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Fatal Stroke in a Child With Severe Iron Deficiency Anemia and Multiple Hereditary Risk Factors for Thrombosis

Posted on: Friday, 18 March 2005, 03:00 CST

Introduction

The term "thrombophilia" is used to describe inherited or acquired disorders of hemostatic mechanisms that are likely to increase the risk of thrombosis. The acquired risk factors for thrombosis include surgery, immobilization, trauma, dehydration, infection, hyperviscosity, indwelling vascular catheter, prosthetic cardiac valves, disseminated intravascular coagulation, autoimmune disorders, oral contraceptive agents, antiphospholipid antibodies, and malignancy. ' There are a number of genetic predisposing factors that have been identified for thrombophilia. The inherited prothrombotic states may be divided into four major categories based on etiology: (i) deficiencies or qualitative abnormalities of activated coagulation factor inhibitors (antithrombin deficiency, protein C or S deficiency, activated protein C resistance), (ii) impaired clot lysis (dysfibrinogenemia, plasminogen deficiency), (iii) Metabolic defects such as hyperhomocysteinemia, CBS (Cystathionine-p-synthase) or MTHFR (methyltetrahydrofolate reductase) deficiency, and (iv) abnormalities of coagulation zymogens or cofactors (prothrombin gene mutation, elevated factors VIII or IX).a The morbidity associated with a significant thromboembolic event in children can be very severe and may have implications on the whole family; hence, all the associated risk factors must be fully investigated. The presence of a prothrombotic state is rarely the only etiology of thrombotic vascular occlusion in children, but a combination of genetic predisposition and environmental factors can trigger a major arterial ischemie stroke.3 We present a case report of 1 such patient seen in our institution.

Case Report

A 4-year-old white female child presented with a two-month history of decreased activity, easy fatigability, and the acute onset of vomiting, abdominal pain, cough, and dyspnea for 1 day. She also had one tarry stool. She had history of milk intake in excess of 40 ounces per day. She was initially seen by her primary care physician and was found to be tachypneic (respiratory rate 70/min), tacliycardiac (heart rate 180-190/min), pale and lethargic. She was transferred to the emergency department (ED) for further evaluation and treatment. On arrival in the ED, she was found to be afebrile, tachypneic, tachycardiac but normotensive. On examination, she was noted to be very pale and lethargic with mottled skin and capillary refill of 4 seconds. No other significant findings were noted on the initial examination, including the absence of hepatosplenomegaly and no neurologic deficits. Her initial CBC showed a white cell count of 20.3 10^sup 9^/L, Hb of 58 g/L, MCV < 50 CL, and platelet count of 748 10^sup 9^/L. The initial impression was compensated shock with severe iron deficiency anemia (Figure 1) and acute gastrointestinal hemorrhage.

She received aggressive rehydration with normal saline and then transfusions of packed red blood cells. She was electively endotracheally intubated for progressive respiratory distress with evolving clinical cardiac failure denoted by the development of new hepatomegaly and a gallop rhythm on cardiac auscultation. An echocardiogram in the ED revealed bilateral atrial masses, suggestive of thrombi. Her initial chest X-ray and abdominal series were normal. The abdominal ultrasound revealed ascites, periportal edema and decreased portal venous blood flow. Abdominal computed tomography (CT) scan revealed no diagnostic findings. She was transferred to the pediatric intensive care unit (PICU) for further management.

In the PICU, she continued to require vendlatory support and received Digoxin to treat supraventricular tachycardia that subsequently developed. Heparinization was initiated to prevent further progression of her suspected intracardiac thrombi after head CT revealed no intracranial thrombus or hemorrhage. Repeat echocardiography revealed the large right atrial thrombus but the left atrial mass was no longer visualized.

Right-sided seizures developed early in the morning of the second hospital day requiring therapy with fosphenytoin. Repeat head CT demonstrated an acute right middle cerebral artery (MCA) infarction. Low dose heparinization was continued. Myocardial magnetic resonance imaging and chest CT revealed bilateral pulmonary artery thrombi in addition to the thrombus within the right atrium. A bone marrow examination revealed 80-90% cellularity, no stainable iron, no viral inclusions and no evidence of malignancy (Figure 2). Examination of peritoneal fluid also revealed inflammatory cells, with no evidence of malignancy. Culture results of blood, urine, tracheal aspirates and peritoneal fluid were all negative.

Figure 1. Post-transfusion peripheral blood smear showing 2 populations of red blood cells: One is the patient's microcytic hypochromic (arrowheads), and another is normocytic normochromic (transfused cells).

Her neurologic status worsened over the ensuing 24 hours. Repeat head CT scan demonstrated evidence for progression of the right MCA infarct and a new right anterior cerebral artery (AC]A) infarction with mass effect evidenced by midline shift. Her clinical status and radiographie findings worsened over the next 48 hours despite aggressive medical management. Edema of the entire right hemisphere was noted on the fifth hospital day. Neurologic examination and CNS perfusion studies were consistent with brain death and supportive measures were withdrawn. Permission for an autopsy was denied.

The thrombophilia workup was initiated in the PICU. Detection of genetic mutations predisposing to thrombosis was performed on DNA isolated from peripheral blood leukocytes using the Rapid Cycle PCR method (Light Cycles, Roche Molecular Biochemicals).4 This patient was found to be heterozygous for prothrombin gene mutation (20210G0[arrow right]A), MTHFR mutation (667C[arrow right]T) as well as for factor V Leiden (506A[arrow right]G). Her antithrombin III level was within the normal range. She also demonstrated increased levels of IgG anti-phospholipid antibody. Her serum homocysteine level was normal at 4 mol/L. Her family members were also screened and the results are summarized in Table 1. Although the patient's father carries similar genetic mutations, he has so far been asymptomatic.

Figure 2. Bone marrow biopsy specimen revealing adequate cellularity, with progressive differentiation of erythroid and myeloid cells with abundant megakaryocytes.

Table 1

SUMMARY OF PROTHROMBOTIC STATES IN THE PATIENT AND HER FAMILY

Discussion

Arterial thromboembolic disease leading to myocardial infarction and stroke is the leading cause of death and disability in the adult population, and venous thromboembolic disease results in 200,000 deaths per year in the United States primarily due to pulmonary embolism.5 Thrombotic disease has a lower incidence in pediatrics but it is also associated with severe morbidity and mortality. The reported incidence of arterial and/or venous occlusive disease varies from 1 to 2.5 per 100,000 children from newborn period to 15 years of age.6,7 About 150 years ago, the German pathologist Virchow8 postulated that thrombosis was due to a triad of factors: alteration of blood flow, vessel wall injury and changes in the eomposition of blood. However, Virchow's "changes in the composition of blood" was not elucidated in detail until 1965 when Egeberg described hereditary antithrombin III deficiency. In the past decade, immense progress has been made in the diagnosis of new hereditary and acquired hypercoagulable states.

The overall incidence of a thrombophilic state in children with arterial ischemic strokes (AIS) is reported in the range of 10-50%, depending on the study population. Most patients with AIS tend to have more than one thrombophilic tendency. As a cause of thrombophilia, factor V Leiden mutation (506A[arrow right]G) is the most common genetic mutation affecting 5-8% of the white population.9 This mutation is inherited as autosomal dominant and is responsible for 95% of cases of inherited activated protein C resistance. The heterozygous state of factor V Leiden is associated with an eightfold increase in the risk for thrombosis while the homozygous state increases the risk 91 fold.10-12 There is also evidence that it plays a role in the early onset of childhood ischemie stroke.13-15

The next common cause of thrombophilia is prothrombin 20210G[arrow right]A gene mutation seen in 1-3% of the population.16 Prothrombin gene mutation results in increased circulating levels of prothrombin, and consecutively, increased thrombin and fibrin generation. The overall risk of venous and arterial thrombosis in children is increased 3 fold as well as the risk for cerebrovascular ischemic disease.14,17,18 The heterozygous carrier state is associated with a 30% increase in prothrombin levels.

Hyperhomocysteinemia, defined as serum homocysteine levels greater than 15 mol/L, is associated with increased risk of arterial and deep vein thrombosis.14,19,20 Hyperhomocysteinemia may result from nutritional folate, vitamin B6 or Bl 2 deficiency, or it may be an inherited deficiency of 1 of 2 enzymes. A defect in the homocysteine me\tabolism is caused by a mutation in the methyltetrahydrofolate reductase gene (MTHFR 667C[arrow right]T), which is found in the homozygous state in 10% of the population. The presence of MTHFR gene mutation with elevated fasting homocysteine levels is associated with increased risk for thrombosis. Rarely, hyperhomocysteinemia may also result from cystathionine-β- synthase deficiency.

Deficiencies or qualitative abnormalities of activated coagulation factor inhibitors (Antithrombin deficiency, Protein C or S deficiency) can also predispose to thrombosis. Antithrombin (AT) is a physiologic inhibitor of activated serine proteases, including factors Ua, XIIa and Xa. Complete AT deficiency is probably incompatible with life, while in the heterozygous state, the life- time risk of thrombosis is 17-100%.21 The prevalence of protein C deficiency is 1 in 500 individuals and is transmitted as an autosomal dominant trait. Protein C is activated by the binding of thrombin to thrombomodulin to become activated protein C (APC), which in turn inactivates factors Va and Villa. Protein S acts as a cofactor for this APC-mediated inactivation.

The antiphospholipid syndrome (APL) is caused by a heterogeneous group of antibodies to various proteins complexed with negatively charged phospholipids. It can be primary or secondary to autoimmune diseases (SLE, rheumatoid arthritis), drugs or infections. APL is present in 2% oj the general population and is implicated in 14% of arterial and venous thromboembolism cases.

There have been case reports of association of iron deficiency anemia with strokes in children but many of reported children had other risk factors like dehydration or the presence of a thrombophilic state.22,23 Three mechanisms have been proposed for this association with iron deficiency. Thrombocytosis, which is frequently associated with iron deficiency, may cause strokes. Secondly, iron deficiency may induce a hypercoagulable state by reduced red cell deformabilily due to microcytosis and subsequently increased viscosity. And finally, anemia may worsen regional hypoxia in areas of decreased perfusion and embolism. It is very likely that our patient, along with her multiple thrombophilic states also had severe iron deficiency anemia that predisposed her to AlS. In children, thrombosis may be the result of several genetic and acquired risk factors that occur simultaneously.2'1

It is of paramount importance for pediatricians and family practitioners to realize the high prevalence rate of thrombophilic disorders and the associated risks. Although the exact figures are still unknown, it is likely that a combination of hereditary risk factors in a patient increases the risk of arterial and venous thromboembolism multiple fold and the patients tend to present at an earlier age.12,17,18 In one prospective study, the risk for developing idiopathic thromboembolism was 20 times higher among patients with both hyperhomocysteinemia and factor V Leiden as compared with individuals without either defeet,25 an observation corroborated by others.26 Thrombophilia screening in asymptomatic relatives of symptomatic patients carrying genetic abnormalities such as factor V Leiden, prothrombin gene mutation, protein C or protein S deficiency is still controversial and subject of much discussion.27,28 If there is a family history of strokes or venous thrombosis in a symptomatic patient, there should be a low threshold for a complete thrombophilia workup, in consultation with a hernatologist. An initial thrombophilia workup includes a complete blood cell count, protein C and protein S activity, antithrombin activity, antiphospholipid antibody assay, serum homocystcine level, and the evaluation for genetic mutations of factor V Leiden, prothrombin 2021OG[arrow right]A, and MTHFR 667C[arrow right]T. The presence of a hereditary thrombophilic state should alert the physician regarding the need for antithrombotic prophylaxis, or more aggressive clinical monitoring during periods of increased thrombotic risks like surgery, fractures and immobilization. Medical conditions that increase the risk of thrombosis are listed in Table 2. Also these patients should be aware of the importance of prevention of dehydration and the necessity to seek immediate medical attention during episodes of infection (e.g., sinusitis) and dehydration. Women who are carriers of factor V Leiden mutation should be made aware of the greater than 30-fold increased risk of venous thrombosis by oral contraceptive use.29 Also any child with ischemic stroke should undergo a complete evaluation for thrombophilia regardless of the presence of clinical risk factors or lack of family history of thrombosis.30 Testing for prothrombotic slates will also identify patients or families who are prone to recurrences of thromboembolism and would be candidates for long- term antithrombotic prophylaxis.

Table 2

PREDISPOSING MEDICAL CONDITIONS THAT INCREASE THE RISK OF THROMBOSIS IN CHILDREN

REFERENCES

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8. Virchow R. Phlogose und Thrombose im Gefassystem. 1856.

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10. Koster T, Rosendaal FR, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet. 1993;342:1503-1506.

11. Rosendaal FR, Roster T, el al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995; 85:1504-1508.

12. Segel GB, Francis CW. Anticoagulant proteins in childhood venous and arterial thrombosis: a review. Blood Cells Mol Dis. 2000;26(5):540-560.

13. Ganesan V, Kelsey H, et al. Activated protein C resistance in childhood stroke [letter]. Lancet. 1996;347:260.

14. Nowak-Gottl U, Strater R, et al., for the Childhood Stroke Study Group. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in children. Blood. 1999;94(11 ) : 3678-3682.

15. Heller C, Becker S, et al. Prothrombotic risk factors in childhood stroke and venous thrombosis. Eur J Pediatr. 1999;158(Supplement 3):S117-S121.

16. Poort SR, Rosendaal FR, et al. A common genetic variant in the 3' untranslated region of the prothrombin gene is associated with elevated prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698-3703.

17. Margaglione M, Branacaccio V, et al. Increased risk for venous thrombosis in carriers of the prothrombin G to A 20210 gene variant. Ann Intern Med. 1998:129:89-93.

18. De Stefano V, Chiusolo P, et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood. 1998:3562-3565.

19. Den Heijer M, Roster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996;334:759-762.

20. Van Beynum IM, Smeitink JAM, et al. Hyperhomocysteinemia A risk factor for ischemic stroke in children. (Circulation. 1999;99:2070-2072.

21. Nachman RL, Silverstein R. Hypercoagulablc states. Ann Intern Med. 1993:119:819-827.

22. Hartfield DS, Lowry NJ, et al. Iron deficiency: a cause of stroke in infants and children. Pediatr Neural. 1997:16:50-53.

23. Ready WK, Lowry NJ. Anemia causing cerebral infarction in a child. Can Med Assoc J. 1989:140:303-304.

24. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999; 353:1167-1173.

25. Ridker PM, Hennckcns CM, et al. Interrelation of Hyperhomocysteinemia, Factor V Leiden, and the risk of future venous thromboembolism. Circulation. 1997;95:1777-1782.

26. Mandel H, Brenner B, et al. Coexistence of hereditary Homocystinuria and Factor V Leiden-effect on thrombosis. NEnglJMed. 1996;334:763-768.

27. Green D. Genetic hypercoagulability: screening should be an informed choice. Blood. 2001;98(1):20.

28. Mannucci PM. Genetic hypercoagulability: prevention suggests testing family members. Blood. 2001;98(1):21-22.

29. Vandeiibroucke JP, Roster T, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453-1457.

30. Bonduel M, Sciuccati G, et al. Prcthrombotic disorders in children with arterial ischemie stroke and sinovenous thrombosis. Arch Neural. 1999:56:967-971.

Kapil Saxena, MD, MS1

Mark Ranalli, MD1

Nadeem Khan, MD2

Carol Blanchong1

Samir B. Kahwash, MD3

Clin Pediatr. 2005;44:175-180

1 Division of Hematology/Oncology, 2 Division of Critical Care, and 3 Department of Laboratory Medicine, Children's Hospital, The Ohio State University, Columbus, OH.

Reprint requests and correspondence to: Mark A. Ranalli, MD, Department of Pediatric Hematology/Oncology, Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH 43205.

2005 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

Copyright Westminster Publications, Inc. Mar 2005

Source: Clinical Pediatrics

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