• Thrombocytopenia with absent radii (TAR) syndrome
• Amegakaryocytic thrombocytopenia
• Wiskott-Aldrich syndrome
• May-Hegglin anomaly
• Chédiak-Higashi anomaly
• Fanconi anemia
• Metabolic disorders

• Aplastic anemia
• Drug-induced marrow suppression
• Virus-induced marrow suppression
• Chemotherapy
• Radiation injury

• Neoplasia (leukemia, neuroblastoma)
• Histiocytosis
• Osteopetrosis
• Myelofibrosis
• Storage diseases

• Idiopathic thrombocytopenic purpura (ITP)
• Neonatal alloimmune thrombocytopenia
• Maternal autoimmune [e.g., maternal ITP and systemic lupus erythematosus (SLE)]
• Drug-induced (heparin, sulfonamides, digoxin, chloroquine)
• Infection
• Viral, bacterial, fungal, rickettsial

• von Willebrand disease (vWD)

• Aspirin, NSAIDs, guaifenesin, antihistamines, phenothiazines, anticonvulsants

• Uremia
• Paraproteinemia

• Deficiency of factor VIII, IX, XI, or XII
• Acquired inhibitor or lupus anticoagulant
• vWD (often normal)

• Mild vitamin K deficiency
• Liver disease, mild to moderate
• Deficiency of factor VII
• Factor VII inhibitor

• Liver disease, severe
• DIC
• Severe vitamin K deficiency
• Hemorrhagic disease of the newborn
• Deficiency of factors II, V, or X or fibrinogen
• Dysfibrinogenemia
• Hypoprothrombinemia associated with a lupus anticoagulant

• vWD
• Factor XIII deficiency

• Hereditary hemorrhagic telangiectasia
• Ehlers-Danlos syndrome
• Osteogenesis imperfecta
• Marfan syndrome

• Vasculitis (SLE, HSP, etc.)
• Scurvy

Questions that help confirm presence of a bleeding disorder and assist in determining severity:

• Spontaneous bleeding?
• Bleeding in unusual places without significant trauma (intracranial, joints, etc.)?
• Bruising and bleeding disproportionate to injury? Large or palpable bruising?
• Poorly controlled epistaxis? [localized trauma (nosepicking) can exacerbate epistaxis, or be the sole cause of it, unilateral epistaxis may indicate local vascular problems, rather than bleeding disorder]
• Excessive bleeding with tooth extraction?
• Abnormal bleeding at or after circumcision or surgical procedure?
• Prolonged bleeding from minor cuts?
• Excessive bleeding following a fracture?
• Familial history of bleeding disorder?

Questions that help target the defective component of hemostasis.

Question: Mucosal bleeding (gum bleeding, epistaxis)?
Significance: Platelet disorder, vWD, hereditary hemorrhagic telangiectasia, dysfibrinogenemia)

Question: Petechiae?
Significance: Platelet disorders, vWD

Question: Menorrhagia?
Significance: Common in vWD and platelet disorders

Question: Recent medications?
Significance: Aspirin and other drugs affect platelet function

Question: Presence of renal or liver disease?
Significance: Azoturia contributes to bleeding. Liver disease reduces clotting factors.

Question: Severe malnutrition?
Significance: Scurvy, decreased hepatic synthesis

Finding: Petechiae in skin and mucous membranes
Significance: Disorder of platelet number or function, vWD

Finding: Small bruises in unusual places (trunk)
Significance: Possible platelet disorder, vWD

Finding: Large bruises or palpable bruises
Significance: Coagulation deficiencies, severe platelet disorders, or vWD

Finding: Delayed wound healing
Significance: Factor XIII deficiency and dysfibrinogenemia

Finding: Purpura localized to lower body (buttocks, legs, ankles)
Significance: Henoch-Schönlein purpura (HSP)

Phase 1: Initial Laboratory Screening

• Platelet count
• PT and aPTT
• Bleeding time to screen for qualitative platelet disorders and may also help identify vWD (may be delayed until phase 2)

Phase 2

• Qualitative platelet defect suspected
  • Platelet aggregation studies with ristocetin, collagen, thrombin, and ADP
  • vWD suspected
  • Factor VIII:C
  • von Willebrand factor (vWF; VIIIR:Ag)
  • Ristocetin cofactor activity
  • vWF multimeric analysis
• Thrombin time or fibrinogen assay to screen for hypo- or dysfibrinogenemia

Phase 3: Discriminating Laboratory Studies for Abnormal Phase 1 Tests

When thrombocytopenia is present:

• Inspection of blood smear (screening for bone marrow diseases)
• Mean platelet volume (elevated in destructive causes, low in Wiskott-Aldrich)
• Bone marrow aspiration (rarely necessary)
  • When DIC is suspected (infection, liver disease, massive trauma, PT/aPTT prolonged, etc.):
• Fibrinogen
• D-dimer or fibrin split products
• Peripheral smear inspection for RBC fragments
  • Prolonged aPTT
• Inhibitor screen (50:50 mixing study of patient's and normal plasma)
• aPTT fully corrects
  • Specific factor assays in the following order: VIII, IX, XI, X
• Partial or no correction after mixing study
  • Inhibitor present
  • Confirmatory test for the presence of a lupus anticoagulant with a platelet neutralizing procedure

• Inhibitor screen should also be considered for prolonged PT
• Specific factor levels (II, VII, X)
• Prolonged PT and aPTT
  • Test for DIC, liver disease, and fibrinogen disorders, as described previously
  • Vitamin K deficiency, moderate to severe
  • Factor assays: X and II (prothrombin)

• May be prolonged when platelet count below 100,000/mm³
• Affected when aspirin is ingested within 7 days
• Other drugs taken within 8 to 12 hours may also effect result (NSAIDs, antihistamines)
• Prolongation does not correlate with bleeding risk
• Result depends on method and on experience of technician

• Clotting times are longer and standard deviation wider in neonates than in adult controls
• Polycythemia (Hct.65%) or too little blood collected will result in a spuriously high result
• Consider heparin contamination in samples from arterial or central venous catheters

• Normal reference ranges depend on patient's ABO blood group type
• Values fluctuate over time and may periodically be normal in affected individuals
• May require repeated testing to make diagnosis

• Pressure, elevation, and ice are generally helpful for most bleeding disorders when active bleeding is present.
• Monitoring for complications of significant blood loss in the acute setting is important.
• More definitive care is dictated by the nature of the underlying hemostatic defect. Platelet transfusions are useful in disorders of thrombocytopenia due to decreased production and for intrinsic qualitative platelet disorders but not for immune platelet disorders. Frozen plasma should only be used in severe cases when the exact diagnosis is not readily available but a defect in coagulation is suspected.
• Head injuries in patients with thrombocytopenia or hemophilia require immediate medical attention.

Q: What are the proper preoperative screening tests for bleeding disorders prior to elective surgery such as tonsillectomy?
A: A thorough personal history, familial history, and physical examination are by far the most important screening tests. The bleeding time is not recommended. A CBC and PT/aPTT are often requested by the surgeon but normal results do not assure that a bleeding complication will not occur. Overall the sensitivity and specificity of these screening tests is poor.

Q: Bruising is a normal part of childhood. How does one know when bruising is “too much”?
A: There is no proven set of clinical criteria that can reliably predict who should undergo an evaluation and who should not.

• If the history and physical examination strongly suggest the presence of a bleeding disorder or if the screening tests are abnormal the patient should be referred to a pediatric hematologist.
• If von Willebrand disease is suspected, referral to a pediatric hematologist is usually necessary to determine the exact type and for testing that will assess the patient's response to ddAVP therapy.
• Patients with hemophilia should have regular visits to a hemophilia treatment center for follow-up and coordination of care.
• Consultation with a hematologist is recommended prior to invasive procedures, surgery, or dental work.

Most clinical laboratories can do PT/aPTT and CBC, but may not be able to do bleeding times in young children.

Bell B, Canty D, Audet M. Hemophilia: an updated review. Pediatr Rev 1995;16(8):290–298.

Laposata M, Connor AM, Hicks DG, Phillips DK. The clinical hemostasis handbook. Chicago: Year Book, 1989.

Manno CS. Difficult pediatric diagnoses—bruising and bleeding. Pediatr Clin North Am 1991;38:637–655.

Pramanik AK. Bleeding disorders in neonates. Pediatr Rev 1992;13(5):163–173.