Thrombotic Disorders

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Thrombotic Disorders

Thrombotic Disorders 2013 ASPHO Board Review Course

  1. 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?

  1. 100%

  2. 75%

  3. 50%

  4. *25%

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.

  1. A 3500 gram female infant has neonatal purpura fulminans.

Which of the following is the most likely explanation of this condition?

  1. Heterozygous protein C deficiency

  2. Heterozygous antithrombin deficiency

  3. Heterozygous factor V Leiden

  4. *Homozygous protein C deficiency

  5. 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.

  1. 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?

  1. aPTT

  2. PT/INR

  3. Factor VIII activity

  4. *antithrombin activity

  5. plasminogen 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.

  1. 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?

  1. *Serum pregnancy test

  2. Serum creatinine

  3. PIVKA (proteins induced by vitamin K absence ) II assay

  4. 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.

  1. 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?

  1. aPTT

  2. *PT/INR

  3. Anti-factor Xa assay

  4. Chromogenic factor X assay

  5. Genotyping for warfarin resistance

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.

  1. 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?

  1. Low molecular weight heparin is completely reversible with protamine

  2. Low molecular weight heparin is renally cleared

  3. *Low molecular weight heparin is associated with a lower risk for heparin induced thrombocytopenia

  4. Low molecular weight heparin mechanism of action is independent of antithrombin

  5. 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.

  1. 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?

  1. Evaluate for heparin induced thrombocytopenia

  2. *Evaluate for disseminated intravascular coagulation

  3. Evaluate for immune thrombocytopenic purpura

  4. Evaluate for renal vein thrombosis

  5. 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.

  1. 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?

  1. 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

  2. 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

  3. *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

  4. 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.

  1. 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?

  1. Excessive vitamin K replacement in the TPN

  2. Antithrombin deficiency

  3. Protein C deficiency

  4. Protein S deficiency

  5. *PICC

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.

  1. 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?

  1. *Superior vena cava syndrome

  2. Cerebral sinovenous thrombosis

  3. Delayed hemolytic transfusion reaction

  4. Allergic reaction to anesthesia given during port placement

  5. 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.

  1. 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?

  1. Methylenetetrahydrofolate reductase

  2. Dihydrofolate reductase

  3. *Cystathionine beta-synthase

  4. Methionine synthase

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.

  1. 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?

  1. anabolic steroid use

  2. *anatomic abnormality

  3. heterozygosity for methylene tetrahydrofolate reducatase (MTHFR) C677T

  4. 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.

  1. 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?

  1. Observation; repeat ultrasound if there is progressive swelling

  2. V/Q scan to evaluate for pulmonary embolus

  3. CT scan to evaluate for pulmonary embolus

  4. *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.

  1. 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?

  1. fibrinogen of 120 mg/dL [nl 200-400 mg/dL] after 6 hrs of treatment

  2. plasminogen of 50% [nL 85-150%] after 12 hrs of treatment

  3. oozing at peripheral IV sites after 4hrs of treatment

  4. no resolution of thrombosis after 12 hrs of treatment

  5. *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.

  1. 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?

  1. Argatroban is dependent on antithrombin for its efficacy

  2. Argatroban has been associated with heparin induced thrombocytopenia

  3. A Food and Drug Administration approved indication of argatroban is treatment of venous thrombosis in children

  4. *Argatroban dosing is titrated based on the aPTT

  5. 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.

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