Neonatal coagulation disorders Mehran Karimi MD Tehran September

Neonatal coagulation disorders Mehran Karimi MD Tehran, September 14, 2017

Agenda § § § § Background Causes of bleeding and Clinical manifestations Classification of coagulation disorders in neonates Primary investigation and diagnostic evaluation Interpretation and differential diagnosis of coagulation disorders Management Approach to Specific diseases: Hemophilia, RBD

Background (1) § When evaluating a neonate with a disorder of hemostasis it is crucial to recognize differences of coagulation factors compared to older children and adults § Coagulation factors are synthesized by the fetuses, • Begin to appear at 10 weeks’ gestational age § In the neonate, plasma concentrations of vitamin-K dependent coagulation factors (II, VII, IX, X) and contact factors (XI, XII, prekallikreine and high molecular weight kininogen) are about 50% of adult values § The levels of FV, FVIII and FXIII are similar to adult group § VWF concentration, function and VWF large multimers are enhanced in neonates

Background (2) § Platelet numbers of neonates are within adult limits; however the evaluation of platelet function is difficult and deserves specific attention § The onset of hemorrhage in a healthy term, late preterm or young infant with a normal platelet count is strongly suggestive of a congenital bleeding disorder § Neonatal bleeding results from disorders of platelets, coagulation proteins, and disorders of vascular integrity. § While healthy newborns have low levels of some coagulation proteins, this is normally balanced by the paralleled decrease in fibrinolytic activity. Kenet G, et al. Haemophilia, 2010, 16(supp. 51), 168 -174

Neonatal hemostasis versus older children/adult hemostasis Preterm neonates versus term neonates Neonates vs older children/adults Approximate age of adult values ( Max age reported) Primary hemostasis: -Platelet count -Platelet function -% of reticulated platelets - VWF level -VWF large multimers Decreased (< 32 w) Decreased Higher NA NA Same Decreased(to thrombin, collagen, epinephrine) Higher Same 2 -4 wk NA 3 mo Coagulation factors -FII, FVII, FIX, FX - FV -FVIII -FXII - Fibrinogen level -Fibrinogen function Lower Higher Lower Same NA lower Same or higher Lower Same Decreased 16 y 1 mo (Lower level reported from 1 mo to 16 y). 1 y 16 y Same 5 y Regulation of coagulation - Antithrombin -Protein C -Total Protein S -Free Protein S -APCR generation -Free TFPI Lower NA NA NA Lower Higher Reduced Lower 3 mo 16 y 1 mo NA NA Adult Lower NA Same§ Lower Same(Higher levels in extremely preterm neonates on d 10 of life) Lower Decreased Higher Lower Higher Same or Higher 6 mo NA 5 d 5 d Adult 5 d Fibrinolysis -Plasminogen level -Plasminogenfunction -t. PA -a 2 antiplasmin -a 2 M -PAI

CAUSES OF NEONATAL BLEEDING (1) § Platelet Disorders • Thrombocytopenia (<150 x 109/L): v 1 -4% of term newborns, v 40 -72% of sick preterms v 25% of ICN admissions; Of these, v 75% present before age 72 h • Impaired platelet function v. Von Willebrand’s Disease University of California, USCF Children’s Hospital guideline for neonatal coagulation disorders *TAR: Thrombocytopenia Absent Radius. § Causes of thrombocytopenia § Decreased platelet production: v Congenital infections (e. g. , CMV, Rubella, HIV) v Certain syndromes (TAR*, Fanconi) v sepsis and Hemolytic Disease of Newborn. § Increased platelet consumption : v Maternal auto-immune disease (e. g. , ITP, SLE) v Asphyxia/Shock v Neonatal Alloimmune Thrombocytopenia v Maternal thiazide intake – v IUGR with toxemia of pregnancy v Necrotizing enterocolitis – v Thrombosis (due to catheters, hemangiomas) v Sepsis , Hemolytic disease of the newborn v Exchange transfusion, Heparin-induced thrombocytopenia v Polycythemia/Hyperviscosity

CAUSES OF NEONATAL BLEEDING (2) § Coagulation Protein Disorders • Congenital factor deficiencies v X-linked recessive: Hemophilia A (Factor VIII) and Hemophilia B (Factor IX) v Autosomal recessive (rare): Factors V, VII, X, XII, XIII, afibrinogenemia • Acquired deficiencies v Vitamin K deficiency § Combined Platelet and Coagulation Factor Disorders • Disseminated Intravascular Coagulation (DIC) v Secondary to inappropriate systemic activation of normal clotting mechanisms after endothelial injury. v Infants have low platelet counts and fibrinogen levels, prolonged PT and PTT, and elevated Fibrin Degradation • § Products. Hepatic Dysfunction v shock, infection, inherited conditions v Prolonged PT and decreased factor and fibrinogen levels. Disorders of Vascular Integrity • hemangiomas or vascular malformations University of California, USCF Children’s Hospital guideline for neonatal coagulation disorders

Clinical presentations in neonates with a coagulation disorder § The clinical presentations of bleeding disorders in neonates are variable: • Cephalhematomas • Intracranial hemorrhage (ICH), subdural is the most common • Hematuria, pulmonary hemorrhage, • Post circumcision • Venipuncture bleeding When loss is large, the infant may present with • Injury related blood bleeding following invasive procedures • Facial purpura following birth and oral mucosaweak membrane bleedings signs of hypovolemia, pallor, pulses, tachycardia, v Thrombocytopenia or platelet dysfunction hypotension and acidosis. • Injury related bleeding or bleeding into themetabolic skin v Petechiae, purpura or ecchymosis • Persistent oozing from the umbilical stump v Defective fibrinogen production or function v FXIII deficiency • Joint bleed within the first year of life v Typical for severe hemophilia 1 -Thrombosis Research 135, Suppl. 1 (2015) S 41–S 43 2 -G. KENET et al. Haemophilia (2010), 16 (Suppl. 5), 168– 174

Classification of coagulation disorders in neonates §Most of bleeding problems in neonates are acquired Inherited Acquired Hemophilia A Vitamin K deficiency Hemophilia B Liver disease von Willebrand disease Disseminated intravascular coagulation Deficiency of factor II, V, VII, X, XII or XIII Disorders associated with malignancy Dysfibrinogenaemia/or hypofibrinogenaemia Acquired inhibitors of coagulation Massive transfusion syndrome Dysfibrinogenaemia/hypofibrinogenaemia Paediatrics and child health. 2007; 17(8): Pages 322– 327

DIAGNOSTIC EVALUATION OF ABNORMAL BLEEDING (1) § Of 864 male infants aged 0 -2 years with hemophilia at US hemophilia treatment centers • 633 (73%) were diagnosed within first month of birth v. Carrier mother 47. 2% v. Bleeding events 28. 8% v. Family history 23. 2% v. Unknown 0. 8% § Post circumcision (45%) , Head (17. 7%) and head stick (14. 8%) bleedings were the most common hematologic complications § Gum bleeding and epistaxis are very rare and hardly seen Kenet G, et al. Haemophilia, 2010, 16(supp. 51), 168 -174

DIAGNOSTIC EVALUATION OF ABNORMAL BLEEDING (2) § History: • Family history of bleeding disorders or neonatal deaths v May be negative even with inherited disorders • Maternal history of bleeding disorders, medication intake, previous neonatal deaths, auto-immune disease • Perinatal: v Toxemia of pregnancy, IUGR, infections, antepartum bleeding • Neonatal: v History of asphyxia, birth trauma, administration of Vitamin K, gender (X-linked disorders) § Neonatal physical examination: • Signs of bleeding • Signs of infection (hepatosplenomegaly) • Signs of hypovolemia • Hemangiomas, vascular malformations • Other illness (e. g. , NEC, hemolytic disease) University of California, USCF Children’s Hospital guideline for neonatal coagulation disorders, 2004

DIAGNOSTIC EVALUATION OF ABNORMAL BLEEDING (3) § Laboratory investigation: (Draw blood from non-heparinized source ) • Initial screen v CBC, differential, smear, Platelet count v Prothrombin time (PT) , Partial Thromboplastin Time (PTT) v Fibrinogen • If Neonatal Allo-Immune Thrombocytopenia (NAIT) is suspected, v Send mother’s and infant’s blood for platelet count and typing. v With NAIT, maternal platelet count is normal and, in most cases, the mother will be HPA-1 negative (Only 2% of population is HPA-1 negative. ). v Infants with NAIT are at risk for serious intracranial hemorrhage. v For severe thrombocytopenia, platelet transfusion is indicated. – Washed maternal platelets (to remove antibody) are the treatment of choice. v If not practical, HPA-1 negative platelets are the second choice, but are difficult to obtain. v Random-donor platelets should be used if other choices are not available. IVIG therapy will often increase the platelet count. • Subsequent evaluation: v If abnormal bleeding is not secondary to an underlying illness and appears to be a primary coagulopathy, obtain Hematology consult immediately.

How to interpret tests leading to differential diagnosis

MANAGEMENT (1) For secondary bleeding disorders, treat underlying disease. Replacement of clotting factors is often necessary § Severe, life threatening bleeding: • Maintain adequate circulating blood volume. • Send blood for clotting studies • If clotting defect is not known, consider giving all of the following: v Vitamin K 1 mg IV slowly over 1 min – Rapid infusion of Vitamin K can cause cardiac dysrhythmias. v Fresh Frozen Plasma 10 m. L/kg over 5 -10 min. v Platelets 1 unit v Cryoprecipitate 1 unit • Send repeat clotting studies in 4 -6 h • Obtain Hematology Consult if bleeding is not controlled quickly. § University of California, USCF Children’s Hospital guideline for neonatal coagulation disorders, 2004

MANAGEMENT (2) § Bleeding with known abnormal clotting screening tests • Prolonged prothrombin time (PT), normal PTT, platelets and fibrinogen: v Give Vitamin K 1 mg IV slowly over 1 min. v Repeat PT in 4 h. If not improved, consider specific factor deficiency. • Prolonged PT and PTT: v The low levels of contact activation factors contribute to the normally prolonged activated partial thromboplastin time (a. PTT) in neonates – PT, PTT, TT and INR are normally prolonged in neonate v Give Fresh Frozen Plasma 10 m. L/kg and Vitamin K 1 mg. Send repeat clotting studies in 2 h. • Low fibrinogen: v Give cryoprecipitate 1 unit or fibrinogen concentrate if available • Thrombocytopenia: v Serious bleeding usually does not occur unless there is severe thrombocytopenia (i. e. , <20 x 109/L ). v With “sick” infants (i. e. , other severe disease; receiving assisted ventilation), bleeding may occur at higher levels. v So, for these infants, use platelet transfusions to maintain platelets >50 x 109/L. v Platelets should be type and Rh specific, irradiated, and CMV negative (If infant is possibly immunocompromised). § For significant bleeding from any cause, consider cranial ultrasound, especially in preterm infants.

Further investigations of a suspected coagulation disorder in a neonate § Biochemical screen, • Renal and hepatic function tests § Coagulation screen • In vitro BT (closure time): BT and PFA-100 are longer in preterm VS term but shorter in term VS Adult • If PT or APTT prolonged, make a 50: 50 mix with normal plasma to distinguish between possible factor deficiency and presence of inhibitor § Factor assays: • Selection of which are appropriate depends on which parameter is prolonged in the coagulation screen • v. W screen § Reptilase time and other TT corrections to check for presence of heparin or dysfibrinogenaemia § Tests for presence of lupus anticoagulant § Factor XIII screening/clot stability test or factor XIII activity § In vitro bleeding time, flow cytometry, platelet aggregation and nucleotides 1 -Paediatrics and child health. 2007; 17(8): Pages 322– 327 2 -J Clin Med. 2017; 6(5). pii: E 54

Products for Treatment of Coagulopathies Product Factor content Usual Dose Indications Fresh frozen plasma All factors 10 -20 m. L/kg Disseminated intravascular coagulation (DIC); liver disease; protein C deficiency Exchange transfusion* All factors, platelets Double volume Severe DIC; liver disease Factor VIII concentrate Factor VIII 25 -50 U/kg Factor VIII deficiency (Hemophilia A) Factor IX 50 -100 U/kg Factor IX deficiency concentrate 1 -2 mg Vitamin K deficiency Vitamin K Platelet concentrate Platelets 1 -2 units/5 kg‡ Severe thrombocytopenia Intravenous gamma globulin Ig. G 1 -2 g/kg Severe sepsis; thrombocytopenia due to transplacental antibodies *If fresh whole blood is used. ‡Response to platelets can vary markedly, depending on underlying condition.

Hemophilia § In hemophilia A, factor VIII (FVIII) is reduced or absent and in hemophilia B, factor IX (FIX) is affected. Hemophilia A is 5 -6 times more common than hemophilia B § Hemophilia A and B are X-linked recessive disorders which affects 1 in 5, 000 and 1 in 30, 000 males respectively, with an equal ethnic distribution § FVIII concentrations are similar in infants and adults, but FIX concentrations are lower in newborns, rising to adult values after age 6 months § Mild-to-moderate hemophilia B cannot be diagnosed in the neonate and assessment of FIX must be repeated at or after age 6 months to confirm the diagnosis § Because activated FVIII functions as a co-factor for activated FIX in the subsequent activation of factor X, they have a similar clinical phenotype BMJ 2012; 344: e 2707

Management of the fetus at risk of hemophilia during pregnancy and at delivery. § General Antenatal Management. • In the presence of a positive family history of hemophilia, pregnancy should be managed by an obstetric unit with experience of hemophilia and access to both laboratory monitoring and appropriate factor replacement therapy. • Written management plans should be readily available. These plans should reflect input from the multidisciplinary team and include the hemostatic management of the mother and baby. § Genetic Screening and fetal sexing. • Fetal sexing should be undertaken either by maternal blood sampling at around 10 weeks gestation or by USS at between 18 -20 weeks. • Third trimester amniocentesis may be considered where confirmation of an affected male fetus will influence management at delivery Elizabeth C. et al. Guideline on the management of haemophilia in the fetus and neonate, A United Kingdom Haemophilia Centre Doctors’ Organisation Guideline

Management of Delivery in hemophilia § Mode of delivery should be informed by both obstetric and hemostatic factors; • hemophilia carrier status itself is not a contraindication to vaginal delivery § The option of elective caesarean section in an attempt to reduce the risk of neonatal ICH may be considered on an individual basis taking into account knowledge of the fetal hemophilia status and potential maternal morbidity. § Ventouse (vacuum) extraction, rotational and mid-cavity forceps are associated with an increased risk of bleeding and should be avoided § Invasive monitoring procedures such as placement of intrapartum scalp electrodes and fetal scalp blood sampling should be avoided § Decisions regarding the management of labor should always involve a consultant. Elizabeth C. et al. Guideline on the management of haemophilia in the fetus and neonate, A United Kingdom Haemophilia Centre Doctors’ Organisation Guideline

Diagnosis of Hemophilia in the Newborn Infant. § The diagnosis of hemophilia should be established using uncontaminated cord blood as soon as possible following delivery. § Results should be interpreted using age (gestation) adjusted normal ranges. § FVIII/IX assays should be carried out on the cord sample regardless of the APTT. § Intramuscular vitamin K should be withheld until hemophilia is excluded. • Oral vitamin K should be given if there is a delay in diagnosis or if hemophilia is confirmed. Elizabeth C. et al. Guideline on the management of haemophilia in the fetus and neonate, A United Kingdom Haemophilia Centre Doctors’ Organisation Guideline

Management of the newborn infant with hemophilia (1) § Management of Bleeding • Recombinant factor VIII or IX concentrate is the treatment of choice for Hemophilia A or B and should be immediately available • Replacement therapy during the neonatal period should be monitored v As neonates may require higher doses to achieve desired factor levels and may demonstrate a shortened factor half life • Virally inactivated fresh frozen plasma 15 -25 mls/Kg may be given if treatment is urgently required before the diagnosis of hemophilia has been confirmed. • Desmopressin should not be given to a neonate as treatment for hemophilia • Heel stab sampling or careful venipuncture for other neonatal screening procedures should not be omitted and should be carried out with care by experienced staff § Early Detection & Prevention of Intra-cranial and Extra-cranial Bleeding • Where there is a strong clinical suspicion of ICH (or other bleeding), factor concentrate should be given immediately and not withheld pending definitive imaging studies.

Management of the newborn infant with hemophilia (2) § Radiological assessment of intracranial bleeding. • Cranial US should be undertaken prior to discharge in all neonates with severe or moderate hemophilia. • Due to the low sensitivity of US for the detection of subdural bleeding cranial MRI or CT scan should be undertaken in symptomatic neonates even if an US is normal. § Prophylactic treatment of neonates with factor concentrate. • Following confirmation of diagnosis, short term prophylactic replacement therapy should be given in neonates at increased risk of bleeding: v Following traumatic delivery, v Instrumental delivery (particularly Vacuum or forceps extraction), or v A prolonged second stage of labor. • Short term prophylaxis should be considered following preterm delivery. § Information on diagnosis • Parents of an affected neonate should be informed of the diagnosis and presenting features of significant bleeding prior to discharge from hospital. • Early follow up by Hemophilia clinician should be arranged prior to discharge. § Female Carriers. • Newborn hemophilia carriers or potential carriers should receive routine obstetric and neonatal management.

Rare Bleeding Disorders (RBD) § The RBDs are inherited quantitative or qualitative deficiencies of factors • Fibrinogen, FII, FVII, FXI, FXIII, combined FV and FVIII deficiency, • Congenital deficiency of vitamin K-dependent factors (VKCFD) with underlying defects in activation of g-carboxylation (FII, FVII, FIX, FX), • Disorders of fibrinolysis (PAI-1 deficiency, a 2 -antiplasmin deficiency) § Diagnosis is challenging because of the rarity, variable clinical presentations, and sometimes the lack of family history § The most common manifestation is mucocutaneous bleeding § The bleeding of FI deficiency may be similar to that seen with moderate-to-severe hemophilia • Umbilical cord bleeding and mucosal bleeding are more characteristic of FI deficiency § Severe FII deficiency presents early in childhood with mucosal and musculoskeletal bleeding and intracranial hemorrhage. Serious bleeding, such as umbilical cord bleeding, hemorrhagic ovarian cysts, hemoperitoneum during ovulation, and hemarthrosis, are more common in FII deficiency than in other RBDs § FX and FXIII deficiencies are characterized by early onset of bleeding such as ICH and umbilical cord bleeding § Umbilical cord bleeding is characteristic of FXIII deficiency, and usually bleeding symptoms are delayed because the role of FXIII is stabilization of the fibrin clot Haemophilia. 2014; 20(0 4): 71– 75.

Hemorrhagic disease of the newborn § Hemorrhagic disease of the newborn is a rare bleeding problem that can occur after birth. § The disease is caused by vitamin K deficiency. • It’s often called vitamin K deficiency bleeding (VKDB) § VKDB is categorized according to the timing of first symptoms: • Early onset occurs within 24 hours of birth • Classic onset occurs within two to seven days • Late onset occurs within two weeks to six months § Clinical symptoms • Umbilical bleeding • mucous membranes bleeding of nose and mouth • After circumcision • Areas where they’ve been stuck by a needle, for example, for vaccinations • GI bleeding J Pediatr Health Care. 2013; 27(3): 215 -21 Blood Rev. 2009; 23(2): 49 -59

Risk factors for hemorrhagic disease of the newborn § Early onset • Early onset VKDB occurs within the first 24 hours after birth. Certain medications during pregnancy cause to higher risk including: v Antiseizure drugs that interfere with vitamin K metabolism, such as phenytoin, phenobarbital, caramezepine, or primidone v Blood thinning medications, such as warfarin (Coumadin) or aspirin v Antibiotics, such as cephalosporins v Antituberculosis medications, such as rifampin and isoniazid § Classic onset • Classic onset VKDB occurs within the first week after birth, typically in babies who have not received prophylactic vitamin K at birth § Late onset • Late onset VKDB is seen in babies up to 6 months old. This form is also more common in babies who did not receive a vitamin K shot. Risk factors include: v Low levels of vitamin K in breast milk, biliary atresia (which causes slow bile flow), cystic fibrosis, celiac disease, chronic diarrhea, hepatitis, A 1 -antitrypsin deficiency, which may cause lung and liver disease Blood Rev. 2009; 23(2): 49 -59

Acquired bleeding disorders § Acquired bleeding disorders typically are related to an underlying disease process § Liver disease can cause coagulopathy due to impaired hepatic synthetic capability § Chronic renal disease can cause abnormal platelet function associated with uremia § Intestinal malabsorption or chronic antibiotic therapy can cause vitamin K deficiency and consequently lead to VKCFD § DIC is a consumptive coagulopathy characterized by intravascular activation of coagulation that leads to unregulated thrombosis and secondary fibrinolysis or inhibited fibrinolysis • Clinical manifestations involve thrombosis or bleeding, but the most frequently observed are bleeding § Massive transfusion syndrome can occur when a child requires a transfusion of blood equal to his or her blood volume within a period of a few hours Pediatr Rev. 2016; 37(7): 279 -91

Treatment of acquired coagulation disorders Vitamin K deficiency Vitamin K 1– 5 mg i. v. FFP (if bleeding severe) Liver disease FFP Cryoprecipitate or fibrinogen concentrate (if fibrinogen deficient) Vitamin K Platelet concentrates (if thrombocytopenic) DIC Treat underlying cause Coagulation support with FFP, cryoprecipitate, platelet concentrates Massive transfusion syndrome Platelets (if count <50 × 109/l) FFP (if PT/APTT >1. 5 × control) Cryoprecipitate or fibrinogen concentrate (if fibrinogen <0. 8 g/l) Consider recombinant factor VIIa for uncontrolled bleeding, especially if no surgical cause and coagulation parameters corrected (u. Unlicensed-discuss with hematologist) Paediatrics and child health. 2007; 17(8): Pages 322– 327

Summary § In neonates and infants with a bleeding disorder the correct diagnostic assays and appropriate management vary according to the underlying medical condition § Therapeutic options for treatment of the various bleeding disorders in neonates and infants are as follows: • Vitamin K for neonatal prophylaxis (to avoid vitamin-K-deficiency bleeding) • Fresh-frozen plasma, • Various specific factor concentrates for treatment of specific factor deficiencies, e. g. v Recombinant or plasma-derived FVIII or FIX (hemophilia A or B), v Prothrombin complex concentrates, v FXIII concentrate (FXIII deficiency), v Recombinant activated factor VII (hemophilia patients with inhibitors, FVII deficiency, or Glanzmann thrombasthenia), v Cryoprecipitate (hemophilia A, von Willebrand disease, and fibrinogen disorders: in case specific concentrates are not available), platelet transfusions for platelet function disorders, and v Adjunctive anti-fibrinolytic therapy for infants with bleeding Thrombosis Research 135, Suppl. 1 (2015) S 41–S 43

Thank you for your attention karimim@sums. ac. ir