Anemia & Anticoagulation
Anemia is a common complication in people with HHT. It is typically diagnosed in adulthood and rarely in children with HHT. It is generally the result of chronic bleeding from epistaxis and GI bleeding. These six guidelines cover testing and treatment of iron deficiency and anemia, as well as the use of anticoagulation therapy. Full background can be found after the recommendations.
Recommendations from the Second International HHT Guidelines (2020)
- All adults, regardless of symptoms
- All children with recurrent bleeding and/or symptoms of anemia.
Three case series have reported iron deficiency anemia as a common complication of HHT, typically in adults (36, 46, 47).
Clinical considerations: Testing typically includes complete blood count (CBC) and ferritin. If anemic but ferritin is not reduced, serum iron, total iron binding capacity, and transferrin saturation should be performed, and a hematology consultation should be considered. As severe epistaxis and/or GI bleeding is not routinely encountered in children with HHT, routine testing for iron deficiency and anemia is not deemed necessary in asymptomatic children with HHT.
- Initial therapy with oral iron
- Intravenous iron replacement for patients in whom oral is not effective, not absorbed or not tolerated, or presenting with severe anemia.
Evidence for iron replacement and initial dosing is based on case series in HHT and non-HHT iron deficiency anemia (48-53).
Clinical considerations: Iron replacement typically starts with once daily oral dosing of 35-65 mg of elemental iron, 2 hours before or 1 hour after meals. If this is not tolerated, every-other-day dosing of oral iron or an alternate oral iron preparation (such as a heme-iron preparation or a non-heme iron preparation with lower elemental iron content) can be attempted. If initial dosing is inadequate for correction of the iron deficiency, increasing the daily dose or twice daily dosing should be considered. The patient should be counseled about various dietary factors and medications which can affect iron absorption. In general, an interval of 2-12 hours between iron supplements and these medications is preferred (www.RXfiles.ca Drug Comparison Charts). Follow-up CBC, iron panel and/or ferritin 1 month after initiation of iron replacement is recommended to assess response. An increase in hemoglobin of at least 1.0 gram/dL is expected and, if not achieved, should be considered an inadequate response. When oral iron supplementation is pursued in people with iron deficiency without anemia, improvement in ferritin and transferrin saturation is expected after 1 month. For intravenous iron, routine monitoring of CBC and ferritin is necessary and helpful in guiding prescription of dose intervals, understanding that ferritin levels may be unreliable for 2 weeks post-infusion. In patients with chronic, recurrent bleeding, regularly scheduled iron infusions, with interval adjusted based on follow-up bloodwork, may be considered to maintain iron stores and prevent the development of severe anemia. The dose of intravenous iron can be guided by the total iron deficit, which can be calculated using the Ganzoni formula(54). Alternatively, a total initial dose of 1 gram of intravenous iron can be provided, as a single infusion or in divided doses based on institutional protocols and preferences. Unless chronic bleeding is successfully halted through systemic therapies and/or procedural interventions, repeated administrations of intravenous iron every few months is expected to prevent recurrence of iron deficiency. A few considerations specific to the type of intravenous iron preparation warrant mention: a significantly higher incidence of hypophosphatemia (>20%) has been reported in patients receiving multiple doses of ferric carboxymaltose(151, 152); ferumoxytol can affect the quality of MRI imaging and therefore MRIs should be avoided for at least 4 weeks following infusion of ferumoxytol(153, 154).
- Hemodynamic instability/shock
- Comorbidities that require a higher hemoglobin target
- Need to increase the hemoglobin acutely, such as prior to surgery or during pregnancy
- Inability to maintain an adequate hemoglobin despite frequent iron infusions.
Expert consensus in HHT.
Clinical considerations: Hemoglobin targets and thresholds for RBC transfusion should be individualized in HHT, depending on patient symptoms, severity of ongoing HHT-related bleeding, response to other therapies and iron supplementation, the presence of comorbidities and the acuity of the care setting.
One case series has reported folate deficiency and hemolysis as additional causes of anemia in HHT patients(55).
Clinical considerations: Evaluation should include measurement of folate, Vitamin B12, MCV, smear, reticulocyte counts, TSH and work-up for hemolysis, with referral to hematology in unresolved cases.
Expert consensus in HHT and two case series demonstrated that anticoagulation or antiplatelet therapy is well tolerated by the majority of HHT patients(56, 57).
Clinical considerations: When anticoagulation is pursued, unfractionated heparin, low molecular weight heparin and vitamin K antagonists are preferred over direct-acting oral anticoagulants, which are less well tolerated in HHT(58).For HHT patients with atrial fibrillation who do not tolerate anticoagulation or are considered too high risk for anticoagulation can be considered for alternate approaches to decreasing cardioembolic risk, such as left atrial appendage closure(59).
Quality of Evidence: Low (expert consensus) (Agreement 83%)
Expert consensus in HHT.
Clinical considerations: If dual or combination therapies are required, duration of therapy should be minimized and patients should be monitored closely.
Iron Deficiency Anemia
Anemia is a common complication in people with HHT, with an estimated prevalence of around 50%(36, 46). Anemia is typically diagnosed in adulthood and rarely in children with HHT(47). The primary etiology of anemia is iron deficiency secondary to chronic mucocutaneous bleeding (epistaxis and/or GI bleeding from telangiectases). The average age of onset of epistaxis is 12 years and epistaxis tends to worsen with age(36, 135). GI bleeding is less common than epistaxis, occurring in approximately 30% of older adults(118), and is not typically encountered in the pediatric population.
Manifestations of anemia depend on its severity and can range from fatigue to exertional dyspnea and palpitations. Anemia results in high cardiac output and therefore exacerbates HHT-associated high cardiac output states most commonly encountered with significant liver VMs. Clinical features specific to iron deficiency anemia include a craving to eat certain substances, referred to as pica (typically ice but can include starches, clay, etc.)(136), and findings of angular cheilitis and koilonychia on physical examination(137). Iron deficiency can result in symptoms even in the absence of anemia, such as exercise limitation, fatigue, restless leg syndrome, hair loss, myalgias and decreased attention span(138-140). Correction of the iron deficiency leads to resolution of these symptoms.
Screening for anemia typically involves the following laboratory tests: complete blood count (CBC), iron panel (serum iron, total iron binding capacity, transferrin saturation), and ferritin. A CBC alone could miss underlying iron deficiency without anemia. A low ferritin level is very sensitive and specific for iron deficiency(141, 142). However, as ferritin is an acute phase reactant, it can be normal or slightly elevated in patients with iron deficiency who have a coexisting inflammatory process(137). An iron panel will often help in discerning whether there is underlying iron deficiency in such cases.
While a healthy and balanced diet (per WHO guidelines) is likely to provide the required daily allowance of iron, this will often be inadequate to replete total body iron stores in people with HHT who experience chronic bleeding and have developed iron deficiency either with or without anemia. The initial approach to treatment of iron deficiency in the HHT patients should be with oral iron replacement (with important and common exceptions discussed below). Oral iron preparations come in varying strengths, which are commercially listed in two ways: the total iron content and the amount of elemental iron. Of these, the elemental iron content is the measure of ‘absorbable iron’ and we therefore use elemental iron content in these guidelines. Published guidelines for treatment of iron deficiency anemia typically recommend oral replacement of 100-200 mg of elemental iron in three divided daily doses(48-50). Recent developments in the understanding of iron biology have suggested that lower doses of elemental iron replacement may be more effective. Moretti et al.(51) demonstrated that the levels of hepcidin increase acutely following intake of oral iron. This occurs with both higher amounts of elemental iron per dose as well as multiple daily doses of oral iron, and results in a decreased fractional absorption of iron from the GI tract(51). The optimal dose of daily elemental iron was identified to be 40-80 mg per dose, with either once daily dosing or every-other-day dosing(52).
The most common cause for poor adherence to oral iron replacement is GI intolerance (constipation, nausea, epigastric pain, diarrhea). This occurs more frequently with non-heme based oral iron preparations compared to heme-sourced iron, and is primarily related to the amount of elemental iron per dose(48, 53). If oral iron replacement is associated with constipation, the use of a daily stool softener or other such bowel regimen should be considered to help with adherence. Various factors can affect absorption of iron from the GI tract. Oral iron is best absorbed from an empty stomach in an acidic environment(143) so is frequently co-administered with Vitamin C. Oral iron can be taken with food if needed, such as in people with GI intolerance, however foods that can interfere with or inhibit iron absorption should be avoided, as well as tea, coffee and milk(144). Many medications and supplements can affect iron absorption, such as aluminum containing phosphate binders, antacids, H2-receptor antagonists, proton-pump inhibitors, calcium supplements, and cholestyramine; these should therefore not be taken at the same time as oral iron.
Intravenous iron replacement should be considered in people with HHT who do not tolerate oral iron despite dosing and interval adjustments, in people in whom oral iron is ineffective in adequately treating iron deficiency anemia, and in people who do not absorb oral iron due to comorbid conditions (e.g. inflammatory bowel disease, people gastric bypass surgery, etc.). Intravenous iron can be considered over oral iron supplementation in the first line setting in patients who present with severe, symptomatic iron deficiency anemia, and where blood transfusion is considered inappropriate, because of the immediate availability of considerable amounts of iron for erythropoiesis with this approach compared to oral iron, particularly in the setting of coexisting chronic bleeding. In patients who have failed a brief trial of oral iron or in whom it is not expected to be effective, immediate initiation of intravenous iron is reasonable.
Intravenous iron is generally well tolerated. Common side effects include nausea/vomiting/cramping, arthralgias, flushing, back pain, low blood pressure, headache, fever, and dark urine. These are dose related and typically short lived when they occur. Allergic/hypersensitivity reactions are rare and include bronchospasm, rash, itching, low blood pressure, and anaphylaxis. Transient but significant worsening of epistaxis following iron infusion has been reported(145, 146). Adverse effects can be minimized by slowing the rate of intravenous iron infusion. Premedication with a single dose of antihistamines and/or steroids can be helpful in patients with a history of or concern for adverse effects like myalgias after intravenous iron infusions(147). Intravenous iron should be avoided in the acute phase of infectious disease given concern over potentiating severity of infections.
Dosing of intravenous iron is dependent on the severity of iron deficiency and the preparation of intravenous iron used. Not all intravenous iron preparations are available in every country and considerations such as distance from the clinic, availability, history of allergic reactions, cost and patient preference should factor into the decision regarding choice of intravenous iron preparation. Unless chronic bleeding is successfully halted through systemic therapies and/or procedural interventions, repeated administrations of intravenous iron every few months is expected to prevent recurrence of iron deficiency.
Transfusion of packed red blood cells (RBCs) is also required in some people with HHT, typically when the hemoglobin needs to be urgently raised(41), or when aggressive iron supplementation is not sufficient to compensate for rapid blood loss. The hemoglobin value below which transfusion of RBCs is typically recommended in the general population is 7 g/dL. This transfusion threshold is applicable to some people with HHT as well. In addition to acute, large volume blood loss, chronic recurrent bleeding can result in severe anemia requiring RBC transfusions. When HHT patients have comorbidities, such as severe cardiac disease or hypoxemia from pulmonary AVM-associated shunting, they may require maintenance of higher baseline hemoglobin levels to maintain their arterial oxygen content. A higher hemoglobin threshold (such as 8-9 g/dL) may also be considered in HHT patients with poorly controlled chronic and recurrent bleeding, or when there is a need to acutely increase hemoglobin levels to prevent complications related to decreased oxygen delivery, such as during pregnancy or prior to surgical procedures.
It is important to consider alternate causes of anemia in people with HHT, when appropriate. In situations where anemia is normocytic or macrocytic (normal or high MCV), rather than the typical microcytic MCV seen in iron-deficiency, evaluation for an alternate etiology for anemia should be pursued. People with HHT can develop a folate deficiency as a result of chronically increased erythropoiesis due to chronic bleeding, or hemolysis(55). Finally, unrelated primary bone marrow processes, such as myelodysplasia, should also be considered in the evaluation of anemia that persists despite correction of iron deficiency, particularly in older patients.
Anticoagulation and Antiplatelet Therapy in HHT
Though HHT typically results in mucocutaneous bleeding and is recognized as a rare bleeding disorder by the Center for Disease Control, it is important to recognize that HHT does not protect against the development of thrombosis. On the contrary, people with HHT may be at increased risk for thrombotic complications, with one large series reporting a prevalence of thrombotic events at 6%, higher than that for the age matched general population(148, 149). Further, the risk for thrombosis was found to be independent of comorbidities and therapeutic approaches to mitigate bleeding, but interestingly correlated with presence of iron deficiency and elevated levels of circulating coagulation factor VIII(148). In addition, an increased risk for thrombotic stroke has also been observed by the same group(150). Given these considerations, people with HHT should receive appropriate pharmacological thromboprophylaxis during periods of increased risk as any other patient would (e.g. prolonged immobility, following major surgery or orthopedic surgery, etc.). This may prevent need for subsequent therapeutic anticoagulation, which would be associated with a higher risk for bleeding complications. Also, therapeutic anticoagulation and/or antiplatelet therapy should also not be automatically withheld in all people with HHT given concern over potential increase in bleeding risk. Both anticoagulation and use of antiplatelet therapy can be well tolerated by the majority of HHT patients(56, 57). However, the decision to pursue these therapies will need to be considered on an individual basis, taking into account the personal severity of bleeding and anemia, patient acceptance of possible worsening of bleeds, and other comorbidities. While anticoagulation or antiplatelet therapy in isolation is encouraged when indicated, the bleeding risk with combining anticoagulation and antiplatelet therapy or with dual antiplatelet therapy in people with HHT is considered to be significant. Therefore, these combinations should be avoided if possible.