Adrenal insufficiency is a contraindication for omalizumab therapy in mast cell activation disease: risk for serum sickness.

Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer's Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting.

[Surgical interventions in patients with systemic mast cell activation disease : Recommendations for perioperative management]. / Chirurgische Eingriffe bei Patienten mit systemischer Mastzellaktivierungserkrankung : Empfehlungen für das perioperative Management.

BACKGROUND: Systemic mast cell activation disease (MCAD, prevalence 5-10%) is a multifactorial, polygenic disease with multisystemic symptoms that is characterized by an unregulated increased release of mast cell mediators and an accumulation of activated mast cells potentially in all organs and tissues. Due to the high prevalence of the disease, physicians involved in surgical, anesthesiological and interventional procedures are often unknowingly faced with MCAD patients experiencing unexpected preoperative, intraoperative and postoperative complications, if no mast cell-specific treatment regimens have been applied. OBJECTIVE: The findings from a literature search, consensus recommendations of the various international expert groups and extensive own experience in the treatment of MCAD patients enable an empirical and evidence-based care of MCAD patients in association with invasive procedures. RESULTS AND CONCLUSION: Due to the high prevalence of MCAD in the population, it can be assumed that patients with MCAD are correspondingly frequently represented in the surgical patient collective. When MCAD-specific peculiarities are preventively considered in the anesthesiological and surgical procedures in patients with proven or suspected mast cell disease, MCAD patients should not be classified as being at risk.

[Surgical interventions in patients with mast cell activation disease. Aspects relevant for surgery using the example of a cholecystectomy]. / Chirurgische Eingriffe an Patienten mit Mastzellüberaktivitätserkrankung. Operationsrelevante Aspekte am Beispiel einer Cholezystektomie.

BACKGROUND: Systemic mast cell activation disease (MCAD) is characterized by an increased and unregulated release of mast cell mediators which can evoke a multifaceted clinical picture often resembling irritable bowel syndrome or fibromyalgia. Because of the considerable prevalence (~ 17 %) of MCAD surgeons are frequently unwittingly confronted with MCAD patients in whom unexpected intraoperative and postoperative complications may occur. Therefore, knowledge of the particular requirements is of relevance for surgical treatment of MCAD patients. OBJECTIVE: The present paper outlines a concept of surgical treatment of MCAD patients based on the literature which is illustrated by a case report on emergency laparoscopic cholecystectomy. CONCLUSIONS: Due to the high prevalence of MCAD in the general population it can be assumed that the frequency in the surgical patient population is similar. If a patient has MCAD, specific characteristics should be taken into account in the surgical procedure to avoid increased operative and complication risks resulting from MCAD.

The coagulation system of extremely preterm infants: influence of perinatal risk factors on coagulation.

OBJECTIVE: Little is known about the influence of preterm delivery and perinatal risk factors on development and expression of the coagulation system in extremely preterm infants. The objective of this study was to determine reference values for the components of the coagulation system at the first day of life in extremely preterm infants. STUDY DESIGN: Components of the coagulation system were examined retrospectively in 132 extremely preterm infants. Patients were grouped according to clinical criteria for preterm delivery: group A: maternal indication; group B: uteroplacental dysfunction; group C: systemic inflammation. RESULT: Levels of coagulation factors VII and X rose with increasing gestational age, whereas fibrinogen and coagulation factors II, V and VIII remained constant. Levels of factors V and VIII were higher than those of vitamin K-dependent factors. If preterm delivery was caused by placental disorder (group B) or chorioamnionitis (group C), levels of factor II, VIII and X were significantly lower, whereas factor V and VII levels did not differ. In group C fibrinogen levels in group C were higher compared with group A. CONCLUSION: Identification of perinatal risk factors may help to define patients at risk of bleeding disorders.

Evidence for mast cell activation in patients with therapy-resistant irritable bowel syndrome.

Previous findings suggested an involvement of mast cells in the pathogenesis of irritable bowel syndrome (IBS). The pathophysiological significance of mast cells is defined both by their number in tissue and by their activity. In the present pilot study activity of mast cells in patients with therapy-resistant IBS was investigated for the first time systematically. Twenty patients with therapy-resistant IBS were investigated for the presence of a pathologically increased mast cell mediator release by means of a validated structured interview suitable to identify mast cell mediator-related symptoms and by determing selected surrogate parameters for mast cell activity. Nineteen of the 20 patients presented mast cell mediator-related symptoms. Pathologically increased mast cell activity-related coagulation and fibrinolysis parameters were detected in 11 of 12 patients investigated in that regard. One patient had an elevated level of methylhistamine in urine. The present data provide evidence that in patients with therapy-resistant IBS a pathologically increased systemic mast cell activity may occur with high prevalence. This finding fits to the idea of an assumed contribution of activated mast cells in the pathophysiology of IBS.

[Studies on low protein C-expression in severe sepsis]. / Untersuchungen zur verminderten Protein-C-Expression in der schweren Sepsis.

OBJECTIVES: Low concentration of protein C in severe sepsis may be associated with increased morbidity and mortality. The present study was designed to clarify to what extent there are differences in the time course of plasma concentrations of protein C in patients with systemic inflammatory response syndrome or patients with severe sepsis. In addition, the cause of decreased expression of protein C in severe sepsis was examined. METHODS: 32 patients with severe sepsis and 10 patients with systemic inflammatory response syndrome admitted to a surgical intensive care unit were enrolled in the study. While the patients stayed in the intensive care unit protein C plasma concentrations and the clotting factors thrombin-antithrombin-complex and factor VII were determined twice weekly. RESULTS: Comparing patients with severe sepsis and systemic inflammatory response syndrome there was no significant difference concerning plasma levels of protein C, thrombin-antithrombin-complex and factor VII. In contrast, surviving patients with severe sepsis exhibited significant higher protein C levels compared to non-survivors. In addition, significant lower plasma levels of thrombin-antithrombin-complex were determined in survivors compared to non-survivors. However, factor VII displayed no significant group difference. CONCLUSIONS: Surviving patients with severe sepsis exhibited higher plasma concentrations of protein C than patients who died during severe sepsis. The lower plasma concentrations of protein C in non-survivors may be caused by an increased turnover of protein C served as endogenous anticoagulant in sepsis associated activation of coagulation.

The fibrinolytic system in chronic renal failure.

BACKGROUND: Patients with chronic renal failure (CRF) face a high risk of cardiovascular morbidity and mortality. Impaired fibrinolysis has recently been acknowledged to function as a risk factor for cardiovascular ischemic complications. Whether changes in fibrinolytic function contribute to the increased cardiovascular risk in CRF, however, remains unclear. METHODS: In the present study, tissue-plasminogen activator (t-PA) and its main antagonist plasminogen activator inhibitor-1 (PAI- 1) were determined in 12 subjects with normal renal function (group A) [serum creatinine (Cr) <1.3 mg/dl], 24 patients with impaired renal function (Cr 1.3-6.5 mg/dl) (group B) and 22 patients with endstage renal disease (ESRD) on hemodialysis (Cr>6.5 mg/dl) (group C). RESULTS: Plasma concentrations of PAI-1 and t-PA antigen as well as the PAI-1:t-PA molar ratio were unchanged in group B as compared to group A. However, in ESRD patients (group C), t-PA concentrations markedly decreased [13.7 +/- 2.9 ng/ml vs. 32.8 +/- 4.7 ng/ml (group B, p <0.01) and 35.4 +/- 8.4 ng/ml (group A, p <0.01)] while PAI-1 antigen concentrations remained in the control range. Thus, the PAI-1:t-PA molar ratio significantly increased in group C patients [12.4 +/- 4. 0 vs. 6.0 +/- 2.5 (group B; p<0.01) and 4.5 +/- 1.7 (group A; p<0.01]. CONCLUSIONS: From our data it may be suggested that fibrinolysis is markedly disturbed in ESRD due to a decreased availability of t-PA. Thus, it may be speculated that the development of atherothrombotic events in hemodialysis patients is, at least in part, due to an impaired fibrinolysis.

[An uncommon cause of severe soft tissue bleeding during phenprocoumon treatment]. / Seltene Ursache einer schweren Weichteileinblutung unter Therapie mit Phenprocoumon.

HISTORY AND ADMISSION FINDINGS: A 66-year-old patient presented to our clinic with extensive left arm and left flank haematomas, anaemia, a prolonged activated partial thromboplastin time (aPTT), and reduced factor IX activity 6 weeks after prosthetic mechanical aortic valve implantation. INVESTIGATION: Treatment with both vitamin K and a single injection of factor IX concentrate led to normalization of the activated partial thromboplastin time and factor IX activity, which remained constant for several days. No acquired factor IX inhibitor was detectable. Analysis of exon 2 of the factor IX gene revealed a C-->T mutation in codon 10 of the propeptide region, resulting in the substitution of alanine by valine. Echocardiography revealed a significant paravalvular leak. TREATMENT AND COURSE: The substitution of valine for alanine in the factor IX propeptide leads to an impaired affinity of factor IX to the vitamin K-carboxylase complex. In this situation, treatment with coumarin derivatives can profoundly reduce factor IX activity and result in severe bleeding episodes. This patient was re-exposed to warfarin under close hematological monitoring. After 4 days factor IX activity had decreased to 15%, which was associated with an increase of the aPTT and a mild decrease of the prothrombin time. Due to rapid progression of the paravalvular leak and almost impossible long-term orale anticoagulation with coumarin derivatives, we recommended replacement of the prosthetic mechanical valve with a biological device. CONCLUSION: The development of severe bleeding in the context of initiating warfarin therapy raises the suspicion of a factor IX propeptide mutation. The initial screening test is the activated partial thromboplastin time, which is elevated in the presence of the mutation. If concomitantly diminished factor IX activity is found the factor IX propeptide mutation should be excluded. Use of lifelong coumarin derivatives is contraindicated in patients with this mutation. However, a general screening of the activated partial thromboplastin time after coumarin initiation is not justified by cost/benefit analysis.

Fibrinolytic function in diuretic-induced volume depletion.

Accumulating evidence suggests that the renin-angiotensin system (RAS) may participate in the regulation of fibrinolytic function. In clinical studies, however, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonist losartan have failed to consistently affect endogenous fibrinolysis. Because such an effect may depend on the degree of prestimulation of the RAS, we have studied parameters of fibrinolytic function in 15 healthy volunteer subjects during baseline (day 1) and after 10 days of treatment with 25 mg of hydrochlorothiazide (HCT)/day (day 11). On the last day of the study (day 12), a single oral dose of 50 mg of losartan was given to the volunteers in addition to HCT and fibrinolytic function was assessed at the peak effect of losartan (5 h later). Plasma renin activity (PRA) was significantly stimulated during diuretic treatment (1.35 +/- 0.21 v 0.34 +/- 0.06 ng mL(-1) x h(-1) [P < .001]) and further increased after losartan (6.39 +/- 1.16 ng mL(-1) x h(-1) [P < .001]). No effects of either the diuretic or losartan could be observed on tissue-type plasminogen activator (t-PA) antigen concentration and activity. However, 10 days of treatment with HCT significantly increased plasminogen activator inhibitor-1 (PAI-1) antigen (26.8 +/- 5.8 v 21.1 +/- 3.4 ng/mL [p = .037]). In addition, PAI-1 activity was also tentatively raised by HCT treatment (5.48 +/- 1.82 v 3.88 +/- 0.79 IU/mL [P = .067]). In spite of the marked further rise in PRA after losartan, the stimulation of PAI-1 antigen and activity was blunted by losartan (24.4 +/- 3.6 ng/mL and 4.55 +/- 0.99 IU/mL, respectively). Our results demonstrate that volume depletion induced by HCT treatment is associated with a rise in PAI-1. Acute administration of losartan is capable of blunting this effect, suggesting that the angiotensin II type 1 receptor may participate in this effect of angiotensin II.

[Renin-angiotensin-aldosterone system and fibrinolysis]. / Renin-Angiotensin-Aldosteron-System und Fibrinolyse.

Experimental, genetic and clinical evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the pathogenesis of thromboembolic cardiovascular disorders such as coronary heart disease. This interrelationship may involve mechanisms other than changes in arterial blood pressure. In addition to various possible interactions, accumulating evidence suggests that the RAAS is involved in the regulation of the fibrinolytic system. Several recent studies have shown that stimulation of the RAAS may be associated with an activation of plasminogen activator inhibitor 1 (PAI-1). Since profibrinolytic factors (especially tissue plasminogen activator [t-PA]) remain unchanged, increased activity of the RAAS may thus alter the fibrinolytic balance towards a decreased fibrinolytic activity. These findings may be of special importance for a variety of clinical problems such as the long-term effect of a low NaCl-intake on cardiovascular morbidity and mortality and the possible value of drugs indirectly or directly interfering with the RAAS such as diuretics, ACE-inhibitors and angiotensin II Type 1 (AT1) receptor antagonists.

Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects.

Recent evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the regulation of fibrinolytic function. Angiotensin II (Ang II) is the primary candidate to mediate this inter-relationship, since this peptide is capable of stimulating plasminogen activator inhibitor-1 (PAI-1) in vitro and in vivo. It has been suggested that aldosterone may also modulate fibrinolysis, possibly by interacting with Ang II. The present study therefore investigates the effect of short-term treatment with the synthetic mineralocorticoid fludrocortisone (F) on fibrinolytic function. Ten healthy male volunteers, aged 25 to 30 years, on a constant intake of 160-180 mmol Na(+) and 60-80 mmol K(+), were studied on a control day (C1), after two days of oral administration of F (0.1 mg b.d.), and again three days after cessation of F (C2). F was associated with a marked decrease in plasma renin activity (PRA) from 0.91 +/- 0.45 ng ml(-1) h(-1) to 0.34 +/- 0.29 ng ml(-1) h(-1) (p=0.005), which returned to the baseline range at C2 (0.65 +/- 0.45 ng ml(-1) h(-1); p=0.032). The experimental protocol was not associated with significant changes in the activity or antigen concentration of tissue plasminogen activator (t-PA). PAI-1 exhibited a circadian rhythm with highest values at 0800 hours (41.8 +/- 9.1 ng/ml), decreasing by 1230 hours (22.6 +/- 5.9 ng/ml), with a further decrease at 1630 hours (12.3 +/- 3.1 ng/ml). At all three time points, PAI-1 remained unchanged by the mineralocorticoid. Our results therefore do not support a major mineralocorticoid effect on PAI-1. However, our study does not exclude a modulatory role of F, since unchanged PAI-1 could be observed in spite of a marked suppression of the RAAS.

Standardization of the PFA-100(R) platelet function test in 105 mmol/l buffered citrate: effect of gender, smoking, and oral contraceptives.

The PFA-100(R) (PFA) diagnostic system for the detection of platelet dysfunction was evaluated to determine reference ranges in a normal population. The PFA determines the primary haemostasis capacity (PHC) of anticoagulated whole blood, expressed by the system's closure time (CT). In this study the CT reference ranges were determined for blood samples collected in 105 mmol/l (3.2%) buffered citrate and the effect of gender, smoking, and use of oral contraceptives on reference ranges was assessed. Each of the 309 healthy blood donors from five blood centres was confirmed to have normal platelet function before inclusion in the study. Blood samples were tested in duplicate with both the collagen/epinephrine (Col/Epi) and collagen/ADP (Col/ADP) test cartridges. PFA reference ranges (90% central intervals of measured closure times) for both cartridge types were similar for all groups. Subgroup analysis showed that neither gender nor oral contraceptive usage had any effect on PHC. The 95% cut-off value for the Col/Epi CT was slightly higher for smokers than for non-smokers, an effect more pronounced in female than in male donors. However, the small difference did not justify establishment of specific reference ranges for smokers. Data from all included subjects were pooled to calculate the CT reference ranges for blood samples collected in 105 mmol/l buffered citrate (Col/Epi 82-150 s; Col/ADP 62-100 s). Normal levels of fibrinogen, as well as normal platelet counts and normal haematocrit levels, appeared not to influence the PHC. Because slight but significant differences of the reference ranges were observed between some of the participating sites, in-house confirmation of these reference range guidelines is recommended.

Lethal capillary leak syndrome after a single administration of interferon beta-1b.

Interferon beta-1b (IFNbeta-1b) is a potent immunomodulatory drug in the treatment of MS. We report a lethal capillary leak syndrome after the administration of IFNbeta-1b in a patient with disseminated white matter disease, monoclonal gammopathy, and acquired C1 inhibitor (C1-INH) deficiency. IFNbeta-1b may cause a transient release of proinflammatory cytokines finally resulting in an uninhibited activation of the complement cascade in patients with C1-INH deficiency.

Effects of captopril on fibrinolytic function in healthy humans.

Several lines of evidence point to an interrelation of the renin angiotensin system (RAS) with the endogenous fibrinolytic system. In the present study, we have therefore investigated the effect of the ACE-inhibitor captopril on various parameters of the fibrinolytic system in healthy volunteer subjects. 10 male subjects aged 28-38 years were given captopril 25 mg b.i.d. over 2 weeks. Venous blood was drawn before and at the end of the treatment period at 09.00 AM, after the volunteers had received their last dose of captopril by 07. 30 AM. Blood samples were processed for the determination of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both parameters were determined with respect to their abundance (as antigen concentrations) and function (activity). In addition, the concentration and activity of the von Willebrand factor were also determined. Two weeks of captopril treatment had no significant effect on any of the above mentioned parameters. Our results thus show that short-term treatment with the ACE-inhibitor captopril, at least in healthy subjects on an unrestricted NaCl intake, does not affect the fibrinolytic balance between t-PA and PAI-1 or the von Willebrand factor.

[Progress of acute liver failure and indications for liver transplantation]. / Verlauf des akuten Leberversagens und Indikationsstellung zur Lebertransplantation.

OBJECTIVE: To analyse the course of acute liver failure and the indications for liver transplantation. PATIENTS AND METHODS: In 16 patients who developed acute liver failure between July 1992 and July 1997 the indications for liver transplantation and total survival time were analysed retrospectively. RESULTS: Intensive medical care (ventilation, dialysis) was necessary in 60% of the patients to bridge organ failure until liver transplantation. In 14 patients liver transplantation was indicated. Eleven of the patients, with a minimal Quick value of less than 10%, presented with the prognostically poorest London criteria. In two patients the combination of three additional criteria of the London classification led to liver transplantation being indicated. In one patient with Wilson's disease the transplantation was undertaken despite good clotting factor synthesis, because an encephalopathy occurred. In two patients liver transplantation was not undertaken even though indicated, in one because liver functions improved, in the other because necrotizing pancreatitis had occurred. In another patient, who had been poisoned by eating the mushroom Amanita phalloides, the attempted transplantation was cut short, because intestinal necrosis had developed, and the patient died during the operation. Nine of the eleven patients who had a transplantation and three of the four treated conservatively survived. CONCLUSION: The 60-day survival rate in this series, achieved in a recently established transplantation programme, is high (12 of 16; 75%), being comparable to those in larger transplantation centres.

Antihypertensive drug treatment and fibrinolytic function.

Thromboembolic complications such as ischemic stroke and myocardial infarction are significantly more frequent in patients with arterial hypertension. From the available intervention studies, it appears that pharmacologic treatment of hypertension-at least with diuretics and beta-blockers-may more effectively protect against cerebrovascular as compared to coronary thromboembolic events. Whether other antihypertensive substances provide a more effective protection with respect to cardiac morbidity and mortality is the subject of numerous studies presently underway. These studies will help to answer the question of whether the extent of protection from coronary events during antihypertensive treatment depends on factors beyond blood pressure control. The fibrinolytic system is crucially involved in the pathogenesis of thromboembolic events. One determinant of this system is the balance between plasminogen activators (tissue-type plasminogen activator [t-PA]) and inhibitors (plasminogen activator inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least some of the drugs used in the treatment of hypertension may alter the activity of the fibrinolytic system. Scarce and controversial data with respect to such an interaction exist with respect to diuretics, beta-blockers, and calcium antagonists. In addition, experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin. Thus, antihypertensive drugs acting within the renin angiotensin system should exert effects also within the fibrinolytic system. However, results from clinical studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor antagonists do not unequivocally support such a concept. The discrepancy in the results may, at least in part, be explained by studies performed in healthy volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis only during stimulation of the renin angiotensin system by NaCL restriction.

Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy.

Bleeding complications are the most common and unwanted side-effect of oral anticoagulant therapy. We report three patients in whom mutations in the factor IX (FIX) propeptide were found to cause severe bleeding during coumarin therapy. Strikingly, the bleeding occurred within the therapeutic ranges of the prothrombin time (PT) and international normalized ratio (INR). In all three patients coumarin therapy caused an unusually selective decrease of FIX activity (FIX:C) to levels below 1-3%. Upon withdrawal of coumarin, FIX:C increased to subnormal or normal values of 55%, 85% and 125%, respectively. Analysis of the FIX gene revealed two different missense mutations affecting the Ala-10 residue in the propeptide coding region: Ala[GCC] to Val[GTC] in two patients and Ala[GCC] to Thr[ACC] in one patient. No further mutation was detected by screening 195 random blood donors for mutations at Ala-10, thus excluding a frequent polymorphism at this position. The mutation in the FIX propeptide at a position which is essential for the carboxylase recognition site causes a reduced affinity of the carboxylase enzyme to the propeptide. This effect leads to an impaired carboxylase epoxidase reaction which is decisively triggered by the vitamin K concentration. Determination of FIX and APTT in addition to PT and INR is therefore recommended in coumarin-treated patients with an uncommon bleeding pattern.

Severe bleeding in two patients due to increased sensitivity of factor IX activity to phenprocoumon therapy.

Two male patients with severe and recurrent bleeding episodes under phenprocoumon therapy are reported. Both patients exhibited a strong decrease of their factor IX activities below 1% of normal, whereas the activities of the vitamin K-dependent factors prothrombin, VII, and X were found to be within or above the expected therapeutic ranges of 20-40%. Upon removal of phenprocoumon and substitution with vitamin K, the factor IX activities increased to 85% and 55%, respectively. Reexposition to phenprocoumon in one patient confirmed the rapid and selective decrease of the factor IX activity. These findings provide the first report of an abnormally high sensitivity of factor IX activity to oral anticoagulant therapy.

[Recurrent arterial thromboembolism in hereditary hypoplasminogenaemia]. / Rezidivierende arterielle Thromboembolien bei hereditärer Hypoplasminogenämie.

HISTORY: A 26-year-old man sustained a wasp bite 5 years ago which caused arterial embolism to the right brachial artery. Now he again had a wasp bite with allergic reaction and an arterial embolus to the left brachial artery. 2 days later, after embolectomy and heparinisation, he had a cerebrovascular accident due to an embolus to the left internal carotid artery. 15 days later, despite oral anticoagulation (Quick value 10%), he had an embolism to the left femoral artery. INVESTIGATIONS: The source of the emboli was found by echocardiography to be a spherical floating thrombus on the aortic valve. The plasminogen level was only 45-61%. His mother and sister also had a low plasminogen level, i.e. he had congenital plasminogen deficiency. TREATMENT AND COURSE: At surgery, when the thrombus had been removed, a slit-like defect was found on one of the aortic leaflets and covered with a pericardial patch. At first heparin then phenprocoumon were administered, plus 250 mg ticlopidine twice daily. There have been no further complications. CONCLUSION: As the patient's fibrinolysis activity was normal, additional, probably allergic, factors must have been present to disturb the equilibrium between thrombogenesis and fibrinolysis thus causing thrombosis at a predisposed site.