BLEEDING DISORDERS  Coagulation Cascade

HEMOSTASIS
 A complex process which is well regulated that maintains blood in a fluid, clot-free
state in normal blood vessels
 An active process that clots blood in areas of blood vessel injury and limits the clot
size only to the areas of injury
 Clot is lysed by the fibrinolytic system to restore normal blood flow
 Main components:
o Blood vessels
o Platelets
o Coagulation proteins
o Anticoagulant problems
o Fibrinolytic system
 Three mechanisms:
o Vascular spasm – damaged blood vessels constrict
o Platelet plug formation – platelets adhere to damaged endothelium to form
platelet plug (primary hemostasis) and then degranulate
o Blood coagulation – clots form upon the conversion of fibrinogen to fibrin, and
its addition to the platelet plug (secondary hemostasis)
Following and injury to blood vessels…

 Fibrinolysis

Local Vasoconstriction

(a) The coagulation cascade, which favors clot formation, is initiated in vivo by tissue factor and
factor VIIa (FVIIa) and leads to the conversion of prothrombin to thrombin by the prothrombinase
complex (FXa and FVa). Subsequent cleavage of fibrinogen by thrombin, along with the
aggregation of platelets, can result in formation of a thrombus. The fibrin clot is further stabilized
by FXIII, which is also activated by thrombin, and the clotting process is magnified by other
positive-feedback loops (not shown). (b) Plasmin-mediated fibrinolysis, resulting in fibrin
degradation products and clot lysis, occurs following the conversion of plasminogen to plasmin by
tissue-type plasminogen activator (tPA). Plasminogen activator inhibitor 1 (PAI-1) rapidly inhibits
tPA. a-2-Antiplasmin (a-2-AP) inactivates plasmin by forming a 1:1 inhibitory complex with
circulating plasmin. Thrombin-activatable fibrinolysis inhibitor (TAFI) cleaves the C-terminal lysine
residues of fibrin, preventing the co-activation of plasminogen by fibrin

Primary Hemostasis (Platelet plug formation)  Natural anticoagulants

o Antithrombin III (AT-III)
- Inhibits factor Xa and thrombin
- Inhibits IXa, XIa, XIIa
o Protein C and S
- Activated by thrombin-thrombomodulin complex
- Degrade factor Va and VIIIa
o Tissue Factor pathway Inhibitor (TFPI) – inactivates Xa by VIIa and Tissue factor
 The Hemostatic Balance: Hemorrhage = Thrombosis
 Abnormalities of Hemostasis

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Practical Approach:  LABORATORY EVALUATION
 Evaluation of a child with bleeding o Screening Tests:
1. Comprehensive medical history, including bleeding history  CBC
2. Family History  Peripheral Blood Smear
3. Detailed Physical Examination  Bleeding Time
4. Selected Laboratory Tests  Prothrombin Time
 Bleeding History must consider:  Activated Partial Thromboplastin Time
o Age PT aPTT Platelet Count Defect:
o Sex
o Clinical Presentation vWD, F VIII, IX, XI deficiency, acquired
Normal Prolonged Normal
o Past History autoantibody anti-against F VIII
o Family history Severe vitamin K deficiency, Liver
Prolonged Prolonged Normal
 MEDICAL HISTORY disease, Excessive coagulation
o Type of Bleeding Prolonged Normal Normal Excessive coumarin, Congenital FVII
- Epistaxis? deficiency
- Gum bleeding? Normal Normal Normal vWD, Platelet Function defect
- Menorrhagia? – Excessive uterine bleeding occurring at the expected intervals of the
Platelet Disorder, Von Willebrand,
menstrual periods. Petechiae, Ecchymosis +/- mucous
Disease, Hereditary Telangiectasia,
- Bruising? membrane bleeding
Pinpoint flat round red spots under the skin surface caused by intradermal
Dysfibrinogenemia
hemorrhage (bleeding into the skin) THROMBOCYTOPENIA (Other screening tests normal)
Petechiae
Contain red blood that has leaked from the capillaries into the skin Large Platelets Normal Size Platelets
Tiny (< 3 millimeters in diameter) and do not blanch when pressed upon
ITP
Hemorrhage (bleeding) into the surface of the skin.
HUS Acute leukemia
> 3 millimeters in diameter.
Purpura The appearance of an individual area of purpura varies with the duration of TTP Aplastic Anemia
the lesions. Early purpura is red and becomes darker, then purple, and brown- NAITP
yellow as it fades.
Nonraised skin discoloration caused by the escape of blood into the tissues Manifestation Defect
Ecchymosis from ruptured blood vessels.
Vasculitic Henoch Schonlein Purpura
Can occur in mucous membranes (for example, in the mouth)
A localized swelling that is filled with blood caused by a break in the wall of a Hematoma Coagulopathy, Hemophilia A or B
Hematoma blood vessel. Confluent purpura, Ischemic Disseminated Intravascular
Palpable necrosis Coagulopathy
Clotting factor
Clinical Characteristics Platelet Disorders
deficiency VON WILLEBRAND DISEASE
Site of bleeding Skin, mucous  Most common inherited bleeding disorder with qualitative &/or quantitative defects
Deep in soft tissues of multimeric, glycoprotein, Von Willebrand Factor
membranes (gingivae,
nares, GI and GUT)
(joints, muscles)  Autosomal inheritance
o Autosomal dominant (Types 1, 2)
Bleeding after minor cuts YES Not usually
o Autosomal recessive (Type 3)
Petechiae Present Absent
Ecchymosis Small, Superficial Large, Palpable  Males = Females
 Von Willebrand Factor (vWF):
Hemarthrosis, muscle
Rare Common o Adherence of platelets to damage endothelium
hematomas
o Carrier protein for plasma Factor VIII
Bleeding after surgery Intermediate, mild Delayed, Severe
o Stored in the endothelial cells and in platelet Weibel-Palade bodies
o Response to hemostatic challenge
 Types:
 Surgery: Circumcision, tonsillectomy, Tooth extraction
Type 1 vWD Type 2 vWD Type 3 vWD
 Phlebotomy
 Immunization/ Intramuscular injection Most common variant Most severe type,
 Childbirth (60-80%) Quantitative defects
*Absence of bleeding during surgery affecting the mucosal surfaces rules out a vWF structurally Qualitative defects of vWF completely absent
congenital bleeding disorder. normal, reduced in vWF Plasma vWF and FVIII
o Underlying Medical conditions with known associations with hemostatatic concentration levels <10 units/dl
defects (<30IU/dl)
 Liver disease Mild to moderate Subtypes: 2A, 2B, 2N, ICH, Major epistaxis,
 Renal Failure quantitative defects 2M, Platelet-type Joint bleed and
 Connective Tissue Disorder Pseudo menorrhagia
 Malabsorption Syndrome Autosomal dominant Autosomal dominant Autosomal recessive
 Vitamin K deficiency Treatment:
 Malignancies – Leukemia DDAVP vWF replacement vWF replacement
o Medications that can affect: (Desmopressin) therapy therapy
PLATELET FUNCTION PLATELET COUNT CLOTTING FACTORS platelet Type (Psuedo)
Aspirin Quinidine Anticoagulants: vWD = Platelet
NSAIDs – Naproxen, Ibuprofen, Penicillin Warfarin, transfusion
Phenylbutazone, Piroxicam Anticonvulsants Heparin, LMW  Signs & Symptoms:
Ticlopidine Quinine heparin o Epistaxis
Antibiotics: Sulfonamides Antimetabolites: L- o Ecchymosis
PCN – Carbenicillin, Pen G, Digoxin asparginase o Menorrhagia
Ampicillin, Ticarcillin, Nafcillin, Heparin o Post-traumatic. Post-surgical Bleed
Azlocillin Mezlocillin o Post dental extraction
Cephalosphorin – Moxalactam, o CNS bleed
Cefotaxime  Laboratory Evaluation
Nitrofurantoin o Screening Tests:
Volume expanders: Dextran,  BT prolonged
Hodroethyl starch  aPTT prolonged
Heparin  PT normal
Fibrinolytic agents  Platelet count normal
o Cannot be ruled out on the basis of a normal BT and aPTT
o No reliable screening tests
o Suboptimal sensitivity and specificity

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 Accurate diagnosis requires the following measurements:  Clinical Features:
1. VWF: Ag o Hemarthroses – Hallmark of hemophilia
2. VWF: Rco o Easy bruising
3. VWF: Rco / VWF: Ag o Intramuscular hematomas
4. F VIII:C o Bleeding from minor traumatic lacerations
5. VWF: multimer analysis o Life-threatening bleeding from vital structures (CNS, Upper airways, GI, or
Iliopsoas hemorrhage)
HEMOPHILIA  Laboratory Tests:
 Inherited, X-linked recessive, lifelong disorder o aPTT – always prolonged (2-3x) in severe hemophilia
 Affects males almost exclusively - slightly prolonged or may be normal in mild/moderate hemophilia
 Hemophilia A – Factor VII deficiency o Confirmatory: Factor VIII, IX assay
- Classic Hemophilia - FVIII/FIX levels – below the normal range
- More common Severity based on patient’s circulating FVIII/FIX
 Hemophilia B – Factor IX deficiency Spontaneous bleeding
- Christmas Disease Recurrent hemarrthrosis
 Most serious congenital coagulation factor deficiency SEVERE <1%
Serious hemorrhages into vital organs
 X-linked recessive Replacement needed several times per month
 ↓ blood levels of procoagulant FVIII or FIX Less frequent bleeding
 1:5,000-6,000 live male births MODERATE 1-5% Trauma, surgery or dental work
 Hemophilia A = 85%; Hemophilia B = 10-15% Occasional hematomas or hemarrthrosis
 No apparent racial predilection Infrequent bleeding
6 to <50%
 High rate of spontaneous mutation (~30%) MILD Disease undiagnosed for years
6-25%
Inheritance Pattern: Bleeds after severe trauma or surgery
 X-linked recessive, expressed primarily in males with defective gene  Lower Limit of FVIII & FIX in normal individual ~50%
 Symptomatic Carriers:  Hemostatic level for FVIII >30-40%; FIX >25-30%
o Factor level: 30-50%  Differences: Von Willebrand Disease and Hemophilia
o Daughter of a maternal carrier and a hemophilic father Characteristics Von Willebrand Disease Hemophilia
Symptoms Bruising Joint bleeding
Mucosal Bleeding Muscle bleeding
(epistaxis, menorrhagia)
Sexual Distribution Males = Females Males
Frequency 1:200 to 1:500 1:6000 males
AbN protein vWF Factor VIII
Inhibitor freq Rare 14-25% of patients
Bleeding time Often abnormal Usually normal
PTT Normal or ↑ Prolonged
Factor VIII Borderline or ↓ ↓ or Absent
vWF Ag ↓ or Absent Normal or ↑
vWF R:Co ↓ or Abnormal Normal or ↑
vWF multimers Normal or Abnormal Normal
 Treatment
1. Factor replacement therapy – mainstay of TX
- Degree of correction depends on the site & nature of bleeding episode
o Factor VIII or IX concentrates
o Cryoprecipitate – rich in factor VIII, vWF, fibrinogen and FXIII
Hemophilia Inheritance – Father with Hemophilia and Mother Who is Not a Carrier o FFP – contains all clotting factors
2. Ancillary TX
o DDAVP (Stimate) – ↑ FVIII levels 2.5 – 6 fold by releasing endogenously
produced FVIII in mild hemophiliac
o Antifibrinolytic agent – prevents activation of plasminogen to plasmin
 Ex: Epsiolon aminocaproic acid, Trenexamic acid
 Inhibitor Formation to Hemophilia – Inhibitor alloantibodies, IgG, against factor VIII
or IX that blocks the clotting activity
o 25-35% in Hemophilia A (Hemophilia A>B)
o Severe cases treated; Less common in mild and moderate cases
o Appearance unpredictable
o Clinical Features:
 Failure of standard replacement therapy to stop muscle bleed &
hemarthroses
 First sign of an inhibitor
Hemophilia Inheritance – Carrier Mother and Father without Hemophilia  Decline in half of transfused factor concentrate
 Treatment Guidelines in Hemophilia
o Factor VIII – Half life: 8-12 hours
 Minor Bleed: 15-25 IU/kg
 Major Bleed: 40 – 100 IU/kg
 Expected response: 1IU/kg = 2% rise
 Dose of Factor VIII = % desired (rise in FVIII) x body wt (kg) x 0.5
o Factor IX – Half life: 12-24 hours
 Minor Bleed: 15-22 IU/kg
 Major Bleed: 40 – 100 IU/kg
 Expected response: 1IU/kg = 1.0-1.5% rise
 Dose of Factor VIII = % desired (rise in FIX) x body wt (kg) x 1.4
o Childhood immunization:
 Avoid IM injections unless administered under factor cover
 Venipuncture of superficial veins – safe press on area >5 minutes
 Apply ice
 Femoral or jugular venipunctures should not be attempted

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 Treatment for Inhibitors in Hemophilia  LABS: marked prolongation of PT and PTT, prolonged thrombin time,
o Desensitization Program – to saturate the antibody and permit the body to unmeasurable fibrinogen level (diagnostic). In addition to the quantitative
develop tolerance deficiency
- High dose factor VIII or IX concentrate, continuous infusion  Dysfibrinogenemia – dysfunctional fibrinogens; Rarely present with thrombosis
o Alternative Approaches:  TX: Human fibrinogen concentrate, FFP or cryoprecipitate
a. Activated Prothrombin Complex Concentrate o Fibrinogen t1/2 = 2-4 days
- Activated PCC: Feiba, Atuplex o Hemostatic level of fibrinogen is >60 mg/Dl
- Activation of Factor X o 1 cryoprecipitate = 100-150 mg of fibrinogen
- Dose: 75 IU/kg q12hrs  Inhibited by high doses of heparin  reptilase time = Prolonged = confirms that
b. Recombinant Factor VIIa functional levels of fibrinogen are low and that heparin is not present.
- Activates Factor X that bypasses Factor VIII
- Dependent steps
PROTHROMBIN (FACTOR II) DEFICIENCY
- Dose: 90 IU/kg q2hrs  CAUSE:
c. Immunosuppression o ↓↓Prothrombin level (hypoprothrombinemia) OR
- Cyclophosphamide, Azathioprine o Functionally abnormal prothrombin (dysprothrombinemia)
- IVIG, Cyclosphorin A  LABS: Prolonged PT and PTT. Factor II / prothrombin assays: markedly reduced
d. Plasmapheresis  CMX: Mucocutaneous bleeding in infancy and posttraumatic bleeding later
 Comprehensive Care for Hemophilia  TX: FFP / Prothrombin complex concentrates
o State-of-the-Art approach to Hemophilia RX: o Prothrombin t1/2 = 3.5 days
- Coordinated care plan for the patient o 1 IU/kg of prothrombin will increase the plasma activity by 1%
- Family education/prevention/treatment COMBINE DEFICIENCIES OF FACTOR V AND VIII
o Patient is evaluated by a multidisciplinary team:  Occurs secondary to the absence of an intracellular transport protein
- Hematologist, Orthopedist, Nurse, Dietician, Infectious disease specialist,  Paradoxical deficiency of 2 factors in chromosome 1 & X chromosome.
Social worker, Physical therapist, Dentist, Occupational Therapist,  Milder Bleeding symptoms
Psychologist and Genetic counselor
 TX: FFP – replace both factors V and VIII.
FACTOR XI DEFICIENCY (HEMOPHILIA C) FACTOR XIII DEFICIENCY – FIBRIN STABILIZING FACTOR
 Autosomal, Mild to Moderate bleeding  Responsible for the crosslinking of fibrin to stabilize the fibrin clot
 Bleeding not correlated with amount of Factor XI  CMX: Trauma 1 day and then have a bruise or hematoma the next day.
 Bleeding: major surgery o Mild bruising
 Chronic joint bleed – rare o Delayed separation of the umbilical stump beyond 4 wk in neonates
 PTT prolonged o Poor wound healing
 Factor XI assay o Recurrent spontaneous abortions in women
 Dental extraction: antifibrinolytic (aminocaproic acid)  LABS: normal screening tests, clot dissolves in the presence of 5M urea
 FFP – used for replacement therapy  TX: Heat-treated, lyophilized concentrate of coagulation factor XIII – treat
bleeding episodes or for prophylaxis.
OTHER COAGULATION FACTOR DEFICIENCIES o Factor XIII t1/2 = 5-7 days
FACTOR VII DEFICIENCY o hemostatic level = 2-3% activity
 Rare autosomal bleeding disorder
 Usually detected only in the homozygous state. DEFICIENCIES OF CONTACT FACTORS (NONBLEEDING DISORDERS)
 CMX: Mild to severe with hemarthroses, spontaneous intracranial hemorrhage,  Factor XII, Prekalikrein, HMWK (High Molecular Wt Kininogen)
and mucocutaneous bleeding, especially nosebleeds and menorrhagia  PTT – prolonged, no bleeding
 LBAS: Markedly prolonged PT but normal PTT, ↓↓↓Factor VII assays  No need for Treatment – even with major surgery
 TX: Recombinant factor VIIa
o Factor VII plasma t1/2 = 2-4 hr HEMORRHAGIC DISEASE OF THE NEWBORN
CLASSIC HDN
FACTOR V DEFICIENCY (PARAHEMOPHILIA)
 Accentuate and prolongation of deficiency of Vit. K dependent factors: II, VII, IX,
 Autosomal recessive, mild to moderate bleeding disorder
and X
 CMX:
 Onset: 2-7 days
o Hemarthroses – rare
 Bleeding: GIT, ENT-mucosal, ICH, Post circumcision
o Mucocutaneous bleeding and hematomas – most common symptoms.
 Risk Factors: Vit K deficiency, Breastfeeding
o Severe menorrhagia in women
 HDN more common among breastfed babies since human milk has less Vit K –
 LABS: Prolonged PTT and PT, Factor V assays: ↓
ranges from 1-4cg/L. (1.5ug/L) that cow’s milk (6-12ug/L)
 TX: FFP is the only currently available therapeutic product that contains factor V.
LATE ONSET VITAMIN K DEFICIENCY BLEEDING IN THE NEWBORN
o Factor V is lost rapidly from stored FFP
 This usually occurs between age 2-12 weeks; however late-onset vitamin K
o Infusion rate: 10 mL/kg every 12 hr
deficiency can be seen as long as 6 months after birth
 Acquired antibody to factor V – negative family history of bleeding; does not
 This disease is most common in breastfed infants who did not receive vitamin K
bleed because the factor V in platelets prevents excessive bleeding.
prophylaxis at birth
FACTOR X DEFICIENCY  Lab: ↑PT, ↑PTT in severe cases
 Rare: 1/1,000,000 autosomal disorder with variable severity  Prevention: Vitamin K administration (IM, PO)
o Mild deficiency = Mucocutaneous and posttraumatic bleeding  TX: Vit K, FFP
o Severe deficiency = Spontaneous hemarthroses and intracranial hemorrhages. POST NEONATAL VITAMIN K DEFICENCY
 Quantitative deficiency or a dysfunctional molecule.  Vitamin K Deficiency Bleeding:
 LABS: Prolongation of both PT and PTT o Vit K dependent clotting factors II, VII, IX, X
 TX: FFP or prothrombin complex concentrate o Lack of oral intake of vitamin K
o Factor X plasma t1/2 = 30 hr o Long term use of Broad-spectrum antibiotics – alter GUT flora
o 1 unit/kg will increase the plasma level of factor X by 1% o Liver Disease
 Systemic amyloidosis – may be associated with factor X deficiency, owing to the o Malabsorption of Vitamin K: Biliary atresia, Cystic Fibrosis
adsorption of factor X on the amyloid protein. Transfusion therapy often is not  Prophylaxis:
successful because of the rapid clearance of factor X. o Oral Vitamin K
- Children: 2-3 mg/24hr
FIBRINOGEN DEFICIENCY (FACTOR I)
- Adolescents/Adults: 5-10 mg/24hr
 Congenital afibrinogenemia
o Parenteral Vitamin K: 1-2mg, IV
 Rare AR disorder inwhich there is an absence of fibrinogen
 CMX:
o Do not bleed as frequently, rarely have hemarthroses.
o Neonatal period: GI hemorrhage or hematomas after vaginal delivery

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HENOCH-SCHONLEIN PURPURA THROMBOPHILIA OR HYPERCOAGULABILITY
 Also known as anaphylactoid purpura  Abnormality in the system of coagulation
 Common vasculitis of small vessels with cutaneous and systemic complications  Genetic vs. Acquired Defects
 Most common cause of nonthrombocytopenic purpura in children  Inherited: Unprovoked thrombolytic events in children
 Etiology: Unknown  Family History of Thrombosis
 Clinical Features:  Prothrombotic risk factors:
1. Palpable cutaneous purpura – dependent areas of the body or in areas of o Lower extremity casting/ prolonged immobility
greater tissue distensibility o Sedentary lifestyle
2. Arthritis – in 2/3 of patients; localized to the knees and ankles concomitant o Dehydration, Obesity, Smoking
with edema o Estrogen based contraceptives
3. Visceral involvement  Inherited Thrombotic Disorders:
a. GIT – colicky abdominal pain; >1/2 occult heme (+) stools a. Deficiency or Qualitative Abnormalities of Inhibitors of activated coagulation
b. Kidneys – 25-30% with nephritis or nephrosis factors
b. Impaired Clot lysis
c. Metabolic Defect
d. Abnormality of coagulation zymogen or cofactor
 Common Inherited Thrombophilias:
o Factor V Leiden mutation
o Prothrombin 20210 mutation
o Antithrombin Deficiency
o Protein S deficiency
o Hyperhomocystinemia
o Elevated Factor VIII

INHERITED THROMBOTIC DISORDERS

FACTOR V LEIDEN MUTATION
 Most common inherited risk factor for thrombosis
 Factor Va becomes resistant to inactivation by activated protein C, also known as
“Activated Protein C Resistance”
 Heterozygous state: 5-7 fold increase for venous thrombosis
 Homozygous state: relative risk of 80-100 fold
PROTHROMBIN GENE MUTATION G20210A
 Increased levels of prothrombin messenger RNA
 Relative risk 2-3 fold
PROTEIN C, S AND ANTITHROMBIN III DEFICIENCY
 Deficiency of naturally occurring anticoagulants
 Rare but stronger risk for thrombosis
 Heterozygous state: Do not often present during childhood
 Homozygous state: Present as pupura fulminans
NEONATAL PURPURA FULMINANS
 Due to homozygous state deficiency of AT, Protein C,S
 Life threatening clinical entity
o Rapidly spreading purpuric skin lesions
o Necrotic purpura of the skin
o Thrombosis of major vessels
o Cerebral thrombosis, Opthalmic thrombosis
 Definitive DX of Vasculitis: Biopsy of cutaneous site showing leukocytoclastic angitis o DIC
–when presentation is typical  Treatment: FFP, Protein C and AT concentrates
 Treatment:
o Symptomatic
HOMOCYSTINURIA
o Steroids for intestinal symptoms  An inborn error of metabolism
o Hydrostatic reduction or resection of intussusceptions when necessary  Deficiency of cystathione -synthase, resulting to an increase in homocysteine
>100umol/L
DISSEMINATED INTRAVASCULAR COAGULOPATHY  Associated with venous and arterial thrombosis
 Consumption of coagulation factors, platelets and anticoagulant proteins ELEVATED FVIII (>150 IU/dl)
Widespread intravascular deposition of fibrin Ischemia, Necrosis, a generalized  Regulated by genetic and environmental factors
hemorrhagic state and Microangipathic Hemolytic Anemia  Increased risk for thrombosis
 Life threatening pathologic process: Hypoxia, Acidosis, Tissue necrosis, Shock and  Acute phase reactant – increase transiently during inflammation
Endothelial damage mat trigger DIC
 Secondary event associated with septic shock, incompatible blood transfusion, Giant THROMBOTIC DISORDERS IN CHILDREN
Hemangioma, Malignancy (APL), Purpura fulminans, Snakebite, Ricketsial Infection VENOUS THROMBOEMBOLISM (VTE)
 Clinical Manifestations:  Central Venous Catheter (CVC) – single most important risk factor
o Bleeding frequently occur in sites of venipunctures/ Surgical incision  90% neonatal VTE; 60% childhood VTE
o Petechiae and Ecchymosis  Damage endothelial lining, Blood flow disruption
o Tissue necrosis/infarction of skin, Subcutaneous tissues, or Kidney
 Acquired Risk Factors: Trauma, Infection, Vasculitis, Medications
 Lab Findings:  Hypercoagulable states:
o Consumption of Factors II, V, VIII, Fibrinogen, Platelets
o Prematurity
o Prolongation of PT, aPTT, Thrombin Time
o Congenital heart diseases
o Thrombocytopenia
o Pregnancy, Malignancy
o PBS: RBCs are fragmented, helmet-shaped, burr cells (Schistocytes)
o Nephrotic Syndrome
o FDPs, D-dimers – more specific for activation of coagulation and fibrinolysis
o Antiphospholipid Syndrome
 Treatment:
o Treat the underlying cause (trigger)
o Restore normal hemostasis by correcting shock, acidosis, hypoxia
o Blood components for replacement: Platelets, FFP, cryoprecipitate

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CLINICAL MANIFESTATIONS (THROMBOSIS) PLATELETS
 Extremity Deep Vein Thrombosis  Non-nucleated cellular fragments produced by megakaryocytes
- Pain, swelling, discoloration  Thrombopoietin (TPO) – growth factor for platelet production
- History of current or recent CVC in that extremity  Life span of platelets: 10-14 days
 Pulmonary Embolism  Normal platelet count: 150 – 450 x 109/L
- Shortness of breath, pleuritic chest pain, cough, hemoptysis, fever  Platelets play multiple hemostatic roles
- Massive: hypotension, right heart failure o Platelet adhesion: vWF
 Cerebral Sinovenous Thrombosis (CSVT) o Platelet aggregation: Agonists – ADP, ATP, Collagen, Ristocetin, Epinephrine,
- Neonates: Seizure Arachidonic acid, Thrombin
- Children: Headahce, vomiting, seizures, focal signs
- Concurrent sinusitis, Mastoiditis PLATELET DISORDERS
 Renal Vein Thrombosis (RVT) I. Platelet Function Defects (inherited/ Acquired)
- Most common spontaneous TE in neonates II. Platelet Disorders with Thrombocytopenia
- Hematuria, abdominal mass, and/or thrombocytopenia
PLATELET FUNCTION DISORDERS
- Infants of Diabetic Mothers – increased risk
 Most inborn platelet pathologies predispose to hemorrhage
- 25% bilateral
 Rare conditions
 Peripheral Arterial Thrombosis
- Neonates: Umbilical catheters  Laboratory Findings:
o Bleeding Time (platelet-vessel wall interaction) – prolonged
- Cardiac defects: Cardiac catherization
o PFA – 100 (platelet adhesion/aggregation) – prolonged
- Extremities: Cold, Pale, Blue, Poor/absent pulses
o Platelet aggregometer
 Stroke
o Normal platelet count
- Acute Ischemic Stroke: Hemiparesis, Loss of consciousness, Seizures
- Intracranial arteries – Sickle Cell Disease, Vasculopathy, Traumatic arterial CONGENITAL PLATELET DEFECTS
dissection  Glanzmann’s Thrombasthenia – deficient GP IIb-IIIa
- Venous thrombi – Congenital heart disease (patent foramen ovale) o Fibrinogen receptor on the platelets
 Rapidly Progressive Thrombosis  Bernard-Soulier Syndrome – abnormal glycoprotein Ib-IX-V complex
- Rare complication of APS, Heparin-induced thrombocytopenia with o VWF receptor on platelets
thrombosis, thrombotic thrombocytopenic purpura (while on antithrombotic  Gray Platelet Syndrome – deficient alpha granules
therapy)  Delta Storage Pool Deficiency – deficient dense granules
- Multiple organ dysfunction, Elevated D-dimer levels  Von Willebrand disease – deficiency or abnormal vWF
- Treatment: anticoagulation, direct thrombin inhibitor, fondaparinux followed
ACQUIRED DEFECTS
by prolongated warfarin therapy
 Liver Disease
DIAGNOSIS  Kidney Disease (Uremia)
 Ultrasound with Doppler Flow – Upper/Lower Extremity VTE  Drug-induced (Aspirin) – Valproic acid, High dose Penicillin
 Spiral CT – diagnose PE
 CT and MR Venography PLATELET DISORDERS (THROMBOCYTOPENIA)
 Brain MRI with Venography (MRV) – cerebral sinovenous thrombosis and acute  Causes:
ishemic stroke o Decreased production – congenital or acquired
 Laboratory Findings: o Sequestration of platelets by an enlarged spleen
o CBC, PT, aPTT o Increased destruction – immune or nonimmune
o D-dimer
I. DECREASED PRODUCTION OF PLATELETS
o Renal & Hepatic Fucntion tests
A. Congenital Causes:
o Work-up for APS – lupus anticoagulant, anticardiolipin, -glycoprotein
 Congenital Amegakaryocytic Thrombocytopenia
antibodies
 Thrombocytopenia Absent Radius (TAR)
o Thrombophilia Testing – inherited risk factors
 Wiskott-Aldrich Syndrome
TREATMENT: B. Acquired causes:
Therapeutic options: Anticoagulation, Thrombolysis, Surgery, Observation  Infiltrative: Leukemia, Histiocytosis, Lymphoma
a. Anticoagulation  Aplastic Anemia
 Goal: reduce the risk of embolism, stop clot extension, prevent recurrence  Myelodysplastic Syndrome (MDS)
 Anticoagulants: catalyzes action of Antithrombin (AT)  Drug/Radiation-induced
o Therapeutic heparin dose – aPTT 1.5 – 2.5x (upper limit of normal)
 Nutirtional: Folate, Vitamin B12
 Unfractioned Heparin (uFH): 75-100 u/kg (bolus); 20-28 U/kg (continuous
infusion) II. SEQUESTRATION OF PLATELETS
 Low Molecular Weight Heparin (Enoxaparin)  Hypersplenism (Massive Splenomegaly)
o <2 months old: 1.5mg/kg, every 12 hrs, subcutaneous o Pancytopenia
o >2 months old: 1 mg/kg, every 12 hrs, subcutaneous  Etiology:
o Monitoring: Anti-Xa activity (4 hrs after 2nd or 3rd dose) = 0.5 to 1 IU/ml o Infectious
o Caution for patients with renal insufficiency, avoided in renal failure o Inflammatory
 Warfarin – oral anticoagulant o Infiltrative
o MOA: Decrease concentration of Vitamin K dependent factors II, VII, IX, X, o Neoplastic
Protein C,S o Obstructive
o Dose: 0.1-0.2 mg/kg, orally o Hemolytic
o PT – monitoring using International Normalized Ratio (INR)
o VTE: INR 2.0 -3.0 III. PLATELET DESTRUCTION
 Direct Thrombin or Factor Xa Inhbitors A. IMMUNE:
b. Thrombolytic Therapy – hasten thrombus resolution (tissue plasminogen  Acute and Chronic ITP, HIV-associated
activator)  Autoimmune disorders: SLE
 Thromboprophylaxis  Antiphospholipid Antibody Syndrome
 Antiplatelet Therapy  Neonatal Immune Thrombocytopenia
 Drug-induced Immune Thrombocytopenia
 Post-transfusion purpura, Post-transplant pupura
B. NONIMMUNE:
 Infections: Viral, Bacterial, Protozoan
 Thrombotic Microangiopathic Disorders: HUS, TTP
 DIC, Kasabach-Merirtt Syndrome, Drug-induced
 Congenital Heart Disease

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IMMUNE THROMBOCYTOPENIC PURPURA NON-IMMUNE THROMBOCYTOPENIA
 Most common cause of acute thrombocytopenia in an otherwise well child HEMOLYTIC UREMIC SYNDROME
 1/20,000  Acute disease of infancy & early childhood following acute gastroenteritis,
 Antibody coated platelets are recognized by Fc receptor on the splenic E.coli0157:H7 (Verotoxin)
macrophages, thus are ingested and destroyed  Hemolytic anemia, Thrombocytopenia, Acute renal failure
 RBC morphology: Helmet cells, Spherocytes, Schistocytes, Burr cells
 D-dimers: increased
 Urinalysis: Proteins, RBCs, Casts
 Treatments: Fluid therapy, Prompt dialysis, Plasmapheresis: HUS with neurologic
complications
 Etiology: Unknown
o Antecedent viral infection in 1-4 wks (50-65%) THROMBOTIC THROMBOCYTOPENIC PURPURA
o Autoantibodies against platelet surface – a1 1b-3 and GP1b  Rare
o EBV-related ITP: Short duration, follows course of Infectious Mononucleosis  Pentad: Fever, Microangiopathic hemolytic anemia, Thrombocytopenia, Abnormal
o HIV-associated ITP: Chronic renal function, CNS changes
o Helicobacter pylori  Clinically similar to HUS
o Following vaccinations  Congenital, Adults (usually), Adolescents (occasional)
 Clinical Features:  Etiology:
o Generally well-looking, unless with serious bleeding (CNS, intraabdominal) o Antibody-mediated deficiency of metalloproteinase (ADAMTS-13)
Platelet Count <10,000 o Cleaves HMW multimers of VWF
o Normal PE except for mucocutaneous bleeding o Thrombotic microangiopathy
o Splenomegaly, Lymphadenopathy, Bone pain, Pallor – Rare  Laboratory findings:
o (UK) Severity of Bleeding: No symptoms, Mild, Moderate and Severe o Microangiopathic hemolytic anemia (PBS: abnormal RBCs – schistocytes,
o 70-80% spontaneous remission w/in 6 months spherocytes, helmet cells)
o 10-25% develop chronic ITP o Reticulocytosis, Thrombocytopenia
 Acute ITP (80%) – complete resolution of platelet CT in 6 months o Coagulation studies – non-diagnostic
 Chronic ITP (20%) – persistence of thrombocytopenia > 12 months o BUN: creatinine – elevated
o Monitor for SLE (ANA)  Treatment:
 Lab findings: o Plasmapheresis
o Thrombocytopenia <20 x 109/L o Rituximab, Corticosteroids, Splenectomy (refractory)
o Platelet size – normal to large platelets
o Normal WBC, RBC
o BMA: increased megakaryocytes, normal granulocytes, Erythroid
 Indications for bone marrow aspiration:
1. Abnormal WBC count or differential count
2. Unexplained anemia
3. Findings suggestive of BM disease
 Coombs (+) = IT w/ AIHA = Evans Syndrome
 In adolescents with new onset ITP, ANA test should be done to evaluate for SLE
 Management:
o Major bleedings are rare if the platelet counts are >10,000
o Treatment goal for ITP is to get safe platelet levels and prevent bleeding
o American Society of Hematology hives the following guidelines for treatment of
ITP:
 Don’t treat if: Platelet count >50,000 and patient is Asymptomatic
 Consider treatment if: Platelet count >50,000 and there is mucus
membrane bleeding
 Definitely treat if: Platelet count <50,000
 IVIG or Glucocorticoid:
- Platelet counts <20,000/ul + Significant mucosal membrane bleeding
- Platelet counts <10,000/ul & Minor purpura
- Treatment: Corticosteroids, IVIG, anti-D, Rituximab, Monitoring of
platelet count

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