Portal Vein Thrombosis in Patients with β-Thalassemia

Abstract

Beta (β)-thalassemia major, a chronic inherited hematological disease, leads to chronic anemia in affected children. One of the options for treatment is splenectomy. However, this treatment involves risk of many complications, one of which is portal vein thrombosis (PVT). The risk factors include exposure of phosphatidyl-serine of abnormal red blood cells (RBCs), increased activation, aggregation and a number of platelets and nucleated RBCs after splenectomy, increased endothelial activation, decreased nitric oxide, organ dysfunction, and thrombophilia. PVT is either complete or partial obstruction and has fatal complications, especially after splenectomy and late diagnosis without effective treatment. Diagnosis is typically made with X-ray. Generally, the incidence of PVT is between 1.7% and 9.2%. Initially, it is asymptomatic; symptoms appear gradually as thrombosis progresses. The easiest way to differentiate it from other conditions is via imaging study like Doppler ultrasound. It is usually associated with prolonged prothrombin time (PT). D-dimer and alkaline phosphatase are generally high. The treatment is the same for both the acute and chronic forms and includes the treatment of causal factors, prevention of thrombus extension, and achievement of patency of the portal vein via regular RBC transfusion and antithrombotic agents.

1. Introduction

1.1 Thalassemia syndrome

Beta (β)-thalassemia disease is one of the common hereditary hemolytic anemias with high prevalence in the malarial belt areas including the Mediterranean, the Middle East, Transcaucasia, Africa, South and Southeast Asia, and China. It results from mutations on chromosomes 11 and 16 for cases of β-thalassemia and alpha (α)-thalassemia, respectively, with more than 150 different mutations [1, 2]. It describes all the inherited genetic abnormalities that affect the synthesis of α- or β-globin chains and consequently normal erythropoiesis and oxygen-carrying capacity of blood.

Thalassemia is an autosomal recessive disorder classified into two main categories: α- and β-thalassemia. It commonly presents as chronic hemolytic anemia [2]. β-Thalassemia major results from homozygous or compound heterozygous mutations. It involves early presentation, multi-organ complications, frequent hospitalization, and lifelong management. Its treatment depends mainly on blood transfusion. The severe form of β-thalassemia results from defects in two globulin genes and severely reduced production of β-globulin genes [1]. β-Thalassemia minor is an asymptomatic condition due to heterozygous mutations, whereas β-thalassemia intermedia involves two defective genes and is characterized by mild-to-moderate reduction in β globulin production. It is associated with absence of regular blood transfusion and iron chelation therapy, and it may lead to serious specific complications like gall and renal stones, leg ulcer, thrombophilia, and right heart failure [1].

1.2 Pathophysiology

α-Thalassemia occurs when one or more of the four α-globin genes are missing, damaged, or changed. β-Thalassemia occurs when both β-globin genes are affected [2, 3].

β-Thalassemia is characterized by the reduced synthesis or absence of the β-globin chains in the hemoglobin molecule, resulting in accumulation of unbound α-globin chains that precipitate in erythroid precursors within bone marrow and mature erythrocytes, ultimately resulting in ineffective erythropoiesis and peripheral hemolysis [3].

Anemia stimulates the production of erythropoietin with consequent intensive but ineffective expansion of the bone marrow (up to 25–30 times more than normal), which in turn may cause the typical bone deformities. Prolonged, severe anemia and increased erythropoietic drive result in hepatosplenomegaly and extramedullary erythropoiesis [3].

The molecular and pathophysiological mechanisms underlying the disease process in patients with thalassemia have substantially increased over the past decade. There are many factors that highlight the pathophysiology of β-thalassemia. These include ineffective erythropoiesis, chronic anemia/hemolysis, and iron overload, which is secondary to increased intestinal absorption in thalassemia intermedia and excessive blood transfusion in β-thalassemia major. Thromboembolic events are common in β-thalassemia intermediate in comparison to β-thalassemia major [3], as shown in Figure 1.

Figure 1.

Pathophysiology of patients with thalassemia.

1.3 Iron toxicity

One unit of transfused blood contains 200–250 mg of elemental iron. The body has no ability to excrete such quantities of iron. Therefore, the development of iron overload in patients receiving chronic blood transfusion is inevitable. The free or unbound iron accumulates in various organs, such as the liver, heart, pancreas, pituitary, and gonads, and causes the catalysis of injurious compounds, such as free radicals, which will begin to damage cells, leading to fibrosis or organ dysfunction [3]. Iron is highly reactive and easily alternates between two states-iron III and iron II-in a method that results in loss and gain of electrons and the generation of unsafe free radicals. This can damage lipid membranes, organelles, and DNA, ultimately causing cell death and fibrosis [1]. In a healthy individual, iron is kept safe by binding to transferrin, whereas in patients with iron overload, the transferrin capacity to bind iron is exceeded within the cells and in the plasma. This results in the production of free iron within cells or plasma, damaging many tissues in the body, which can be fatal unless treated by iron chelation therapy [4], as shown in Figure 2.

Figure 2.

Summary of mechanism of iron toxicity.

The most common complication of β-thalassemia is iron overload, caused either by recurrent blood transfusion in β-thalassemia major or excessive iron absorption in β-thalassemia intermedia. Iron overload results in multiple organ damage [5]. Cardiac complications include cardiomyopathy, arrhythmia, and pericarditis. Liver complications include liver fibrosis and cirrhosis. Endocrine complications include hypothyroidism, pituitary failure, hypoparathyrodism, growth hormone deficiency and sex organ failure. There is also risk of embolism resulting in portal vein thrombosis and portal vein hypertension.

1.4 Treatment

Treatment involves early and regular transfusion to maintain hemoglobin (Hb) levels greater than 9–10 gm/dl. This helps to improve growth and development, reduce hepatosplenomegaly and bone deformity, improve survival, and decrease severity of disease and hemolysis (because chronic transfusion may ameliorate ineffective erythropoiesis) [1].

Chelation therapy is used to maintain safe levels of body iron at all times [5].

Dosing of the drugs involved in chelation therapy (desferrioxamine, deferasirox, jadenu, and deferiprone) and treatment require careful monitoring by serum ferritin and MRI techniques.

1.5 Portal vein thrombosis

PVT refers to a total or partial obstruction of the blood flow in the portal vein due to formation of thrombus or clot [6] that blocks the main portal vein going to the liver. It may result from previous use of an umbilical catheter during the neonatal period, a clotting disorder, or infection or injury. In 50% of cases, it may be idiopathic [7, 8]. It is an important cause of portal hypertension in the pediatric age group with high morbidity rate due to its main complication of upper gastrointestinal bleeding [6].

PVT is a risky disease with potentially fatal complications, mainly post splenectomy, especially if there are delays in diagnosis and treatment. It can be diagnosed early with advanced X-ray imaging [9].

Risk factors of PVT can be systemic or local [10]. Inherited systemic risk factors include:

• factor V Leiden mutation

• factor II (prothrombin) mutation

• protein C and S deficiency

Acquired systemic risk factors include:

• myeloproliferative disorder

• paroxysmal nocturnal hemoglobinuria

• hyperhomocysteinemia

Local risk factors for PVT include: focal inflammatory lesion:

• neonatal omphalitis, umbilical vein catheterization, diverticulitis, appendicitis, pancreatitis, duodenal ulcer, cholecystitis, Crohn disease, ulcerative colitis, cytomegalovirus hepatitis

• injury to the portal venous system: splenectomy, cholecystectomy, abdominal trauma, liver transplant, iatrogenic (fine needle aspiration of abdominal mass), surgical portosystemic shunting

• cirrhosis.

1.6 Clinical presentation of PVT

PVT leads to portal hypertension and can cause growth of new blood vessels called varices around the blockage. It may connect blood flow from the intestine directly to the general circulation, bypassing the liver [7].

Portal hypertension can produce an enlarged spleen, low platelet count, and gastrointestinal bleeding, and may increase production of ammonia, leading to encephalopathy [7].

1.7 Portal vein thrombosis in thalassemia

PVT is a rare serious complication post splenectomy, especially for thalassemia. It requires a very high index of suspicion to confirm early diagnosis and administer urgent therapy to prevent fatal complications such as portal vein hypertension in a thalassemia patient or bowel infarction [11].

Studies have shown that red blood cells (RBCs) from β-thalassemia major and β-thalassemia intermedia increase adhesion to endothelial cells (ECs). Also, thalassemia patients have low levels of protein C and S compared with healthy people. Prothrombin fragment 1.2 (F1.2) is a marker of thrombin generation and increases in thalassemia intermedia patients [3].

There is no role for prothrombotic mutations on the increasing incidence of coagulopathy in thalassemia patients. Studies in Lebanon and Italy show that the presence of factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase mutations is not related to the increased risk of thrombosis in thalassemia patients [12].

The presence of hepatic, cardiac, or endocrine dysfunction may contribute to hypercoagulability in thalassemia; when pathologic processes overwhelm the regulatory mechanisms of hemostasis, the result is increasing amount of thrombin formation, which leads to thrombosis [12].

1.8 Incidence

The incidence of PVT in all thalassemia patients is between 1.7% and 9.2%, which is approximately ten times greater than in the normal population. The incidence is 4.4 times more prevalent in non-transfusion-dependent thalassemia patients (NTDT) than patients with transfusion-dependent thalassemia (TDT). However, PVT can occur in patients with either α- or β-thalassemia diseases [2].

Around 4% of β-thalassemia major patients and 9.6% of thalassemia intermedia patients develop TEE. The same group have shown 6 years later that 1.1% of TM patients in seven Italian centers had thrombosis [3].

PVT incidence in thalassemia is different in many centers. Some centers have reported single case reports, whereas others have reported cases in 3.3–6.6% of patients. Some centers recommend screening those patients referred for blood transfusion due to the risk of thrombosis [12].

Studies in different countries show varying incidence rates, for example, 5.5% in Al Najaf, Iraq [9], 3.12% in Babol, Iran [12], 3.5% in Ahvas, Iran [13], 3.85% in Italy [12], and 8.4% in Greece [13].

Different results could be explained by the different methods and cohorts used in different studies. Some studies included younger patients and used only Doppler ultrasound for diagnosis of PVT, while other studies used more advanced investigations in the detection of PVT, including magnetic resonance imaging (MRI), computed tomography (CT) scan, angiography, and Doppler ultrasound, in addition to using older cohorts [9].

1.9 Pathophysiology

PVT is the combination of abnormalities in different parts of the hemostatic system [2]. We discuss some of these abnormalities in the paragraphs that follow. Figure 3 shows the pathophysiology of PVT.

Figure 3.

Factors contributing to a hypercoagulable state and subsequent thrombotic events in thalassemia.

Exposure of the external membrane of abnormal RBCs to phosphatidylserine (PS) results in reduction of normal dissemination of RBC membrane phospholipids. In addition, free iron stimulates lipid oxidation and increases the level of membrane-bounded hemichromes and immunoglobulin, leading to changes in the structures of spectrin and band 3 protein of RBC membrane. This results in aggregation and adhesion of abnormal RBCs to endothelial cells [2, 3].

In PVT, there is an elevated number of circulating and aggregated platelets, which are found mostly post splenectomy. The lifespan of these platelets is usually short, and they have a good response to many agonists like adenosine diphosphate (ADP), epinephrine, and collagen. PVT patients also have greater levels of plasma beta-thromboglobulin than the platelets in normal populations [3].

Increased activation of endothelial cells (due to the activation of granulocytes and monocytes) causes endothelial injury and excess level of endothelial adhesion. This leads to thromboembolic events [5].

Low nitric oxide (NO) (due to hemolysis secondary to reduced arginine level) results in pulmonary vasoconstriction and subsequently leads to chronic pulmonary thromboembolism [2].

Thrombocytosis and nucleated RBCs (NRBCs) can occur post splenectomy, especially when the platelet count is more than 600,000/mm³ and the NRBC count is greater than 300/mm³ [2].

In PVT, iron overload organ failure may develop, such as cardiac siderosis, which is complicated by cardiac arrhythmia and cardiomyopathy [2].

Deficiencies of proteins C and S and elevated anti-phospholipid antibodies (i.e., lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein) are seen in thrombophilia [2].

Excess RBCs with negatively charged phospholipids in combination with increased cohesiveness and aggregation of RBC results in thrombus formation [2].

Prothrombin mutation is also seen in PVT [2].

1.10 Presentation

PVT presents clinically as acute or chronic. The acute form usually appears within 60 days from hospital investigation and assessment. It may present initially as upper gastrointestinal bleeding or bowel ischemia, which is suggested by an increase of bleeding, abdominal pain, abdominal distention, vomiting, and melena [10].

Initially, PVT may be asymptomatic, but symptoms gradually increase as thrombosis progresses. The easiest way to differentiate it is by using imaging study like Doppler ultrasound (to look for the presence or the absence in significant portal collateral) or by using CT of abdomen, angiograph, MRI technique [9].

1.11 Acute portal vein thrombosis

Acute PVT is associated with immediate thrombus formation, leading to partial or total obstruction of the portal vein. The cute form may present with an increase in body temperature, abdomen pain and distention, diarrhea, vomiting, rectal bleeding, and anorexia [9, 10].

1.12 Physical examination

Upon physical examination, the abdomen may be distended, guarding against internal abdominal inflammation, intestinal infarction, and perforation [9, 10].

Splenomegaly is present in 37% of patients. Sepsis may be associated with perforation, which can lead to peritonitis, shock, and even death. Ascites are rare but may develop if there is collateral circulation (mild ascites occur because of congestion of the intestinal venous without liver cirrhosis).

1.13 Chronic portal vein thrombosis

Chronic PVT is usually nearly asymptomatic except if it causes development of varices and ascites. Typically, those patients with advanced thrombosis do not remember a previous event or disease [9, 10]. Chronic PVT usually presents in the first and second decades of life as left upper abdominal pain (due to splenomegaly or splenic infraction) and recurrent gastrointestinal bleeding (in 20–40% of cases), which usually occurs in association with liver congestion or swell.

1.14 Physical examination

Splenomegaly is present in 10% of patients, but most cases present with multiple other signs. Ascites develop in 20% of cases and encephalopathy is unusual and transient. Cholangitis, obstructive jaundice, and sometimes gallstones or extra hepatic biliary obstruction occurs in 80% of cases. In addition, hypersplenism complicated by pancytopenia is common in chronic PVT.

2. Diagnosis of PVT

2.1 Laboratory tests

The liver function test is usually normal unless it is associated with cirrhosis or extrahepatic portal vein obstruction [9].

Level of prothrombin and other factors may be low (PT is prolonged), and D-dimer and alkaline phosphatase are usually high [9].

Total serum protein is usually low, especially if albumin is decreased with prolonged PVT [9].

Liver biopsy shows atrophy and regenerative nodular hyperplasia, which is due to apoptosis and compensatory arterial vasodilation in the chronic form of PVT [14].

2.2 Other lab tests

There is derangement of proteins in the hemostatic systems of β-thalassemia patients, including increased aggregation of platelets and coagulation factors (von Willebrand factor and factor VIII) as well as low levels of proteins C and anti-thrombin [9].

Annual monitoring of thrombin-generation markers by thrombin and anti-thrombin factor and D-dimer tests is recommended post-splenectomy thalassemia patients [9].

2.3 Ultrasound

Ultrasound displays hypo echoic, hyper echoic, or isochoric within the portal vein causing obstruction either completely or partially. It is the most cost-effective imaging modality, but its specificity and sensitivity vary (80–100%) depending on the patient and the experience of the administering radiologist. Its accuracy ranges from 88 to 98% [9].

Contrast-enhanced ultrasound is superior to ultrasound in detecting the patency of the portal vein [9, 15] and it is more reliable in patients with very low portal vein velocity [9].

Endoscopic ultrasound has specificity of 93% and sensitivity of 81% and is capable of diagnosing small and non-occluded thrombi. It is also more efficient than ultrasound or CT in detecting portal invasion by tumors [9, 10].

2.4 Computed tomography and magnetic resonance imaging

CT and MRI are more accurate for the detection of thrombus extension with presence or absence of collaterally vessels (that bypass the obstruction) especially after splenectomy. PVT appears as isodense to adjacent soft tissue [9]. Following administration of intravenous (IV) iodinated contrast, PVT shows a bland thrombus, which is seen as a low-density, non-enhancing defect within the portal vein. MRI is better than Doppler ultrasound in diagnosing a partial thrombosis and obstruction of the main portal venous trunk. In addition, it detects more sufficient portosplenic collaterals and portal vessels [9, 10]. However, currently used therapeutic methods have an essential in prolong life expectancy of thalassemia patients [9].

2.5 Treatments

The main goal of management is the same in both acute and chronic PVT. Treatment depends on causal factors and is used to prevent expansion of the thrombus and achieve portal vein patency. However, in chronic thrombosis, the treatment of complications associated with portal hypertension must be considered [10].

Recently, anticoagulant therapy has become the preferred treatment to obtain portal vein recanalization or patency. Other modalities of treatment should be used if there is partial or absent PVT resolution [10].

Before administering anticoagulant treatment, conditions such as new or old thrombosis and presence of thrombophilic condition or hepatic disease must be considered [10, 16].

RBC transfusion is indicated for management of β-thalassemia patients, especially NTDT patients (who are at risk of thromboembolism or have thromboembolic events because of transfusion native patients who are more risky to develop this complication [2]. Hemoglobin should be maintained at a level greater than 9 g/dL. The aim is to correct hypercoagulopathy and protect against thrombosis [3].

3. Antithrombotic agents

3.1 Antiplatelets

Acetylsalicylic acid (2–5 mg/kg/day) is the most important treatment for the prevention and management of thromboembolism in β-thalassemia patients, especially those who have undergone splenectomy and who have thrombocytosis (platelet count greater than 500,000/mm³) [2]. Resistance to acetyl salicylic acid has been reported in some thalassemia patients, especially after spleen removal [2].

3.2 Anticoagulants

Anticoagulants are used to reduce risk of embolism, halt clot extension, and prevent recurrence [1, 17].

3.3 Anticoagulants for acute PVT

There is no randomized controlled trial regarding the use of anticoagulants in acute PVT. After 6 months of therapy, a complete recanalization has been reported in about 50% of patients, with good results in the case mesenteric vein involvement and a low incidence of complications. In contrast, there was 10% of cases of PVT which are resistant to anticoagulants [10].

Better outcomes are achieved in acute PVT when anticoagulants are given as early as possible. Rate of recanalization is about 69% if treatment is started within the first week after diagnosis. Rate of recanalization decreases to 25% when treatment starts later (e.g., the second week after diagnosis) [10].

Anticoagulant therapy should continue for 3–6 months to complete recanalization [10].

3.4 Anticoagulants for chronic PVT

Anticoagulants are only administered in 30% of chronic PVT chases, which reflects concerns about their use in the presence of varices and coagulation dysfunction. However, the number of hemorrhage episodes in chronic PVT patients on anticoagulants has not shown to increase; however, long-term follow-up may be needed. Anticoagulants have proven effective in the prevention of new thrombotic events with a low mortality rate [10].

Anticoagulants include vitamin K antagonists (warfarin), low-molecular-weight heparin (enoxaparin), and unfractionated heparin (standard heparin). Direct oral anticoagulants include direct oral anti-activated factor X (Xa) (e.g., rivaroxaban) and direct oral antithrombin (IIa) (e.g., dabigatran). These medications are used to manage thrombosis in beta-thalassemia patients [2].

In hemoglobinopathies including thalassemia, rivaroxaban is effective without increasing the risk of bleeding or thrombosis after 18 years of age [2].

4. Unfractionated standard heparin

4.1 Mechanism of action

Unfractionated standard heparin enhances the rate by which antithrombin III neutralizes the activity of several coagulation factors including factor Xa and thrombin [17].

Average half-life when administered intravenously is 60 minutes in adults. Its half-life is dose dependent (higher dose has more duration in the circulation). It has a shorter half-life than normal in patients with thrombotic disease and a longer half-life than normal in cirrhosis or uremia patients.

Contraindications of unfractionated standard heparin include recent bleeding in the central nervous system, bleeding from an inaccessible site, malignant hypertension, bacterial endocarditis, and recent surgery.

Partial thromboplastin time (PTT) may not reflect the correct degree of anticoagulation, therefore specific heparin level should be determined (heparin level is 0.35–0.70 U/ml by anti-factor Xa assay or 0.2–0.4 U/ml by protamine sulfate assay).

Protamine sulfate can neutralize heparin immediately. Because of the rapid clearance rate of heparin, stopping the infusion is adequate treatment for most patients (1 mg of protamine sulfate can neutralize 90–110 units of heparin). In addition, heparin has rapid metabolic decay and therefore it needs only one-half of a total dose of protamine.

4.2 Enoxaparin

Enoxaparin is an effective and convenient alternative to standard heparin therapy [17]. Adult patients rarely need to have their heparin level monitored, but in pediatric patients there is more diversity of response. Monitoring is critical to ensure that a therapeutic level is achieved.

PTT cannot be used to monitor heparin levels; a specific assay should be used. Once therapeutic range is achieved, routine monitoring is not required or is required infrequently.

When enoxaparin is used for prophylaxis against thrombosis, the dose is 0.5 mg/kg/12 hr subcutaneously.

4.3 Warfarin

Warfarin is an oral anticoagulant drug that acts to reduce the functional level of vitamin K-dependent factors II, IIV, IX, and X as well as proteins S and C [17]. Warfarin will reduce the level of following factors gradually depending on the half life, factor VII is firstly as the shortest its half life, followed by factor IX and X and lastly factor II, it usually needed 4-5 days to decrease all these factors. PT is a clotting test used to monitor warfarin therapy.

The most adverse effect is hemorrhage, which is related to dose or metabolism and is treated by discontinuation of the drug along with administration of vitamin K (vitamin K given is equal to the daily warfarin dose) either orally, subcutaneously, or intravenously (not intramuscularly). The parenteral route has a much longer half-life and may overshoot the correction. Sometimes, warfarin is associated with life-threatening bleeding. When severe hemorrhage develops, 15 ml/kg of fresh frozen plasma should be given in addition to vitamin K.

5. Dabigatran (Pradaxa)

5.1 Mechanism of action

Dabigatran prevents thrombus development through direct, competitive inhibition of thrombin (thrombin can convert fibrinogen to fibrin) and can inhibit free and clot-bound thrombin and thrombin-induced platelet aggregation [18, 19].

Dabigatran can be given when converting from warfarin when international normalized ratio (INR) is less than 2.0. It can also be used when converting from parenteral anticoagulant. In this case, give dabigatran 0–2 hours before next dose of parenteral drug.

When converting from dabigatran to warfarin, starting time of warfarin should be adjusted based on creatinine clearance.

6. Rivaroxaban (Xarelto)

6.1 Mechanism of action

Rivaroxaban is a factor Xa inhibitor that blocks the active site of factor Xa as well as prothrombinase activity and clot-associated factor Xa [20]. It also inhibits thrombin generation. The drug’s half-life is 6–7 hours.

Rivaroxaban can lead to prolonged PT and activated partial thromboplastin time (aPTT), but it has no effect on thrombin and antithrombin activity.

It does not require routine monitoring of coagulation, but it may need anti–factor Xa chromogenic and PT assay to quantify its plasma level. However, it does require periodic assessment of renal function.

There are limited data on the drug’s use in children 1 year or age or older with moderate-to-severe renal impairment. There is also no clinical data available in pediatric patients younger than 1 years old with serum creatinine above the 97.5th percentile. This drug is not recommended for use in children younger than 6 months.

6.2 Other drugs

Fetal hemoglobin-inducing agents [3, 21] like hydroxycarbamide and decitabine also appear to reduce plasma markers of thrombin formation. Hydroxycarbamide may change hypercoagulability in many ways; it may lower phospholipid expression on the surface of RBCs and platelets, and it reduces RBC adhesion to thrombospondin, a thrombin-sensitive protein. It may also reduce white blood cell (WBC) count, especially monocytes expressing transcription factor.

Hydroxyurea is a hemoglobin F stimulating agent. It increases hemoglobin F and improves the clinical symptoms of β-thalassemia disease and reduces hypercoagulability state due to decreased exposure of phosphatidylserine on the membranes of RBCs [2, 21].

6.3 Hematopoietic stem cell transplantation (HSCT)

Hematopoietic stem cell transplantation (HSCT) can normalize abnormal hemostatic derangement in β-thalassemia patients by increasing natural anticoagulant proteins and activating platelets in the circulation and reducing microparticles and Exposure of abnormal RBCs membrane to PS (results in reduction of normal dissemination of RBC membrane phospholipids) [2].

7. Conclusion

Thrombosis in β-thalassemia patients is the result of several risk factors, a combination of which is often the cause of clinical thromboembolism. Splenectomy, anemia, and iron overload are increasingly important risk factors for hypercoagulability in β-thalassemia. An individualized approach is highly indicated to create an optimal strategy for preventing occurrence of this complication through adequate post-operative monitoring via Doppler ultrasound and blood investigations, including D-dimer and PT tests.

Acknowledgments

The authors thank all the patients, their families, all investigators and medical staff in Babylon hereditary blood disease center participated in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

None.