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HISTORY

Previous thrombosis

Family history of thrombosis

PHYSICALEXAM

Family history of factor V Leiden mutation

Findings suggestive of VTE in any form (DVT, PE, cerebral brail thrombosis): 10–26% of patients with VTE are carriers of the factor V Leiden mutation.

Thrombosis in unusual locations, such as the sagittal sinus or mesentery and portal systems, although these are less common in patients with factor V Leiden than in patients with deficiency of protein C or S

There is a weak, however significant, association between procoagulant states (including factor V Leiden) and coronary events in younger patients (4).

DIFFERENTIALDIAGNOSIS

Protein C deficiency

Protein S deficiency

Antithrombin deficiency

Other causes of APC resistance (e.g., antiphospholipid antibodies)

Dysfibrinogenemia

Dysplasminogenemia

Homocystinemia

Prothrombin 20210 mutation

Elevated factor VIII levels

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

For evaluation of a new clot in patient at risk: CBC with peripheral smear, PT/INR, activated partial thromboplastin time (aPTT), thrombin time, lupus anticoagulant, antiphospholipid antibodies, factor VIII, anticardiolipin antibody, anti-β2 glycoprotein I antibody, APC resistance, protein S antigen and resistance, antithrombin III assay, fibrinogen, factor V Leiden, prothrombin G20210A

Genetic test: DNA-based test for factor V mutation; will be unaffected by anticoagulation and other drugs

Functional test: plasma-based coagulation assay using factor V–deficient plasma to which patient plasma is added along with purified APC. The

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relative prolongation of the aPTT is used to assay for the defect. Heparin, direct thrombin inhibitors, and factor Xa inhibitor may cause false-negative results. In the absence of exposure to anticoagulants, functional testing is preferred to genomic due to cost and time to diagnosis (5)[A].

Extremity US for DVT

V/Q scan or spiral CT for PE

Follow-Up Tests & Special Considerations

US may not show DVT acutely; repeat in 5 to 7 days if strong suspicion.

V/Q scan for evaluation of PE may be difficult to interpret in smokers or those with underlying lung disease.

Diagnostic Procedures/Other

Magnetic resonance angiography (MRA), venography, or arteriography to detect thrombosis

TREATMENT

Only indicated if thrombotic event

GENERALMEASURES

Like general VTE treatment, patients with factor V Leiden and a first thrombosis should be anticoagulated initially with heparin or low-molecular- weight heparin (LMWH) and warfarin for at least 3 months.

Treatment with LMWH is recommended over unfractionated heparin, unless the patient has severe renal failure (6)[A].

Treat as outpatient, if possible (6)[A].

Initiate warfarin with LMWH on the first treatment day and discontinue LMWH after minimum of 5 days and when INR >2 for 2 consecutive days (6) [A].

Patients should be maintained on warfarin with an INR of 2 to 3 for at least 3 months (6)[A].

For those patients with recurrence, the risks and benefits of indefinite anticoagulation need to be assessed.

MEDICATION

First Line

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LMWH:

–Enoxaparin (Lovenox): 1 mg/kg SC BID; start warfarin simultaneously; continue enoxaparin for minimum of 5 days and until INR is >2 for 2 consecutive days, at which time enoxaparin can be stopped.

–Fondaparinux (Arixtra): 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC daily

–Tinzaparin (Innohep): 175 anti-Xa IU/kg SC daily for minimum of 5 days and patient is adequately anticoagulated with warfarin (INR of at least 2 for 2 consecutive days)

–Dalteparin (Fragmin): 200 IU/kg SC daily

Oral anticoagulant

– Warfarin (Coumadin) PO with dose adjusted to an INR of 2 to 3 (3)[A] Contraindications

–Active bleeding precludes anticoagulation.

–Risk of bleeding is a relative contraindication to long-term anticoagulation.

–Warfarin is contraindicated in patients with history of warfarin skin necrosis (6)[A].

–Warfarin is contraindicated in pregnancy.

Precautions

–Observe patient for signs of embolization, further thrombosis, or bleeding.

–Avoid IM injections. Periodically check stool and urine for occult blood; monitor CBCs, including platelets.

–Heparin: thrombocytopenia and/or paradoxic thrombosis with thrombocytopenia

–Warfarin: necrotic skin lesions (typically breasts, thighs, or buttocks)

–LMWH: Adjust dosage in renal insufficiency; may also need dose

adjustment in pregnancy Significant possible interactions

–Agents that intensify the response to oral anticoagulants: alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen

–Agents that diminish the response to anticoagulants: aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives

Second Line

Heparin 80 mg/kg IVbolus followed by 18 g/kg/hr continuous infusion

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Adjust dose depending on aPTT.

In patients requiring large daily doses of heparin, measure an anti-Xa level for dose guidance.

Alternatively, for outpatients, weight-adjusted subcutaneous unfractionated heparin with 333 U/kg first and then 250 U/kg, without monitoring (6)[A]

Consider deficiency of antithrombin as a comutation in patients with significant elevated heparin requirements.

Factor Xa inhibitors are FDA-approved for VTE/PE prophylaxis and treatment but there is not enough evidence to support their long-term use in factor V Leiden patients yet.

ISSUES FOR REFERRAL

Recurrent thrombosis on anticoagulation

Difficulty anticoagulating

Genetic counseling

Homozygous state in pregnancy

SURGERY/OTHER PROCEDURES

Anticoagulation must be held for surgical interventions.

For most patients with DVT, recommendations are against routine use of vena cava filter in addition to anticoagulation except when there is contraindication for anticoagulation (6)[A].

Thrombectomy may be necessary in some cases.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

Admission criteria/initial stabilization: complicated thrombosis, such as PE Nursing

–Teach LMWH and warfarin use.

–See earlier for drug interactions.

Discharge criteria: stable on anticoagulation

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

Patient Monitoring

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Warfarin use requires periodic (~monthly after initial stabilization) INR measurements, with a goal of 2 to 3 (6)[A].

DIET

No restrictions

Large amounts of foods rich in vitamin K may interfere with anticoagulation with warfarin.

PATIENT EDUCATION

Patients should be educated about the following:

–Use of oral anticoagulant therapy

–Avoidance of NSAIDs while on warfarin

The role of family screening is unclear, as most patients with this mutation do not have thrombosis. In a patient with a family history of factor V Leiden, consider screening during pregnancy or if considering oral contraceptive use.

PROGNOSIS

Most patients heterozygous for factor V Leiden do not have thrombosis.

Homozygotes have about a 50% lifetime incidence of thrombosis.

Recurrence rates after a first thrombosis are not clear, with some investigators finding rates as high as 5% and others finding rates similar to the general population.

Despite the increased risk for thrombosis, factor V Leiden does not increase overall mortality.

COMPLICATIONS

Recurrent thrombosis

Bleeding on anticoagulation

REFERENCES

1.Rosendaal FR, Koster T, Vandenbroucke JP, et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504–1508.

2.Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121(15):1706–1712.

3.Eichinger S, Weltermann A, Mannhalter C, et al. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first

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spontaneous venous thromboembolism. Arch Intern Med.

2002;162(20):2357–2360.

4.Ye Z, Liu EH, Higgins JP, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006;367(9511):651–658.

5.Prüller F, Weiss EC, Raggam RB, et al. Activated protein C resistance assay and factor V Leiden. N Engl J Med. 2014;371(7):685–686.

6.Guyatt GH, Akl EA, Crowther M, et al; for American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl 2):7S–47S.

ADDITIONALREADING

Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344(16):1222–1231.

SEE ALSO

Deep Vein Thrombophlebitis

CODES

ICD10

D68.51 Activated protein C resistance

CLINICALPEARLS

Extremely rare in Asian and African populations

Asymptomatic patients with factor V Leiden do not need anticoagulation. For pregnant women homozygous for factor V Leiden but no prior history of VTE, postpartum prophylaxis with prophylactic or intermediate-dose LMWH or vitamin K antagonists with target INR 2 to 3 for 6 weeks is recommended. Antepartum prophylaxis is added if there is positive family of VTE.

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FAILURE TO THRIVE

Durr-e-Shahwaar Sayed, DO

BASICS

DESCRIPTION

Failure to thrive (FTT) is not a diagnosis but a sign of inadequate nutrition in young children manifested by a failure of physical growth, usually affecting weight. In severe cases, decreased length and/or head circumference may develop.

Various parameters are used to define FTT, but in clinical practice, it is commonly defined as either weight for age that falls below the 5th percentile on more than one occasion or weight that drops two or more major percentile lines on standard growth charts.

Acombination of anthropometric criteria rather than one criterion should be used to identify children at risk of FTT (1)[C].

Pediatric Considerations

Children with genetic syndromes, intrauterine growth restriction (IUGR), or prematurity follow different growth curves.

25% of children will decrease their weight or height crossing ≥2 major percentile lines in the first 2 years of life. These children are failing to reach their genetic potential or demonstrating constitutional growth delay (slow growth with a bone age < chronologic age). After shifting down, these infants grow at a normal rate along their new percentile and do not have FTT.

EPIDEMIOLOGY

Incidence

Predominant age: 6 to 12 months; 80% <18 months

Predominant sex: male = female

Prevalence

As many as 10% of children seen in primary care have signs of growth failure.

1–5% of pediatric inpatient admissions are for FTT. Occurs more frequently in children living in poverty (1)

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ETIOLOGYAND PATHOPHYSIOLOGY

Mismatch between caloric intake and caloric expenditure Often grouped into four major categories:

–Inadequate caloric intake (most frequent)

–Inadequate caloric absorption

–Excessive caloric expenditure

–Defective utilization

Traditionally, FTT was classified as organic or nonorganic, but most cases are multifactorial.

FTT often begins with a specific event and may lead to persistent difficulties. Causes of FTT can be grouped by pathophysiology (including examples):

–Inadequate intake: breastfeeding difficulty, incorrect formula preparation, poor transition to food (6 to 12 months), poor feeding habits (e.g., excessive juice, restrictive diets), mechanical problems (e.g., oromotor dysfunction, congenital anomalies, GERD, CNS, or PNS anomalies), oral aversion, poverty, neglect, poor parent–child interaction, caregiver feeding style

–Inadequate absorption: necrotizing enterocolitis, short gut syndrome, biliary atresia, liver disease, cystic fibrosis, celiac disease, milk protein allergy, vitamin/mineral deficiency, environmental enteric dysfunction

–Increased expenditure: hyperthyroidism, congenital/chronic cardiopulmonary disease, HIV, immunodeficiencies, malignancy, renal disease

–Defective utilization: metabolic disorders, congenital infections (TORCH: toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex)

Genetics

Multiple genetic disorders can cause FTT.

RISK FACTORS

Psychosocial risks

– Poverty, parent(s) with mental health disorder or cognitive impairment, poor parenting skills or hypervigilant parents, families with unique health/nutritional beliefs, physical or emotional abuse, substance abuse, and social isolation

Medical risks

–Intrauterine exposures, history of IUGR (symmetric or asymmetric), congenital abnormalities, oromotor dysfunction, premature or sick newborn, infant with physical deformity, acute or chronic medical

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conditions, developmental delay, lead poisoning, anemia

Pregnancy Considerations

FTT is linked to intrauterine exposures, IUGR, and prematurity.

GENERALPREVENTION

Educate parents on normal feeding and parenting skills.

Access to supplemental feeding programs (Women, Infants, and Children [WIC])

DIAGNOSIS

HISTORY

Successful treatment of FTT almost always is accomplished by a careful and detailed history as most cases are due to underfeeding or inappropriate feeding.

Prenatal and developmental history

Past medical history: acute/chronic disease affecting caloric intake, digestion, absorption, or causing increased energy need or defective utilization

Medication history, including complementary and alternative medications

Family history: stature of parents and growth trajectories of siblings, chronic diseases, genetic disorders, developmental delay

Diet history from birth: breastfeeding or formula feeding; timing and introduction of solids; who feeds the child, when, and how often; placement of child during feeds; amounts consumed/caloric intake; beverages consumed; snacking; vomiting or stooling associated with feeds; oral aversions or unusual behaviors during feeding

Social history: family composition, socioeconomic status, hygiene practices, child-rearing beliefs, stressors, parental depression, parental substance abuse, caretaker personal history of abuse/neglect

Review of systems: anorexia, activity level, mental status, fevers, dysphagia, vomiting, gastroesophageal reflux, stooling pattern/consistency, dysuria, urinary frequency

PHYSICALEXAM

Acombination of anthropometric criteria, rather than one criterion, should be used (1)[C].

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Accurate measurement of height, weight, and head circumference on National

Center for Health Statistics (NCHS) growth charts (www.cdc.gov/growthcharts)

The World Health Organization (WHO) growth charts may be more appropriate for breastfed infants (www.who.int/childgrowth/standards/en/).

Growth charts exist for many other syndromes/conditions such as Down syndrome, Turner syndrome, and the premature infant.

Exam should assess for the following:

–Signs of dehydration or severe malnutrition are as follows:

Severity of malnutrition estimated via Gomez classification: Compare current weight for age with expected weight for age (50th percentile): severe, <60% of expected; moderate, 61–75%; mild, 76–90%.

–Underlying medical disease

–Dysmorphic features

–Mental status (alert, responsive to stimuli)

–Any signs of physical abuse and/or neglect

Observe interaction with caregivers and feeding techniques, specifically bonding and social/psychological cues.

DIFFERENTIALDIAGNOSIS

Differentiate based on growth patterns.

FTT classically presents as low weight for age, normal linear growth, normocephalic or low weight for age, followed by decreased linear growth or low weight for age, leading to decreased linear growth and decreased head circumference (without neurologic signs).

–In this situation, consider differential diagnosis as outlined in “Etiology and Pathophysiology.”

If low linear growth with normal weight for length or low linear growth and proportionately low weight and decreased head circumference:

–Consider genetic potential (constitutional short stature or growth delay), genetic syndromes, teratogens, endocrine disorders.

If microcephaly with prominent neurologic signs, with poor growth secondary to presumed neurologic disorder:

–Consider TORCH infections, genetic syndromes, teratogens, brain injury (i.e., hypoxic/ischemic).

DIAGNOSTIC TESTS & INTERPRETATION

Labs useful only in ~1% of cases and are generally not recommended (1)[C],

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