Von Willebrand disease-associated angiodysplasia: a few answers, still many questions

Authors


Correspondence: Pier Mannuccio Mannucci, Scientific Direction, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital, Via Pace 9, 20122 Milan, Italy.

E-mail: piermannuccio.mannucci@policlinico.mi.it

Summary

The association between angiodysplasia and von Willebrand disease (VWD) has been known for more than 40 years. Bleeding in the gastrointestinal tract associated with angiodysplasia worsens the clinical course of this inherited haemorrhagic disorder and management may become difficult and challenging. Angiodysplasia associated with acquired defects or dysfunctions of von Willebrand factor (VWF) has also been reported in a variety of conditions such as monoclonal gammopathies, Heyde syndrome and in carriers of ventricular assist devices. The most recent advances concerning the mechanistic, clinical and therapeutic aspects of VWD-associated angiodysplasia are summarized in this review, together with the limitations of our knowledge that warrant further research in the frame of international cooperation.

Von Willebrand factor (VWF) is a large multimeric plasma glycoprotein that mediates platelet adhesion to the subendothelial matrix and acts as a carrier for coagulation factor VIII (FVIII) in plasma. VWF is produced constitutively in endothelial cells, where, under normal conditions, it is stored together with several other substances in Weibel-Palade bodies in the form of ultralarge multimers, that are processed by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type I motif-13) after secretion in plasma (Franchini & Lippi, 2007a). VWF – physiologically located in megakaryocytes, platelets, endothelial cells and the subendothelial matrix (Ruggeri, 2001)– plays a pivotal role in primary haemostasis, and its deficiency or dysfunction causes von Willebrand disease (VWD), a relatively common inherited bleeding disorder (Mannucci et al, 2009). Acquired qualitative or quantitative abnormalities of VWF (acquired von Willebrand syndrome, AVWS) occur seldomly in association with a variety of conditions, including solid and haematological malignancies, autoimmune and cardiovascular disorders (Federici et al, 2000; Franchini & Lippi, 2007b). Since 1967, when the first case was described (Quick, 1967), many investigators have reported the association between VWD, AVWS and angiodysplasias (Warkentin et al, 2003; Makris, 2006). The latter are vascular ectasias, affecting first the submucosal veins, then mucosal venules and capillaries and sometimes developing into arteriovenous communications (Fig 1). Angiodysplasia most often occurs as multiple lesions all along the gut, mainly in patients older than 65 years. This review focuses on these vascular abnormalities, which are recognized as a major cause of gastrointestinal bleeding (GI) in congenital VWD as well as in AVWS, in the light of recent advances regarding the link between VWF and angiogenesis.

Figure 1.

Angiodysplasia of the ileum as seen by video-endoscopy in a 70-year-old patient with type 3 von Willebrand disease and recurrent gastrointestinal bleeding.

Von Willebrand factor and angiogenesis

A regulatory role for VWF in angiogenesis was postulated upon the clinical observation that qualitative or quantitative VWF defects are associated with the frequent occurrence of neoangiogenesis, particularly in the gastrointestinal (GI) tract. Recent research provided the molecular mechanisms underlying this association (Lenting et al, 2012). Starke et al (2011) demonstrated that lack of VWF in the Weibel-Palade bodies of endothelial cells triggers angiogenesis, as documented experimentally by a markedly increased proliferation of these cultured cells in the absence of VWF, and by the occurrence of increased neo-vascularization in VWF-deficient mice. The molecular basis for this effect is a VWF-dependent negative modulation of angiogenesis, which occurs via multiple intra- and extra-cellular pathways involving vascular endothelial growth factor receptor-2 (VEGFR-2), integrin αvβ3 and angiopoietin-2, the latter being both ligands for VWF (Starke et al, 2011) (Fig 2). Other VWF-associated pro-angiogenic regulators, such as galectin-1 and -3, connective tissue growth factors (CTGF) and the insulin-like growth factor binding protein-7 (IGFBP7) may be involved in this process (van Breevoort et al, 2012; Odouard et al, 2012; Pi et al, 2012). In agreement with data suggesting that VWF is a negative modulator of angiogenesis are the findings reported by Gritti et al (2011), that circulating endothelial cells and cytokines involved in angiogenesis are increased in patients with VWD. Collectively, these studies indicate that VWF deficiency or dysfunction in congenital VWD and AVWS does contribute to promote neoangiogenesis.

Figure 2.

(Courtesy of Anna Maria Randi and Richard Starke): A model explaining how von Willebrand factor (VWF) may control the angiopoietin-Tie-2 pathway and angiogenesis. In stable, mature blood vessels, angiopoietin-1 (Ang-1) is produced by mural cell signals through the Tie-2 receptors and promotes stability of the endothelial cell (EC) monolayer and its quiescence. Ang-2 can antagonize Ang-1 signalling and promote destabilization of junctions and angiogenesis. Ang-2 is normally stored in Weibel Palade Bodies (WPB), together with VWF and several other components. Because VWF is required for WPB assembly, a decrease in VWF levels in EC results in released depletion of Ang-2 from the EC, which can then bind to the Tie-2 receptor and antagonise the effects of Ang-1.

Angiodysplasia and congenital von Willebrand disease

The GI bleeding complications associated with angiodysplasia are a severe clinical symptom in VWD (Fressinaud & Meyer, 1993; Castaman et al, 2012). Affected patients may need to be hospitalized for long periods of time and often require several weeks of treatment leading to high costs and poor quality of life. In an international retrospective survey conducted in 4503 VWD patients from 297 haemophilia centres (Fressinaud & Meyer, 1993), angiodysplasia was reported exclusively in type 2 (2%) and type 3 (4·5%) VWD, i.e. in patients lacking high molecular weight (HMW) multimers. More recently, Castaman et al (2012) found that angiodysplasia-related GI bleeding was more prevalent in the VWD 2A subtype than in VWD 2M, distinguished by the lack or presence of HMW multimers, respectively. There are other reports of GI bleeding from angiodysplasia occurring mainly in VWD 2A and VWD 2B subtypes, both characterized by lack of HMW VWF multimers in plasma (Iannuzzi et al, 1991; Morris et al, 2001; Satoh et al, 2004;). Considering these findings altogether, it can be hypothesized that the VWF defect or dysfunction in VWD is responsible for enhanced endothelial cell proliferation leading to the development of neoangiogenesis and the vascular malformations typical of angiodysplasia.

Treatment of acute bleeding

The management of these patients is challenging due to recurrent and severe episodes of GI bleeding, that usually develop and increase in severity with age (Veyradier et al, 2001). Replacement therapy with plasma-derived products containing VWF and FVIII (so called VWF/FVIII concentrates) is the mainstay of the episodic treatment of acute GI bleeding in patients with VWD. Even though this treatment is usually clinically efficacious, it appears somewhat less efficacious than in other bleeding sites. For instance, in the most recent prospective study that evaluated the clinical effectiveness of a VWF/FVIII concentrate in VWD, the average daily dose needed to control GI bleeding was 44 u/kg (contrasting with 29 u/kg for bleeding at other sites) and 4·23 treatment days were needed to stop this type of bleeding (contrasting with 1·93 days at other sites) (Berntorp & Windyga, 2009).

Long-term secondary prophylaxis

With a marked tendency to recur in patients with angiodysplasia, GI bleeding is the epitome of the situations that warrant secondary prophylaxis with VWF/FVIII concentrates (Berntorp & Petrini, 2005; Franchini et al, 2007; Federici, 2008; Abshire, 2009). The main results are summarized in Table 1. Coppola et al (2006) were the first to demonstrate the clinical benefit of long-term secondary prophylaxis with a VWF-FVIII concentrate given at a dose of 40 IU/KG thrice weekly in a patient with type 3 VWD who had recurrent GI bleeding due to angiodysplasia. An Italian cohort study (Federici et al, 2005) of 452 VWD patients regularly followed up included 11 patients on long-term prophylaxis because of frequent recurrence of bleeds at the same sites. Regular prophylaxis, started somewhat more frequently for GI bleeds (in 7 patients) than for joint bleeds (in 4 patients), stopped bleeding in 7 patients (4 with GI bleeds and 3 with joint bleeds) and reduced the need for red cell transfusions and hospitalization in the remaining 4 (3 with GI bleeds and 1 with joint bleeding). Another Italian multicentre study retrospectively collected data on 8 additional VWD patients on long-term secondary prophylaxis with a VWF-FVIII concentrate in order to prevent recurrent GI bleeding (Federici et al, 2007). The clinical responses were rated as excellent/good in all cases, with no significant adverse effect. Based on the results obtained in Swedish patients, Berntorp (2008) included recurrent GI bleeding among the symptoms that warrant regular prophylaxis. More recently, the von Willebrand Disease Prophylaxis Network retrospectively investigated the indications and efficacy of secondary prophylaxis in 59 patients with clinically severe VWD from 20 centres in 10 countries (Abshire et al, 2013). Among them, 13 (23·6%) patients were on secondary prophylaxis owing to recurrent GI bleeding, representing a frequent indication for this mode of treatment delivery (epistaxis, 23·6% and joint bleeding, 21·8%). Although the number of GI bleeding episodes occurring during prophylaxis was significantly smaller than before, the clinical outcome (expressed as percent reduction in bleeding frequency) was less for GI bleeding (49%) than for joint bleeding (86%) (Abshire et al, 2013).

Table 1. Secondary long-term prophylaxis for recurrent gastrointestinal bleeding in congenital VWD patients
ReferenceProduct used for replacementCases (n)VWD typesTreatment regimenEfficacyb
  1. NR, not reported.

  2. a

    Median dose.

  3. b

    Percent of resolution in bleeding frequency.

  4. c

    Although not specified by the authors, some cases reported in these three studies may overlap.

Coppola et al (2006)Haemate P®1type 340 iu/kg × 3/weeklyFull
Federici et al (2005)Haemate P®, Fandhi®, Alphanate®7c1 type 1, 3 type 2, 1 type 340 iu/kg × 3/weeklyFull
Federici et al (2007)Haemate P®8c1 type 1, 2 type 2, 5 type 360 iu/kg × 2-3/weeklyaFull
Berntorp and Petrini (2005)Haemate P®33 type 224 iu/kg × 1-3/weeklyaMarked reduction in bleeding frequency (0·4 bleeds per patient/year)
Abshire et al (2013)Haemate P®, Fandhi®, Alphanate®13cNR60 iu/kg × 2-3/weeklya49%

All in all, these data establish the usefulness of on demand replacement therapy to stop acute GI bleeding, and of regular prophylaxis to reduce its recurrence. However, the results are somewhat less efficacious than for bleeding in other sites. The reason for these differences is perhaps that GI bleeding due to angiodysplasia is only partially controlled by the post-infusion attainment of normal plasma levels of VWF, but also warrants the normalization of this adhesive protein in cellular compartments (endothelial cells, platelets, subendothelial matrix). Indeed, replacement therapy replenishes the plasma compartment of VWF, but not the cellular compartments in which VWF remains deficient or dysfunctional post-infusion, at least in type 3 and 2 VWD (Mannucci et al, 1976).

Other therapeutic approach

Owing to the limitations of replacement therapy and the frequent recurrence of GI bleeding, a number of adjuvant approaches have been attempted in patients with VWD and angiodysplasia. Endoscopic procedures (thermo-, electro- and photo-coagulation) and angiographic arteriography with the embolization of the main vessel supplying the affected areas are sometimes used in cases unresponsive to replacement therapy (Morris et al, 2001; Makris, 2006). However, they are not consistently effective, because the angiodysplasic lesions are usually multiple and diffuse in the GI tract. For the same reasons surgical resection is not useful, even when the actually bleeding area is identified by endoscopic videocapsules (Fig 1). The somastatin analogue octreotide, the antifibrinolytic amino acid tranexamic acid and desmopressin are usually of little help to stop bleeding refractory to replacement therapy (Chey et al, 1992; Bowers et al, 2000; Siragusa et al, 2008). When aneamia is severe (below 90 g/l), red blood cell transfusion is needed, whereas iron administration is helpful only for less severe chronic anemia. Attempts have also been made to employ drugs endowed with antiangiogenic properties, such as thalidomide and very large doses of atorvastatin (up to 80 mg daily). A few cases have reported positive effects on the frequency of GI bleeding (Hirri et al, 2006; Li & Losardo, 2007; Sohal & Laffan, 2008; Alikhan & Keeling, 2009; Nomikou et al, 2009), but larger and more controlled studies are warranted to establish the clinical usefulness of these therapies.

Angiodysplasia in acquired von Willebrand syndrome

The role of VWF in preventing angiodysplasia and related GI bleeding was also demonstrated by their occurrence in patients with AVWS (Pareti et al, 2000; Veyradier et al, 2001; Vincentelli et al, 2003; Franchini & Lippi, 2007a; Slaughter, 2010; Blackshear et al, 2011; Castaman et al, 2012).

Cardiac causes of AVWS

The first description was by Edward J. Heyde in 1958, who reported a case series of 10 patients with aortic stenosis and GI bleeding (Heyde, 1958). Subsequent reports confirmed the association between aortic stenosis and unexplained blood loss, known as Heyde syndrome (Sadler, 2003). Warkentin et al (1992, 2003) postulated that the link between aortic stenosis and GI bleeding was a deficiency of the largest VWF multimers, and this was confirmed by a prospective study (Vincentelli et al, 2003) in 42 consecutive patients with severe aortic stenosis who underwent valve replacement. In almost all patients, VWF multimers or the platelet-function analyser PFA-100 results were abnormal, resembling acquired type 2A VWD. During the 6 months before surgery, GI bleeding occurred in 4 of the 42 patients. The mean transvalvular pressure gradient correlated with the degree of loss of HMW multimers, and valve replacement reversed the forementioned laboratory abnormalities on the first postoperative day. Importantly, recurrence of aortic stenosis was associated with the reappearance of VWF abnormalities.

The generally accepted notion is that the development of AVWS is due to elevated shear stress through the stenotic valve, which causes linear elongation of the VWF molecule from its normal globular conformation and exposure of hidden cleavage sites to the proteolytic enzyme ADAMTS13, thereby resulting in the generation of smaller fragments and a deficit of the HMW more haemostatically effective multimers (Sadler, 2003). The association between aortic stenosis and angiodysplasia occurred at an incidence higher than expected by chance alone (odds ratio 4·5, 95% confidence interval 3·0–6·8) (Pate & Mulligan, 2004). Furthermore, ceasing of GI bleeding was achieved by aortic valve replacement in a number of case reports and case series in patients with Heyde syndrome (Abi-akar et al, 2011). More recently, another cardiac cause of AVWS was observed during left ventricular assist device support (Slaughter, 2010) in patients with hyperthrophic obstructive cardiomiopathy, who recovered from AVWS and associated GI bleeding after septal myectomy (Blackshear et al, 2011).

Haematological causes of AVWS

A type 2A AVWS-related bleeding angiodysplasia has also been reported in association with lymphoproliferative disorders, including monoclonal gammopathy of uncertain significance (MGUS), multiple myeloma and chronic lymphocytic leukaemia (Wautier et al, 1976; Rosborough & Swaim, 1978; Cass et al, 1980; Rahmani et al, 1990; Lamboley et al, 2002). In these cases, treatment with chemotherapy or high-dose intravenous immunoglobulin (IVIG) corrected or ameliorated VWF abnormalities and the associated bleeding tendency. In particular, an open-label crossover study conducted in MGUS-associated AVWS (Federici et al, 1998) reported that two IgG-MGUS cases with chronic GI bleeding were successfully managed by repeated (every 21 days) IVIG infusions. The pathogenesis of AVWS associated with blood disorders seems to involve a sequestration of HMW multimers onto malignant cells or abnormal immunoglobulins. However, how this mechanism leads to angiodysplasia it is still unknown, considering that, at variance with VWD-associated angiodysplasia, the endothelial content of VWF is normal in these cases.

Conclusions

Recent experimental studies revealed that VWF has previously unrecognized biological functions, including that of modulating angiogenesis (for review, Lenting et al, 2012). These studies have provided the mechanistic explanation for the onset and maintenance of angiodysplasia in patients with congenital or acquired VWF abnormalities. The HMW multimers seem to be involved in this mechanism, because in most cases angiodysplasia is associated with VWD subtypes (type 2 or 3) typically lacking the largest multimeric forms of VWF. However, why VWF devoid of the largest multimers predisposes to an increased risk of vascular malformations is unknown (Veyradier et al, 2001).

The mainstay of treatment of angiodysplasia is replacement therapy when this abnormality causes GI bleeding in patients with congenital VWD. When bleeding episodes recur frequently, regular prophylaxis should be implemented, leading to an acceptable degree of prevention of bleeding. Larger series than those currently available are warranted to establish the optimal prophylaxis regimen. When GI bleeding due to angiodysplasia occurs in association with AVWS, the best approach is to remove the cause underlying the VWF defect. When this direct approach is not possible (as, for instance, in MGUS), regular prophylaxis with IVIG is often capable of restoring VWF levels and controlling GI bleeding. The role of enhanced neoangiogenesis in the mechanism of GI bleeding in VWD and AVWS paved the way for the use of antiangiogenic agents (i.e., thalidomide, statins) to control the progression of VWD–associated angiodysplasia and related bleeding. However, although promising, the data on the use of these agents stem only from anecdotal reports and thus, further investigations are needed to assess their efficacy and safety in this clinical setting.

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