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

2. 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

3. 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

4. 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),

5. 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
Same
Decreased(to thrombin,collagen,epinephrine)
2-4 wk
3 mo
Coagulation factors
-FII,FVII,FIX,FX
- FV
-FVIII
-FXI
-FXII
- Fibrinogen level
-Fibrinogen function
Lower
lower
Same or lower
Same or higher
16 y
1 mo (Lower level reported from1mo to16y).
1 y
5 y
Regulation of coagulation
- Antithrombin
-Protein C
-Total Protein S
-Free Protein S
-APCR generation
-Free TFPI
Reduced
1 mo
Adult
Fibrinolysis
-Plasminogen level
-Plasminogenfunction
-tPA
-a2 antiplasmin
-a2M
-PAI
Same§
Same(Higher levels in extremely preterm neonates on d10 of life)
Same or Higher
6 mo
5 d

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

7. CAUSES OF NEONATAL BLEEDING (2)
Coagulation Protein Disorders
Congenital factor deficiencies
X-linked recessive: Hemophilia A (Factor VIII) and Hemophilia B (Factor IX)
Autosomal recessive (rare): Factors V, VII, X, XI, XII, XIII, afibrinogenemia
Acquired deficiencies
Vitamin K deficiency
Combined Platelet and Coagulation Factor Disorders
Disseminated Intravascular Coagulation (DIC)
Secondary to inappropriate systemic activation of normal clotting mechanisms after endothelial injury.
Infants have low platelet counts and fibrinogen levels, prolonged PT and PTT, and elevated Fibrin Degradation Products.
Hepatic Dysfunction
shock, infection, inherited conditions
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

8. 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
Injury related bleeding following invasive procedures
Facial purpura following birth and oral mucosa membrane bleedings
Thrombocytopenia or platelet dysfunction
Injury related bleeding or bleeding into the skin
Petechiae, purpura or ecchymosis
Persistent oozing from the umbilical stump
Defective fibrinogen production or function
FXIII deficiency
Joint bleed within the first year of life
Typical for severe hemophilia
When blood loss is large, the infant may present with signs of hypovolemia, pallor, weak pulses, tachycardia, hypotension and metabolic acidosis.
1-Thrombosis Research 135, Suppl. 1 (2015) S41–S43
2-G. KENET et al. Haemophilia (2010), 16 (Suppl. 5), 168–174

9. 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, XI, 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

10. 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
Carrier mother %
Bleeding events %
Family history %
Unknown %
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),

11. DIAGNOSTIC EVALUATION OF ABNORMAL BLEEDING (2)
History:
Family history of bleeding disorders or neonatal deaths
May be negative even with inherited disorders
Maternal history of bleeding disorders, medication intake, previous neonatal deaths, auto-immune disease
Perinatal:
Toxemia of pregnancy, IUGR, infections, antepartum bleeding
Neonatal:
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 malformations
Other illness (e.g., NEC, hemolytic disease)
University of California, USCF Children’s Hospital guideline for neonatal coagulation disorders,2004

12. DIAGNOSTIC EVALUATION OF ABNORMAL BLEEDING (3)
Laboratory investigation: (Draw blood from non-heparinized source )
Initial screen
CBC, differential, smear, Platelet count
Prothrombin time (PT) , Partial Thromboplastin Time (PTT)
Fibrinogen
If Neonatal Allo-Immune Thrombocytopenia (NAIT) is suspected,
Send mother’s and infant’s blood for platelet count and typing.
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.).
Infants with NAIT are at risk for serious intracranial hemorrhage.
For severe thrombocytopenia, platelet transfusion is indicated.
Washed maternal platelets (to remove antibody) are the treatment of choice.
If not practical, HPA-1 negative platelets are the second choice, but are difficult to obtain.
Random-donor platelets should be used if other choices are not available. IVIG therapy will often increase the platelet count.
Subsequent evaluation:
If abnormal bleeding is not secondary to an underlying illness and appears to be a primary coagulopathy, obtain Hematology consult immediately.
Incidence – NAIT is the most common cause of severe thrombocytopenia in heathy term neonates and occurs in 1/1,000-5,000 births • 80% of NAIT in Caucasians is caused by maternal antibodies directed against HPA-1a and ~20% by antibodies directed against HPA-5b • Posttransfusion purpura occurs in 1/50, ,000 transfusions Symptoms • Severe thrombocytopenia in an otherwise healthy newborn • Intracranial hemorrhage – may occur in utero, at birth, or postnatally o Fatal in 5-10% of affected neonates o May cause intellectual disability, seizures, cerebral palsy, or cortical blindness in up to 25% of survivors • Widespread petechiae or purpura • Visceral hemorrhage – often of gastrointestinal or bladder mucosa

13. How to interpret tests leading to differential diagnosis

14. 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:
Vitamin K 1 mg IV slowly over 1 min
Rapid infusion of Vitamin K can cause cardiac dysrhythmias.
Fresh Frozen Plasma 10 mL/kg over 5-10 min.
Platelets 1 unit
Cryoprecipitate 1 unit
Send repeat clotting studies in 4-6h
Obtain Hematology Consult if bleeding is not controlled quickly.
University of California, USCF Children’s Hospital guideline for neonatal coagulation disorders, 2004

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

16. 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
vW 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: E54

17. Products for Treatment of Coagulopathies
Factor content
Usual Dose
Indications
Fresh frozen plasma
All factors
10-20 mL/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
U/kg
Factor IX deficiency concentrate
Vitamin K
1-2 mg
Vitamin K deficiency
Platelet concentrate
Platelets
1-2 units/5 kg‡
Severe thrombocytopenia
Intravenous gamma globulin
IgG
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.

18. 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
Because about 30% of hemophilias can develop as spontaneous mutations, the lack of family history does not rule out this disorder
FVIII and FIX should be measured in any male infant with suspected hemophilia
BMJ 2012;344:e2707

19. 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 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

20. 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

21. 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

22. 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
As neonates may require higher doses to achieve desired factor levels and may demonstrate a shortened factor half life
Virally inactivated fresh frozen plasma 15-25mls/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.

23. 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:
Following traumatic delivery,
Instrumental delivery (particularly Vacuum or forceps extraction), or
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.

24. Rare Bleeding Disorders (RBD)
The RBDs are inherited quantitative or qualitative deficiencies of factors
Fibrinogen, FII, FV, FVII, FX, 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, a2-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.

25. 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

26. 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:
Antiseizure drugs that interfere with vitamin K metabolism, such as phenytoin, phenobarbital, caramezepine, or primidone
Blood thinning medications, such as warfarin (Coumadin) or aspirin
Antibiotics, such as cephalosporins
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:
Low levels of vitamin K in breast milk, biliary atresia (which causes slow bile flow), cystic fibrosis, celiac disease, chronic diarrhea, hepatitis, A1-antitrypsin deficiency, which may cause lung and liver disease
Blood Rev. 2009;23(2):49-59

27. 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

28. 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 (uUnlicensed-discuss with hematologist)
Paediatrics and child health. 2007;17(8): Pages 322–327

29. 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.
Recombinant or plasma-derived FVIII or FIX (hemophilia A or B),
Prothrombin complex concentrates,
FXIII concentrate (FXIII deficiency),
Recombinant activated factor VII (hemophilia patients with inhibitors, FVII deficiency, or Glanzmann thrombasthenia),
Cryoprecipitate (hemophilia A, von Willebrand disease, and fibrinogen disorders: in case specific concentrates are not available), platelet transfusions for platelet function disorders, and
Adjunctive anti-fibrinolytic therapy for infants with bleeding
Thrombosis Research 135, Suppl. 1 (2015) S41–S43

30. Thank you for your attention