Approach to the adult with a suspected bleeding disorder

I. Elements of a bleeding history

II. Laboratory initial testing
III. Thrombocytopenia
● Immune thrombocytopenic purpura
● Thrombotic thrombocytopenic purpura
● Hemolytic uremic syndrome
IV. Intrinsic vs Extrinsic: Coagulation cascade
● PT and aPTT both prolonged
o Disseminated intravascular coagulation (DIC)
● aPTT prolonged, PT Normal
o Von Willebrand Disease
o Hemophilia A
o Hemophilia B
● PT prolonged, aPTT Normal

Discussion
I. Elements of a bleeding history
1. Reason for the consultation (Chief complaint)
2. Prior bleeding events over time
• Bleeding during infancy (eg umbilical stump bleeding) and childhood (eg
bleeding with loss of deciduous teeth)
• Bleeding during adolescence and adulthood (eg menstruation,
pregnancy)
• Any bleeds severe enough to require surgical intervention, nasal packing
or cautery, a visit to the ER or transfusion
3. History of iron deficiency or iron-responsive anemia
4. History of poor wound healing
5. Menstrual history (esp the presence of nighttime “flooding”, passage of clots larger
than approx 2.5cm, duration of menses longer than 8 days)
6. Pregnancy history (bleeding with delivery or postpartum; early pregnancy loss)
7. Family history
8. Antibiotic/medication use

II. Laboratory initial testing

1. CBC with PC and morphology
2. Prothrombin time (PT)
3. Activated partial thromboplastin time (aPTT)

III. Thrombocytopenia
● Results from:
1. Decreased bone marrow production
2. Sequestration
 3. Increased platelet destruction

*Drugs - Most common cause of thrombocytopenia

*Infection induced thrombocytopenia – Most common non-iatrogenic cause

Drugs which can cause isolated thrombocytopenia

● Immune thrombocytopenic purpura
⮚ Also termed Idiopathic thrombocytopenic purpura
⮚ Immune-mediated destruction of platelets and possibly inhibition of platelet release
from the megakaryocyte
⮚ Other cell lines are unaffected (ie, ITP does not cause anemia or leukopenia)
⮚ ITP is termed secondary if it is associated with an underlying disorder (eg SLE, HIV,
hepatitis C)
⮚ Characterized by:
▪ Very low platelet count
▪ Normal peripheral blood cells and smear
▪ Usually present either with ecchymoses and petechiae

⮚ Treatment
o First line therapy
▪ Prednisone 1mg/kg/day for 1-2 weeks followed by gradual taper OR High
dose dexamethasone 40mg/day for 4 days with no taper
● An increased or normalized platelet count is generally seen within
two weeks of therapy
● Platelet count response after high-dose dexamethasone generally
occurs faster than prednisone
● Dexamethasone 40 mg daily is approximately equivalent
to prednisone 4 mg/kg daily (equivalent to 280 mg daily for a 70
kg patient); this is based on a per-mg potency for dexamethasone
that is approximately 7.5 times greater than prednisone.
▪ IVIG at 1 g/kg daily for one or two days (Alternative dosing:
400 mg/kg daily for five days)
 ● Can raise the platelet count within 24 to 48 hours in most patients
with ITP

▪ Anti-RhD 50 to 75 mcg/kg intravenously

● For patients who have an Rh+ blood type
● May be ineffective in patients who have had a splenectomy
o Second line therapy
▪ Splenectomy
● Greatest chance of altering the disease course and resulting in a
sustained remission
● Platelet counts typically rise within the first two weeks
postoperatively
▪ Rituximab (375 mg/m2 intravenously once a week for four consecutive
weeks)
● Chimeric monoclonal antibody directed against the B cell surface
protein CD20
● For patients who either are not candidates for or prefer to avoid
splenectomy
● Risk of hepatitis B reactivation
▪ Thrombopoietin receptor agonists (TPO-RAs)
● Persistent thrombocytopenia despite splenectomy and rituximab
● Romiplostim, Eltrombopag, Avatrombopag

● Thrombotic thrombocytopenic purpura

⮚ Severely deficient activity of the ADAMTS13 (<10%)
⮚ Function as a von Willebrand factor (VWF)-cleaving protease
⮚ Pentad:
- Microangiopathic hemolytic anemia
- Thrombocytopenia
- Renal failure
- Neurologic findings
- Fever
⮚ Triggers
- Drugs (quinine, ticlopidine, clopidogrel, cyclosporine, tacrolimus, mitomycin C)
- SLE
- Pregnancy
- HIV
- Malignancies
⮚ Other findings to support the diagnosis
- Increased lactate dehydrogenase
- Increased indirect bilirubin
- Increased reticulocyte count
- Peripheral blood smear: Schistocytes
 ⮚ Mainstay of treatment
- Plasma exchange

● Hemolytic Uremic syndrome

⮚ Most common cause of HUS is Shiga toxin-producing Escherichia coli (STEC) O157:H7
⮚ Triad
- Microangiopathic hemolytic anemia (Hgb <8g/dl)
- Thrombocytopenia
- Acute renal failure

⮚ Peripheral blood smear

- Schistocytes (up to 10 percent of red cells)
- Helmet cells caused by the RBC fragmentation
IV. Intrinsic vs Extrinsic
⮚ PT and aPTT both PROLONGED
o Suggests a deficiency (or inhibitor) in a common pathway factor (eg, factor X, V,
II [prothrombin], or fibrinogen) or a combination of deficiencies (or inhibitors)
affecting both the intrinsic and extrinsic pathways
o Differentials
1. Disseminated intravascular coagulation (DIC)
2. Vitamin K deficiency
3. Liver disease
4. Anticoagulants
5. Acquired inhibitor of prothrombin, fibrinogen, factor V or factor X
6. Amyloidosis associated factor X deficiency

o Disseminated Intravascular Coagulation (DIC)

● The processes of coagulation and fibrinolysis become abnormally (and often
massively) activated within the vasculature, leading to ongoing coagulation
and fibrinolysis.
● Clinical manifestations are related to the magnitude of the imbalance of
hemostasis, to the underlying disease or both.
● Most common findings: bleeding ranging from oozing from venipuncture
sites, petechiae, and ecchymoses to severe hemorrhage from the GI, lung or
into the CNS.
 ● Treatment
• For active bleeding or high risk of bleeding
• FFP and/or platelet concentrates
• For low grade DIC assc with solid tumor, acute promyelocytic
leukemia
• Heparin 5-10U/kg per h – no proven survival benefit

⮚ aPTT prolonged, PT Normal

o Prolongation of the activated partial thromboplastin time (aPTT) with a normal
prothrombin time (PT) suggests a deficiency or inhibitor in the intrinsic pathway
(eg, factor VIII, IX, or XI)
o Differentials
1. Von Willebrand Disease (if factor VIII sufficiently decreased)
2. Hemophilia A (Factor VIII deficiency)
3. Hemophilia B (Factor IX deficiency)
4. Congenital factor XI deficiency
o Von Willebrand Disease
● Most common inherited bleeding disorder
● VWF has 2 roles:
▪ Major adhesion molecule that attaches the platelet to the
exposed subendothelium
▪ Binding protein for factor VIII
● Clinical manifestations
▪ Easy bruising
▪ Skin bleeding
▪ Prolonged bleeding from mucosal surfaces (eg oropharyngeal, GI,
uterine)
● Initial screening tests
▪ Plasma von Willebrand factor (VWF) antigen
▪ Plasma VWF activity
▪ Factor VIII activity (FVIII)
● Treatment
▪ Desmopressin
● Promotes the release of VWF from endothelial cell storage
sites
● IV dosing: 0.3 mcg/kg (maximum 20 mcg) is diluted in 50
mL of normal saline and infused over 20 to 30 minutes
o 3-5x increase in baseline levels of VWF and factor
VIII levels is expected at approximately 30 to 60
minutes after the infusion, with the response
persisting for 6 to 12 hours
● SC dosing: Same formulation and dosing as the
intravenous form
● Intranasal dosing: 150 mcg for individuals weighing less
than 50 kg and 300 mcg for larger individuals

o Hemophilia
● X-linked recessive hemorrhagic disease due to mutation in the F8 gene
(Hemophilia A or classic hemophilia) or F9 gene (Hemophilia B)
● Present in male children of carrier females
● Disease affects 1 in 10,000 males worldwide
● Hemophilia A represents 80% of all cases
● Most common mutation: Inversion of the intron 22 sequence
● Clinically, hemophilia A and B are indistinguishable
● Disease phenotype correlates with the clotting factor level
● Classified as:
▪ Severe (<1%)
● Most common bleeding manifestations: Recurrent
hemarthroses (knees, elbows, ankles, shoulders, hips)
 ● Bleeding into CNS, retroperitoneum, oropharyngeal spaces
▪ Moderate (1-5%)
▪ Mild (6-30%)
● Treatment

Computation:
Computation: Patient's weight (in kg) X desired rise in factor VIII level (as a whole
number, such that a desired level of 100 percent is entered as 100) X by
the volume of distribution (for factor VIII, this equals 0.5)

Ex: 60 kg patient who requires an increase to 100 percent, the dose would be 60
kg x 100 x 0.5 = 3000 units of factor VIII.

▪ Therapies other than factor replacement:

o Desmopressin
• Causes a transient rise in FVIII and VWF but not FIX
• Doses of 0.3ug/kg body weight, over a 20 minute
period, is expected to raise FVIII levels by 2-3 fold over
baseline
• Antifibrinolytic drugs (eg Tranexamic acid)

⮚ PT prolonged, aPPT Normal

o Prolongation of the prothrombin time (PT) with a normal activated partial
thromboplastin time (aPTT) suggests a deficiency or inhibitor in the extrinsic
pathway (eg, factor VII)
o Differentials
1. Factor VII deficiency - Rare inherited coagulation disorder
2. Mild vit K deficiency
3. Liver disease
4. Warfarin