The Crimson River is even more significant than the legends of the River Nile and the Yellow River (as translated) in Egypt and China respectively. Its history goes back to the times when people first died from excessive loss of blood. The Crimson River flows from the mouth to the rectum. It derives its essence from mischievous blood that escaped from a break in the wall(s) of the gastrointestinal tract. The shade of its colour sheds an inkling as to where the bleeding comes from. This traces back to the idea of blood as a solution of infinite complexity, where it houses materials such as platelets and erythrocytes. These materials change in quality in its passage and in time. Upper gastrointestinal (GI) bleeding, usually a term encompassing bleeding from the oesophagus and the stomach, is differentiated from lower gastrointestinal (GI) bleeding by the colour of the blood (since it's the easiest parameter to define and decipher). If vomited, blood from upper GI bleeding appears red or coffee ground. If admixed with excrement, it usually appears dark red or outright black. This is known as 'tarry stool'. The opposite exists for lower GI bleeding, although, to be fair, you will be hard-pressed to find a case of vomiting when this occurs (it is not impossible though, since iatrogenic injury leading to surgical anastomosis of the small bowel and stomach can lead to it; it isn't a pretty picture).
This clinical picture shows an endoscopic view of bleeding of the mucosal lining of the stomach after endoscopic submucosal dissection of a neoplasm. It is extracted from: https://www.researchgate.net/figure/Endoscopic-appearance-of-post-ESD-ulcer-with-active-bleeding_fig4_224847666.
However, as medical professionals, searching for the location of the bleeding isn't enough. There are additional considerations. This includes unearthing the aetiology of the bleeding (or making an educated guess) and administering life-saving therapy to the patient. Once it involves heavy bleeding, it is a matter of life or death. Resuscitation must preside over academic curiosity and quenching any intellectual draught. This is particularly true when the diagnosis is not as straightforward as it seems. Medics are well-versed in the list of common conditions precipitating upper GI bleeding. However, as we shall see, despite the age-old maxim 'common things come first', we should be more open-minded and prepare to be amazed by our body which is, in itself, a miracle of infinite wonders.
Vascular Anatomy - Upper GI Style:
Before we start, as usual, it's wise to have a refresher session on the vascular anatomy of the upper GI system. It's about bleeding after all.
All illustrations contained below are extracted from Teach Me Anatomy and Gray's Anatomy - they have all the credit for the artwork.
This diagram shows the abdominal aorta, which is the master of all the arteries of the abdomen. Originating from the thoracic aorta (which in turn comes from the heart; note that the thoracic and abdominal aortas are collectively known as the 'descending aorta', since blood flows all the way down from the heart), the abdominal aorta is the most important organ in the abdomen, with regard to the lethality of any pathologies arising there. In abdominal examinations, the one thing we always have to check is whether the patient has an abdominal aortic aneurysm (and whether it has ruptured). Checking its patency makes sure the patient receives timely medical and surgical treatment.
The abdominal aorta gives rise to three different big boys until it ends at the point L4 (vertebral level) where it gives rise to the left and right common iliac arteries (supplying the lower limbs and pelvis). The three big boys are:
Coeliac Trunk / Artery (given out at T12) (there is considerable discussion as to which one's correct in my private circles- the word 'trunk' carries the correct connotation, in my opinion, since it refers to a super=short vascular segment; calling it an artery appropriately identifies its histological category, but fails to capture its short length);
Superior Mesenteric Artery (given out at L1);
Inferior Mesenteric Artery (given out at L3).
Note that the anatomical origins of these vascular structures are all reflective of the norm only. There are individual anatomical variations and this alone already demands our open-mindedness. Some patients may have a coeliac trunk originating from L1, adjacent to the superior mesenteric artery. That's totally possible and might lead to more problems in surgery of the abdomen.
A very simplistic idea is that the coeliac trunk gives rise to the common hepatic, splenic and left gastric arteries. Its role is to serve the abdominal structures up north, encompassing the gallbladder, liver, duodenum, stomach, oesophagus, pancreas and spleen (from right to left). The superior mesenteric artery's territory goes from the second half of the duodenum to the transverse colon. Afterwards, it is the inferior mesenteric artery's kingdom, right to the point of the pectinate line in the anal canal. The borders are ancient - going all the way back to embryonic development where the gastrointestinal system was divided into the foregut, midgut and hindgut. Each of the three big boys is in charge of each one of them.
As this article focuses on the upper GI system, we will mostly be looking at the coeliac trunk and its various branches.
This diagram illustrates the intricate network of branches of the coeliac trunk. To be honest, whenever I look at these vascular structures, I am reminded of Thomas the Tank Engine and the numerous railroads traversing the green plains of the Island of Sodor. The coeliac artery, as mentioned above, gives rise to the left gastric artery, common hepatic artery and splenic artery. The left gastric artery is the smallest and goes on to supply the narrower curve (sophisticated term alert: lesser curvature) of the stomach, as well as the oesophagus. The splenic artery is safely tucked into the middle of the ladder and supplies the spleen and the stomach (through short gastric arteries and left gastro-epiploic arteries). The largest of them all is the common hepatic artery, which is the only branch going to the right. This always reminds me of the Southwest trains heading off to some seaside resort in Devon from Waterloo, their hub. The common hepatic artery gives different branches, including the proper hepatic artery and gastroduodenal artery. The pancreas, as a side note, is supplied by the superior and inferior pancreatico-duodenal arteries, where the former is given out by the gastroduodenal artery, a branch of the common hepatic artery; the latter is given out by the superior mesenteric artery.
This diagram shows the distribution of arteries along the stomach - as you can see, there are many different branches supplying the lesser and greater curvatures, working their way inwards.
This diagram is an upside-down view of the distribution of the branches of the coeliac trunk. As we can see, it shows particularly the branches of the splenic artery.
This diagram shows the territorial distributions in the stomach, of the three main branches of the coeliac trunk. The cross denotes the borders between them, where they anastomose (connect with each other).
Cutting straight to the chase, let's dive into the case I present today.
The Case:
Edward Coke** is a 21-year old gentleman who presents to the A&E department having vomited a lot of blood. He's dizzy and fatigued. He's also experiencing abdominal pain. His parents are very worried about his condition and has thus taken him to the hospital in the middle of the night. Owing to the patient's circumstances, we've taken the patient's vital signs and are inclined to do the emergency ABCDE algorithm (airway, breathing, circulation, disability and environment/exposure) as well as administer fluid resuscitation.
Patient Particulars:
VITAL SIGNS & KEY CLINICAL INFORMATION UPON ADMISSION:
Blood Pressure - 102/66 mmHg (hypotensive);
Heart Rate - 92 beats per minute (within normal range, but close to upper limit);
Respiratory Rate - 20 breaths per minute (borderline, on upper limit);
Temperature - 35.8 degrees Celsius (non-feverish; not hypothermic);
Pulse Oximetry - 96% (normal, above 95%);
Normal urinary output and insignificant urinalysis results;
The pulses are symmetrical bilaterally. They are regular in rhythm and reduced in volume.
There is no peripheral or central hypoxia.
The patient has prolonged capillary refill time (>2 seconds) and dry mucous membranes (e.g. tongue). The patient also has loss of skin turgor. All these point towards dehydration and this can be pointed straight to possible excessive loss of blood.
Group & Save and Crossmatching, full blood count and clotting profile are urgently done in fear of acute deterioration of the patient's condition.
CHIEF COMPLAINTS & ASSOCIATING FEATURES:
Haematemesis and Vomiting: the issue of vomiting started two hours ago; two episodes in total with no past episodes (associated with the index incident) identified; the two events happened with an interval of roughly twenty minutes; the episodes are of acute, spontaneous onset in occurrence; the exact amount of vomitus cannot be quantified but the patient feels dizzy afterwards. According to his parents, the entire bathroom floor is soaked in blood. The vomitus is described as 'coffee-ground' in appearance, which is essentially dark yellow/black in colour with a tinge of red (coffee-ground vomitus indicates gastric, rather than oesophageal involvement, due to the admixture between blood and hydrochloric acid in gastric juice). Blood clots are also claimed to be present. The vomitus looks the same in both episodes in quality and severity (i.e. no identifiable progression). There are no identifiable exacerbating or ameliorating factors.
Abdominal Pain: Localised in the epigastrium, with no radiation; acute and spontaneous onset which accompanies the haematemesis and vomiting (suggestive that they originate from the same pathology); persistent and not progressive in course; the patient has experienced episodic pain for the five days preceding the persistent pain experienced from two hours ago; graded at 6-7/10 on the Visual Analogue Scale in terms of severity; dull in quality; no amelioration from eating, or taking milk of magnesium or Gaviscon; no exacerbation by eating or at night.
Anaemic Symptoms: The patient is fatigued and has malaise. The patient also experiences shortness of breath. There are no palpitations felt.
Constitutional Symptoms: Absent.
Review of Symptoms: The patient has also complained of reddish spots over the lips and tongue, suspecting that they might mean something serious. They are persistent and first emerged three months ago. They have progressed in quantity and breadth of distribution. The patient also has frequent nosebleeds, which have first occurred since childhood. No traumatic event is identified with their onset. The patient has not defaecated during this two-hour window. However, prior to this, the patient does not have any change in stool morphology or colour (i.e. no haematochezia identifiable). There are no changes in bowel habit. The patient has experienced no other symptoms.
This clinical picture shows reddish spots scattered across the lips and tongue. This indicates an underlying issue with the blood vessels, such as hereditary haemorrhagic telangiectasia, chronic liver disease, or generalised essential telangiectasia (unknown origin). [6] This diagram is extracted from: https://www.natural-health-news.com/wp-content/uploads/2016/06/Hereditary-Hemorrhagic-Telangiectasia.jpg.
PAST MEDICAL HISTORY:
The patient does not have prior peptic ulcer disease, chronic liver disease (including Hepatitis B) or cancer.
The patient has received vaccination for Hepatitis B (two doses plus booster dose);
The patient does not have any known coagulopathy, hypertension, or other vascular disorders.
The patient does not have known diabetes mellitus.
There is no known history of endocrine dysfunction, such as MEN1/MEN2 Syndrome (this is related to the rise of gastrinomas - Zollinger-Ellison Syndrome arises when there is predisposing gastrinoma(s) which can lead to excessive gastric acid production. This culminates into severe, recurrent peptic ulcer disease).
PAST SURGICAL HISTORY:
The patient has received surgery for a wrist fracture five years ago. Post-operative recovery was unremarkable and the procedure was uneventful;
The patient received no other surgical operation.
DRUG HISTORY:
No history of taking aspirin, other NSAIDs***, steroids, anticoagulants, or any other chronic medication;
No known drug allergies (crucial for administering treatment and diagnosis, whereby drug hypersensitivity reactions can contribute to the issue at hand, albeit unlikely given the clinical picture);
No illicit drug use (as alleged).
AUTOIMMUNE HISTORY: Unremarkable.
FAMILY HISTORY:
Father also has reddish spots over the lips. These reddish spots are absent from the tongue but are also found over the scapulae, buttocks and thighs. He also had an operation for cerebral aneurysmal rupture last year and recovered uneventfully.
Mother's health is unremarkable.
Both parents have received Hepatitis B vaccination and have always been sero-negative for HBsAg (no active disease).
Grandfather died of subarachnoid haemorrhage, attributable to rupturing of a basilar artery aneurysm.
There is no family history of any form of coagulopathy, including Haemophilia A and von Willebrand Disease.
No other remarkable family history.
SOCIAL HISTORY:
Non-smoker and non-drinker (the patient alleges to have never touched tobacco or alcohol);
Living with parents; freshly graduated from university; no identified life stressors that require medical/psychiatric attention.
INFECTIOUS HISTORY: Unremarkable. The patient has not left the country for the past three months (thus negative travel history) and people living in the same household do not have the same clinical manifestations.
DIETARY HISTORY: Mediterranean diet (good for cardiovascular health).
Physical Examination:
It cannot be performed straight away. As the patient's being admitted to the general admissions ward (yes, we've got a hoard of wards; the general admissions wards are for receiving all manners of cases, where patients are transferred to more specialised ones if required), we've given him anti-emetics to stop the vomiting and paracetamol to reduce the abdominal pain. We've also given IV fluids (crystalloids; 0.9% NaCl solution) to stabilise the patient's falling blood pressure and increasing heart rate. As the patient's doing better, I have performed the following physical examinations:
Abdominal & General Examinations;
Digital Rectal Examination (again, I don't have a choice).
Findings:
Digital Rectal Examination: Unremarkable, with no faeces seen (rather clean, I have to say). The main point of performing digital rectal examination is to see if there is blood in the stool. However, since the GI bleeding has arisen quite rapidly, this can easily be missed or false-negative;
General Examination: Pallor present and numerous reddish spots scattered over the Vermillion processes of the lips, as well as the tongue; but unremarkable otherwise; key negatives: no stigmata of chronic liver disease; no finger clubbing; no peripheral oedema;
Abdominal Examination: Tenderness over the epigastrium; three, small reddish lesions found on the surface of the left hypochondria; no masses, scars or other overlying skin changes; no abdominal guarding and no abdominal distension; otherwise unremarkable.
Clinical Picture showing tarry stool, also known as melaena. It indicates upper GI bleeding due to the presence of dried blood. The clinical picture is extracted from: https://curehows.com/wp-content/uploads/2017/12/red-brown-dark-tarry-stool-adults.jpg.
Clinical picture showing coffee-ground vomitus which indicates bleeding of a gastric origin. This is extracted from: https://amecs.education/wp-content/uploads/2018/05/642x361_Coffee_Ground_Vomitus_IMAGE_2.jpg.
I have to admit, albeit reluctantly, that I am still not impervious to these pictures - I have that primal instinct to look away.
Analysis:
This case is interesting in the aspect where we can still evaluate it using the usual list of differential diagnoses for GI bleeding, but rarer diagnoses might have to be consulted considering the fact that the patient has the rather uncommon finding of reddish spots over the lips, tongue and abdominal surface. From the clinical picture, we can successfully localise it to the upper GI tract, since there are coffee-ground vomitus and epigastric pain. There is also no change in bowel habit, which could be more suggestive of a lower GI pathology.
Let's run through the common things we think of before diving into the world of unknowns.
(a) Peptic Ulcer Disease: There are two types of ulcers, respectively duodenal and gastric ulcers. They are quite different in terms of manifestations. Gastric ulcers bear the highest malignant potential and can be relieved by Gaviscon/milk of magnesia. It cannot be relieved by eating. The opposite applies to duodenal ulcers. Moreover, duodenal ulcers are usually serious enough to wake the patient up at night, where gastric acid production is at its peak. They both present with episodic pain, melaena and coffee-ground vomit (haematemesis). However, risk factors include middle-aged and increasing age, male gender, previous peptic ulcer disease (due to H. pylori exposure, the single most important risk factor), Zollinger-Ellison Syndrome and gastrinoma formation, NSAID and steroid use, Alcoholism and smoking are also possible risk factors. However, the patient's clinical picture is incompatible with most of the features stated here, apart from being male and suffering from epigastric pain. I hate to say this, but peptic ulcer disease is unlikely in this scenario, in spite of the coffee-ground vomit which suggests the bleeding is gastric in origin.
However, due to the prevalence of peptic ulcer disease, we should only rule it out when investigations say so.
Endoscopic view of a gastric ulcer (the whitish zone). The picture is extracted from Medscape.
(b) Oesophageal Varices: They arise in the context of portal hypertension, as explored in the article titled 'Liver encased in bubble-wrap film'. Other manifestations of portal hypertension include caput medusa, Budd-Chiari Syndrome (rare), internal haemorrhoids, ascites, and splenomegaly. The patient has none of these things and has no family or past medical history of any form of liver disease, including Hepatitis B. The patient was born and bred in the UK (not mentioned upstairs for the sake of simplicity), a country not of high burden of Hepatitis B. Moreover, oesophageal varices lead to vomiting of fresh blood, which contradicts with what this patient has experienced.
We are ignoring gastric varices here, since they are very rare and usually arise only in very severe chronic liver disease or splenic venous thrombosis.
Endoscopic view of oesophageal varices, where there is marked engorgement of the veins draining from the oesophagus. Tortuosity is also observed. Due to the nature of oesophageal varices, at most, they only occupy 1/3 of the oesophageal lumen and are incapable of causing dysphagia. The picture is extracted from: https://media.sciencephoto.com/image/c0239014/400wm/C0239014-Oesophageal_varices,_endoscope_view.jpg.
(c) Malignancies (gastric/oesophageal): This is not likely since the patient has an acute issue, whereas malignancies usually take their time. Having said that, malignancies can also cause acute bleeding by initiating vascular erosion fairly recently. This can lead to acute manifestations, like the ones experienced by the patient. However, in the absence of family history, plus the patient's relatively young age, cancer remains a remote possibility. The patient is also negative for the major risk factors for oesophageal and gastric cancers, which include but are not limited to: smoking, alcoholism, H. pylori (prior peptic ulcer disease) (gastric cancer only), megaloblastic anaemia (gastric cancer only), and processed meats.
(d) Coagulopathies: We usually think of Haemophilia A and von Willebrand Disease. However, in this case, no family and past medical history suggest so. The patient is also not taking any anti-coagulants such as warfarin, which can increase the risk of bleeding.
With the more common differentials eliminated, what are we left with? A crucial piece of information - the postulated origin of the bleeding: the stomach. We just need to think about what lies inside, beside or adjacent to the stomach precipitating such effects. But first, let's look at the findings in this patient which deviate from the norm of those experiencing upper GI bleeding:
Reddish spots over the vermillion processes of the lips, tongue and abdominal surface;
Frequent nosebleeds since childhood;
Father experiencing a similar issue, with reddish spots over the lips, buttocks, scapulae and thighs; the father also had a surgery for treating a ruptured cerebral aneurysm (subarachnoid haemorrhage);
Grandfather died of subarachnoid haemorrhage.
Judging by these features, it is easier to be steered into the direction of blood vessels and their health in this patient. Is this patient likely to be predisposed to weakened blood vessels therefore enhanced risk of bleeding? Probably. At this stage, there is one diagnosis that stands out from the crowd: Haemorrhagic Hereditary Telangiectasia (HHT).
HHT occurs in at least 1 / 100,000 persons worldwide. It is rare. With the disease, blood vessels are malformed. There are numerous telangiectasias across the body - they are dilated venules which sprawl out, forming small reddish spots. Over 90 per cent of all patients also experience nosebleeds and over 81 per cent, gastrointestinal bleeding events. Diagnosis is made through matching clinical manifestations and test results with the established Curaçao Criteria (I always mistake this with coraçao, which means 'heart' in Portuguese). [7, 10]
Both figures below are extracted from [7].
The Curaçao diagnostic criteria as applied in this case: (1) ticked, (2) ticked, (3) ticked and (4) ticked --> definite HHT. If there are two criteria present, then the patient has probable HHT which still requires symptomatic treatment.
This figure shows the percentages of HHT patients with different genetic mutations. As you can see, ACVRL1 and ENG are the most commonly affected genes. Enhancing our understanding in this arena bolsters the development of targeted therapy (just like lung cancer, where EGFR-mutants are targeted by certain antibodies) for HHT.
However, we cannot be certain of it since genetic testing is rarely performed. Genes whose mutations are of clinical significance in HHT are ACVRL1, ENG, EPHB4, GDF2, RASA1, and SMAD4 (which is a tumour suppressor gene, present in many carcinogenic processes as well). These 6 genes are evaluated in a single panel in assessment of the likelihood of the patient having the disorder. [8]
Even so, genetic testing is not of high efficacy since there is no one magic panacea resolving all the issues pertinent to HHT. The truth is, symptomatic treatment is often what we can administer. In this patient, This includes surgical ablation and removal of the aneurysms/vascular malformations in question, argon plasma coagulation through endoscopy to stop the bleeding, as well as the administration of tranexamic acid to reduce the extent and amount of bleeding [9]. Bevacizumab is found to be efficacious too in a study [10], where it is a VEGF inhibitor, targeting specifically at angiogenesis. Bevacizumab leads to the improvement of epistaxis symptom severity and reduces the need for transfusion. The study focuses, however, on patients who have at least failed one previous treatment for HHT, indicating that this cohort exhibits more severe forms of the disease.
Investigations:
In light of these developments, I'm just going to show the most significant findings from the investigations done.
No problems in clotting profile - no increase in PT, APTT or decrease in platelet count: this means the problem does not rest with the blood, but with something else, like blood vessels;
The patient has microcytic anaemia, pointing towards iron-deficiency anaemia. The most likely cause is excessive blood loss;
No derangement in liver and renal function tests (ruling out oesophageal varices);
No metabolic derangement or leucocytosis (ruling out malignancies and inflammatory causes preliminarily);
Imaging: Conventional Angiography (pre-endoscopic imaging), Endoscopy (both diagnosis and treatment).
The patient has a large, bleeding aneurysm over the left gastric artery. There are also two bleeding aneurysms (much smaller) over the short gastric arteries, which are the terminal branches of the splenic artery.
Endoscopic interventions involve argon plasma coagulation to stop the bleeding.
This is a PA Chest X-Ray showing a pulmonary arteriovenous malformation in the left lateral lung field, which is connected with the left hilum. It is located just proximal to the heart. This is not done in this patient since there is no clinical indication. This scan is extracted from Radiopaedia.
Conventional Angiography showing three splenic artery aneurysms (extracted from: https://www.researchgate.net/figure/Angiography-of-the-splenic-artery-showing-three-splenic-artery-aneurysms-SAAs-of-30-mm_fig3_221737345.
Conventional angiography showing a large splenic artery aneurysm (no extravasation of blood) (extracted from Thoracic Key).
Two scoring systems are employed when dealing with patients with upper GI bleeding. These include the Glasgow-Blatchford Score which assesses whether a patient should be treated out- or in-patient; and Rockall Score which assesses the mortality rate. For the purposes of convenience, the scoring systems are posted below.
[11]
This table is extracted from: https://www.researchgate.net/figure/The-Rockall-scoring-system_tbl5_224853924.
In this case, the patient is also given iron tablets since there is iron-deficiency anaemia. As the patient's condition is stabilised, the patient is discharged. The patient is also followed-up for any complications.
Concluding Remarks: This case study is rather interesting and illustrates our common way of doing things - we first tend to the patient's immediate needs and aim at stabilising the patient's condition. Afterwards, we move on to more comprehensive history-taking, physical examination and investigations so as to see what the patient really has (unearthing the aetiology). We then see if the manifestations match any of the more common diagnoses (differential) and work our way downwards. This way, we make sure that nothing is really missed. At the same time, open-mindedness allows us to move to rarer diagnoses. Since I've written this case myself to prove the point (haha, grand reveal is always reserved towards the end), the patient's HHT condition is quite obvious. However, in many cases, there might only be 2 or 3 criteria met. Seeing that HHT does not come with any magic panacea / treatment modality, we go for symptomatic treatment.
*The cover picture is extracted from: https://cdn.shopify.com/s/files/1/1655/2447/products/LPA316_f6f47dd0-8795-4733-94c4-9e8880272741_900x.jpg?v=1550204255.
**Again, this case features a made-up patient and details so that I can make my point. By the way, Sir Edward Coke was a famous judge in the 17th century.
***I do get very annoyed whenever people make the mistake that aspirin is not an NSAID (non-steroidal anti-inflammatory drug, targeting COX-1/COX-2 signalling). Aspirin is a drug under the class 'salicylates', which is a type of NSAID. In general, the classes can be expressed in the acronym: SOFAP - salicylates, oxicam (e.g. piroxicam), fenamate (e.g. meclofenamate, which is used particularly in obstetrics and gynaecology), acetate (e.g. indomethacin), and propionic acid (e.g. ibuoprofen and naproxen).
References and Further Reading:
[1] Selvaraj L, Sundaramurthi I. Study of Normal Branching Pattern of the Coeliac Trunk and its Variations Using CT Angiography. J Clin Diagn Res. 2015;9(9):AC01-AC4. doi:10.7860/JCDR/2015/12593.6523.
[2] Standring S, Gray H. Gray's anatomy: The anatomical basis of clinical practice. 41st ed. Churchill Livingstone/Elsevier; 2015.
[3] McMullan DM, McBride M, Livesay JJ, Dougherty KG, Krajcer Z. Celiac artery aneurysm: a case report. Tex Heart Inst J. 2006;33(2):235-240.
[4] Kim BS, Li BT, Engel A, et al. Diagnosis of gastrointestinal bleeding: A practical guide for clinicians. World J Gastrointest Pathophysiol. 2014;5(4):467-478. doi:10.4291/wjgp.v5.i4.467.
[5] Laine L. Upper Gastrointestinal Bleeding Due to a Peptic Ulcer. New England Journal of Medicine. 2016;374(24):2367-2376. doi:10.1056/nejmcp1514257.
[6] Oakley A. Telangiectasia. DermNet NZ. https://dermnetnz.org/topics/telangiectasia/. Published 2014. Accessed December 21, 2020.
[7] McDonald J, Bayrak-Toydemir P, DeMille D, Wooderchak-Donahue W, Whitehead K. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genetics in Medicine. 2020;22(7):1201-1205. doi:10.1038/s41436-020-0775-8.
[8] Genetic testing for Hereditary hemorrhagic telangiectasia | Blueprint Genetics. Blueprint Genetics. https://blueprintgenetics.com/tests/panels/cardiology/hereditary-hemorrhagic-telangiectasia-hht-panel/. Published 2020. Accessed December 22, 2020.
[9] Gaillard S, Dupuis-Girod S, Boutitie F et al. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. Journal of Thrombosis and Haemostasis. 2014;12(9):1494-1502. doi:10.1111/jth.12654.
[10] Gossage J. The Current Role of Bevacizumab in the Treatment of Hereditary Hemorrhagic Telangiectasia–Related Bleeding. Mayo Clin Proc. 2018;93(2):130-132. doi:10.1016/j.mayocp.2017.12.019.
[11] Stanley A, Ashley D, Dalton H et al. Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation. The Lancet. 2009;373(9657):42-47. doi:10.1016/s0140-6736(08)61769-9.