deficiency may enjoy a respite from attacks. Obviously, the cascade systems must be looked upon as a whole to further understand how this intricate interplay affects pathophysiology and cause symptoms in hereditary angioedema.

27

Purpose of the study

Background The investigation of the family started at the Department of Pediatrics, Nordland Central Hospital, Bodø, Norway, in 1987. On the authors duty a five year old boy was admitted with edema of an arm, face and larynx. The boy responded poorly to conventional treatment with antihistamines, steroids and adrenaline. After some time it became clear that his mother and grandfather had received the diagnosis hereditary angioneurotic edema by the Ear, Nose and Throat Department. The further investigations revealed that the boy also suffered from C1-INH deficiency, and that the kindred presumably comprised several undiagnosed members.

Aim The main intentions in the present investigation were: I

Characterise affected members of the family.

II

To analyse clinical data from the largest family in Norway with HAE in order to extend the limited number of clinical reports on this disease.

III

Establish a new functional analysis of C1-INH and to explore its availability and limitations, in order to diagnose HAE in mailed samples to our laboratory.

IV

Diagnose HAE in newborns.

VI

Apply

new

and

simultaneously involvement.

sensitive

explore

the

activation extent

assays of

in

multiple

order

to

cascade

28

Summaries of Findings

Paper I Hereditary angioedema. New clinical observations and autoimmune screening, complement and kallikrein-kinin analyses. Thirty-one affected members were identified. Through examples of inciting events and symptoms the study confirms the wide variation in symptomatology and the difficulty in taking general precautions. An extensive biochemical autoimmune screening did not show positive tests more frequently in affected members. HAE may be symptomatic in infancy. Symptoms of urinary tract infections during attacks and heartburn or ulcer is common. Sex-hormones seriously influence the character of the disease. Original observations indicate a role of HAE in provoking premature labour.

Paper II Effect of time, temperature and additives on a functional assay of C1 inhibitor. The functional C1-INH test with methylamine eliminates any disturbing effect of a variable alpha-2-macroglobulin concentration. After incubations of fresh plasma samples with different additives at different time and temperature conditions, it was found that the functional assay will discriminate well between normals and patients suffering from C1INH deficiency. This was of interest as samples from family members living in remote areas were to be examined, and the findings suggest that serum samples sent by ordinary mail can be used. Only a modest influence of temperature was demonstrated in these samples. The known experience of cold promoted activation of some normal plasma or sera which falsely yield low C1-INH functional values, also experienced in our laboratory, is discussed. We advise the keeping of samples at room temperature prior to analysis. Citrated plasma is significantly diluted proportional to the hematocrit, a fact that should be kept in mind when comparing reference intervals. Heparin or polybrene added to plasma gave falsely high or low C1-INH functional values, respectively.

Summaries of findings

29

Paper III C1 Inhibitor and diagnosis of hereditary angioedema in newborns. By establishing a functional assay for C1-INH and by utilising a reliable sampling procedure, reference intervals for C1-INH function in newborns were derived for the first time. The diagnosis of HAE was made in a newborn child. A new C4 activation assay and novel clinical observations of HAE in a baby were presented that validated the findings. The importance of providing adequate treatment to babies suffering from C1-INH deficiency was demonstrated. Paper IV C3 is activated in hereditary angioedema and C1/C1-inhibitor complexes rise during physical stress in untreated patients

The study was undertakened as physical exercise is known to incite bouts of angioedema, and several of the tests we wanted to apply necessitated that samples were analysed instantly. During analyses of the data it became clear that the intake of small doses of danazol as prophylaxis in two of the patients had profound effects on their biochemical parameters. The exercise provoked a significant increase of complexes between C1 and C1-INH only in untreated patients. It is shown that a substantial part of the low amount of C4 in HAE patients in fact consists of activation products. The study also demonstrated directly for the first time a modest activation of C3 in HAE patients, independent of exercise. The broad investigation by reliable and sensitive assays in the coagulation, white cells and the fibrinolytic systems did not disclose an influence of C1-INH deficiency on these systems during moderate physical stress.

Paper V Factor VIIa in patients with C1-inhibitor deficiency. Unopposed factor XIIa in HAE patients could theoretically activate factor VII. This was investigated by a completely new method, which for the first time reliably could measure the amount of FVIIa formed in vivo. Compared to 23 normal relatives, 21 remission HAE patients had nearly two-times higher FVIIa levels.

30

Summaries of findings

Paper VI Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. The sensitivity of the new C4bc assay and particularly the ratio C4bc/C4 as shown in papers III and IV, was once again visualised by the ability to characterise attacks. Statistically significant rise of C1/C1INH complexes during attacks is shown. The paper further examines how multiple cascade systems act in concert during attacks in HAE patients, and signs of activation of all 4 cascades could be demonstrated. By novel assays terminal complement activation was shown for the first time in hereditary angioedema, as was a modest activation of the coagulation system. By originally applying recently developed assays for FXI/serpin complexes, activation via FXI was not found in HAE patients.

31

Discussion

Clinical Aspects Apart from a few studies (4-6,11) reports on the clinical expression of HAE are mostly in the form of case reports in which one or a few symptoms are in focus. This investigation thus expands the limited number of larger family studies on HAE. By analysing a whole kindred we also hoped to be able to systematise information in order to detect patterns made visible by the relatively high number of affected members. The clinical studies ran in part in parallel with the mapping of affected family members. We were quite surprised to learn that many of these individuals were deeply grateful to be given an explanation for what had been an enigma to themselves and the medical personnel. As a result, family members were generally interested in participating in the study, and the fact that answers were obtained from every member provided information amenable to reliable statistical evaluation. Sensitivity was achieved by applying an extensive questionnaire as the basis of an interview. During the exploration of symptoms and inciting events, the affected persons were also given the opportunity to convey information which at first could seem loosely connected with the disease. This was important, as previous family studies have shown that e.g. abdominal symptoms in many cases were not coupled to peripheral swellings, when these in fact were manifestations of the same disease (4). This approach soon paid off, and several original discoveries were made as e.g. the association of eruption of primary teeth with swellings in the oral cavity. We have also presented symptoms and events which at first did not fit in a model, as it is very unlikely that all details of this disease is known. This information may be of value for future studies, when they can be validated or disputed.

Brain edema The possibility of a coexisting brain edema is often omitted in case reports and even review articles covering HAE. Less dramatic, but probably of wider relevance is the intriguing idea of a subtle influence of a mild cerebral edema in the beginning of an attack, as mental stress is

32

Discussion

so often cited by the patients as a triggering factor. It may be that a part of these so-called emotionally induced attacks in fact are a prodrome of the attack itself (45). Headache often precede attacks (5). Later on, the brain may be intimidated by a series of mechanisms during HAEattacks, including a primary edema, compromised perfusion pressure due to hypovolemia, and probably also by the increased viscosity of the blood due to extravasation of fluid. In cases where the hematocrit reach 75% (47), rheologic disturbances of small vessels in the brain could be a matter of concern. After respiratory arrest due to laryngeal obstruction and hypoxic brain damage (243), a developing cerebral edema could also be complicated by the liability of edema formation in HAE patients. This is a hitherto unreported phenomenon with therapeutical implications. C1-INH concentrate should be given in this phase (31).

Pulmonary edema In this thesis pulmonary edema was not observed in any patient., in agreement with statements from a researcher and clinician with thorough knowledge of HAE; « It is interesting to note that the pulmonary tree is never involved in attacks of HAE» (11). Several other authors have, however, observed pulmonary edema in HAE (31,33-36). As these cases with pulmonary edema coincide with laryngeal edema, it is conceivable that the apparent contradiction may be explained by the high negative intrathoracic pressure the patient has to generate to inhale air through a narrow glottis (244). A similar non-cardiogenic pulmonary edema is seen in Intensive Care Units, and is not related to HAE. Following removal of an endotracheal tube which have caused edema near the laryngeal or cricoid cartilages, or because of a subglottic edema in children, large negative intrathoracic pressure can cause transcapillary filtration and edema (245,246). This edema can also follow abrupt relief of a closed or narrow airway, as e.g. when laryngeal spasms suddenly fade or the intubation of the trachea abruptly opens up the airway (247). The latter mechanism may also be highly relevant in HAE patients, whenever intubation or tracheostomy become necessary. The etiology of pulmonary edema following upper airway obstruction represents an interplay between several factors: cardiogenic and neurogenic mechanisms, as well as hypoxia contribute (248).

Discussion

33

Edema in infancy The two clinical studies (I & III) in this thesis both draw attention to the fact that HAE might manifest during the child’s first year. In contrast to the message from some comprehensive family studies and case reports (5,6,29), in which e.g. a high number of «colicky babies» were reported as early as in 1966 (4), many reports focus on the adolescence as the period during which HAE manifests. Consequently, few studies are really concerned with the implications HAE might have in childhood. Only recently, a review on the management of HAE in pregnancy in the journal Anaesthesia stated that «HAE is always asymptomatic in infancy» (249). This thesis emphasize even early infancy as a likely age of debut, and encourage physicians dealing with newborns from HAE parents, to suspect an underlying C1-INH deficiency as a potential cause of e.g. unspecific recurrent abdominal pain, diarrhea, upper respiratory disease or skin rash.

Hormonal aspects This thesis shows that hormonal changes and the intake of estrogen containing medication heavily influence the course of the disease. However, women with two normal C1-INH alleles, may also experience C1-INH reductions. During normal pregnancy C1-INH activity drops (250-253), with a further substantial reduction in preeclampsia (254). These conditions are often accompanied by a marked tendency to edema, during which e.g. a moderate laryngeal edema sometimes hinders intubation of the larynx in the case of cesarean section. The role C1-INH play in the formation of these edematous conditions in normal women not suffering from HAE is unsatisfactorily examined and invites the planning of further studies.

Medication In the present thesis the adverse effect of estrogen containing pills on HAE, is underlined, including substition in postmenopausal women. Anti-androgen therapy or estrogen to men with HAE, as e.g. when treating prostatic cancer, would most likely lead to aggravation of attacks. Other drugs, possibly contraindicated in HAE include ACEinhibitors (255,256). The administration of C1-INH concentrate should be concidered to forego the infusion of intravenous contrast media (257), streptokinase (241,258) or t-PA (259), as these agents could readily exhaust the tiny C1-INH pool in HAE patients.

34

Discussion

Premature labour Although case reports show how early uterine contractions, placental abruption or premature labour coincide with abdominal attacks of HAE (96,260,261), systematic evaluation has not previously been published that can corroborate our findings of increased frequency of premature labour in HAE patients. Six of ten women suffering from HAE experienced spontaneous abortions or premature labours in conjunction with symptoms of HAE compared to none of the mothers without HAE (p= 0.037 for number of pregnancies). In one previous case report, the finding of a dilated cervix was an unexpected discovery, and the cause of referral was the recurrent abdominal cramps the woman usually had during attacks (260). It is therefore possible that other HAE-women suffering from a severe increase of abdominal attacks during pregnancy may in fact have uterine contractions which are masked by the crampy abdominal pain they usually experience during HAE attacks. Even in normal women not suffering from HAE, the recognition of premature labour is difficult, both for the women and the general practitioner. Quite a few women suffering from premature contractions are initially mistaken to have low back pain or abdominal discomfort due to diarrhea or cystitis. In conclusion, the occurrence of premature contractions in pregnant women suffering from abdominal attacks of HAE may be greater than anticipated. Edema of the uterus may also complicate pregnancy, as a «twentypound cannon ball large» uterus has been reported during attacks in a non pregnant women (96). The mechanisms underlying the start of a normal birth is at present largely unknown. If, however, the generation of bradykinin should prove to be an important physiological mechanism in humans as well as recently shown in rodents (148), very interesting perspectives emerge for a potential use of C1-INH concentrate in the treatment of premature labour in both HAE- and normal women. A preferably recombinant produced C1-INH concentrate could also have advantages compared to the newly developed B2 antagonists, as these oligopeptides cross the placental barrier and may have untoward effects on the fetal kallikreinkinin system. The 105 kd C1-INH is unlikely to do so (262). Functional assay of C1 inhibitor Diagnosis of HAE type II

Discussion

35

Determination of C1-INH function is necessary to make the diagnosis of HAE type II, when the presence of a dysfunctional protein from the mutant allele makes the antigenic concentration of C1-INH normal or higher than normal measured by e.g. a Manchini technique. About ¼ of new HAE families have type II HAE. A quantitative functional assay for diagnostic routine purposes did not exist in Norway when the study started. An assay based on a recently developed chromogenic method (263) was therefore established. To take advantage of reagents in a commercial kit kindly provided by Behringwerke AG, the method was modified slightly. The method includes methylamine to prevent the influence of varying alpha-2-macroglobulin concentration. The unpredictable effect of different alpha-2-macroglobulin concentrations has in fact been mentioned as a cause of unreliable C1-INH functional results (264). The method is also easy to perform, and can be carried out in less than 30 minutes. By applying this method in our laboratory, a new family with HAE, the second in the county of Nordland with this disease known so far, was recently found to have HAE type II. The functional assay has also recently been included by the Immunological Laboratory of the National Hospital of Norway

Further employment of C1-INH functional assay Functional assay of C1-INH may also be applicable in research projects when studying sepsis and conditions with extensive proteolysis like streptokinase infusion. Under these circumstances, C1-INH may be degraded or bound to several proteases which make a gap between the antigenic remnants of the protein and the functional inhibitory capacity (265). Proper function requires an integer, unbound C1-INH protein.

Dilution by citrate The collection of 9 parts blood into vacutainer tubes containing 1 part citrate solution, results in a dilution of the plasma only, as the isotonic solution stays outside the red blood cells. With a hematocrit of 0.42 the actual protein concentration in citrated plasma would be 84% of that in serum or EDTA-plasma. This bias is accentuated with increasing hematocrit and consequently smaller plasma volume, and all analyses performed in plasma in newborns would heavily depend on the type of additive. In our experience, this is a point which seldom is mentioned when different reference intervals or protein concentrations are compared, and information of additive is in fact regularly omitted in

36

Discussion

tables citing normal blood chemistry values in the newborn (266). A search on Medline 1989-to date on citrate and dilution yielded no hits.

Effect of heparin Several functional C1-INH assays are based on exogenously added C1s. As discussed in paper II, heparin can clearly influence these functional assays. Analysis of functional C1-INH values in heparinized plasma may therefore interfere with measurements. It is important to know the effect of in vitro heparin on each functional test, as some authors advocate the use of heparinized samples as the sample of choice for functional analyses of C1-INH (267). A second point of interest is when samples are obtained from patients having a high content of heparin in vivo. An example is patients undergoing cardiopulmonary bypass or those receiving fullheparinisation. Concentration of heparin during extracorporal circulation may amount to 5-7 IU/ml, and patients treated by full heparinisation 0.20.7 IU/ml. This is probably enough heparin to yield falsely high C1-INH functional values in some functional assays. In a Norwegian thesis heparin was also recently shown to seriously disturb functional analyses of the kallikrein-kinin system, presumably by complexing to prekallikrein to build an enzyme capable of cleaving small chromogenic substrates (268). Heparin has been shown to inhibit activity of the alternative, classical and terminal pathways of complement by regulating C1, C1 inhibitor, C4 binding protein, C3b, factor H and S-protein (269). Heparin has in fact been used to suppress experimental autoimmune disease in animals (270). Interestingly, inhaled heparin has also been given to HAE patients, apparently to take advantage of the enhancement of heparin on the reaction between C1 and C1-INH (271), although further studies are required to validate the beneficial effects in these two patients.

Cascade activation All studies of blood samples from HAE patients during attacks suffers from one major approximation; it is not known to what extent local

Discussion

37

tissue concentrations of C1-INH and the proteases are reflected in the circulation. In the edematous regions, which generally are well delimited, it is conceivable that the protease/inhibitor ratio in fact is quite different from that in the circulation, and that samples from the circulating blood at best can give clues to the ongoing reactions in the tissues. This is further illustrated by the lack of correlation between serum values of C1-INH and attacks (272). The fact that approximately 70% of the C1-INH pool is located extravascularly, also points to a crucial role of this compartment (273). Future studies should analyse specimens from edematous tissue if possible, and the examination of lymphatic fluid, especially when draining edematous regions could also yield important information as to the tissue cascade balance.

A possible influence of hemoconcentration on results Attacks of angioedema have been shown to be accompanied by serious hemoconcentrations in some cases (4). Unfortunately, hematocrit measurements were not obtained throughout our attack series. To our knowledge no reports have actually dealt with the problem of comparing remission samples with normal hematocrit to attack samples with potentially severely decreased plasma volume. There are several interesting aspects regarding hemoconcentration; Firstly, the use of citrated plasma could result in a higher dilution in the attack samples with low plasma volume, compared to remission samples, and thus give falsely low values (see previous discussion). The second question is how the loss of fluid from the vascular compartment affects protein concentration in the remaining plasma. Hemoconcentration of red blood cells does not necessarily mean plasma-protein concentration. How the passage of plasma proteins during attacks of HAE depends on molecular weight of the proteins is a very crucial question, but to our knowledge largely unknown. Since the edema is non-pitting the protein concentration can be assumed to be higher than if only water were let out, and the demonstration of wide endothelial gaps allowing even small amounts of platelets to cross, suggest that nearly all plasma proteins can escape in areas of HAE attacks (88,274,275). If the endothelial gaps observed during attacks let all proteins pass freely, the protein concentration would be expected to be almost the same inside the vessel as outside. If only water and proteins with a small MW could pass then the MW of the actual protein

38

Discussion

investigated should be of interest before making any corrections for the increase in hematocrit.

As this issue was raised by a referee, we examined our samples in the attack-study for the concentration of 4 plasma proteins with different MW, namely Albumin, IgG, IgA and IgM. Median values (range in parentheses) Albumin IgG 66 kDa 150 kDa g/L g/L

controls attack remission

45 (39-48) 41 (35-44) 43 (41-53)

12.1 (10.1-15.3) 11.3 (7.7-11.5) 12.1 (11.7-15.6)

IgA 160 kDa g/L

IgM 900 kDa g/L

1.9 (1.8-3.2) 1.7 (1.0-2.1) 2.0 (1.5-3.5)

1.8 (1.2-2.3) 1.3 (0.9-3.3) 1.6 (1.2-4.8)

We could not detect differences between the attack and remission samples with respect to the protein concentration of these proteins. The findings coincide with those found when examining the same attack and remission samples with analyses of the cascade systems; activation products were markedly increased while no difference in native proteins between attack and remission samples were observed. This pilot investigation of how proteins with different molecular weight cross the endothelium in HAE, suggests that proteins with a wide MW move freely through the large gaps in endothelial cells that emerge during attacks of angioedema. Due to lack of space, these results were not included in paper V.

Coagulation is moderately enhanced in HAE A modest enhancement of fibrinolysis has been shown in HAE patients as previously mentioned and also discussed in papers V and VI, but a tendency of bleeding is absent. By using a sensitive assay, this work revealed a very modest increase of thrombin during attacks. This could indicate that the slight increase in fibrinolysis could be balanced by a correspondingly enhanced coagulation. Our finding of a moderate increase in activated FVII during remission may be one mechanism by which thrombin is generated. This pathway is believed to be via an increase of FXIIa in HAE patients that directly activates FVII. Previous studies, however, have failed to directly demonstrate an increase of FXIIa in HAE. Our analyses of FXIIa/C1-INH complexes did not detect a significant increase either. Very recently though, Agostoni and

Discussion

39

colleagues presented FXIIa activation in HAE, measured by a new and very sensitive monoclonal antibody (207), (Kinin 95, C55). Newly, FXI was demonstrated to have C1-INH as one of its major inhibitors (215). We could not demonstrate an increase in FXIa activating during attacks. This may be explained by the new concept of coagulation, where FXI does not participate in the initiating steps, but participates later in the coagulation process to sustain the process (208). The minute amounts of thrombin formed in HAE patients may not have been able to activate FXI. The role of a possible functional protein S deficiency in HAE is a very interesting debate, but one which has barely started, and theories for a mechanism are lacking (219,220). The question of whether C4b split products in HAE interferes with the binding of protein S by the common binding protein, C4BP, represent a challenging future research area. Of interest in this aspect is the fact that serum amyloid P component (SAP), a normal constituent of blood and extravascular tissues, inhibits C4BP function, even though SAP and C4b bind to distinct sites on C4BP (276). Recent reports of activated protein C resistance interfering with functional protein S assays must be kept in mind, as this can give spuriously low protein S function (277).

Complement activation throughout the cascade in HAE Both the paper on physical stress and the study of attacks showed for the first time directly a modest activation of complement beyond C2. A mild activation of C3 has previously been suggested by the indirect observation of case reports of increased radiolabelled C3 turnover. Ruddy et al. apparently found increased C3 turnover in 4 HAE patients, but controls were patients with kidney disease (278). Later the same values were compared to normals in another study, but statistics were not performed (279). The frequently cited study by Alper and Rosen (280) also used this method, and found C3-turnover normal during remission in one HAE patient (2.98%), and slightly increased (3.62%) in another during an attack, and concluded that «No important abnormalities of metabolism were found in hereditary angioedema». The finding of C3 and even terminal complement activation implicates that in addition to bradykinin, which presumably is the dominating mediator, the liberation of the potent anaphylatoxins C3a and C5a may contribute to the edema. C4a, which is liberated in advance of C3a and C5a in the cascade, but in higher amounts in HAE, is far less potent

40

Discussion

than C3a or C5a, and would therefore be expected to play a minor role (94,281). The anaphylatoxins liberate histamines which participate in edema formation. In the ventricular mucosa histamine is likely to increase acid secretion in HAE patients. This may explain the concurrence of ulcer and heartburn with attacks and why some reports have shown increased level of histamine in urine (14,47). Bradykinin may actually also stimulate histamine release (88) but the relative contribution of these mediators in liberating histamine in HAE is unknown. C3a and C5a are also potent chemotactic factors, and leucocytosis is in fact sometimes observed during attacks (282). Finally, this observation also lends support to the findings by a few authors of some beneficial effect of antihistamines in HAE patients (8). The effect of antihistamines and steroids is limited, however. They are insufficient as acute therapy and their use has not prevented fatal outcomes (283).

Applicability of HAE-studies to edema in non-HAE patients Hereditary angioedema is an important example of the so-called «experiments of nature», which include disorders that are characterized by a well-defined biochemical defect that provide an opportunity to define basic pathophysiological mechanisms. In addition to those previously mentioned in this thesis, several reports now show that the pathophysiological mechanisms studied in HAE patients may apply to other persons in extreme situations, although they originally have normal C1-INH production.

Clinical applicability of cascade blockers, bradykinin antagonists or C1-INH concentrate Cascade activation obviously play a role in cerebral pathology in nonHAE patients as well. Nafamostat mesilate (Fut -175), a potent synthetic inhibitor of the complement and kallikrein-kinin systems, reduces focal or diffuse cerebral ischemia in the acute stage after subarachnoid hemorrhage in humans (284). As previously discussed, bradykinin is proposed to play a key role in brain edema after cold lesion, concussive brain injury, traumatic spinal cord and ischemic brain injury, and by administering bradykinin antagonists, advantageous effects on brain edema in humans suffering from traumatic brain injury have lately been presented (KININ 95, L56,L58, L59). Bradykinin antagonists have recently been approved for clinical trials, and makes it

Discussion

41

possible for the first time to selectively block the effect of bradykinin on B-2, the most important bradykinin receptor (157,285-287). According to the formerly mentioned role of bradykinin, it would now be attractive to employ bradykinin blockers against snake venoms, acute pancreatitis, septic states, the capillary leakage following major operations or cardiopulmonary bypass, and streptokinase infusion. Some clinical trials are already running. These and the suggestions of other exiting trials mentioned above will eventually outline the importance of bradykinin in edematous states also in humans without HAE. Many of these beneficial effects could possibly also be achieved by using high doses of C1-INH concentrate, which will have the advantage of both blocking the production of bradykinin and limiting classical complement activation (288-298). It would be an advantage if C1-INH could be produced by recombinant techniques, thereby providing generous and affordable amounts for both virus-safe HAE substitution therapy and research purposes. The potential for a therapeutical use of C1-INH concentrate is a very challenging issue, and reaches far beyond substituting HAE patients. Bradykinin antagonists may also have therapeutical advantages in HAE patients, as it is not derived from human plasma, and the molecule is so small that administration via routes other than the intravenous may succeed.

Conclusions In addition to a broad presentation of clinical symptoms and triggering factors, original observations demonstrate the effect of estrogen substitution as a cause of flares of angioedema and suggest a role for HAE in provoking premature labour. Observations were based upon personal interviews and extensive questionnaires, with a 100% response rate, in a large family with 63 members. Guidelines for the interpretations of a new and modified functional assay for C1-INH are presented, along with original reference intervals for newborns. The significance of making the diagnosis of HAE at birth is demonstrated. For the first time all cascades are studied simultaneously in HAE patients, utilizing several new sensitive monoclonal antibodies not previously applied on this condition, and the study confirms that the

42

Discussion

disease seriously influence the kallikrein-kinin and the complement system. In the latter an activation beyond C3, throughout the terminal part is presented for the first time in HAE, suggesting a role for the anaphylatoxins in mediating symptoms. A modest increase in fibrinolysis during attack is confirmed and new observations of higher FVIIa levels in HAE patients and a modest thrombin production during attacks, suggest a minor involvement of coagulation as well. Finally, the study of the mechanisms underlying the capillary leakage in hereditary angioedema suggest a potential use of C1-INH concentrate also in the treatment of several disorders in humans not suffering from HAE.

43

References

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