Table 1.

Management of NTDT-related complications

Clinical morbidity/special clinical context	Management
Endocrine and bone disease	Referral to endocrinology department for treatment per local standards	Positive experience with bisphosphonates in thalassemia but lack of supporting data specific to NTDT
Extramedullary hematopoietic pseudotumors	MRI is currently the standard of care for diagnosis of extramedullary hematopoiesis with active pseudotumors showing intermediate signal intensity in both T1- and T2-weighted images with no enhancement with gadolinium Biopsy is not routinely pursued, given the risk of hemorrhage Management strategy includes blood transfusion therapy, hydroxyurea, radiotherapy, and/or surgery depending on severity and acuity of symptoms	We use hypertransfusion for a pretransfusion target hemoglobin >10 g/dL as the cornerstone of management for extramedullary hematopoietic pseudotumors Surgical decompression and radiotherapy offer faster control of paraspinal lesions causing sensory and/or motor deficits; use of dexamethasone before and after surgery can minimize the risk of exacerbation of tissue edema and worsening of symptoms
Hepatosplenomegaly	Splenectomy is indicated in cases of hypersplenism or symptomatic splenomegaly Otherwise, we avoid splenectomy and treat patients initially with transfusion therapy to avoid the increased risk of thrombosis and infection	The use of agents such as ruxolitinib to decrease spleen size is experimental
Gallstones	Cholecystectomy if recurrent painful attacks
Leg ulcers	Keep legs and feet raised above the level of the heart Apply topical antibiotics and occlusive dressing Consider applying topical sodium nitrite cream	Consider pentoxifylline, hydroxyurea, and transfusion Referral to dermatology or vascular medicine/surgery for treatment per local standards
Liver fibrosis, cirrhosis, and hepatocellular carcinoma	Immunization against hepatitis A and hepatitis B Adequate management of concomitant viral hepatitis, if present (direct-acting antiviral therapy, such as glecaprevir-pibrentasvir, ledipasvir-sofosbuvir, or sofosbuvir-velpatasvir for patients with active hepatitis C); it is our practice to comanage with hepatology	Referral to hepatology department for treatment per local standards
PH	Referral to a multidisciplinary or specialized PH clinic for treatment per local standards, and consideration of bosentan, ambrisentan, sildenafil, tadalafil, macitentan, riociguat, angiotensin-converting enzyme inhibitors, calcium channel blockers, and β-blockers	Potential role of transfusion therapy (2 units of packed RBCs every 3 or 4 wks, targeting a pretransfusion hemoglobin of >10 g/dL)
Thrombotic disease (including overt/silent strokes)	Treatment per local standards in consultation with cardiology, neurology, and vascular surgery Antiplatelet therapy in patients who underwent splenectomy at any platelet count, especially with platelets ≥500 × 109/L	Primary and secondary prophylaxis with anticoagulant/antiplatelet therapy according to medical and surgical risk assessment models in patients without thalassemia, with added risk considerations for patients with NTDT with the following risk factors: age >35 y, splenectomy, minimal blood transfusion, hemoglobin <10 g/dL, platelets ≥500 × 109/L, nucleated RBC ≥300 × 106/L, PH, immobility, surgery, pregnancy
Pregnancy	Assess iron overload:  Optimize iron overload management before conception Hold oral iron chelation for conception and pregnancy; may switch to deferoxamine if needed during the second and third trimesters especially if worsening iron overload resulting in cardiac dysfunction Hold deferasirox and deferiprone during breastfeeding Monitor serum ferritin levels monthly Evaluate cardiac status: Transthoracic echocardiogram before conception and every trimester Cardiology assessment for PH and risk management Evaluate liver function every trimester Evaluate thyroid function every trimester	Screen for gestational diabetes at 16 and 28 wks Check calcium and vitamin D; replete as necessary Screen for RBC antibodies before conception Establish viral status (hepatitis B, hepatitis C, and HIV) Provide appropriate immunizations (hepatitis B, pneumococcal vaccine, and influenza) Start folic acid before conception Assess hemoglobin concentration: if <10 g/dL, consider transfusion therapy Consider prophylactic anticoagulation with aspirin or LMWH for women considered at high risk (pre- and/or post-partum) Monitor fetal health: monthly fetal ultrasound

LMWH, low molecular- weight heparin; RBC, red blood cell.