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Home , Birth trauma (physical), Factor IX, Factor V, Factor XIII deficiency, Hemarthrosis, Hyperhomocysteinemia

Neonatal

Tung Wynn, MD April 28, 2016 Disclosures

• I am site principal investigator for Baxalta, Novonordisk, Bayer, and AstraZeneca studies Hemophilia Factor VIII Def C Def Factor IX Def Def Rare factor deficiencies III Def Factor XIII Leiden Mut Factor VII Prothrombin Mut Von Willebrands AntiPhospholipids Hyperhomocysteinemia dysfunctions MTHFR Disease Factor VIII elevation deficiency Afibrinogenemia Dysfibrinogenemia Alpha-2 antiplasmin Def inhibitor-1 mut Plasminogen activator Inhibitor-1 Def Anti-Coagulation Overview

• Three phases of Coagulation – Vascular phase – Platelet phase • Platelet adhesion • Platelet aggregation – Coagulation phase • Intrinsic pathway • Extrinsic pathway • Clot contraction • Activation of coagulation also initiates the process of Neonatal Hemostatic System Differences

Coagulation Anticoagulation – Factor II – Plasminogen – Factor VII – Antithrombin III – Factor IX – – – Protein S – Factor XI – Factor XIII – Platelet levels are normal, but have wider variability

Physiologic “deficiencies” of both coagulation and anticoagulation “balance” each other out in the neonate. General Approach to Neonatal • History – Fever – PPROM – Chorioamnonitis – Fetal Distress – Birth Trauma – Maternal infection – Maternal CBC – Family history autoimmune disease, coagulation disorder, low – Vitamin K administration • Physical – Well or Sick Infant – Confounding medical conditions (Trisomy 21) – Signs of birth trauma – – Petechiae – Flank Masses – Hepatosplenomegaly Platelets

• By 11 weeks, platelets can be recovered • Platelet reference ranges are similar in premature and term newborns to adults, but may vary more widely • Lifespan 7-10 days • Removed in the RES by macrophages • 25-35% of platelet located in the spleen Bozza FA, Shah AM, Weyrich AS, Zimmerman GA.Amicus or Adversary : Platelets in Biology, Acute , and , Volume 40, Issue 2, American Journal of Respiratory Cell and Molecular Biology Platelets

• Cellular fragments formed in bone marrow from regulated primarily by • Discoid in circulation, but once activated they release their granules and form multiple pseudopodia and become spherical • Platelet problems present either as quantitative deficiency or bleeding complication Thrombocytopenia

• Infections – TORCH – HIV – DIC – Bacterial • Drug exposure – Salicylates – – Hydralizine – Tolbutamide – Thiazide diuretics Thrombocytopenia

• Immune Mediated Treatment may be with IVIg, Steroids, and/or transfusions – NAIT • Severely affects platelet function because antibodies blocks GPIIb/IIIa (VWF receptor); keep platelets >50K • Transfusions should be with HPA- (PLA-) negative or with maternal pheresis product • Random donor platelets can be given with IVIg, but steroids are not as helpful • More severe upon second exposure/ • Manage future pregnancies with maternal weekly IVIg or daily or fetal platelet transfusions – Isoimmune thrombocytopenia (maternal ITP) • Does not affect platelet function; platelets may be >30K – Autoimmune thrombocytopenia (ITP) • Very rare in the neonate Thrombocytopenia

• Syndromes – Trisomy 21 • Transient myeloproliferative disorder or – Spontaneously resolves in 3-6 months – 20% will recur as AML • AML – GATA1 mutations help to distinguish – Trisomy 13, 18 • – Paris-Trousseau Syndrome – 11q23 deletion – Large platelets, thrombocytopenia, cardiac defect, mental retardation characteristic facial feature Thrombocytopenia

• TAR Syndrome (Thrombocytopenia, Absent Radii) – Severe thrombocytopenia that improves spontaneously as babies become older – Platelet transfusions recommended if bleeding; but high risk of alloimmunization

• MYH9 related disorders – May-Hegglin Anomaly (large platelets with Döhle bodies) – Sebastian syndrome (cataracts, deafness) – Fechtner’s syndrome (nephritis, cataracts, deafness) – Epstein’s syndrome (deafness, nephritis, no döhle bodies) Thrombocytopenia

• Wiskott Aldrich Syndrome (WAS) – Triad: small platelets, immune deficiency, eczematous rash – X-linked disorder – WASP – HSCT may be curative

• Congenital AMegakaryocytic Thrombocytopenia (CAMT) – Mutation of TPO receptor (c-mpl) – High risk of developing bone marrow failure – HSCT may be curative Miscellaneous Causes of Thrombocytopenia • Kasabach-Merritt Phenomenon – Consumptive associated with hemangiomas • ECMO – – Chronic platelet activation – Factor deficiencies – hypoxia Pseudo-thrombocytopenia Platelet Dysfunctions

• Bernard-Soulier Syndrome – Large platelets with mild thrombocytopenia caused by deficiency of GP 1b/IX/V complex – Absent aggregation with – High risk of alloantibody due to – Responsive to DDAVP

• Glanzmann’s Thrombasthenia – Rarely seen in neonates – Most commonly present with GI bleeding or menorrhagia – Respond well to Factor VIIa – High risk of alloantibody with frequent platelet transfusions Platelet Dysfunctions

• Hermansky-Pudlak Syndrome – oculocutaneous – mild/mod bleeding tendency – Colitis, pulmonary fibrosis in 2nd-3rd decade – Most common form of albinism in Puerto Rico – May respond to DDAVP, F VIIa, plasma, platelets

• Chediak-Higashi Sydrome – Partial albinism – Immune deficiency – Neurologic deterioration – Autosomal recessive – Lymphoproliferation/lymphoma often fatal in 1st decade – intracellular disorder of organelle transport and synthesis – HSCT is curative Coagulation Coagulation

• Coagulation are not likely to cross placenta • Levels are 10-30% of adults • At 32 weeks, , Factors V, VIII, XIII, and VWF are similar to adults • II, VII, IX, X and XI and XIII remain low Coagulopathy

• PT, aPTT – PT: 16 sec (13-20) – aPTT: 55 sec (+/- 10) – Factors primarily made in liver, except VWF • Factor V – Megakaryocytes • Factor VIII – Endothelial Cells • Factor XIII – Macrophages – VWF made in endothelial cells and megakaryocytes Coagulopathy

• Hemorrhagic Disease of the Newborn – Hemorrhaging that occurs in first 1-5 days of life in an otherwise healthy infant – Caused by Vitamin K deficiency, and increased sensitivity because of lowered Vit K dependent factor levels (II, VII, IX, X and Prot C, Prot S) – Without prophylactic Vit K, 0.25-1.7% incidence – Vit K 0.5-1 mg IM or 2-4 mg PO – Takes 12-24 hours for correction – Emergencies (ICH) should be treated with PCC or aPCC (FEIBA or K- centra) Coagulopathy

• Disseminate Intravascular Coagulation (DIC) – Consumptive coagulopathy secondary to a variety of conditions, most often sepsis, malignancy, major trauma, obstetric complication – Can manifest with bleeding, , or both – Labs: • Increased D-dimer, FDP, , PT, aPTT, TT • Decreased factors, platelets, fibrinogen – Treatment: • Manage primary condition • Supportive management. – Replacement if bleeding – Anticoagulation if thrombotic Hemophilia

• X-linked diseases • Cord may be used for initial factor determination if there is a family history • Avoid fetal scalp blood sampling and electrodes, prolonged labor, delivery with forceps or vacuum. • Carriers may be in the moderate or severe range due to extreme lyonization. • Mother may need peripartum factor replacement. • Circumcision bleeding most frequent presentation – , Vit K injection, Heel stick, immunization • FFP if unknown factor deficiency • Factor product if deficiency is known Hemophilia

• Incidence: 20-25 per 100,000 males • Factor VIII deficiency accounts for about 85% of the cases

Hemophilia B Hemophilia A 15% 85%

• Approx. 30% of the cases are due to spontaneous mutations with no family history. Hemophilia: Laboratories

• Prolonged aPTT, Normal PT, Normal Platelet counts • Mixing Studies correct • Specific Factor Assays (-quantitative, activity-qualitative – Hemophilia A (Classic) • Factor VIII is linked through non-covalent bonds with vWF in plasma and this may cause confusion for the diagnosis of VWD (type 2 N) – Hemophilia B (Christmas) – Hemophilia C • Factor XI deficiency is sometimes known as this • Gene profiling is available – Deletions are associated with more severe diseases while point mutations are associated with milder disease – Consider gene testing if clinical state does not match up with the Factor activity assay, in a child you are considering VWD, or if you are asked to assess a carrier state Laboratories

• Lab values change with age

Lab Test Newborns Adults

Platelets 214 +/- 55 258 +/- 66

PT 13.1 +/- 0.9 11.9 +/- 0.6

aPTT 35 +/- 4.5 28.8 +/- 2.7

Factor VIII 113 +/- 38 92 +/- 21

Factor IX 86 +/- 18 94 +/- 16

Adapted from Nathan and Oski, 7th ed. Factor VIII and IX molecules

Factor VIII gene is approximately 180 kb long while Factor IX gene is only 34 kb Current Treatment of Hemophilia

• Severe – < 1% Bleeding with minor injuries, spontaneous bleeds – Usually require prophylaxis starting as they are able to ambulate • Moderate – 1-5% Mild to moderate – May or may not need prophylaxis but occasional bleeds • Mild – >5-50% Asymptomatic, bleeding with severe trauma or – Rarely needs factor and may be treated with DDAVP/desmopressin Current Treatment of Hemophilia

Type of Bleed Hemophilia A Hemophilia B

Epistaxis Pressure, Local Treatments (QR, packing), Pressure, Local Treatments (QR, packing), , 20 U/kg Factor if needed antifibrinolytics, 30 U/kg Factor if needed

Mouth Bleeds, Teeth Extractions 20 U/kg Factor and antifibrinlytics 40 U/kg Factor and antifibrinolytics

Gross Hematuria Bed rest, 1.5X maintenance IVF, Bed rest, 1.5X maintenance IVF, then 20 U/kg Factor if not controlled in 1-2 days, then 30 U/kg Factor if not controlled in 1-2 days, Prednisone if HIV negative Prednisone if HIV negative

Muscle or significant SQ 50 U/kg Factor, 80 U/kg Factor then 20 U/kg every other day until resolution then 40 U/kg every other day until resolution

Hemarthrosis 50 U/kg Factor initially, 80 U/kg Factor initially, then 20 U/kg daily, then 40 U/kg daily, then continue every other day until resolution then continue every other day until resolution

Iliopsoas Hemorrhage 50 U/kg Factor initially, 80 U/kg Factor intially, then 25 U/kg BID until asymptomatic, then 20-40 U/kg every 12-24 hrs (to maintain levels then 20 U/kg every other day for 10-14 days total >40%) until asymptomatic, then 30 U/kg every other day for 10-14 days total Major Surgery, life-threatening hemorrhage 50-75 U/kg Factor initially, 80-100 U/kg intially (i.e., CNS, GI, airway bleeding) then continuous infusion 3 U/kg/hr (to keep levels then 20-40 U/kg every 12-24 hrs (to keep levels >100%) for 24 hrs, >40%) for 5-7 days, then continue infusion 2-3 U/kg/hr (to keep levels then additional Factor (to keep levels >30%) for >50%) for 5-7 days, another 5-7 days then additional Factor to keep levels >30% for another 5-7 days

Adapted from Nathan and Oski’s Hematology of Infancy and Childhood, 7th ed. Current Treatment of Hemophilia

• Blood Products – (FFP) • Contains all factor proteins • By definition 1 mL of FFP is equivalent to 1 unit of factor activity – • DOES NOT CONTAIN FACTOR IX • Never used unless emergency and no other products available – Factor concentrates • VIII: Humate-P®, Alphanate®, Wilate® – Contain VWF as well as Factor VIII – Used primarily to treat VWF • IX: Alphanine ® • Can be used if recombinant factor not available, but small risk of infection remains Current Treatment of Hemophilia

• Recombinant Factor VIII products – Preferred for the vast majority of Hemophilia patients – Most commonly used products Helixate FS® (this is what’s on formulary), Advate®, Kogenate FS®, Xyntha® • Factor IX products – BeneFIX® (on forumulary), Extended Half-Life products: Eloctate ®, Adynovate ®, Nuwiq ®, Alprolix ®(IX), Idelvion ® (IX) Current Treatment of Hemophilia

• Dose calculations: – Factor VIII: 1 unit/kg = 2 % activity • Standard half- life 8-12 hours • Extended half-life 19-21 hours – Factor IX: 1 unit/kg = 1 % activity • Standard half-life 18-24 hours • Extended half-life 86-104 hours Inhibitors

• Antibodies that neutralize Factor activity – Causes a failure to respond to treatment • 14-25% of severe hemophiliacs will develop – Mild and moderate patients are also at risk • Low-Titer Inhibitors <5 Bethesda Units – Increase Factor dose to overcome • High-Titer Inhibitors >5 Bethesda Units – Pts develop an anamnestic response High-Titer Inhibitors

• Porcine Factor – Now comercially available, rarely used – Porcine antibodies can develop • FEIBA (Factor Eight Inhibitor Bypassing Activity) – Prothrobin Complex Concentrate • Recombinant Factor VIIa – 90 mg/kg IV dosed every 2 hours – High dose has been advocated by some • Immune Tolerance – High frequency exposure to high dose factor • 100-150 Units/kg BID – Tolerizes to factor VIII and gradually increase Factor VIII recovery Hemophilia Management Issues

• Recombinant products are preferable to plasma concentrates – Some studies, including the upcoming SIPPETT trial, show lower inhibitor rates in Previously Untreated Patients (PUPs) with plasma concentrates compared to recombinant • Risk factors for inhibitor development include: – Initial exposure at an early age – Intense exposure within the first 20-50 exposures (like with treatment of bleeds) Von Willebrands Factor gene

• Von Willebrand gene is found on 12 (12p13.3) • There is also a “pseudogene” on chr 22 Von Willebrand’s Multimer

• VWF is made up of varying amounts of identical protein subunits in linear strings known as multimers – Up to 100 subunits make up a large multimer • ADAMTS13 – Proteolytic protein that degrades large VWF multimers – Deficiency is associated with TTP or aHUS VWF stores

• Synthesized by vascular endothelial cells and stored in Weibel-Palade bodies – Desmopressin (DDAVP) causes secretion of these bodies from the endothelial cells of type I patients • Also synthesized by megakaryocytes and stored in platelet α-granules – Desmopressin does not affect these stores • The golgi complex processes the protein for storage Prevalence

• Occurs 23-110 per million population – Actual numbers may be much more than this because VWD is a heterogenous disease and many patients have very mild symptoms, often going undiagnosed – Some studies report that VWD may affect up to 1% of the population • Autosomal dominant – Therefore it occurs in both men and women Laboratory evaluation

• Screen should include – CBC, CMP, PT, aPTT – Consider TCT, Fibrinogen • If screens indicate or if history is highly suspicious then futher testing with – VWF:Ag – VWF:RcoF or VWF:CBA – Factor VIII activity • Retesting is appropriate if you have a high index of suspicion but initial testing is negative because levels may vary (menstrual cycle, stress, ) Von Willebrand’s type

– Fresh Frozen Plasma (FFP) • Contains all factor proteins • By definition 1 mL of FFP is equivalent to 1 unit of factor activity – Cryoprecipitate – Plasma Concentrate: Humate-P®, Alphanate®, Koate DVI ®, Wilate® • Contain VWF as well as Factor VIII • Dose according to vWF:Rcof units • Approximately 1 unit/kg = 2 % activity every 8-12 hrs Other Treatments for VWD

• Antifibrinolytics – , 100 mg/kg IV/PO q4-6 hours X 5 days, max 30g/day – , 650 mg PO TID X 5 days • Oral contraceptives – This is usually given in collaboration with a gynecologist and used in conjunction with other available treatments for VWD Factor XIII deficiency

• Crosslinks clot to stabilize the clot at end of coagulation • Autosomal recessive • Presentations: – Delayed bleeding, intracranial hemorrhages, delayed separation of umbilical stump, delayed wound healing, recurrent loss • PT, aPTT, TT, Fibrinogen all normal • 5M urea solubility test used for screening • Long half life, 5-7 days • FFP, cryoprecipitate, plama concentrate (Corifact ®), recombinant (Tretten®) are available • Dosed every 2-4 weeks Fibrinogen disorders

• Autosomal inheritance • Bleeding symptoms can be mucocutaneous, but also hemarthroses (afibrinogenemia), as well as birth trauma and GI bleeding • TT are characteristically prolonged, but in severe hypofibrinogenemia and afibrinogenemia, PT and aPTT may be prolonged as well – Reptilase time is similar to TT but unaffected by heparin • Low fibrinogen levels = hypofibrinogenema (heterozygotes) • Absent fibrinogen levels = afibrinogenemia (homozygotes) • Qualitative (functional) abnormalities = dysfibringenemia – TT is abnormal (shortened or prolonged) but fibrinogen level is normal – Autosomal dominant inheritance – May cause no symptoms, bleeding symptoms, or clotting symptoms • Treated with cryoprecipitate, FFP, or Riastap ® Thrombosis

+ D dimers Thrombosis

Risk Factors for thrombosis Virchow’s Triad in Newborns 1 Abnormalities in the vessel wall Intravascular catheters damaging 2 Aberration of blood flow Large bore catheters in small veins Increased blood viscosity, Poor deformability of newborn RBC’s 3 Alterations in the constituents of the blood Shock, sepsis, ECMO Thrombosis

• Other considerations: – Antithrombin III deficiency – – – gene mutation – Prothrombin (Factor II) mutation – Antiphospholipid antibodies – Autoimmune disease Thrombosis • History – Venous or arterial – Provoking factors • Immobilization • Lines – Family history • Site • Age • Pregnancy complications or loss • What testing was done Thrombosis

• Physical – DVT • Triad: pain, swelling, discoloration – – Neonatal fulminans • Diffuse ecchymoses which become necrotic bullae presenting in a newborn – Stroke Thrombosis

• Radiologic – Doppler ultrasound – Angiograms – Spiral CT scans – MRI/MRV/MRA • Laboratories – D-dimers, PT, aPTT, CBC – studies • Results of these studies usually do not determine the treatment of a patient during an acute thrombotic event, but will help in determining future risk and long-term management • Decision to test depends if clot was provoked or unprovoked in a patient without family history and with first clot Thrombosis: Treatments

• DIC: – Manage primary condition – Supportive management • Replacement if bleeding • Anticoagulation if thrombotic • Central Lines – Removal of central lines is always appropriate to recommend but may not always be possible • TED hoses/compression stockings/SCD – Below , 30-40 mmHg – Not shown to provide any additional benefit • Activity restriction for 5 days following acute DVT Thrombosis: Treatments

• Aerterial Thrombosis – Higher frequency in neonates compared to (up to 50%) – Most are iatrogenic and catheter associated – Anticoagulation is appropriate – CNS: • Non-embolic: Anticoagulation is NOT recommended especially “large” infarct or associated with hemorrhage • Embolic: Anticoagulate

Thornburg C, Pipe S. Neonatal thromboembolic emergencies. Semin Fetal Neonatal Med. 2006 Jun;11(3):198-206. Thrombosis: Treatments

• Unfractionated Heparin – For treatment of thrombosis, it is run as a continuous infusion and requires close monitoring – Less frequently used due to availability of LMW , but may still be appropriate in unstable patients where rapid stoppage of the effect may be important, i.e. patients • Begin with bolus of 80 units/kg • Initial drip rate of 18 units/kg/hr – Frequent monitoring with CBC (pre and daily), aPTT, Xa, and/or heparin levels – Goal is to maintain aPTT approximately 2X normal or Xa level of 0.3-0.7 – Reverse with protamine Thrombosis: Treatments

• LMW Heparin – Used for both acute and chronic management – Enoxaparin(Lovenox), 1 mg/kg SQ BID, (1.5 for neonates) – (Arixtra), 0.1 mg/kg once daily dosing – Dalteparin (Fragmin) – Tinzaparin (Innohep) – Monitor with Factor Xa assay 4 hours after dosing to keep at 0.5-1 Thrombosis: Treatments

• Newer agents – Direct inhibitors • Indicated for anticoagulation in pts with HIT (or high risk of HIT) • (0.75 mcg/kg/hr), , • Monitor with aPTT • (oral) – Direct Xa inhibitor • (oral), , Thrombosis: Treatments

• – Systemic vs. catheter directed therapy • Cather directed therapy may reduce risk of bleeding and post- thrombotic syndrome(PTS), systemic therapy does not reduce the risk of PTS – Tissue plasminogen activator (tPA, ), , • tPA used commonly for catheter occlussions – Followed by several days of heparin therapy, and routine anticoagulation – High risk of bleeding associated with all forms of thrombolysis • Thrombectomy – Physical removal of clot either by surgery or more commonly interventionally – May be more effective in preventing PTS Long-term management

• Reduce risk factors – -containing oral contraceptives – Smoking – Obesity – Immobilization –

• Life-long anticoagulation – The decision to anticoagulate should take into account the risk of a second clot weighed against the risks of bleeding and the necessary activity restrictions • High Risk – Homozygous FVL, Prothrombin, Prot C, Prot S, AT3 and multiple risk factors • Moderate Risk – All other predisposing conditions • Low Risk – No thrombophilic conditions were found Thrombosis: Other considerations

• is not safe for use in a neonate

• A family history is not justification to test an asymptomatic child

• A heterozygous state in an asymptomatic child does not warrant prophylactic anticoagulation