A fifteen year old girl presents to clinic with a family history of thrombosis and thrombophilia. Her father suffered a deep vein thrombosis at age 30 in the setting of knee surgery; thrombophilia testing was significant for heterozygosity for factor V Leiden. Her mother had a pulmonary embolus in the post-partum setting; thrombophilia testing was significant for heterozygosity for factor V Leiden.
What is the chance that this girl is homozygous for factor V Leiden?
This case illustrates the inheritance of factor V Leiden. In this case, the girl’s parents are both heterozygous for factor V Leiden. Factor V Leiden is inherited in an autosomal fashion. Individuals who are heterozygous have a 5-8 fold increased risk for thrombosis from baseline and those who are homozygous have up to 80 fold increased risk for thrombosis. For each child, there is a 25% that he/she will be homozygous wild-type, 50% chance that he/she will be heterozygous for factor V Leiden, and a 25% chance that he/she will be homozygous for factor V Leiden.
A 3500 gram female infant has neonatal purpura fulminans.
Which of the following is the most likely explanation of this condition?
Heterozygous protein C deficiency
Heterozygous antithrombin deficiency
Heterozygous factor V Leiden
*Homozygous protein C deficiency
Homozygous antithrombin deficiency
A severe inherited prothrombotic state must be considered in any infant presenting with neonatal purpura fulminans. Of the choices, the most likely diagnosis is homozygous protein C deficiency. Heterozygous protein C deficiency, heterozygous antithrombin deficiency and heterozygous factor V Leiden are all inherited prothrombotic states but are not severe enough to result in neonatal purpura fulmnins. Homozygous antithrombin deficiency is not compatible with life.
A five year old female with nephrotic syndrome is being treated for sepsis and develops a catheter-related thrombosis. Unfractionated heparin is initiated at 20 U/kg/hr. Dose adjustments are made based on the anti-factor Xa assay. At a dose of 50 U/kg/hr her anti-factor Xa level is 0.1 U/mL.
Which of the following is the next most appropriate test in the evaluation of this patient?
Factor VIII activity
This patient is demonstrating heparin resistance. The most appropriate test is an antithrombin activity. The mechanism of action of heparin depends on antithrombin. If antithrombin levels are low, it may be difficult to obtain a therapeutic effect. This child may have acquired antithrombin deficiency due to nephrotic syndrome and sepsis. In order to achieve effective anticoagulation with heparin she will require antithrombin replacement. Alternatively, a direct thrombin inhibitor may be used. aPTT has traditionally been used to monitor heparin therapy, but is less reliable than the anti-factor Xa level. PT/INR is used to monitor warfarin therapy. Factor VIII activity is useful when monitoring heparin with aPTT since elevated factor VIII will shorten the aPTT and interfere with the reliability of the assay. Plasminogen activity is most useful for patients being treated with fibrinolytic therapy to determine if plasminogen replacement is needed.
A fifteen year old female develops a right lower extremity venous thrombosis attributed to oral contraceptives and heterozygosity for prothrombin gene mutation. Oral contraceptives were discontinued. She has been anticoagulated with low molecular weight heparin for four weeks. The decision is made to convert to warfarin therapy.
Which of the following tests must be done prior to initiation of warfarin?
*Serum pregnancy test
PIVKA (proteins induced by vitamin K absence ) II assay
Genotyping for warfarin resistance
Since warfarin is embryonic lethal, a pregnancy test must be done in any female of child bearing potential prior to initiation of warfarin. Serum creatinine is not required, because warfarin clearance is not dependent on renal function. The PIVKA assay is used to distinguish between vitamin K deficiency and liver dysfunction. It is not a standard assay prior to initiation of warfarin. Genotyping for warfarin resistance may be useful for predicting warfarin doses. However, this has not been established as standard of care for children initiating warfarin.
A two year old with congenital heart disease requires anticoagulation with warfarin.
Which of the following is the most appropriate test for determining the therapeutic dose of warfarin?
The standard test for determining the therapeutic dose of warfarin is the PT/INR. The warfarin dose is adjusted based on PT/INR and established PT/INR goal range, most often 2-3 or 2.5-3.5 depending on the clinical setting. aPTT and anti factor Xa assays are used to monitor unfractionated heparin. Chromogenic factor Xa levels will decrease with warfarin effect, but this assay is not the established assay for warfarin monitoring. Genotyping for warfarin resistance has been used in adult populations to predict warfarin dose. However, even in adults, the PT/INR must be used to determine if the warfarin dose is actually therapeutic.
A ten day old infant presents with presents with left-sided abdominal mass and hematuria. A diagnosis of renal vein thrombosis is established. You are consulted and asked whether anticoagulation should be initiated with unfractionated heparin or low molecular weight heparin.
Which is the following is an advantage of low molecular weight heparin compared to unfractionated heparin?
Low molecular weight heparin is completely reversible with protamine
Low molecular weight heparin is renally cleared
*Low molecular weight heparin is associated with a lower risk for heparin induced thrombocytopenia
Low molecular weight heparin mechanism of action is independent of antithrombin
Low molecular weight heparin does not require monitoring
Heparin induced thrombocytopenia is an uncommon adverse event associated with anticoagulation in children. The risk is higher for unfractionated heparin compared to low molecular weight heparin.
Low molecular weight heparin is less effectively reversed by protamine compared to unfractionated heparin. Low molecular weight heparin is really cleared, but this is a disadvantage in children with renal insufficiency.
Both low molecular weight heparin and unfractionated heparin exert anticoagulant effects via through antithrombin, and both anticoagulants require monitoring.
A two year old male with trisomy 21 and congenital heart disease is admitted for cardiac catheterization and subsequent cardiac surgery. His course is complicated by sepsis with bleeding from incision sites. He has started a course of vancomycin for methicillin resistant S. Aureus catheter-related infection. Twenty days after the procedure the cardiac intensive unit calls because the platelet count is 10 x 109/L. Three days earlier the platelet count was 150 x 109/L. His last heparin exposure was 15 days prior to consultation.
What is the most appropriate recommendation?
Evaluate for heparin induced thrombocytopenia
*Evaluate for disseminated intravascular coagulation
Evaluate for immune thrombocytopenic purpura
Evaluate for renal vein thrombosis
Evaluate for liver failure
This child most likely has disseminated intravascular coagulation associated with sepsis.
HIT should be considered in any child with recent heparin exposure. However, this child’s clinical course is inconsistent with a diagnosis of HIT. In this case, the timing of thrombocytopenia in relationship to heparin exposure, >10 days, is not consistent with a diagnosis of HIT. Onset of decline in platelet count 5-10 days following most recent exposure to heparin would be consistent with HIT. The degree of thrombocytopenia, < 10 x 109/L, is not consistent with a diagnosis of HIT. This degree of thrombocytopenia is unusual in HIT. This child does have multiple other explanations for thrombocytopenia. Thrombocytopenia is common in the cardiac intensive care unit. Common etiologies include medications and disseminated intravascular coagulation related to sepsis. Children with trisomy 21 frequently have thrombocytopenia.
Immune thrombocytopenic purpura, renal vein thrombosis and liver failure may be associated with thrombocytopenia, but would be unlikely complications in this child.
A fifteen year old female would like to start oral contraceptives. She is referred to hematology clinic because of a family history of venous thrombosis and thrombophilias. Her father reports that he developed a pulmonary embolism at the age 30 after reconstructive knee surgery. He reports a diagnosis of protein C and protein S deficiency, but no longer takes an anticoagulant.
What is the most appropriate counseling to provide to the family?
The father likely has multiple inherited thrombophilias; test the child for protein C and protein S deficiency and do not prescribe oral contraceptives if she has inherited thrombophilia
The father likely has multiple inherited thrombophilias; test the child for protein C and protein S deficiency; initiate anticoagulation and do not prescribe anticoagulation if she has inherited thrombophilia
*The father’s testing was likely influenced by anticoagulation therapy; retest the father for protein C and protein S deficiency prior to testing the child
No testing is necessary, the child definitely has at least one inherited thormbophilia and oral contraceptives should be avoided
Interpretation of thrombophilia testing can be confounded by anticoagulation. Warfarin decreases all vitamin-K dependent factors, including protein C and S. It would be extremely unlikely to co-inherit protein C and S deficiency. Therefore, the father should be retested now that he has stopped anticoagulation. The new test results can guide further discussion of thrombophilia testing with the family.
A two week old infant born at 25 weeks gestation develops a right upper extremity deep vein thrombosis. The neonatal course has been complicated by necrotizing enterocolitis requiring total parenteral nutrition (TPN) via a peripherally inserted central catheter (PICC). There is no family history of venous or arterial thrombosis. Thrombophilia testing reveals antithrombin activity of 30%, free protein S of 45% and protein C of 25%.
Which of the following is the most likely contributing factor to the venous thrombosis?
Excessive vitamin K replacement in the TPN
Protein C deficiency
Protein S deficiency
The most likely etiology of the venous thrombosis is the PICC. Central catheters account for ~80% of venous thrombosis in children. Excessive vitamin K replacement would be highly unlikely, and vitamin K replacement has not been associated with venous thrombosis. The levels of antithrombin, protein C and S are in the normal range for age. Age based-norms must be used when interpreting results of plasma-based coagulation assays in neonates.
A twelve year old male with sickle cell disease with a history of stroke undergoes port placement to facilitate erythrocytapheresis for secondary stroke prevention. Four days later he presents to clinic complaining of facial and arm swelling. His mother had noted the facial swelling that morning. She took him to a local emergency where he was diagnosed with an allergic reaction and given diphenhydramine. He had only transient improvement in his facial swelling.
Which of the following is the most likely diagnosis?
*Superior vena cava syndrome
Cerebral sinovenous thrombosis
Delayed hemolytic transfusion reaction
Allergic reaction to anesthesia given during port placement
Allergic reaction to desferoxamine which he takes for iron chleation
This adolescent has developed superior vena (SVC) syndrome related to his new central venous catheter. Symptoms of SVC syndrome include arm and facial swelling. Cerebral sinovenous thrombosis would most likely present with headache or other neurologic symptoms. Delayed hemolytic transfusion reactions may occur in children with sickle cell disease ~5-7 days after transfusion, but the most common symptoms are fever, back pain and dark urine. The localized swelling is inconsistent with an allergic reaction to intravenous and oral medications.
A fifteen year old male is referred to the hemostasis and thrombosis clinic after vascular surgery to treat a popliteal artery occlusion. The review of systems is significant for myopia, history of lens dislocation and developmental delay. Homocysteine level is 150 micromolar/L [nl 0-13 micromolar/L].
Genetic testing for mutation in which of the following enzymes will establish the diagnosis?
This adolescent has homocystinuria, a rare, autosomal recessive condition, due to mutations in the gene for cystathionine beta-synthase. Individuals present at a young age with hyperhomocysteinemia. Associated symptoms include venous and arterial thrombosis, lens dislocation and developmental delay. Some individuals with homozygosity or compound heterozgyosity for C677T and A1298C polymorphisms in methylenetretrahydrofolate reducatase have hyperhomocysteinemia. The levels of homocysteine are not as high as with homocystinuria and are not associated with the same clinical manifestations.
Dihydrofolate reductase and methionine synthase are involved in folate metabolism, but deficiency of these enzymes is not associated with hyperhomocysteinemia.
A fourteen year old male is diagnosed with a left subclavian vein thrombosis. His past medical history is only remarkable for beta thalassemia trait. He is a pitcher for his high school baseball team. He denies illicit drug use.
Which of the following is the most likely risk factor contributing to his thrombosis?
heterozygosity for methylene tetrahydrofolate reducatase (MTHFR) C677T
beta thalassemia trait
This adolescent has thoracic outlet syndrome. Thoracic outlet syndrome involves compression of the subclavian vein by the cervical rib. Activities such as pitching cause repeated trauma to the vein resulting in thrombosis. Anabolic steroid use has not been linked to risk of venous thrombosis. Heterozygosity for MTHFR C677T and beta thalassemia trait are not prothrombotic.
A four year male with AML had a right sided femoral venous catheter placed at diagnosis for leukocytapheresis. Two days later his mother notices that his right leg is 3 times bigger than his left leg. He denies chest pain and shortness of breath. An ultrasound of the right lower extremity shows that the right common femoral, femoral and popliteal veins are compressible. No thrombus is seen in the common femoral vein, femoral vein, and popliteal veins at gray-scale and color Doppler evaluation.
Which of the following is the next most appropriate step in the evaluation and management of this child?
Observation; repeat ultrasound if there is progressive swelling
V/Q scan to evaluate for pulmonary embolus
CT scan to evaluate for pulmonary embolus
*MRV of the lower extremity and pelvis
This child has right iliac vein thrombosis which was not detected on ultrasound. If deep vein thrombosis is suspected, further imaging is warranted. Observation alone could delay the initiation of anticoagulation and increase risk of extension and/or embolization. It is possible that the child also has an asymptomatic pulmonary embolus, but the first priority is to establish a diagnosis of deep vein thrombosis.
A fourteen year old male presents with occlusive deep vein thrombosis from the popliteal veins up through the IVC to the level of the renal veins. Recommendation is made to initiate thrombolytic therapy with tissue plasminogen-activator (t-PA). t-PA is initiated at a dose of 0.03 mg/kg/hr via a peripheral IV. Unfractionated heparin is administered at 10 units/kg/hr via a separate peripheral IV. The baseline platelet count is 200 x 109/L [nl 150-450 109/L]. After 4 hrs, oozing is note at the peripheral IV sites. Repeat laboratory studies and imaging are done every 6 hrs.
Which of the following is a reason to discontinue t-PA?
fibrinogen of 120 mg/dL [nl 200-400 mg/dL] after 6 hrs of treatment
plasminogen of 50% [nL 85-150%] after 12 hrs of treatment
oozing at peripheral IV sites after 4hrs of treatment
no resolution of thrombosis after 12 hrs of treatment
*resolution of thrombosis after 12 hrs of treatment
t-PA should be discontinued as soon as the thrombosis has resolved. The duration of time to resolution is variable. Despite resolution the patient will still need long-term anticoagulation, for at least six months, to prevent recurrence. It is extremely important to monitor laboratory parameters during t-PA infusion to ensure safety and optimize efficacy. Fibrinogen is expected to decrease during t-PA infusion. In order to prevent bleeding, cryoprecipitate or fresh frozen plasma should be given to maintain the fibrinogen >100 mg/dL. Plasminogen is expected to decrease during t-PA infusion. Plasminogen is required for the fibrinolytic activity of t-PA. Fresh frozen plasma should be given if plasminogen activity is low prior to starting t-PA, if there is no response to treatment or if plasminogen is low during treatment. Oozing from IV sites is expected with t-PA. This can be managed with supportive measures and does not require discontinuation of t-PA. More significant bleeding, especially if associated with decrease in hemoglobin, will require discontinuation of t-PA and possibly reversal with cryoprecipitate and aminocaproic acid.
A three year old with a hypoplastic left heart syndrome undergoes Fontan completion. His post-operative course is complicated by heparin induced thrombocytopenia and thrombosis. His heparin is discontinued and he is started on argatroban for anticoagulation.
Which of the following is a correct statement about argatroban?
Argatroban is dependent on antithrombin for its efficacy
Argatroban has been associated with heparin induced thrombocytopenia
A Food and Drug Administration approved indication of argatroban is treatment of venous thrombosis in children
*Argatroban dosing is titrated based on the aPTT
The anticoagulant effect of argatroban is reversible with protamine
Similar to heparin, argatroban dosing is titrated with the aPTT to a goal of 1.5-3 times baseline aPTT.
Argatroban is a direct-thrombin inhibitor. Its mechanism of action is independent of antithrombin. It has not been associated with risk of heparin induced thrombocytopenia and is a non-heparin alternative for anticoagulation in adults and children with known or suspected heparin induced thrombocytopenia. The primary FDA approved indication for argatroban is prophylaxis and treatment of thrombosis in adults with heparin induced thrombocytopenia. It is also approved for adult patients with or at risk for heparin induced thrombocytopenia undergoing percutaneous coronary intervention. There is some pediatric dosing information on the label, but like most anticoagulants in children they are used off label.
There is no specific reversal agent for argatroban. Protamine reverses heparin and partially reverses low molecular weight heparin.
Janna M. Journeycake, MD 1. You are consulting on a new patient who was recently diagnosed with deep vein thrombosis (DVT) of the right femoral vein. He is a 15-year-old Caucasian male who weighs 90 kg and who developed leg pain and swelling after a football injury to his knee that required bracing. After the DVT was diagnosed, he was placed on heparin infusion and transitioned to warfarin. Current INR is 2.4. Thrombophilia testing was performed prior to discharge from the hospital.
Factor V Leiden
Prothrombin gene mutation
Protein S activity
Protein C activity
Based on these results, the most likely contributed to his thrombosis is
A. Inherited protein C deficiency
B. Inherited protein S deficiency
E. Elevated FVIII
2. A 16-year-old previously healthy African-American girl presents to the emergency room with a 3-day history of leg pain and progressive swelling such that she can no longer walk. Her entire left leg is edematous and discolored compared with the right leg. It is warm to touch. She denies any trauma, but she is on the basketball team at school. Her only medication includes oral contraceptive pills (OCPs), which she started at age 12 for menorrhagia. She weighs 90 kg. Doppler sonogram shows complete occlusion of the left iliac, femoral, superficial femoral, and popliteal veins. She is treated with anticoagulation with good clinical results. Follow-up magnetic resonance imaging to assess extent of the thrombus will likely show
A. Occlusion up to the left renal vein
B. Right iliac artery overriding the left iliac vein
C. Congenital inferior vena cava (IVC) disruption
D. Ovarian mass compressing the left iliac vein
E. No intra-abdominal problems
3. A 5-month-old Caucasian female had open heart surgery 7 days ago. She is on an unfractionated heparin infusion at prophylactic dosing. Her total white blood cell (WBC) count was 13,000/mL with 50% segmented neutrophils, 3% bands, 10% monocytes, and 37 % lymphocytes. Hemoglobin was 10.5 g/dl and platelet count 45,000/mL. Her prothrombin time (PT) is 13 seconds, partial thromboplastin time (PTT) is 45 seconds, fibrinogen is 350 mg/dl, and D-dimers are mildly elevated. Her ALT is 35 U/L, AST 37 U/L, and creatinine 1.0 mg/dl. She has a catheter in her right femoral vein that is not flushing adequately and a Doppler sonogram shows partial occlusion of the right femoral vein. The next best step in this patient’s management is to
A. Test for heparin-induced thrombocytopenia without altering current anticoagulation.
B. Remove the femoral catheter.
C. Discontinue unfractionated heparin and begin warfarin.
D. Test for heparin-induced thrombocytopenia and begin an alternative anticoagulant agent.
E. Discontinue unfractionated heparin and begin enoxaparin.
4. The best alternative anticoagulant medication to use in the baby described in question 3 is
E. No alternative anticoagulation is necessary
5. You are managing a teenage girl on chronic warfarin therapy. The INR has been stable for the past 6 months but is now 1.4. She denies missing any doses except for the day before her routine lab test, and a pill count suggests that no other doses have been missed. Which is the most likely reason for the drop in INR?
A. She has started to drink alcohol on the weekends.
B. She was prescribed an antibiotic for a sinus infection the week before.
C. She has a gene polymorphism making her resistant to warfarin.
D. She started a diet this month consisting of mostly fruits and vegetables.
E. She missed the dose the day before the test.
6. Which of the following statements comparing LMWH and unfractionated heparin (UFH) provides an explanation of the best initial anticoagulant therapy to choose in a neonate with a catheter-related thrombosis. The laboratory results are as follows: creatinine 0.9, platelets 450, antithrombin activity 50%. A head ultrasound is negative for bleeding, and the child has no need for any invasive procedures.
A. LMWH should be chosen because it does not rely on the need for antithrombin.
B. LMWH should be chosen because it does not need to be monitored.
C. UFH should be chosen because it can be safely prescribed in a patient with renal insufficiency.
D. UFH should be chosen because it has shorter half-life.
E. LMWH should be chosen because there is no risk for HIT.
7. Which aspect of the endothelium has anticoagulant properties?
A. Release of thrombomodulin
B. Release of von Willebrand factor (VWF) and cleavage by ADAMTS-12
D. Release of tissue factor
8. A term infant born to a diabetic mother presents with hematuria and a flank mass. A renal ultrasound demonstrates bilateral renal vein thrombosis and extension into the IVC. His creatinine is 0.4, but his urine output is lower than expected. The team consults you to ask about the use of systemic thrombolysis. What would be the strongest contraindication for thrombolysis?
A. Platelet count of <50, 000
B. Guaiac positive stool
C. Decreased creatinine clearance
D. Surgery for placement of central venous catheter in past 3 days
E. Plasminogen deficiency
9. A 4-year-old white female is brought to your emergency room at a large tertiary care medical center for nose bleeds, easy bruising, and altered mental status. She has been staying with her grandparents while her parents are out of town. She has never had any bleeding issues in the past and even underwent tonsillectomy 6 months ago without incident. Family history is negative for bleeding disorders, but her grandfather is on warfarin for atrial fibrillation. Laboratory testing is pending and a head CT is being performed. You suspect warfarin toxicity due to accidental ingestion of the grandfather’s medications. The CT confirms intracranial hemorrhage. The complete blood count (CBC) shows hemoglobin of 8.9 g/dl and platelets of 250, 000. PT is markedly prolonged and corresponds to INR of 10.5. PTT is also prolonged at 60 seconds. What is the best management for this child?
A. Give oral vitamin K at a dose of 5 mg.
B. Give fresh frozen plasma (FFP) at a dose of 10 cc/kg.
C. Give Recombinant activated factor VIIa (rFVIIa) at a dose of 90 mcg/kg.
D. Give a prothrombin complex concentrate (PCC) at a dose of 50 units/kg.
E. Gastric lavage
10. A 15-year-old girl is transferred from an outside emergency room with the diagnosis of pneumonia for which her primary care provider prescribed Augmentin 3 days prior. She has low-grade fever and is hypoxic and requiring 35% FiO2 per facemask. She complains of chest pain over her left ribs. Outside chest X ray shows an infiltrate in the left lower lobe. Her heart rate is 140, respiratory rate is 28, blood pressure is 110/60, and temperature is 38.2 °C. In addition to the Augmentin, she is taking a combined OCP that was prescribed 2 months ago due to dysmenorrhea. Family history is positive for her father developing a DVT at age 44 when he traveled overseas. No thrombophilia testing had even been done in family. What is the best next step in determining the diagnosis in this child?
A. D-dimer testing
B. CT angiogram of chest
D. Activated protein C resistance (APCR) testing
E. Protein S activity testing
11. Which inherited thrombophilia is most likely to lead to a venous thromboembolic event prior to age 40?
A. Heterozygous factor V Leiden gene mutation
B. Double heterozygous MTHFR polymorphism
C. Homozygous prothrombin gene mutation
D. Heterozygous antithrombin deficiency
E. Homozygous PAI-1 mutation
12. Which of the following patients has the strongest risk for developing a DVT?
B. 10-year-old white male in maintenance for acute lymphoblastic leukemia therapy whose central venous catheter was removed 3 months ago due to infection
C. A premature 1-month-old white female on parenteral nutrition
D. 16-year-old white male in the hospital for laparoscopic cholecsytectomy
E. 5-year-old black female in the hospital for asthma exacerbation whose father had DVT at age 40
13. A 15-year-old boy with life-threatening pulmonary embolism is being treated with the thrombolytic agent tPA. Which of the following complications indicates that thrombolysis should be discontinued?
A. Blood oozing from the line site
B. Fibrinogen < 100 mg/dl
C. Platelets < 50,000/mm3
D. Decline in Hgb > 2 g/dl
E. Elevation of D-dimers
14. A 32-year-old Caucasian male comes to your office with his 4-year-old daughter for counseling. He was recently diagnosed with a DVT involving the lower extremity and was found to be heterozygous for the factor V (FV) Leiden gene mutation. The most appropriate counseling to provide for the family is to
A. Advocate for testing for FV Leiden in the child immediately.
B. Educate the family about signs and symptoms of thromboembolic disease.
C. Begin the child on prophylactic aspirin.
D. Consider screening the child for every known cause of thrombosis.
E. Counsel the family that the child is not at risk for thrombosis during childhood.
15. A 12-year-old white male was diagnosed with a DVT of the right lower extremity after knee surgery. A thrombophilia evaluation was performed due to the relatively low risk expected for a DVT in this patient. He has been on anticoagulation for past 3 months and you are asked to provide a recommendation for duration of therapy. Which of the following scenarios would require prolonged or indefinite anticoagulation therapy?
A. Lupus anticoagulant was positive at diagnosis and remains positive.
B. At diagnosis the FVIII activity level was 300% and it is now 150%.
C. He is heterozygous for the FV Leiden mutation.
D. His protein C activity is 60%.
E. His mother had a DVT in the postpartum period.
Thrombotic Disorders: Answers Question 1
Explanation: Although he does have low protein C and S activity levels, he was on warfarin at the time of testing. These are both vitamin K–dependent proteins and will be low when a patient is on warfarin. This will need to be rechecked when the patient is off of warfarin for at least a month. The effect of warfarin on protein S especially can last for up to 4 weeks. Although he does have elevated FVIII activity, the level is not >250% and it was obtained in the acute setting. This is more likely an acute phase reactant and a result of the DVT. It will also have to be rechecked prior to stopping anticoagulation. If FVIII remains elevated after 3–6 months, he has increased risk of post-thrombotic syndrome and recurrent DVT. Although obesity is a risk factor, the most important contributor is an orthopedic injury requiring immobilization of the leg.
Explanation: The most likely anatomic abnormality associated with extensive left-sided ilieofemoral thrombosis, particularly in girls, is the May-Thurner anomaly, which consists of the right iliac vein overriding the left iliac vein, leading to its chronic compression. If an additional trigger is added (trauma, use of OCPs, obesity, acquired thrombophilia), extensive thrombosis can occur. Treatment consists of anticoagulation, thrombolyisis, and stenting of the vessel.
Explanation: Although heparin-induced thrombocytopenia (HIT) is rare in children, it is most common after open heart surgery in infants who have been previously exposed to unfractionated heparin. Because this child has evidence of thrombosis as well, the unfractionated heparin must be discontinued while assessing for HIT, and another form of anticoagulation must be initiated to prevent further thrombotic complications. Enoxaparin is a low-molecular-weight heparin (LMWH)and has cross reactivity with unfractionated heparin. Warfarin cannot be initiated without a bridge with another anticoagulant. Removing the femoral catheter is not emergent and may not be necessary because the thrombus is nonocclusive.
Explanation: Clopidogrel is an antiplatelet agent and would not be an appropriate agent to use for treatment of venous thrombosis. Rivaroxaban is a new oral direct anti-Xa inhibitor that is still in clinical trials in children. Because this child has thrombosis, continuing heparin while assessing for HIT or using no anticoagulant agent is inappropriate care. HIT antibodies place the patient at high risk of recurrent thrombosis in both venous and arterial circulation. Lepirudin and argatroban, direct thrombin inhibitors, are good alternatives that have been used in children with success. However, this child has evidence of renal insufficiency. Lepirudin is cleared by the kidneys. Therefore, argatroban, which relies on liver metabolism, is the best choice.
Explanation: Because she had never had a problem achieving therapeutic INR in the past, a genetic polymorphism for warfarin resistance is unlikely. This should be considered in children in whom it is very difficult to anticoagulate initially with anything other than very high doses of warfarin. Alcohol use and the use of most antibiotics usually increase the INR. Missing one dose of warfarin does not typically decrease an INR between 2 and 3 down to 1.4. Discontinuing warfarin will usually drop the INR to < 1.5 in 3–5 days. Therefore, the most likely reason for this new warfarin resistance is the increase in vitamin K–containing foods in her diet.
Explanation: UFH and its derivatives, including LMWH, exert their anticoagulant effects via potentiation of antithrombin activity, resulting in downregulation of thrombin and factor Xa. The terminal half-life of UFH is shorter than LMWH and this is a good feature if the baby had a high risk of bleeding or if he or she requires invasive procedures. Renal insufficiency reduces clearance of LMWH, requiring less frequent dosing or, in moderate/severe renal insufficiency, often the selection of an alternative anticoagulant. Any heparin derivative can induce HIT, including LMWH. Because this baby has renal insufficiency, the best choice is UFH until the renal disease corrects.
Explanation: When endothelial cell–associated thrombomodulin is activated, it can in turn activate protein C, which, in association with protein S, inactivates FVIIIa and FVa and inhibits thrombin production. Vasoconstriction and release of VWF are steps involved in primary hemostasis. Secondary hemostasis is initiated by the release of tissue factor upon vessel injury.
Explanation: The indications for systemic thrombolysis are life-, organ-, or limb-threatening thrombosis such as arterial thrombosis outside of the central nervous system, intracardiac thrombus, pulmonary embolus (especially when the patient is hemodynamically unstable), and extensive deep venous thrombosis (superior vena cava syndrome, occlusive IVC thrombosis, bilateral renal vein thrombosis with renal compromise). Contraindications include active major bleeding in intracranial, retroperitoneal, or gastrointestinal sites; significant potential for uncontrolled local bleeding; major surgery within the past 10 days; neurosurgery (including spinal surgery) within the preceding 3 weeks; and new or recurrent stroke. The coagulation profile should be checked prior to initiation and platelets, fibrinogen, and hemoglobin should be corrected. Neonates are known to have lower baseline levels of plasminogen than older children and plasminogen should be empirically replaced with fresh frozen plasma prior to initiation of lysis. Because tissue plasminogen activator (tPA) will break down clots but not prevent new clot formation, prophylactic doses of UFH should be administered during lysis.
Explanation: For a symptomatic patient with INR >10, bleeding needs to be controlled and warfarin reversed. Oral vitamin K will reduce INR by half in about 24 hours. Intravenous (IV) formulations are faster (12 hours), but not fast enough for this child with life-threatening bleeding. Vitamin K should be given but in IV form and in addition to an agent that will replace the vitamin K–dependent factors. FFP and PCCs are both good choices to give to an actively bleeding patient with warfarin overdose because they replace all vitamin K–dependent factors inhibited by warfarin. However, 10 cc/kg of FFP will not likely be enough to reverse this degree of anticoagulation. PCCs are plasma-derived factor concentrates that contain factors II, VII, IX and X (the vitamin K–dependent factors) and are effective in small volumes. Unfortunately, they are not readily available at all small centers. A recent new PCC was approved for use with the indication of warfarin reversal. rFVIIa has been shown to be effective but is associated with thrombotic risk and is only replacing the FVII being inhibited by the warfarin. For the INR to be markedly elevated, the warfarin will have had to have been in the child’s system for more than 24 hours. Gastric lavage will have little utility in reversing her coagulopathy.
Explanation: This child has a pulmonary embolism (PE) originally mistaken for pneumonia. The best test to confirm the diagnosis of PE is specific imaging of the pulmonary vasculature such as CT angiography. Echocardiogram can help see if there is evidence of right heart strain, which can determine aggressiveness of therapy. D-dimer testing is helpful in adults with PE and has a good negative predictive value. However, its utility in children and adolescents has not been demonstrated. If there is an index of suspicion for PE, imaging should be done regardless of the D-dimer result. APCR and protein S activity testing may be abnormal in a girl on OCPs and would explain why thrombus developed, but they would not confirm the diagnosis of PE nor guide therapy.
Explanation: Although the mutations of factor V Leiden and prothrombin gene are common, in the heterozygous state they are not strong risk factors for thrombosis at a young age. Combined heterozygous prothrombin and factor V Leiden as well as homozygous factor V Leiden may increase this risk substantially. The strength of homozygous prothrombin mutation is not known. The polymorphisms of MTHFR and PAI-1 are of debatable significance. Deficiencies of the natural anticoagulants are very strongly associated with thrombotic events prior to age 40. See table below for additional details.
Frequency in population
Risk of thrombosis
Factor V Leiden
3%–8% of Caucasians
1.2% African American
Rare in Asian
-Heterozygous state 3–5 X increase over a lifetime
-Minimal increased risk of recurrent events
-Homozygous 18 X increased risk
-Combined with prothrombin gene 30–50 X increased risk
Prothrombin gene mutation
Heterozygous state: 2%–3% of U.S. Caucasians; 0.5% African Americans
-Heterozygous state 3 X increased risk over lifetime
-Possible increased risk of recurrent events in children, but not adults
-Homozygous increased but unclear
-Combined with factor V Leiden 30–50 X increased risk
Heterozygous 1 in 500 to 5,000
-50% risk of event prior to age 40
-Increased risk of recurrent events (10%–17% per year)
-Homozygous state not compatible with life
Protein S deficiency
Heterozygous state 1 in 800 to 3,000
-Heterozygous 31 X increased risk prior to age 55
-Increased risk of recurrent events (44% in 5 years)
-Homozygous state associated with purpura fulminansVTE
Protein C deficiency
Heterozygous state 1 in 500 to 600
Homozygous state 1 in 1,000,000
-Heterozygous 24 X increased risk prior to age 55
-Increased risk of recurrent events (37% in 5 years)
Debatable significance unless leads to elevated plasma homocysteine
Heterozygous state 12% of population
Debatable significance unless PAI-1 activity also elevated
Explanation: The rate of thrombosis is highest in neonates and teens. Even if a child has thrombophilia, the risk of thrombotic events is rare unless they are exposed to additional high-risk situations (admission to the pediatric intensive care unit, presence of a central venous catheter, major surgery with immobilization and bed rest, etc.). The 16-year-old postsurgery will be at some risk, but surgeons will have him be ambulatory as soon as possible after this type of surgery. Having cancer does increase the risk of thrombosis, but this child is in remission and in maintenance therapy. The primary risk factor for thrombosis in any child (central venous catheter) also has been removed from this patient. Therefore, the infant on total parenteral nutrition who by definition has a central venous catheter is at highest risk.
Explanation: Patients receiving thrombolyisis must be monitored very closely. Oozing from line sites and elevation of D-dimers indicate that thrombolysis is occurring and the bleeding can be managed with local pressure. Reduced fibrinogen and platelet counts are expected and can be replaced easily. A drop of hemoglobin > 2 g/dl in a 24-hour period indicates excessive/major bleeding, so thrombolysis should be discontinued to assess and correct the bleeding.
Explanation: Screening children for thrombophilia is heavily debated. However, it is unnecessary to test this child for every thrombophilic abnormality (particularly the acquired ones like antiphospholipid antibodies). Testing only for FV Leiden is not the best approach, either. FV Leiden is the most common inherited mutation (up to 5% of Caucasian population), but the prothrombin gene mutation occurs in 2%–3%. The maternal side of the family also may have either of these mutations and it is well recognized that multiple thrombophilic defects increases a person’s risk more than a single mutation. In addition, a negative FV Leiden screen would not necessarily mean that this child is protected from thrombosis. In a healthy child, there is no reason to initiate prophylactic anticoagulation. Therefore, the best approach is to teach the family signs and symptoms of thrombosis and under which situations the child would be at highest risk. During high-risk situations, the child may benefit from some simple, noninvasive preventive measures such as use of compression stockings, adequate hydration, and early ambulation.
Explanation: Family history of a provoked DVT is not an indication for chronic anticoagulation therapy. Indications would be persistently elevated FVIII activity, strong thrombophilia (protein C, S, or antithrombin deficiency), and antiphospholipid antibody (APLA) syndrome. Although the protein C activity is technically low for an adult, it is normal for a preteen. Normal adult levels are not achieved until adolescence. If there is a concern for inherited protein C deficiency, antigen testing as well as activity testing should be repeated in a couple of years. Heterozygous FV Leiden is a mild thrombophilia and will not require indefinite anticoagulation because risk of recurrence is not higher for these patients; however, they will need DVT prophylaxis in high-risk situations. Antiphospholipid antibody syndrome is defined as the persistence of APLAs or lupus anticoagulant for 12 weeks in context of thrombotic event. This is associated with high risk of recurrent events.