Table 1. Clinical Recommendations from... | American Society of Hematology

Table 1.

Clinical Recommendations from Second International HHT Guidelines of high relevance to hematologists

Clinical recommendation	Clinical considerations
Epistaxis
The expert panel recommends that clinicians consider the use of oral tranexamic acid for the management of epistaxis that does not respond to moisturizing topical therapies (ER2; QOE: high, SOR: strong).	Can be coadministered with systemic antiangiogenic therapy.  Dosing: start at 500 mg twice daily, gradually increasing up to 1000 mg 4 times daily or 1500 mg 3 times daily. Dose per pill varies by country, and these recommended doses can be approximated and adapted given what is available.  Contraindications include recent thrombosis; relative contraindications include atrial fibrillation or known thrombophilia.
The expert panel recommends that clinicians consider the use of systemic antiangiogenic agents for the management of epistaxis that has failed to respond to moisturizing topical therapies, ablative therapies and/or tranexamic acid (ER4; QOE: moderate, SOR: strong).	IV bevacizumab is given as induction (5 mg/kg every 2 weeks for 4-6 doses) followed by maintenance (dosing variable; 5 mg/kg every 1-3 months is an option). Risk of long-term maintenance therapy unknown. Monitor for hypertension, proteinuria, infection, delayed wound healing, VTE. Oral thalidomide can also be considered, though side effects often limit long term use. Risks and benefits of antiangiogenic medications should be considered, as well as alternatives, such as septodermoplasty and nasal closure, in these patients. Shared decision making with patients is crucial.
GI bleeding
The expert panel recommends that clinicians grade the severity of HHT-related GI bleeding and proposes the following framework: Mild HHT-related GI bleeding: patient who meets their hemoglobin goals* with oral iron replacement. Moderate HHT-related GI bleeding: patient who meets their hemoglobin goals* with IV iron treatment. Severe HHT-related GI bleeding: patient who does not meet their hemoglobin goals* despite adequate iron replacement or requires blood transfusions. *Hemoglobin goals should reflect age, gender, symptoms and comorbidities (GR3; QOE: low, SOR: strong).	For most HHT patients (and in particular, those without comorbid conditions resulting in chronic anemia), the hemoglobin goal will be a normal hemoglobin for age and gender. This classification is not for the acutely anemic patient during the initial diagnostic phase, but rather for HHT patients who are post initial iron repletion (≥3 months after diagnosis) and is meant to represent chronic hematologic support requirements. Need for regular, scheduled IV iron (rather than an isolated single dose) defines patients in the moderate or severe category. This classification is considered proposed for future development.
The expert panel recommends that clinicians consider treatment of mild HHT-related GI bleeding with oral antifibrinolytics (GR5; QOE: low, SOR: weak).	Can be coadministered with systemic antiangiogenic therapy. Dosing: start at 500 mg twice daily, gradually increasing up to 1000 mg 4 times daily or 1500 mg 3 times daily. Dose per pill varies by country, and these recommended doses can be approximated and adapted given what is available. Contraindications include recent thrombosis; relative contraindications include atrial fibrillation or known thrombophilia.
The expert panel recommends that clinicians consider treatment of moderate to severe HHT-related GI bleeding with intravenous bevacizumab or other systemic antiangiogenic therapy (GR6; QOE: moderate, SOR: strong).	IV bevacizumab is given as induction (5 mg/kg every 2 weeks for 4-6 doses) followed by maintenance (dosing variable; 5 mg/kg every 1-3 months is an option). Risk of long-term maintenance therapy unknown. Monitor for hypertension, proteinuria, infection, delayed wound healing, VTE. Risks, and benefits of antiangiogenic medications should be considered. Shared decision making with patients is crucial.
Anemia and anticoagulation
The expert panel recommends that the following HHT patients be tested for iron deficiency and anemia: All adults, regardless of symptoms All children with recurrent bleeding and/or symptoms of anemia (AR1; QOE: high, SOR: strong)	Testing includes complete blood count and ferritin; if anemic but ferritin not reduced, obtain serum iron, total iron binding capacity, and transferrin saturation, and consider hematology consultation.
The expert panel recommends iron replacement for treatment of iron deficiency and anemia as follows: 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 (AR2; QOE: moderate, SOR: strong)	Assess adequacy of response (hemoglobin rise of ≥1.0 g/dL, normalization of ferritin and transferrin saturation) at 1 month. Oral iron: can start with 35-65 mg of elemental iron daily; if inadequate, can consider increased daily dose or twice daily dose; if not tolerated, can attempt alternate oral iron preparation. IV iron dose can be guided by total iron deficit (Ganzoni formula ⁷⁹) or a total empiric dose of 1 gram can be provided, with interval reassessment.
	Regularly-scheduled iron infusions may be needed, and should be expected unless chronic bleeding is halted though systemic therapies and/or procedural interventions.
The expert panel recommends RBC transfusions in the following settings: 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 (AR3; QOE: low, SOR: strong)	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.
The expert panel recommends considering evaluation for additional causes of anemia in the setting of an inadequate response to iron replacement (AR4; QOE: low, SOR: strong).	Typically testing should include measurement of folate, vitamin B₁₂, thyroid-stimulating hormone and work-up for hemolysis, with referral to hematology in unresolved cases.
The expert panel recommends that patients with HHT receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when there is an indication, with consideration of their individualized bleeding risks; bleeding in HHT is not an absolute contraindication for these therapies (AR5; QOE: low, SOR: strong).	Heparin agents and vitamin K antagonists are preferred to direct oral anticoagulants, as the latter may be less-well tolerated.⁵⁴ Patients with HHT with atrial fibrillation who do not tolerate anticoagulation or are too high-risk for anticoagulation can consider alternate approaches to decreasing cardioembolic risk, such as left atrial appendage closure.⁸⁰
The panel recommends avoiding the use of dual antiplatelet therapy and/or combination of antiplatelet therapy and anticoagulation, where possible, in patients with HHT (AR6; QOE:low [expert consensus], SOR: weak).	If dual or combination therapies are required, duration of therapy should be minimized and patients should be monitored closely.

Clinical recommendation	Clinical considerations
Epistaxis
The expert panel recommends that clinicians consider the use of oral tranexamic acid for the management of epistaxis that does not respond to moisturizing topical therapies (ER2; QOE: high, SOR: strong).	Can be coadministered with systemic antiangiogenic therapy.  Dosing: start at 500 mg twice daily, gradually increasing up to 1000 mg 4 times daily or 1500 mg 3 times daily. Dose per pill varies by country, and these recommended doses can be approximated and adapted given what is available.  Contraindications include recent thrombosis; relative contraindications include atrial fibrillation or known thrombophilia.
The expert panel recommends that clinicians consider the use of systemic antiangiogenic agents for the management of epistaxis that has failed to respond to moisturizing topical therapies, ablative therapies and/or tranexamic acid (ER4; QOE: moderate, SOR: strong).	IV bevacizumab is given as induction (5 mg/kg every 2 weeks for 4-6 doses) followed by maintenance (dosing variable; 5 mg/kg every 1-3 months is an option). Risk of long-term maintenance therapy unknown. Monitor for hypertension, proteinuria, infection, delayed wound healing, VTE. Oral thalidomide can also be considered, though side effects often limit long term use. Risks and benefits of antiangiogenic medications should be considered, as well as alternatives, such as septodermoplasty and nasal closure, in these patients. Shared decision making with patients is crucial.
GI bleeding
The expert panel recommends that clinicians grade the severity of HHT-related GI bleeding and proposes the following framework: Mild HHT-related GI bleeding: patient who meets their hemoglobin goals* with oral iron replacement. Moderate HHT-related GI bleeding: patient who meets their hemoglobin goals* with IV iron treatment. Severe HHT-related GI bleeding: patient who does not meet their hemoglobin goals* despite adequate iron replacement or requires blood transfusions. *Hemoglobin goals should reflect age, gender, symptoms and comorbidities (GR3; QOE: low, SOR: strong).	For most HHT patients (and in particular, those without comorbid conditions resulting in chronic anemia), the hemoglobin goal will be a normal hemoglobin for age and gender. This classification is not for the acutely anemic patient during the initial diagnostic phase, but rather for HHT patients who are post initial iron repletion (≥3 months after diagnosis) and is meant to represent chronic hematologic support requirements. Need for regular, scheduled IV iron (rather than an isolated single dose) defines patients in the moderate or severe category. This classification is considered proposed for future development.
The expert panel recommends that clinicians consider treatment of mild HHT-related GI bleeding with oral antifibrinolytics (GR5; QOE: low, SOR: weak).	Can be coadministered with systemic antiangiogenic therapy. Dosing: start at 500 mg twice daily, gradually increasing up to 1000 mg 4 times daily or 1500 mg 3 times daily. Dose per pill varies by country, and these recommended doses can be approximated and adapted given what is available. Contraindications include recent thrombosis; relative contraindications include atrial fibrillation or known thrombophilia.
The expert panel recommends that clinicians consider treatment of moderate to severe HHT-related GI bleeding with intravenous bevacizumab or other systemic antiangiogenic therapy (GR6; QOE: moderate, SOR: strong).	IV bevacizumab is given as induction (5 mg/kg every 2 weeks for 4-6 doses) followed by maintenance (dosing variable; 5 mg/kg every 1-3 months is an option). Risk of long-term maintenance therapy unknown. Monitor for hypertension, proteinuria, infection, delayed wound healing, VTE. Risks, and benefits of antiangiogenic medications should be considered. Shared decision making with patients is crucial.
Anemia and anticoagulation
The expert panel recommends that the following HHT patients be tested for iron deficiency and anemia: All adults, regardless of symptoms All children with recurrent bleeding and/or symptoms of anemia (AR1; QOE: high, SOR: strong)	Testing includes complete blood count and ferritin; if anemic but ferritin not reduced, obtain serum iron, total iron binding capacity, and transferrin saturation, and consider hematology consultation.
The expert panel recommends iron replacement for treatment of iron deficiency and anemia as follows: 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 (AR2; QOE: moderate, SOR: strong)	Assess adequacy of response (hemoglobin rise of ≥1.0 g/dL, normalization of ferritin and transferrin saturation) at 1 month. Oral iron: can start with 35-65 mg of elemental iron daily; if inadequate, can consider increased daily dose or twice daily dose; if not tolerated, can attempt alternate oral iron preparation. IV iron dose can be guided by total iron deficit (Ganzoni formula ⁷⁹) or a total empiric dose of 1 gram can be provided, with interval reassessment.
	Regularly-scheduled iron infusions may be needed, and should be expected unless chronic bleeding is halted though systemic therapies and/or procedural interventions.
The expert panel recommends RBC transfusions in the following settings: 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 (AR3; QOE: low, SOR: strong)	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.
The expert panel recommends considering evaluation for additional causes of anemia in the setting of an inadequate response to iron replacement (AR4; QOE: low, SOR: strong).	Typically testing should include measurement of folate, vitamin B₁₂, thyroid-stimulating hormone and work-up for hemolysis, with referral to hematology in unresolved cases.
The expert panel recommends that patients with HHT receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when there is an indication, with consideration of their individualized bleeding risks; bleeding in HHT is not an absolute contraindication for these therapies (AR5; QOE: low, SOR: strong).	Heparin agents and vitamin K antagonists are preferred to direct oral anticoagulants, as the latter may be less-well tolerated.⁵⁴ Patients with HHT with atrial fibrillation who do not tolerate anticoagulation or are too high-risk for anticoagulation can consider alternate approaches to decreasing cardioembolic risk, such as left atrial appendage closure.⁸⁰
The panel recommends avoiding the use of dual antiplatelet therapy and/or combination of antiplatelet therapy and anticoagulation, where possible, in patients with HHT (AR6; QOE:low [expert consensus], SOR: weak).	If dual or combination therapies are required, duration of therapy should be minimized and patients should be monitored closely.

For a complete list of all recommendations, see the full guidelines publication.⁶ Recommendation number, quality of evidence (QOE), and strength of recommendation (SOR) are given after the recommendations. Clinical considerations from the expert panel are summarized from the published guidelines supplement.

RBC, red blood cell.

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