Transcript Grandroundsepistaxis

GRAND ROUNDS
22nd February, 2006
Dr. N. Singh
Dr. O. Ingaramo
Dr. S. Manuel
HISTORY OF PRESENT
ILLNESS
An 8 m old boy was brought to the ER with a
history of several episodes of epistaxis over
the last 12 hrs.
The mother was also concerned about some
scattered bruising on her son’s forehead,
occiput, elbows and flanks over the last 10
days.
DEVELOPMENT HISTORY
Sitting by himself, crawling, in walker.
Imm HX: Delayed – needs 6 mo vaccinations.
PM Hx: 1. Enterococcal Meningitis @
birth
2. ALTE at 1 mo of age – cyanotic
episode at home,  apneas noticed during
hospitalization.
FAMILY AND SOCIAL HISTORY
No h/o bleeding disorders.
Single mother, lives with boyfriend in a trailer
park.
No h/o substance abuse.
Primary caretaker is mother.
Infant also spends time in a daycare and with
father of boyfriend (esophageal cancer).
PHYSICAL EXAM
Afebrile, normal vital signs.
Wt: 5th percentile; Length: 10th percentile; HC: 25th
percentile. Alert, interactive and in no distress
HEENT: With some dried blood in nares.
Neck: No Lymph nodes palpable.
Chest: CTA B/L
CVS-No murmur
PHYSICAL EXAM
Abd - No HSM (hepatosplenomegaly), No
masses.
Ext: FROM, No swelling in joints.
Skin: Several areas of green-yellow areas of
bruising on the forehead, occiput, elbows and
flanks.
SUMMARY
An 8 m old boy with epistaxis over the last
12 hrs.
Bruising on forehead, occiput, elbows and
flanks over the last 10 days.
Enterococcal Meningitis @ birth
ALTE at 1 mo of age – cyanotic episode at
home,  apneas noticed during
hospitalization
SUMMARY
No h/o bleeding disorders
Single mother, lives with boyfriend in a trailer
park.
Father of boyfriend (esophageal cancer).
Afebrile, normal vital signs
Wt: 5th percentile ; Length: 10th percentile;
HC: 25th percentile. Alert, interactive and in
no distress.
SUMMARY
HEENT: With some dried blood in nares.
Neck: No Lymph nodes palpable.
Abd - No HSM (hepatosplenomegaly), No
masses
Ext: FROM, No swelling in joints
Skin: Several areas of green-yellow areas of
bruising on the forehead, occiput, elbows and
flanks
HEMOSTASIS REQUIRES
NORMAL:
Vessels
Platelets
Coagulation pathway components.
DIFFERENTIAL DIAGNOSIS OF
BLEEDING DISORDERS
Platelets
– petechiae, mucosal bleeding
– CNS bleeding in severe cases
Vascular
– contusion, ecchymosis, hemorrhage
– palpable purpura
Coagulation disorders
– Usually cause larger ecchymoses, deep tissue
hemorrhage, and mucosal bleeding
PLATELETS DISORDERS
Thrombocytopenias:
Decreased production.
Platelet pooling and splenic sequestration .
Increased destruction.
– Plt <100 000
– Spontaneous bleeding uncommmon with plt > 20,000.
– Bleeding time prolonged, PT/PTT normal.
PLATELETS DISORDERS (cont.)
Decreased Production:
Malignancies (leukemia, lymphoma, neuroblastoma).
Bone marrow suppression
– Drug-related (aplastic anemia)
– Infection
Congenital
–
–
–
–
Fanconi anemia
TAR syndrome
Wiscott-Aldrich
Glycogen storage diseases
PLATELETS DISORDERS (cont.)
Platelet Dysfunction:
Congenital
– Glanzmanns thrombasthenia (GP11b/IIIa
deficiency)
– Bernard Soulier (vWF receptor deficiency)
Acquired
– Drugs (ASA/NSAIDs, lasix, nitrofurantoin)
– Renal disease
– Liver disease
PLATELETS DISORDERS (cont.)
Increased Platelet Destruction:
Immunologic
–
–
–
–
ITP
SLE
Isoimmunization (post-transfusion, neonatal)
Drug related (heparin, quinine, digoxin, sulphonamides, phenytoin)
Infection
– Sepsis
Mechanical
–
–
–
–
–
DIC
HUS-TTP
Giant hemangioma (Kasabach-Merritt)
Burns
Trauma
PLATELETS DISORDERS (cont.)
Thrombocytopenia:
Sequestration
– Hypersplenism
– Sickle cell anemia
Dilutional
– Massive transfusion
VASCULAR DISORDERS
Loss of Vascular Integrity:
Acquired:
- Trauma/NAI, Scurvy, Steroid induced, Increased
intravascular pressure (coughing, vomiting, straining).
Congenital:
- Disorders of connective tissue: Ehlers-Danlos
syndrome, Osteogenesis imperfecta, Marfan’s.
- Disorders of blood vessels: Hemorrhagic telangiectasia
VASCULAR DISORDERS: Vasculitis
Drug-related
Infection
– Viral
Coxsackie A9, B3
Echoviruses 4,9
Atypical measles
– Bacterial
Meningococcemia
Streptococcal pharyngitis
Septic emboli
SBE
Gonococcus
– Rickettsial
Rocky Mountain spotted fever
Immune-mediated
–
–
–
–
HSP
SLE
Serum sickness
Dysgammaglobulinemia
COAGULATION FACTOR
DISORDERS
Clotting factor deficiencies
Congenital
Von Willebrand’s disease
Hemophilias
II, V, X or Fibrinogen deficiency.
Acquired
Vitamin K deficiency
Liver disease
Malabsorption
Warfarin/superwarfarin
Toxin mediated: Coumadin containing rodenticides.
LABS
LFTs – Bilirubin 0.3 mg/dL
Alk PO4 283 u/L (150-420 u/L)
Aspartate aminotransferase 83 u/L (20-65
u/L)
Protein 5.9 gm/dL (5.6 – 7.2 gm/dL)
Albumin 3.5 gm/dL (3.5 – 5.5 gm/dL)
LABS
WBC 9.0. Hb 13, Hct 48.2 Platelets 212.
S 56, B 0, L 38, M 5, E 1
UA  Normal
PT  59.1 (10-13 secs)
PTT  120 secs (26 – 37 secs)
GRAND ROUNDS
Februay, 2006
Dr. Singh, N.
Dr. Manuel, S.
Dr. Ingaramo, O.
EVALUATIONS OF BLEEDING
DISORDERS
Require a thorough history and physical
exam.
Important questions include prolonged
bleeding following minor trauma,
spontaneous bruising, or hematoma
formation.
Drug history is important since many drugs
cause bleeding. ie Aspirin.
Family history and any possible pattern of
inheritance.
PHYSICAL EXAM
Petechiae and purpura are signs of
platelet dysfunction.
Large firm bruises with nodular centers
are commonly seen in congenital factor
deficiencies.
Icterus and hepatosplenomegaly are
indicative of liver disease, which may be
associated with bleeding disorders
CLASIFICATION OF BLEEDING
DISORDERS
Defects of primary hemostasis (platelets,
vessels, etc.).
Defects of secondary hemostasis
(coagulation cascade and its regulation)
DEFECTS OF PRIMARY
HEMOSTASIS
Vascular disorders:
-Laboratory tests are characterized by a
prolonged bleeding time.
Platelets Disorders:
-Quantitative (thrombocytopenia).
-Qualitative (poor platelet function):
Inherited aggregation defect, Drug effect.
COAGULATION FACTORS
DISORDERS
Congenital factor deficiency
-Hemophilia A and B
-Von Willebrand disease
-Other factor deficiencies (rare)
Acquired factor deficiency
-Vitamin K deficiency
-Liver failure
-DIC
-Drugs: Anticoagulants.
Antiphospholipid antibody
COAGULATION CASCADE
LABORATORY OF BLEEDING
DISORDERS
Most common ordered labs:
Platelet count.
Bleeding time.
PT: Extrinsic and common coagulation pathway.
PTT: Intrinsec and common coagulation pathway.
LABORATORY OF BLEEDING
DISORDERS (cont.)
PTT mixing study: PTT corrects with factor
deficiency, but it does not normalize with circulating
ab/anticoagulants.
If positive, determine whether the inhibitor is a true
antibody to a coagulation protein or an
antiphospholipid ab.
Thrombin time (TT) and reptilase time measure
conversion of fibrinogen to fibrine and the formation
of the initial clot by thrombine.
Ristocetin, vWF antigen, WF quantity, vWD
multimeric assay.
LABORATORY OF BLEEDING
DISORDERS (cont).
Assays for fibrinogen, platelet aggregation or
platelet function assay (e.g. PFA-100), factor
XIII, dysfibrinogenemia (thrombin time or
reptilase time)
Also assays for factors VIII, IX or XI, even with
normal PTT
More esoteric assays include PAI-1 activity and
antiplasmin
LABORATORY OF BLEEDING
DISORDERS (cont).
PT is increased in factor deficiency (I, II, V, VII,
X), liver failure, vitamin K deficiency, coumadin,
warfarins.
aPTT is increased in factor deficiency (XII, XI, IX
and VIII), vWD, lupus anticoagulant and heparin
tx. It is less sensitive than the PT to deficiencies
within the common pathway (X, V, II and I). Not
affected by VII and XIII.
TT is increased in fibrinogen problems and
heparin tx. Not affected by XIII.
LABORATORY OF BLEEDING
DISORDERS (cont).
Routine screening testing with the platelet count, PT, TT,
aPTT should allow the clinician to more narrowly define
the diagnostic possibilities.
Prolonged PT and aPTT:
In a bleeding child who is otherwise well indicates an
inherited disorder within the common pathway (I, II, V, X)
or an acquired disorder involving multiple pathways or
anticoagulant factor. Other: Amyloidosis, coumadin.
In a sick child consider DIC, hepatocellular dysfunction,
severe vit K deficiency, thrombosis, hemangioma.
Normal TT with normal fibrinogen level will exclude
abnormal fibrinogen.
COAGULATION CASCADE
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
Factor X deficiency: rare (1 per 1 million)
AR deficiency characterized by asymptomatic
heterozygotes and by homozygotes with bleeding
symptoms that correlate with factor activity.
May be associated with bruising, epistaxis,
menorrhagia, GI/GU or umbilical stump bleeding or
bleeding after surgery, trauma, dental procedures,
pregnancy or circumcision
Severe deficiencies may resemble hemophilia and
may be associated with intracranial hemorrhage.
Treatment: fresh frozen plasma; Prothrombin
complex concentrates for serious bleeding.
COAGULATION CASCADE
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
Factor V deficiency: rare (1 per 1 million)
AR deficiency in which asymptomatic
heterozygotes and homozygotes manifesting
platelet-type bleeding (easy bruising, epistaxis).
Severe deficiencies associated with intracranial
hemorrhage, although levels do not always
correlate with severity of symptoms
Treatment: 10-20 ml fresh frozen plasma/kg;
commercial concentrates of factor V are not
available
COAGULATION CASCADE
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
Factor II deficiency: rare (1 per 2 million)
AR disorder associated with mucosal and deep
tissue bleeding.
Treatment: 10-20 ml fresh frozen plasma/kg;
prothrombin complex concentrates may be
used for serious bleeding.
COAGULATION CASCADE
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
Factor I / fibrinogen deficiency or disorders
Rare. Autosomal inheritance; most mutations are
in alpha-fibrinogen chain gene, sparing beta and
gamma chains
Afibrinogenemia: homozygous form; causes
severe quantitative deficiency of fibrinogen and
increased risk of bleeding; associated with
intracranial hemorrhages.
Hypofibrinogenemia: heterozygous form;
mild/moderate reductions in fibrinogen; little/no
bleeding.
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
Dysfibrinogenemia: qualitative fibrinogen.
Bleeding due to defective fibrin clot formation
(impaired release of fibrinopeptides A or B)
Thrombosis due to (a) defective thrombin binding to
fibrin, causing increased thrombin in circulation; (b)
defective binding of tPA or plasminogen to fibrin.
Labs: concentration determined by ELISA. Often
prolonged TT and reptilase time, PT and PTT
Treatment: cryoprecipitate; fresh frozen plasma
contains more fibrinogen, but in a much larger volume.
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
Combined factor deficiencies are very rare
Combined factor V and VIII: autosomal
recessive.
Combined factors II, VII, IX and X deficiency:
due to mutation in gamma-glutamyl carboxylase
gene, whose protein carboxylates glutamate
residues in vitamin K-dependent coagulation
factors
Very rare to have bleeding disorders due to
deficiency in PAI-1 or antiplasmin
DIFFERENTIAL DX IN PROLONGED
PT AND PTT
ACQUIRED DEFECTS OF SECONDARY
HEMOSTASIS:
Vitamin K is needed for the synthesis of factors II, VII,
IX and X.
Vitamin K is vital to the carboxylation of glutamic acid
residues which is needed for the activation of these
factors.
The most common circumstance in which vitamin K
deficiency leads to bleeding is hemorrhagic disease of
the newborn.
ACQUIRED DEFECTS OF
SECONDARY HEMOSTASIS:
Vitamin K (cont.)
Without vitamin K supplementation, significant
GI and cutaneous hemorrhage may develop
within a few days.
After the newborn period, vitamin K is absorbed
from the GI tract. Deficiency may then result
from nutritional deficits, malabsorption, or
alteration in intestinal flora.
Treatment must be directed at the underlying
disorder and vitamin K supplementation.
DIFFERENTIAL DX IN
PROLONGED PT AND PTT
ACQUIRED DEFECTS OF SECONDARY
HEMOSTASIS (cont.)
Decreased synthesis of coagulation proteins
occurs in severe liver disease.
Abnormalities in the liver's capacity to
synthesize one or more clotting factors may
result in problems with hemostasis.
Treatment involves replacement of the
decreased factor(s) with fresh frozen plasma.
DIFFERENTIAL DX IN PROLONGED
PT AND PTT
ACQUIRED DEFECTS OF SECONDARY
HEMOSTASIS (cont.):
Acquired factor deficiencies (due to liver
disease, DIC, lupus anticoagulants,
heparin, warfarin or other anticoagulants)
are more common than hereditary factor
deficiencies, and should be ruled out first
ACQUIRED DEFECTS OF SECONDARY
HEMOSTASIS (cont.):
Acquired inhibitors are antibodies that neutralize a
specific clotting factor's function
The most commonly inhibited factor in clinical
practice is factor VIII.
Autoantibodies to VIII:C are characteristically
oligoclonal non-complement-fixing IgG.
The incidence is 0.2 to 1 per million person-years
with a higher incidence in older age groups.
These cause a prolonged PTT which is not corrected
with 1:1 dilution with normal plasma.
Acquired inhibitors (cont.)
Lupus anticoagulant:
Antibodies against protein-phospholipid complexes.
May interfere with assays for factors VIII, IX, XI and
XII without causing a true decrease in factor levels
In adults, it may be associated with spontaneous
abortion, and thromboembolism. In the pediatric
population is transient with rare clinical sequelae.
Soft-tissue bleeding, gross hematuria, and
postsurgical hemorrhage can occur; fatal bleeds may
occur in 15% of patients.
The treatment is aimed at reducing the antibody titer
using immunosuppression, IVIG, or Plasmapheresis.
Acquired Defects of Secondary
Hemostasis (cont.)
Disseminated intravascular coagulation (DIC)
Occurs in patients who are critically ill.
Fever, hypotension, acidosis, oliguria, or
hypoxia may be present. In addition, petechiae,
purpura, and oozing from wounds and
venipuncture sites may develop.
Microvascular and large vessel thrombosis may
occur.
The platelet count is typically decreased due to
consumption and platelet destruction.
DIC (cont.)
The PT and PTT are prolonged from depletion of
factors V, VIII, IX, and XI.
Fibrinogen is decreased. Fibrin degradation
products and the D-dimer assay are increased.
The mainstay of therapy is to treat the
underlying disease.
Additional therapy consists of replacing clotting
factors and platelets and possibly the use of
heparin and antifibrinolytic agents.
Other Acquired Defects of
Secondary Hemostasis
Amyloidosis:
Primary amyloidosis may cause
acquired factor X deficiency due to the
binding of amyloid to factor X.
Also inhibits fibrinogen conversion to
fibrin, causing prolongation of thrombin
time and reptilase time.
SUMMARY
Possible diagnosis in this patient with prolonged
PT and PTT:
Hereditary factor deficiency: I, II, V, X,
antiplasmin and dysfibrinogenemia.
Acquired defects of hemostasis: Vit K
deficiency, liver disease, lupus anticoagulant,
anticoagulant drugs, DIC, amyloidosis.
Child abuse can be a concomitant dx.
Thank you.