Angiogenesis and hereditary hemorrhagic telangiectasia (HHT) -
With similar symptoms to hemophilia, the two diseases were differentiated by Henri Jules Louis Marie Rendu in In Frederick Parkes Weber continued the characterization of the disease, writing a report on a series of cases.
Since its first identification, HHT has been an underdiagnosed disease, affecting more than a million people worldwide. The symptoms associated with HHT vary from person to person. Differences in disease expression phenotype partially reflect the specific gene that is mutated in HHT.
Some individuals may experience symptoms during infancy or early childhood; others may show few signs or symptoms until the thirties, forties or later in life. In many patients, the first apparent symptom of HHT is nosebleeds epistaxis.
While recurrent nosebleeds may develop as early as infancy they most often begin around puberty. Nosebleeds occur because of the formation of small, fragile vascular malformations telangiectases in the mucous membranes lining the inside of the nose. Telangiectases occur when capillaries fail to develop between arterioles and venules and most often affect the skin and the mucous membranes.
The tongue, lips, face, ears, and fingers are the areas most often affected. Telangiectases may develop at any age including during infancy, but usually become apparent during adolescence and later. Telangiectases also occur in the gastrointestinal tract.
Affected individuals with gastrointestinal bleeding may note dark stools — sometimes black and tarry melena — but only rarely do they have red blood in their stools hematochezia or vomit hematemesis. Commonly, blood loss is not detected by the patient, even when it leads to anemia.
Because bleeding episodes become more severe with age, they often lead to chronically low levels of iron in the blood and eventually to a low red blood cell count anemia. Gastrointestinal bleeding can often be slow, chronic and intermittent, with few noticeable symptoms until the onset of anemia.
Many individuals with HHT develop arteriovenous malformations AVMs. AVMs, which are direct connections between blood vessels of larger caliber than in telangiectases, most commonly affect the lungs, brain, spinal cord, and liver.
In recent years AVM have been noted in the pancreas, kidneys, and other organs, though they rarely cause complications in these locations. Serious neurological complications, including brain abscess and stroke, may occur due to passage of blood clots or bacteria through a PAVM.
In rare cases, individuals with AVMs of the brain may experience vision and hearing problems such as double vision diplopia. However, usually they are asymptomatic prior to a hemorrhagic event. Individuals may experience high blood pressure in the veins carrying blood from the gastrointestinal tract back to the heart through the liver portal hypertension and abnormalities of the bile ducts biliary disease.
The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine. Pressure on bile ducts from enlarged blood vessels may result in failure of bile to flow to the small intestine, instead becoming trapped in the liver, resulting in yellowing of the skin and the whites of the eyes jaundice.
Shunting of blood through liver AVM may result in excessive blood flow through the liver. Over time, high output heart failure may occur because the heart is forced to work harder to compensate for the extra blood flow through the liver, in addition to the normal blood flow to the rest of the body.
HHT is caused by changes mutations in five different genes. It is likely that more genes are yet to be discovered. Mutations of the ENG gene and abnormalities of the protein it produces endoglin result in HHT Endoglin is found on the surface of the cells that line the inside of the blood vessels.
Scientists believe that endoglin binds to transforming growth factor-beta TGF-ß. In mice that are deficient in endoglin, the blood vessels do not mature and there is a failure in vascular smooth muscle development.
Mutations of the activin receptor-like kinase 1 ACVRL1 gene and abnormalities of the protein in encodes ALK1 , result in HHT People with mutations in this gene are more prone to complications from liver AVMs such as liver failure and elevated pressure on the right side of the heart pulmonary hypertension.
This type of HHT is caused by mutations in the SMAD4 gene. Mutations in the BMPR9 and RASA1 genes produce syndromes that share phenotypic overlap with HHT including atypical telangiectases similar to cutaneous capillary malformations , mild nosebleeds and AVMs typically in the brain and soft tissue.
Whether these syndromes are truly HHT or merely HHT look-alikes remains controversial. This group of proteins helps regulate many cellular functions such as cell survival, proliferation and differentiation.
With malfunctioning signaling, the cells formation of blood vessels angiogenesis is defective, causing the clinical features of HHT. In rare cases, the disorder occurs randomly as the result of a spontaneous genetic change i.
All relatives affected in a family with HHT will have the same mutation. However, in different families the causative mutation is usually different, with over different mutations found within the five genes known to cause HHT.
In dominant disorders, only a single copy of the disease gene received from either the mother or father is required to cause the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy.
The risk is the same for males and females. HHT affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in approximately 1 per 5, people. However, because some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized.
HHT is known to be underdiagnosed. This makes it difficult to determine the true frequency of HHT in the general population. Symptoms of the following disorders can be similar to those of hereditary hemorrhagic telangiectasia.
Comparisons may be useful for a differential diagnosis:. Von Willebrand disease VWD is a common inherited bleeding disorder in the general population affecting males and females equally. There are three main types of VWD each with differing degrees of severity and inheritance patterns, though AVM are not seen as part of VWD.
Uncommonly, individuals with HHT may also have Von Willebrand disease due to random chance. Scleroderma is a disorder characterized by thickening and hardening of the skin.
Cutaneous telangiectases but not AVM may be present in this disorder. Rarely, individuals with HHT may also have CREST due to random chance.
Ataxia telangiectasia AT is a complex genetic neurodegenerative disorder that may become apparent during infancy or early childhood. The disorder is characterized by progressively impaired coordination of voluntary movements ataxia ; the development of reddish lesions of the skin and mucous membranes due to permanent widening of groups of blood vessels telangiectasia ; and impaired functioning of the immune system i.
Individuals with AT also have an increased risk of developing malignancies of the lymphatic system lymphomas , the blood-forming organs e. A diagnosis of HHT is made based upon a detailed patient and family history, a thorough clinical examination, and imaging studies to identify characteristic findings in organs.
An international group of experts on HHT established diagnostic criteria for HHT. The four criteria are: recurrent spontaneous nosebleeds; the presence of multiple telangiectases in characteristic locations; the presence of internal visceral telangiectases or AVMs; and a family history of definite HHT.
Patient 4 showed an especially rapid and prolonged decrease in epistaxis duration, gushing, and frequency, which tracked with his improvement in Hgb Fig. Four patients showed more than a 2 gm improvement in Hgb relative to baseline at one or more points during the study and 2 Patients 2 and 6 showed more than a 2 gm decrease at one point during the study Table 1 ; Fig.
The only patient who had received RBC transfusion during baseline showed a marked decrease in RBC need during the study none during weeks 4—18 and despite this decrease in RBC requirements did not show a drop in Hgb. Although Patient 5 was only on treatment for 6 weeks, he nonetheless showed a brisk increase in Hg during weeks 1.
Patients 3, 4, and 6 showed a clear pattern of decreased iron infusion relative to baseline and the other four showed no overall change Table 1. Patient 6 showed an early drop in Hg at week 4. There was no appreciable change in ferritin levels for any patient during the study but the importance of this was difficult to assess due to variable iron infusion practices.
Overall, all but Patient 2 showed one or more signs of hematologic response to treatment. Epistaxis severity score ESS for each patient, with group means, reported at baseline, after 6 and 12 weeks of therapy, and at follow-up.
The dashed line represents the time period after drug discontinuation in Patient 5. Health-related QOL scores norm-based improved on all SF domains Table 3 except for general health, for which there was no change at Week 6 or Week At Week 6, the MID was achieved or exceeded on six of the eight SF domains.
Scores on five of the eight domains exceeded the MID threshold at Week Four domains showed improvement at both Weeks 6 and Seven patients experienced a total of 19 adverse events AE Supplementary Table.
Two patients experienced bronchitis and two experienced nausea; all other AE were isolated occurrences. All AE were considered mild to moderate in intensity except for Patient 5 who had elevated alanine aminotransferase considered severe. That patient experienced an elevation in elevated alanine aminotransferase to five times the ULN at Week 6 and was withdrawn from the dosing phase of the study.
The alanine aminotransferase value was within normal limits at an unscheduled follow-up visit 21 days after discontinuing study drug. There were no serious AE. Additionally, no patient experienced a significant elevation in blood pressure or prolongation of QT interval.
Individual plasma pazopanib trough concentration values were obtained at Weeks 3, 6, 9, and 12 after once daily administration of 50 mg pazopanib one patient only had two values. Based on the elimination half-life of pazopanib approximately 1 to 2 days , all patients were expected to be at steady-state by Week 3.
High inter-patient variability was observed as average trough values ranged from 0. These trough values in HHT patients are generally similar to the trough values observed in patients with solid tumors who received 50 mg pazopanib once daily and had trough values obtained at approximately Weeks 1, 2, and 3 individual range: 1.
Although there is high variability within some of the trough concentration profiles, patients typically appeared to exhibit steady-state conditions.
We report here the first human trial of pazopanib for treatment of HHT-related bleeding. This was observed at a dose much lower than typically used for oncologic indications, with no serious adverse events.
These data suggest that further studies of pazopanib efficacy are warranted, as this drug may bring much-needed benefit to HHT patients suffering from chronic bleeding. We studied patients who had chronic HHT-related bleeding, all suffering from epistaxis and secondary anemia, and six from GI bleeding.
Study patients appeared similar to typical HHT patients with these types of complications, with a mean age in the fifties and the population divided equally between men and women, as well as ENG and ACVRL1 gene mutations, with one patient with the rarer SMAD4 gene involvement.
As such, it is reasonable to consider these results as generalizable to other HHT patients. We elected to measure hemoglobin Hgb as a primary outcome but to also study other measures iron requirements, transfusion requirements, epistaxis measures, QOL and patient satisfaction since the degree of anemia is itself dependent on supportive therapy.
We agreed on pre-determined efficacy criteria. In further support of drug effect, three of these four patients showed an obvious fall in Hgb 8—20 weeks after stopping pazopanib. A recent case report of an HHT patient treated with pazopanib mg per day reported similar effect [ 29 ].
We hypothesized that pazopanib which blocks VEGF receptors would reduce bleeding based on preclinical data and anecdotal data derived from intravenous and topical bevacizumab use in HHT patients. However, we speculated that a lower dose of pazopanib would be safer and could still be effective given that it blocks VEGF-R2 signaling downstream of all of its ligands, including VEGF-A, and also affects other angiogenic signaling pathways including PDGF.
In addition, we demonstrated in a mouse model of post-traumatic choroidal neovascularization that pazopanib activity is observable at a trough concentration of 1. An assumed protein binding level of These levels appear otherwise inadequate for tumor reduction, potentially due to the exuberant production of VEGF in tumors, and the restricted pharmacologic access of pazopanib to neoplastic tissue.
The exact mechanism by which pazopanib reduces bleeding is unclear. Involution of the tips of the growing vessel, resorption of the abnormal tuft of capillary and venule connections within an AVM, or general involution of abnormal vessels may be more likely than a reported direct hemodynamic effect [ 32 ].
This is consistent with the need for roughly 3 weeks of therapy prior to observing drug benefit, and then the loss of effect well beyond the expected systemic residence of the drug.
In contrast, the far more common elevation in blood pressure at high doses was not observed in our patients. Given the range of our trough concentration values, we might presume that the lack of virtually any BP rise was the result of IC50 versus IC90 levels of drug, or intrinsic HHT-related vascular protection from such influences.
Overall, these much lower steady-state levels of pazopanib, while effective in HHT patients, appear generally devoid of these side effects.
The study is clearly limited by the small sample size and the absence of controls. The benefits across all seven patients and all three typical HHT genotypes are however provocative, particularly given the chronicity of the disease, and the baseline comprehensive care.
All seven patients were already receiving expert care at specialized HHT Centers, receiving maximal medical therapy, and yet had ongoing anemia, chronic bleeding, and impaired QOL. In other words, pazopanib was added to the ongoing stable comprehensive care regimen in these patients, and we observed both subjective and objective benefit.
To date, there have been few therapies in HHT with such promising preliminary data. Further study, with a controlled clinical trial, as initially planned, is now all the more relevant. In conclusion, pazopanib offers a viable approach towards treatment of chronic bleeding in HHT patients. All seven patients in this study, at a dose of 50 mg daily for 12 weeks, realized a benefit, although of variable individual value, based on objective measures and patient reported outcomes.
A far lower dose of drug is necessary to that of oncology indications. While safety remains unproven at this dose, and for this population, a window does appear to be available to effect benefit, without major safety risk. Donaldson JW, McKeever TM, Hall IP, Hubbard RB, Fogarty AW The UK prevalence of hereditary haemorrhagic telangiectasia and its association with sex, socioeconomic status and region of residence: a population-based study.
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Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF. Abstract Hereditary hemorrhagic telangiectasia HHT is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth.
Use our pre-submission checklist Avoid common mistakes on your manuscript. Dear Editor:. Abbreviations HHT: Hereditary hemorrhagic telangiectasia ENG: Endoglin ACVRL1: Activin A receptor type II-like 1 SARS-CoV Severe Acute Respiratory Syndrome Coronavirus-2 COVID Coronavirus disease RiHHTa: Computerized Registry of Hereditary Hemorrhagic Telangiectasia VEGF: Vascular endothelial growth factor ICU: Intensive care unit.
References Sánchez-Martínez R, Iriarte A, Mora-Luján JM, Patier JL, López-Wolf D, Ojeda A et al Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. Orphanet J Rare Dis Article Google Scholar Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F et al Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid N Engl J Med — Article CAS Google Scholar Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al Clinical features of patients infected with novel coronavirus in Wuhan.
China Lancet — Article CAS Google Scholar Gustafson D, Raju S, Wu R, Ching C, Veitch S, Rathnakumaret K, al, Overcoming barriers: the endothelium as a linchpin of coronavirus disease pathogenesis?
Arterioscler Thromb Vasc Biol — Article Google Scholar Guervilly C, Burtey S, Sabatier F, Cauchois R, Lano G, Abdili E et al Circulating endothelial cells as a marker of endothelial injury in severe COVID Acknowledgements We express our gratitude to Health in Code A Coruña, Spain for supporting this Registry.
Funding No funding was provided for this study. View author publications. Ethics declarations Conflict of interest The authors declare that they have no competing interests.
Informed consent All patients or their relatives provided written consent for participation in the RiHHTa registry. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Immune-boosting remedies Angiogenesis and hereditary hemorrhagic telangiectasia (HHT) don't remember your password, you can reset hemorrhaglc by entering your telangidctasia address and clicking the Angiogenesis and hereditary hemorrhagic telangiectasia (HHT) Password Angiobenesis. You will then receive hereditafy email that contains a secure link for resetting your password. Lab Investin press. Sholvin CL, Letarte M: Hereditary hemorrhagic telangiectasia and pulmonary artiovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax — Cheng T, Shen H, Giokas D, Gere J, Tenen D, Scadden D: Tepmoral mapping of gene expression levels during the differentiation of individual primary hematopoietic cells. Unfortunately, many suspected patients do not Fasting and inflammation reduction a clear Angiogenseis diagnosis or do Anhiogenesis show hemorrhafic mutations in HHT genes, prompting Carbohydrate loading and muscle fatigue need to investigate Protein for athletic performance biomarkers of the disease. Here, Heereditary HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins vascular endothelial growth factor, transforming growth factor β1, soluble endoglin, angiopoietin-2 and microRNA variants miRa, miR, miR On the other hand, differential HHT gene expression fingerprinting, next generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.
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