Pathologic fibrinolysis as a cause of clinical bleeding.

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 16, NO. 3, 1990

Pathologic Fibrinolysis as a Cause of Clinical Bleeding

Normal hemostasis provides the vehicle for main tenance of normal vascular function, targeted to the de livery of oxygen and nutrients to dependent tissues. It consists of several components (Fig. 1) that function together dynamically not only to facilitate tissue perfu sion, but also repair of sites of vascular injury and pre vention of hemorrhage at locations where vessel integrity has been compromised.1 The typical physiologic re sponse to vessel injury is initially adherence of platelets to subendothelial sites followed by secondary aggrega tion and platelet plug formation. Activated platelets di rectly facilitate the assembly of components and activa tion of coagulation, which leads to generation of the enzyme, thrombin. Its action mediates conversion of cir culating fibrinogen to the insoluble protein, fibrin, which forms the insoluble proteinaceous component of the thrombus. Under physiologic conditions, this process then triggers the activation of the fibrinolytic system, responsible for the dissolution of the thrombus and crit ical restoration of vascular patency.

FIBRINOLYTIC SYSTEM In order to understand how altered fibrinolysis can predispose to bleeding, it is first necessary to review the

* Departments of Medicine, Biochemistry, and Pathology, Uni versity of Vermont, Burlington, Vermont. † Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma. ‡ Departments of Pathology, Medicine, and Biochemistry, Queen's University, Kingston, Ontario. § Departments of Medicine and Pathology, New England Dea coness Hospital and Harvard Medical School, Boston, Massachusetts. Reprint requests: Dr. Stump, Clinical Research, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080. 260

system and its components,2 which are listed in Table 1. It is composed of several proenzyme and enzyme forms of serine proteases and their inhibitors, members of the superfamily known as serpins. One exception is strep tokinase, a bacterial protein that, although not itself an enzyme, forms a very tight complex with plasminogen, which then assumes a conformational state as an active enzyme. The general overall scheme for fibrinolysis is shown in Figure 2. Fibrin formed as a result of the action of thrombin on fibrinogen triggers the proteolytic conver sion of the circulating proenzyme plasminogen into its active serine protease form, plasmin. Plasmin is the main fibrinolytic enzyme, responsible for the degradation of fibrin into its degradation products (FDP). The conver sion of plasminogen into plasmin is mediated by another group of serine proteases known as plasminogen activa tors. The activation process is regulated at each enzy matic step by a specific class of protease inhibitors. The main antiplasmin, α2-antiplasmin, is a very rapid inhib itor of plasmin and protects plasma against the very non specific proteolytic effects of plasmin, particularly against fibrinogen and other normal constituents. How ever, α2-antiplasmin is a very inefficient inhibitor of plas min at or near the fibrin surface, which facilitates the duration of the fibrinolytic activity of plasmin when it is generated at its physiologic site of action.3 The fibrin-targeted regulation of plasminogen acti vation is thus an important feature for efficient control of the fibrinolytic system.4 Currently known pathways for this process are shown in Figure 3. As mentioned pre viously, nonphysiologic activation can occur with the exposure of the fibrinolytic system to streptokinase. The remaining physiologic pathways are known as either "in trinsic" or ''extrinsic" pathways. The intrinsic pathway

Copyright © 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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DAVID C. STUMP, M.D.,* FLETCHER B. TAYLOR, Jr., M.D.,† MICHAEL E. NESHEIM, Ph.D.,* ALAN R. GILES, M.D.,* WALTER H. DZIK, M.D.,§ and EDWIN G. BOVILL, M.D.*

PATHOLOGIC FIBRINOLYSIS AS A CAUSE OF BLEEDING—STUMP ET AL

261

involves molecules of contact activation and inflamma tion but is relatively poorly characterized. Therefore it has been difficult to assess its pathophysiologic impor tance. The remaining two extrinsic pathways are mediated by two distinct plasminogen activators, tissue-type (t-PA) and urokinase-type (u-PA). Both are found in plasma and are capable of generating plasmin in the vi cinity of fibrin, where it is protected from rapid neutral ization by α2-antiplasmin. In addition, t-PA has been described in and isolated from many tissues as well as from the vessel wall, presumably originating in the vas cular endothelium. It is rapidly releasable into the blood stream in response to a number of provocative stimuli, such as venous occlusion, exercise, shock, acidosis, or

the administration of epinephrine or arginine vaso pressin. u-PA was first described in and is found pre dominantly in the urine, presumably from synthesis and secretion by the kidneys. Unlike t-PA, its release is not provocable by known stimuli. t-PA- and u-PA-mediated plasminogen activation is directly opposed by a number of plasminogen activator inhibitors (PAIs).5 The main PAI, known as PAI-1, nor mally circulates in plasma as well as being both stored in the platelet and bound to the extracellular matrix. It is synthesized and secreted by a number of cell types in tissue culture, especially the endothelial cell after injury by various biologic compounds, such as endotoxin. The importance of t-PA and PAI-1 to normal hemostasis is reflected by the thrombotic tendencies associated with

TABLE 1. Components of the Fibrinolytic System Plasminogen

Proenzyme form of the fibrinolytic enzyme

Plasmin

Active fibrinolytic enzyme

Tissue-type plasminogen activator (t-PA)

Enzyme present in tissues and released into blood; converts plasminogen to plasmin

Urokinase (u-PA)

Enzyme present in urine; converts plasminogen to plasmin

Single-chain urokinase-type plasminogen activator (scu-PA or prourokinase)

Single-chain form of urokinase present in urine and blood

Streptokinase

Streptococcal protein that indirectly activates the plasma fibrinolytic sys tem

Factor XII (Hageman factor), (pre)kallikrein, high molecular weight kinnogen

Component proteins of the intrinsic plasma system for conversion of plasminogen to plasmin

Antiplasmins

Molecules that inhibit the enymatic activity of plasmin

α2-antiplasmin

Specific rapid inhibitor of plasmin in human plasma

Antiactivators (PAI)

Molecules that inhibit the enzymatic activity of plasminogen activators

PAI-1

Specific rapid inhibitor of t-PA and u-PA present in endothelium and platelets and released into blood

PA1-2

Specific inhibitor of u-PA and t-PA present in placenta and neutrophils and released into blood during pregnancy

PA1-3

Specific inhibitor of u-PA present in urine and plasma identical to inhib itor of activated protein C


FIG. 1. Dynamics of thrombus formation and lysis. The triggering event is typically endothelial injury, but primary activation of platelets, coagulation, and fibrinolysis can occur. (From Stump et al. 1 Reprinted with permission.)


FIG. 2. Convergence of major coagulation and fibrinolytic pathways. The overall result is formation and reactive dissolution of fibrin. (From Stump et al. 2 Reprinted with permission.)

FIG. 3. Pathways of plasminogen activation. Plasmin is generated by intrinsic, extrinsic, or exogenous activators. Regulation occurs via the action of a number of natural inhibitors. (From Stump et al. 2 Reprinted with permission.)

deficient t-PA release or increased circulating levels of PAI-1. The dissolution of fibrin by plasmin is both ordered and efficient,6 as shown in Figure 4. Degradation of Factor XIIIa-mediated cross-linked fibrin leads to gen eration of cross-linked FDP, the prototype for which is known as D-dimer. Noncross-linked fibrin is also sus ceptible to plasmin proteolysis, yielding a variety of

noncross-linked FDP, the prototype for which is peptide Bβ 15-42. Because of the lack of substrate specificity of plasmin, fibrinogen is also quite susceptible to deg radation into noncross-linked FDP, including peptide Bβ 1-42, which has yet to be cleaved by thrombin dur ing the process of initiating fibrin polymerization. De tection and quantitation of these specific peptides be comes important when attempting to assess the


262

263

FIG. 4. Plasmin-mediated degradation of fibrin and fibrinogen. Specific peptides are cleaved at each step by the action of plasmin and provide detectable markers for its activity.

spectrum of plasmin activity in any given pathophysio logic setting.

ANALYSIS OF THE FIBRINOLYTIC SYSTEM WITH LABORATORY ASSAYS The last decade has seen a significant expansion of the ability to measure quantitatively specific components

of the fibrinolytic system within the laboratory. This has been facilitated both by the purification and character ization of t-PA, single-chain u-PA and the PAIs, as well as improvements in assay technology, such as develop ment of monoclonal antibody reagents. Table 2 lists the most relevant fibrinolytic components and the assay tech niques available with which, directly or indirectly, to measure them.7"22 To assess the nature of fibrinolysis in

TABLE 2. Currently Available Assays for Major Components of the Fibrinolytic System Component

Assay

Plasminogen

Plasmin activity after quantitative conversion with SK or UK

1

Plasmin

Direct fibrinolysis

8

α2-Antiplasmin residual function (indirect)

t-PA u-PA α2-Antiplasmin

Reference

9

Total fibrin(ogen) degradation products (FDP)

10

D-Dimer (cross-linked FDP)

11

Bβ 1-42 (fibrinogen FDP)

12

Bβ 15-42 (noncross-linked FDP

13

Plasmin -α2-antiplasmin complex

14

Plasmin generation by acidified plasma or its euglobulin fraction

15

Antigen by immunoassay

16

Plasmin generation after quantitative conversion to two-chain u-PA by acidified plasma or its euglobulin fraction

17


18

Rapid neutralization of exogenous plasmin by plasma Antigen by immunoassay

9 19

Rapid neutralization of exogenous t-PA by plasma

15


20

PA1-2


21

PA1-3


22

PA1-1




any given setting adequately, it is crucial to employ as many of these as possible. When the presence of enhanced fibrinolysis is sus pected, the assay result profile should resemble that shown in Table 3. Overall evidence for potential of ex cess generation of plasmin should be reflected by in creased euglobulin fibrinolytic activity or recovery of increased levels of circulating plasmin-α2-antiplasmin complexes. Indirect evidence of excess plasmin activity can be inferred from decreased plasma α2-antiplasmin activity as well as increased levels of circulating specific or nonspecific FDP. In the most extreme instances, loss of functional fibrinogen can be observed. The plasmino gen activators (more commonly t-PA) that mediate this process can also now be specifically quantitated func tionally as well as antigenically and can be variably el evated in certain pathophysiologic situations. Finally, PAI-1 activity may be decreased. The application of these assays to a number of di verse processes has led to recent refinement and redefi nition of the nature of fibrinolytic derangement in the clinical setting of bleeding. The remainder of this review will focus of selected pathologic situations that serve to help gain a better understanding of this overall process.

FAMILIAL FIBRINOLYSIS

present in the heterozygous state. 26-31 Until recently, all such individuals described were apparently lacking in both α2-antiplasmin function as well as in detection of presence of the circulating molecule. More recently, a dysfunctional but normally circulating α2-antiplasmin molecule has now been described in a Dutch family from Enschede.32 Molecular cloning of genomic DNA for this protein revealed the insertion of three base pairs coding for an extra alanine residue near the reactive site of the molecule. The modification has been shown to render the inhibitor not only inactive but, moreover, an attractive substrate for degradation by its target protease plasmin.33

Excess t-PA Two instances of increased circulating t-PA have now been described, both leading to a bleeding disorder. Plasma from the first patient, in whom a rapid euglobulin lysis time was evident, displayed chromotographic be havior and lysine-Sepharose affinity behavior consistent with high t-PA content. In addition, specific antibodies to t-PA quenched the euglobulin lysis activity in a concentration-dependent manner.34 A Spanish family has also been described with clinical hemorrhage in conjunc tion with increased euglobulin lysis activity. Measurable plasma proteolytic inhibitors were normal, but all mem bers had above normal total and lysine-absorbable t-PA levels measured by immunoassay.35

Congenital α2-Antiplasmin Deficiency Deficiency of PAI-1 A few instances of α2-antiplasmin deficiency have been described and can be accompanied by a bleeding tendency that may vary from mild to severe. Typically, more severe bleeding is associated with homozygous deficiency,23-25 whereas less severe symptoms are

Most recently, a patient with lifelong bleeding has been described with minimal euglobulin lysis activity but normal t-PA antigen levels. Further investigation re vealed a normally circulating but functionally defective

TABLE 3. Laboratory Markers of Enhanced Fibrinolysis Assay

Result

Euglobulin fibrinolytic activity

Increased

Plasmin-α2 antiplasmin complex formation

Increased

α2-Antiplasmin activity

Decreased

Fibrin(ogen) degradation products

Increased

Total FDP

(some or all)

D-Dimer Bβ 1-42 Bβ 15-42 Fibrinogen

Can be decreased (must exclude excess coagulation)

t-PA activity/antigen

Typically increased

u-PA activity/antigen

Rarely increased

PAI-1 activity

Decreased or unmeasurable


264


265

PAI-1 molecule.36 This important observation suggests not only a role for PAI-1 in predisposition to thrombosis, but also in maintenance of normal hemostasis.

FIBRINOLYSIS OF ACUTE LEUKEMIA


It has been well described that some patients with acute leukemia, especially acute promyelocytic leukemia (APL), are especially prone to hemorrhage.37 Evidence of both disseminated intravascular coagulation (DIC) and fibrinolysis can be present, especially concomitant with induction chemotherapy, and it is often difficult to dis tinguish which process is primary. Recently, it was dem onstrated that cultured myeloblasts, in fact, contain and can release PAs of both the t-PA and u-PA type.38 More recently, the plasma of patients with APL has been shown to contain increased levels of u-PA, but not t-PA, in association with increased fibrinolysis and bleeding.39 In such patients, the plasma level of functional α2antiplasmin may be the most useful parameter to follow in monitoring the potential need for antifibrinolytic therapy. 40-42

DISSEMINATED INTRAVASCULAR COAGULATION The process of DIC is known to be associated with multiple systemic illnesses, one of the most common of which is septic shock. The relative balance of coagulation/fibrinolysis in this setting has been poorly characterized until very recently. With the use of many of the fibrinolytic assays listed in Table 2, we and others have undertaken the investigation of the fibrinolytic re sponse to infusion of Escherichia coli endotoxin. As shown in Figure 5 within 1 hour after the infu sion of E. coli into a normal baboon,43 a marked increase in euglobulin fibrinolytic activity was observed, which was followed within 3 hours by an abrupt decrease. A concomitant fall in α2-antiplasmin activity and delayed rise in FDP similarly reflected plasmin generation. Fig ure 6 shows that fibrinopeptide A, and therefore coagu lation activation, was present within the first hour postinfusion and continued to rise through hour 2. Following this peak of thrombin activity, subsequent loss of func tional fibrinogen and recovery of D-dimer ensued. Whether fibrinogen loss was due to coagulation activa tion, plasmin degradation, or both cannot be firmly es tablished, but the measurable increase in circulating Ddimer demonstrates an unequivocal component of fibrinolysis. More precise definition of this fibrinolytic response can be made with the data displayed in Figure 7. A

FIG. 5. Plasmin generation in baboons after intravenous infusion of E. coli. Assays were performed by the methods referenced in Table 2 and the data displayed are the mean of four experiments. Fibrinolysis is evidenced by increased eu globulin fibrinolytic activity at 60 and 120 minutes with pro gressively decreasing α2-antiplasmin activity and increasing recovery of FDP.

continuous rise in plasma t-PA antigen occurred through the first 3 hours and was associated with an early (60 minute) rise in t-PA activity but a subsequent decrease to near or below baseline levels. As shown in the lowest panel, the decline in t-PA activity (and euglobulin fibri nolytic activity) was directly accounted for by a steep rise at 2 to 3 hours postinfusion of t-PA inhibitor activ ity, presumably PAI-1, which persisted until the 6-hour termination of the experiment. Interestingly, despite the profound antiactivator activity of the last 3 hours, levels


FIG. 6. Fibrin formation and lysis in baboons after intrave nous infusion of E. coli. Assays were performed by the meth ods referenced in Table 2, and the data displayed are the mean of four experiments. Fibrin formation is evidenced by an increased rate of generation of fibrinopeptide A over the first 120 minutes. Progressive fibrinolysis is evidenced by continuous generation of D-dimer. The cumulative effect of both is reflected by significant loss of functional fibrinogen.

of FDP, specifically D-dimer, continued to rise steadily. Our results are very consistent with those recently obtained in similarly designed studies in humans follow ing intravenous infusion of endotoxin44 or Rickettsia rickettsii.45 In these investigations, an initial t-PAmediated profibrinolytic response was also observed, fol lowed by an inhibitory response to t-PA in the former and consumption of α2-antiplasmin with generation of FDP in the latter. Overall, this would suggest that the initial response in septic DIC is procoagulant, followed


266

FIG. 7. Plasma t-PA in baboons after intravenous infusion of E. coli. Assays were performed by the methods referenced in Table 2, and the data displayed are the mean of four ex periments. Increased t-PA activity is apparent at 60 and 120 minutes in association with increased t-PA antigen. t-PA ac tivity subsequently fell despite continuously increasing t-PA antigen, due to markedly increased PAI (presumably PAI-1) activity apparent at 180 to 360 minutes.

by brief profibrinolysis then subsequent more pro nounced antifibrinolysis. Furthermore, the plasminogen activator mediating the response appears to be t-PA, which, interestingly, may be continuously fibrinolytic at local sites of fibrin formation despite the high circulating level of PAI activity. Further support for the key role of t-PA in the fi brinolytic response to DIC was obtained in experiments carried out in chimpanzees after administration of vary-


FIBRINOLYSIS AND LIVER TRANSPLANTATION The recent development of orthotopic liver trans plantation in patients with severe hepatic failure has led to the observation that intraoperative bleeding can be profound. To test the hypothesis that excess fibrinolysis might play a role, we performed several fibrinolytic as says in such patients before, during, and after surgical grafting.47 Varying results were obtained, and two ex treme examples are shown in Figure 8. The top panel describes a very stable patient who experienced little change in fibrinogen, α2-antiplasmin, FDP, or t-PA lev els. In contrast, the lower panel shows the course of a patient with intraoperative increases in both t-PA activity and antigen levels associated with loss of both fibrinogen and α2-antiplasmin with commensurate recovery of FDP. Overall analysis of a total of 25 patients studied to date is shown in Table 4. As can be seen, 20% of patients in

this series experienced severe fibrinolysis with four- to fivefold more blood loss. This observation of intraoper ative fibrinolysis is consistent with findings now reported in other series.48'49 Expectedly the fibrinolytic "burst" appeared to co incide with the anhepatic phase where normal hepatic clearance of circulating t-PA would be interrupted. Given the increased fibrin burden of surgery, the associated potential for plasmin generation could be profound. It is perhaps even more surprising that greater numbers of patients do not experience this profibrinolytic syndrome. The extreme blood loss associated with this type of pathologic fibrinolysis makes it imperative that predis posing factors be better defined and potential therapeutic interventions be investigated.

FIBRINOLYSIS IN AMYLOIDOSIS Several instances of increased plasma fibrinolytic activity in association with amyloidosis have been rec ognized. Three cases of fibrinolytic activation due to altered plasminogen activation have now been described in such patients. One case reported increased levels of t-PA antigen,50 one found a monoclonal antibody spe cifically binding PAI,51 and most recently a patient with a bleeding diathesis was shown to have five- to sevenfold increased levels of plasma u-PA activity.52

LOCAL FIBRINOLYSIS Postoperative bleeding has been commonly ob served in patients undergoing genitourinary surgery. Al though the bleeding can be well managed with epsilon aminocaproic acid (EACA), the exact mechanisms have not been well defined. It has been proposed that excess u-PA in urine may account for a significant component of the problem. We have recently applied fibrinolytic assays to both human urine and pooled prostatic fluid. As shown in Table 5, both contain significant levels of t-PA or u-PA, or both, at much higher ratios to total protein than that existing in normal plasma. The paucity of ef ficient inhibitors such as α2-antiplasmin and PAI-1 would further facilitate unopposed local genitourinary hyperfibrinolysis.

IATROGENIC FIBRINOLYSIS WITH THROMBOLYTIC THERAPY The most common fibrinolytic cause of bleeding in clinical medicine today is certainly thrombolytic ther apy. Although both streptokinase and urokinase have


ing mixes of Factor Xa and phospholipid vesicles in order to activate coagulation variably and thus generate thrombin in vivo.46 At points of maximal coagulation within 10 minutes postinfusion, peak levels of circulat ing t-PA rapidly reached approximately 900 IU/ml and 900 ng/ml. This represented sixfold more rapid release and 100-fold higher activity with 30-fold higher peak antigen levels than were observed in baboons receiving intravenous endotoxin. Moreover, this further defines the enormous potential to respond profibrinolytically to the stimulus of intravascular fibrin formation. The relatively short time interval necessary to achieve these peak plasma levels of t-PA further suggests that the mecha nism or mechanisms involved are more likely stimula tion and release rather than cellular t-PA synthesis and secretion. In contrast to injection of endotoxin, direct proteolytic activation of coagulation did not lead to ris ing PAI levels, suggesting that the late antifibrinolytic response to endotoxin is specific, perhaps to the associ ated cell injury rather than actual fibrin formation and t-PA release. This clear and obvious physiologic fibrinolytic re sponse makes it difficult to propose offering antifibri nolytic therapy to the bleeding patient with septic DIC, since t-PA release probably represents a key protective mechanism against the adverse effects of microvascular thrombus formation. Nonetheless, a fibrinolytic compo nent must be considered when such bleeding is occur ring, particularly if it is life-threatening, although such hemorrhage should be expected to subside rapidly when the stimulus for coagulation activation is removed and plasma t-PA levels fall rapidly within minutes through normal rapid clearance mechanisms.

267



268

FIG. 8. Intraoperative fibrinolysis during orthotopic liver transplantation. Plasma samples were collected at the times indi cated, and assays were performed by the methods referenced in Table 2. Case to case variability was evident; minimal evidence of t-PA release and plasmin activity was observed in the patient represented by the top panel. In contrast, marked t-PA release was seen during the anhepatic phase in the patient represented by the lower panel. Systemic plasmin generation was marked by loss of α 2 -antiplasmin activity and functional fibrinogen with recovery of circulating FDP. (From Dzik et al. 47 Reprinted with permission.)

been available for the treatment of acute pulmonary em bolism and deep vein thrombosis for more than 20 years, recognition and fear of bleeding risk have limited their widespread application. In the last decade, however, the clear impact of at last three thrombolytic agents, strep tokinase, recombinant t-PA (rt-PA), and anisoylated streptokinase-plasminogen activator complex (anistreplase [APSAC]) on improved mortality from myocar dial infarction have led to more widespread use of throm bolytic therapy.53

Because all thrombolytic agents are effective via the direct or indirect induction of plasminogen activa tion, a hemostatic defect invariably results. Thus, po tential sites of active bleeding must be considered be fore therapy is instituted, and treatment avoided in patients with active internal bleeding, a history of cere brovascular accident, recent major surgery or trauma, known intracranial neoplasm or vascular defect, a known bleeding diathesis, or severe uncontrolled hyper tension. Despite precautionary prescreening for these


Zero/Mild (n = 10)

Moderate (n = 10)

Severe (n = 5)

Fibrinogen nadir (% baseline)

>90

40-90

75

25-75

Bleeding related to disturbed fibrinolysis.

Bleeding from a gut lesion as a cause of seizure.

Angiodysplasia as a cause of colonic bleeding in the elderly.

[Hemobilia as a rare cause of gastrointestinal bleeding].

[Ileal varices as a rare cause of lower gastrointestinal bleeding].

Malignant hypertension as a cause of massive intestinal bleeding.

Cytomegalovirus as a cause of isolated severe ileal bleeding.

Dieulafoy's vascular malformation as a cause of large intestinal bleeding.

Hypofibrinogenaemia as a cause of bleeding in chronic myeloid leukaemia.

Thrombin activatable fibrinolysis inhibitor as a bleeding predictor in liver transplantation: a pilot observational study.

Massive Bleeding as the First Clinical Manifestation of Metastatic Prostate Cancer due to Disseminated Intravascular Coagulation with Enhanced Fibrinolysis.

Local fibrinolysis of esophagus and stomach as a cause of hemorrhage in liver cirrhosis.

[Pancreatic heterotopia as an unusual cause of upper gastrointestinal bleeding].

A Rare Cause of Obscure Gastrointestinal Bleeding.

No increased systemic fibrinolysis in women with heavy menstrual bleeding.

Bleeding in renal failure: a possible cause.

A Deadly Connection: Aortoenteric Fistula as a Cause of Acute Upper Gastrointestinal Bleeding.

Duodenal plexiform fibromyxoma as a cause of obscure upper gastrointestinal bleeding: A case report.

Bleeding in renal failure: a possible cause.

Fibrinolysis and the bleeding tendency in patients with hepatosplenic schistosomiasis.

Complex haemostatic abnormalities as a cause of bleeding after neurosurgery in a patient with Gaucher disease.

Acquired haemophilia A as a cause of recurrent bleeding episodes in the elderly.

Clinical problem-solving. A not-so-obscure cause of gastrointestinal bleeding.

Intravascular Papillary Endothelial Hyperplasia of the Jejunum as a Cause of Obscure-Overt Gastrointestinal Bleeding.