ANEMIA AKIBAT PERDARAHAN

1. PENDAHULUAN
Bayi kurang bulan dan cukup bulan sering mengalami masalah hemostasis serta fungsi
dan produksi sel darah merah yang penting secara klinis. 1 Menurut Riset Kesehatan Dasar
(Riskesdas) 2007, penyebab utama kematian neonatal di Indonesia adalah karena asfiksia, berat
bayi lahir rendah (BBLR) dan sepsis.2 Berdasarkan hasil Survei Demografi dan Kesehatan
Indonesia (SDKI) tahun 2012, Angka Kematian Neonatus (AKN) pada tahun 2012 sebesar 19
kematian per 1.000 kelahiran hidup, sama dengan AKN berdasarkan SDKI tahun 2007.2
Pendekatan terhadap semua gangguan hematologi yang terjadi pada BBL risiko tinggi
meliputi usaha mendapatkan riwayat keluarga, riwayat obstetric dan perinatal, pemeriksaan fisik
bayi tersebut (dengan perhatian khusus pada penilaian kulit, membrane mukosa, tulang kerangka,
hepar dan lien) serta uji laboratorium selektif yang akan digunakan untuk mengetahui derajat
keparahan dan gangguan hematologi khusus serta megetahui kasusnya.1
The neonatal hemostatic system is continuously developing with rapidly changing
concentrations of many coagulation proteins. Thus, determining the etiology of bleeding in a
newborn has additional challenges beyond those seen in older children or adults. Bleeding can be
seen in both well and sick newborns due to congenital causes, such as hemophilia or von
Willebrand disease, and acquired causes, such as liver failure or disseminated intravascular
coagulation. Traditional coagulation testing should be interpreted with caution and with the help
of a hematologist, if possible, due to the greatly different normal ranges between neonates as
compared with older children and adults. However, despite these challenges, both clinical and
laboratory clues can guide physicians appropriately to diagnose and treat the bleeding newborn.3

2. EPIDEMIOLOGI
Angka kematian bayi (AKB) di Indonesia masih cukup tinggi dibandingkan dengan
negara ASEAN lainnya dimana pada tahun 2012 adalah 34 per 1000 kelahiran hidup.
Berdasarkan kesepakatan global (Millenium Develoment Goals/MDG’s 2000) pada tahun 2015,
diharapkan angka kematian bayi menjadi 23 per 1000 kelahiran hidup dan Renstra Kemenkes
sebesar 24 per 1000 kelahiran hidup, tetapi AKB di Indonesia tahun 2012 masih jauh dari target
Renstra dan target MDG’s. 4
Kematian perinatal yang tercatat dalam Profil Kesehatan Indonesia yang ditunjukkan dari
Angka Kematian Neonatal (AKN) sebesar 20 per 1000 kelahiran hidup pada tahun 2003
kemudian menurun lambat menjadi 19 per 1000 kelahiran hidup dan tetap stagnan pada tahun
2012 sebesar 19 per 1000 kelahiran hidup. Hasil Riskesdas 2013 menunjukkan 78,5% dari
kematian perinatal terjadi pada umur 0-6 hari. Penyebab kematian terbesar adalah gangguan
pernapasan/asfiksia (35,9%), prematuritas dan bayi berat lahir rendah (32,4%), sepsis (12%).4
Dengan mengetahui gangguan hemostasis pada BBL diharapkan mengetahui pendekatan
diagnosis dan tatalaksana gangguan hemostasis yang terjadi pada BBL. Meskipun gangguan
hematologi pada neonatal hanya 6%(SKRT, 2001), namun merupakan masalah kesehatan
masyarakat karena PPN (persarahn pada neonatal) lanjut dapat berakibat fatal (14%),
menyebabkan gejala/penyakit (40%) dan mengakibatkan kehilangan (disability-adjusted-life-
years) yang signifikan (46%).1

3. ETIOLOGI
Bleeding in healthy neonates is rare, but in sick neonates, it is often serious and can be fatal. The
clinical presentation of bleeding in neonates includes intracranial hemorrhage (ICH),
cephalohematoma, bleeding after a procedure or venepuncture, or mucocutaneous bleeding such
as bruising or gastrointestinal bleeding [1]. The etiology of such bleeding may arise from
congenital issues, such as hemophilia, or from acquired issues including liver failure.
Determining the cause of bleeding is a clinical challenge for both primary treating practitioners
as well as hematology consultants due to the continuously evolving coagulation system in
neonates.3

4. PATOFISIOLOGI
A recent study found that 25% of all neonates admitted to eight different NICUs experienced an
episode of bleeding during their hospitalization, with 11% of episodes categorized as
major/severe bleeds, 1% as moderate, and 13% as minor bleeds. Preterm neonates 28 weeks’
gestation, highlighting the increased bleeding risk associated with a lower gestational age at
birth. This high incidence of bleeding, particularly among pre-term neonates, is at least partially
related to factors specific to the neonatal population. These unique risk factors include the trans-
placental passage of some hemostatically active vitamins (i.e., vitamin K) or maternal anti-
platelet antibodies, and the developmental stage of blood vessels, the gastrointestinal tract, and
the hemostatic system at varying gestational ages. In addition to these developmental stage-
specific risk factors for bleeding, neonates are also at risk for more universal causes of bleeding
due to their high incidence of sepsis, DIC, and frequent need for mechanical ventilation and
critical care after birth. As such, the differential diagnosis for neonatal bleeding is broad and a
thorough understanding of developmental stage, risk factors and underlying pathophysiology is
critical to appropriately treat and try to prevent major bleeding in this vulnerable patient
population.5

a. Intraventricular Hemorrhage (IVH)

Intraventricular hemorrhage (IVH) is one of the most serious complications of prematurity owing
to the critical window for brain development that occurs during fetal and neonatal life. IVH puts
infants at risk for long term neurodevelopmental morbidity and mortality and, despite
improvements in IVH rates over recent decades, its incidence remains high, affecting 15–25% of
very- and extremely- premature infants (<32 and <28 weeks’ gestational age, respectively) in the
first week of life. Intraventricular hemorrhages often originate in a highly vascularized collection
of neuronal-glial precursor cells called the germinal matrix. This region is selectively vulnerable
to hemorrhage in premature infants due to its developmental paucity of pericytes, immature basal
lamina, and deficiency of glial fibrillary acidic protein, all of which result in vascular fragility.
When this fragile vasculature encounters disturbances in cerebral blood flow due to the impaired
cerebral autoregulation of premature infants, hemorrhage can result. If the hemorrhage in the
germinal matrix is substantial, the immature ependyma breaks and the cerebral ventricles fill
with blood, becoming visible on head ultrasound evaluation.5

b. Lower Gastrointestinal (GI) Hemorrhage

Bloody stools can be seen in well-appearing newborns due to common causes such as swallowed
maternal blood during delivery, the presence of an anal fissure, or allergic colitis. These cases are
not associated with disorders of hemostasis, and typically resolve with close monitoring and the
removal of cow’s milk protein from the diet (in the case of allergic colitis). In contrast, in
critically ill premature infants, frank rectal bleeding is most frequently seen in the setting of
necrotizing enterocolitis (NEC). Necrotizing enterocolitis is one of the most common and
devastating diseases in pre-term neonates with an estimated incidence of 7% among infants with
a birth weight between 500 and 1,500 g (8) and an estimated incidence of death of 20–30%, with
the highest mortality seen in those infants who require surgery. The typical presentation of NEC
is feeding intolerance, abdominal distension, and bloody stools in a pre-term infant after 8– 10
days of life, associated with bowel wall ischemia and bacterial overgrowth. These symptoms
progress rapidly over hours often leading to systemic hypotension and respiratory failure, and
can culminate with bowel perforation requiring surgery. Infants with severe disease also
frequently develop severe thrombocytopenia ± coagulopathy associated with disseminated
intravascular coagulation, further predisposing them to bleeding in the GI tract and other sites.5

c.Minor Bleeding Events

In addition to the serious etiologies of neonatal bleeding mentioned above, neonates frequently
experience minor bleeding events throughout their hospitalization. The presentations are
numerous but include cephalohematoma sustained at birth, blood tinged endotracheal tube
secretions in mechanically ventilated infants, and oozing from the umbilical stump or from sites
of blood draws. It is unclear whether minor bleeding events are harbingers of more serious
bleeding, but they often resolve with only close monitoring.5
DEK FAIRUZ, NANTI DIKASIH TULISAN GAMBAR 1. …… DALAM BAHASA
INDONESIA YA. GAMBAR DIPERTAHANKAN
Figure. 1. Fetal development of the coagulation system. FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX,
factor X; AT, antithrombin; HCII, heparin cofactor II. 3

The etiology of such bleeding may arise from congenital issues, such as hemophilia, or from
acquired issues including liver failure. Determining the cause of bleeding is a clinical challenge
for both primary treating practitioners as well as hematology consultants due to the continuously
evolving coagulation system in neonates. There are various causes of bleeding in neonates and
provides guidance on how to arrive at the appropriate diagnosis and suggest different treatment
options. 3

a. Congenital causes of bleeding

1) Hemophilia
Deficiencies of FVIII and FIX are known as hemophilia A and B, respectively, and are inherited
in an X-linked recessive pattern. Female relatives are known as hemophilia carriers. The
incidence of hemophilia is 1 per 5000 males (FVIII) and 1 in 20,000 males (FIX). Persons with
hemophilia are classified based on their plasma factor activity [severe (5 to 40%)]. Bleeding in
hemophilia (mostly the severe type) may present in neonates as either post-procedural bleeding
(e.g. circumcision or heel sticks) or even as ICH. Newborns with hemophilia are 44 times more
likely to have symptomatic ICH compared to normal newborns, and it is more likely to occur
after an assisted vaginal delivery. The mean age of patients with hemophilia having their first
bleed is 28.5 days. Although diagnosing hemophilia in neonates is usually straightforward, issues
of developmental hemostasis can make it more challenging than in older children. Up to 70% of
patients are diagnosed in the first month of life. Any newborn with unexpected or excessive
bleeding should have an aPTT, and, though many normal infants have a prolonged aPTT, this
should not preclude an evaluation of factor levels in the above situation. As the FVIII activity in
neonates approximates that of a normal adult, making the diagnosis of severe or moderate
hemophilia A is straightforward. The diagnosis of mild hemophilia can be more difficult due to
increased FVIII activity resulting from the stress of delivery, thus levels should be repeated at six
to 12 months of age if mild FVIII deficiency is suspected. When evaluating FIX levels, however,
as stated previously, FIX activity is about 50% of adult levels at birth, which overlaps with the
range of mild hemophilia, making the diagnosis of mild hemophilia B difficult, and, as above,
testing should be repeated at six to 12 months.3

2) Von Willebrand disease

Von Willebrand Disease (VWD) is the most frequently inherited bleeding disorder, affecting
~1% of the population, and is transmitted in autosomal dominant or recessive patterns. There are
three main categories of VWD based on the quantitative level or function of von Willebrand
factor (VWF): type 1, 2, or 3. Most patients with VWD have type I, which is due to a partial
quantitative deficiency of VWF and is usually associated with a mild phenotypic bleeding
presentation. Type 2 VWD is a qualitative dysfunction of VWF and is typically associated with a
more severe bleeding phenotype. Type 2 is further divided into four separate subtypes, 2A, 2B,
2M, and 2N, which are based on the functional and structural interactions between VWF and
platelets or FVIII. Type 3 is the rarest form of VWD in which patients have complete or almost
complete deficiency of VWF and have the most severe bleeding phenotype. Typically only
patients with type 3 or some type 2 VWD present with bleeding as neonates. Mucocutaneous
bleeding is the hallmark of VWD; patients can have epistaxis, bruising, gum bleeding, and
gastrointestinal bleeding, but also bleeding after trauma or surgery. The diagnosis of VWD is
based on three main laboratory assays: (i) a quantitative measure of VWF in the plasma, (ii) the
activity of VWF and its ability to bind platelets (iii) and FVIII activity. High molecular weight
multimer analysis can also be performed to help differentiate type 2 varieties. Table 1 shows the
laboratory values that are consistent with each type of VWD. At birth, neonates have normal to
increased levels of VWF activity and high-molecular weight VWF multimers compared to adult
levels, which is why most patients with type 1 and 2 VWD do not present with bleeding until
later in life. The management of bleeding in a neonate with VWD is typically with plasma-
derived FVIII (pdFVIII) products that contain VWF, and consultation with a pediatric
hematologist is suggested to assist in management.3

3) Rare inherited bleeding disorders

Patients with rare factor deficiencies represent 3e5% of all coagulation disorders, with an
incidence of 1:500,000 to 1:2,000,000 [22,23]. Deficiencies in fibrinogen, FII, FV, FVII, FX,
FXI, or FXIII may present in neonates, and each will be discussed briefly below.3
4) Disorders of fibrinogen
Fibrinogen is converted to fibrin and, along with platelets, forms the structure of blood clots.
Patients with disorders of fibrinogen may have either decreased or complete absence of
fibrinogen levels (hypofibrinogenemia, afibrinogenemia), or dysfunctional fibrinogen
(dysfibrinogenemia). Afibrinogenemia is inherited in an autosomal recessive pattern, whereas the
heterozygous form is hypofibrinogenemia. Neonates may present with prolonged bleeding from
the umbilical cord stump, post circumcision, ICH, or mucocutaneous bleeding. Patients with
disorders of fibrinogen will have a prolonged PT and aPTT. Decreased functional or antigenic
fibrinogen assays are the confirmatory tests. Normal term neonates have fibrinogen levels equal
to adult normal values at birth. Fibrinogen concentrates are the ideal treatment for bleeding
episodes. Fresh frozen plasma (FFP) or cryoprecipitate may also be used for bleeding when
fibrinogen concentrates are unavailable.3
5) Prothrombin (FII), FV, FVII, FX, and FXI deficiency
Patients with FII, FV, FVII, FX, and FXI deficiency are inherited in an autosomal recessive
pattern, and there is a higher incidence of FXI deficiency in those of Ashkenazi Jewish descent
[25]. Most factor deficiencies in neonates can lead to mucocutaneous bleeding, ICH, prolonged
umbilical stump bleeding, or bleeding after procedures or trauma. FVII and FXI levels do not
correlate well with bleeding phenotype; some patients with very low factor levels do not have
any bleeding, and those with higher factor levels may have profuse bleeding.3

6) FXIII deficiency
 FXIII, composed of two A and two B subunits, cross-links fibrin and stabilizes clots. FXIII
deficiency is inherited in an autosomal recessive pattern and clinical manifestations may occur in
neonates, most commonly with umbilical cord stump bleeding (50e70% of cases), ICH, and
prolonged bleeding after procedures or trauma. Low levels of FXIII do not prolong the PT or
aPTT. Thus if both the PT and aPTT are within the normal range for age, and a bleeding disorder
is suspected, then a quantitative FXIII assay should be performed. The clot solubility assay
previously used to diagnose FXIII deficiency lacks sensitivity for very low levels of FXIII.
Plasmaderived and recombinant FXIII products are available, although the recombinant form can
only be used for A-subunit deletions. Cryoprecipitate should be used if FXIII concentrate is
unavailable.3

b. Acquired causes of bleeding

1) Liver failure
The liver is responsible for the synthesis of most pro- and anticoagulant proteins (except FVIII
and VWF) and thrombopoetin, which stimulates platelet production. A disruption in liver
function may have a significant impact on the coagulation system, exacerbating the effects in
neonates whose systems are already delicately balanced. Patients with liver failure may present
with both bleeding and thrombosis, and the etiology, diagnosis, and treatment are all challenging.
Neonates with liver disease may present with any manner of bleeding. Coagulation laboratory
abnormalities seen in liver failure are elevated PT, aPTT and D-dimer, decreased fibrinogen
activity, and decreased platelet count. 3

2) Vitamin K deficiency bleeding

Vitamin K is a crucial cofactor in the production of procoagulant proteins factors II, VII, IX and
X, and of natural coagulation inhibitors, proteins C and S. Vitamin K is essential for the
gcarboxylation of these clotting factors which is required for their functionality. Vitamin K
deficiency bleeding (VKDB) is classified as early, classical, or late (see Table 1). Early onset
VKDB is due to cross-placental transfer of compounds that interfere with vitamin K metabolism.
Classical VKDB is due to a physiologic deficiency in vitamin K at birth combined with either a
lack of vitamin K in breast milk or inadequate feeding. Late onset VKDB is again due to
inadequate vitamin K content in breast milk and is thus found almost universally in exclusively
breastfed infants. Prior to the widespread use of vitamin K prophylaxis, the incidence of classical
VKDB was reported to be as high as 1.5%; however, the condition is only rarely seen today, and
is almost always associated with situations where vitamin K was not administered in the
immediate newborn period. 3
The clinical features of VKDB are similar to other bleeding diatheses and include
bruising, mucus membrane bleeding, bleeding after trauma or invasive procedures, ICH, or signs
of internal bleeding such as hematuria. 3
The diagnostic evaluation for VKDB is straightforward as the PT is always prolonged
and the aPTT is nearly always prolonged. In the typical scenario, the PT is prolonged out of
proportion to the aPTT. In a newborn with the above clinical and laboratory findings, eliciting a
history in which vitamin K was not administered is sufficient to make a presumptive diagnosis,
and the administration of parenteral vitamin K should be undertaken immediately. Improvement,
if not complete correction, of the PT and aPTT several hours after the administration of
parenteral vitamin K serves as confirmation of the diagnosis. Whereas measuring factor levels
(specifically FII, FVII, FIX, and FX) may assist in the diagnosis, they are not necessary and
delays in instituting appropriate therapy could lead to severe, even catastrophic, bleeding
complications. 3

DEK FAIRUZ JANGAN LUPA TABELNYA DITRANSLATE KE INDONESIA DULU YA

3) Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is a disorder characterized by consumption of
procoagulant, anticoagulant, fibrinolytic proteins, and platelets. Patients may develop
hemorrhagic and/or thrombotic complications. In some patients significant hemorrhage and
thrombosis may occur simultaneously. DIC is always caused by an underlying medical disorder.
In neonates, the most frequent etiology is sepsis. 3
The pathophysiology of DIC is complex and not completely understood. Briefly, an
inciting event triggers the release of proinflammatory cytokines, especially interleukin-6 (IL-6)
and tumor necrosis factor-a (TNF-a). IL-6 leads to tissue factor-mediated activation of the
coagulation system that in turn leads to enhanced fibrin formation, mostly in the
microvasculature. TNF-a leads to inhibition of both the natural anticoagulants (antithrombin,
proteins C and S) and fibrinolysis by increasing levels of plasminogen activator inhibitor-1. The
sum of these effects is microvascular thrombosis, which often leads to organ dysfunction and
consumption of procoagulant proteins and platelets, which may lead to hemorrhage. 3
Bleeding may occur at any site but frequently involves the skin (at vascular access sites)
and mucus membranes. Severe internal hemorrhage is less frequent, but ICH may occur and be
catastrophic. 3
When a patient at risk for DIC presents with hemorrhage, specific laboratory
abnormalities can only provide supportive evidence, not confirm the diagnosis of DIC. Routine
laboratory assays such as the CBC, PT, aPTT, and fibrinogen are often abnormal as a result of
fibrin formation and degradation as well as consumption of coagulation proteins.
Thrombocytopenia is often present, and e depending on the etiology e leukocytosis, leukopenia,
and anemia. When DIC is suspected, measurement of fibrin degradation products (FDP) or D-
dimers is helpful. The combination of thrombocytopenia, hypofibrinogenemia, prolonged PT and
aPTT and elevated FDP or D-dimer is strongly suggestive for the presence of DIC. A scoring
system has been developed by the ISTH which incorporates the results of the above assays. 3
The management of DIC most importantly requires treatment of the underlying condition
causing the DIC. Correcting the coagulopathy will be impossible if the underlying disorder
cannot be controlled. Since DIC is a derangement of all aspects of the coagulation system, both
FFP (coagulant protein replacement) and cryoprecipitate (fibrinogen replacement) are usually
first-line therapy. Importantly, FFP should be given to manage bleeding complications, not to
improve laboratory values. In one study in neonates with DIC, FFP did not have an impact on
survival or resolution of DIC. For severe bleeding in patients with DIC, PCCs and rFVIIa can be
used, but with caution due to the risk of thrombotic complications. 3

4) Therapeutic hypothermia
Recently, therapeutic hypothermia has been used as a treatment for severe asphyxia to prevent
the neurologic sequelae of hypoxiceischemic events (such as neonatal ICH) and to improve
outcomes. However, hypothermia may further increase the risk of ICH by causing changes in
cerebral blood flow, increased fragility of injured tissues, hypotension, changes in the function of
the coagulation system, thrombocytopenia, and metabolic derangements. Current evidence
suggests that coagulopathy, thrombocytopenia and bleeding may not be significantly increased
with hypothermia. Close attention should be paid to platelet count, coagulation measures (PT,
aPTT, fibrinogen), and clinical signs of bleeding when neonates undergo hypothermic cooling
protocols. If derangements in the coagulation measures are found and bleeding is present, they
should be replaced with FFP or cryoprecipitate as indicated. 3
5) Extracorporeal life support
Neonates requiring extracorporeal life support (including cardiopulmonary bypass surgery or
extracorporeal membrane oxygenation) are at risk for significant bleeding. These patients often
undergo large, complicated surgical procedures that stress the coagulation system. A discussion
of all the issues related to bleeding related to extracorporeal life support is beyond the scope of
this review, but in summary, treatment is based on supportive care with FFP, cryoprecipitate,
platelet transfusions, and monitoring. 3
Figure. 2. Algorithm for the approach to a bleeding neonate. aPTT, activated partial thromboplastin time; CBC,
complete blood count; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; FII, factor
II; FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor IX; FXI, factor XI; FXII, factor XII;
FXIII, factor XIII; pdFVIII, plasma-derived factor VIII; pdFXIII, plasma-derived factor XIII; PT,
prothrombin time; rVIIa, activated recombinant factor VII; rXIII, recombinant factor XIII; VWD, von
Willebrand disease. 3

REFERENSI
1. Etika R. Gangguan Hemostasis pada Bayi Baru Lahir. In: M. Sholeh Kosim, Ari Yunanto,
Rizalya Dewi, Gatot Irawan Santosa AU, editor. Buku Ajar Neonatologi. Jakarta: Ikatan
Dokter Anak Indonesia; 2008. p. 188–98.
2. Tapin DIK. Faktor-Faktor yang Berhubungan dengan Kematian Neonatal di Kabupaten
Tapin. J Publ Kesehat Masy Indones. 2015;2(2):64–71.
3. Jaffray J, Young G, Ko RH. The bleeding newborn: A review of presentation, diagnosis,
and management. Semin Fetal Neonatal Med [Internet]. 2015;1–6. Available from:
http://dx.doi.org/10.1016/j.siny.2015.12.002
4. Meisuri NP, Irianto MG, Ungu B, Kedokteran F, Lampung U, Ilmu B, et al. Faktor
Determinan yang Mempengaruhi Kejadian Kematian Perinatal. J Major. 2018;7:121–7.
5. Davenport P, Sola-visner M, Sola-visner M. Hemostatic Challenges in Neonates. Front
Pediatr. 2021;9(March):1–11.