Hematology: Secondary Hemostasis D/o

Front 1

Localized bleeding d/o.

Back 1

- Single location- indicates trauma, nfection, ,tumor, isolated bleeding vessel defect.
- Rarely implies a hemostasis d/o.

Front 2

Generalized bleeding d/o.

Back 2

- Multiple sites, spontaneous & recurring, intervention/transfusion.
- Concern w/ hemostasis d/o.

Front 3

Mucocutaneous bleeding.

Back 3

Associated w/ thrombocytopenia, primary hemostasis defects/disorders.

Front 4

Soft tissue/joint bleeding.

Back 4

- Associated w/ secondary hemostasis procoagulant deficiencies.
- Hemophilia A, B, & C.

Front 5

Hemostasis bleeding d/o: symptoms.

Back 5

- Purpura: purple lesion of the skin.
- Petechiae: small red spots (<3mm)- small amount of blood escaping the skin epithelium (most often primary).
- Ecchymoses: bruise or small hemorrhage (>3mm).

Front 6

Acquired hemostasis bleeding d/o.

Back 6

- Liver dz, kidney failure, chronic infections, autoimmune d/o, OB complications, dietary deficiencies, inflammatory d/o.

Front 7

Most common congenital hemostasis bleeding d/o.

Back 7

- von Willebrand's Disease
- Hemophilia A
- Hemophilia B
- Plt function d/o

Front 8

Liver disease

Back 8

- Leads to procoagulant deficiency.
- Liver: produces most of the plasma coagulation factors & regulatory proteins.
- Thrombocytopenia: due to hepatosplenomegaly & decreased production of TPO.

Front 9

Vitamin K deficiency

Back 9

- Rare due to its presence in most foods.
- Most ofen seen in newborns.
- Theraputic overdose (Warfarin) & rat poison ingestion--> hemorrhage

Front 10

Vitamin K dependent factors

Back 10

- Factor II, VII, IX, & X.
- Protein C & S.

Front 11

von Willibrand's Disease (vWD)

Back 11

- Most common congenital bleeding d/o.
- Autosomal dominat inheritance
- Impaired primary hemostasis: mucocutaneous bleeding d/o caused by quantitative or qualitative abnormalities of vWF--> factor 8 deficiency (protelysis).
- Can be congenital or acquired.

Front 12

von Willibrand's Factor

Back 12

- Normal plasma conc'n: 0.5-1.0mg/dl, but more can be released on demand.
- Synthesized as a monomer that forms multimers of various sizes.
- Each monomer has different functional domains that bind factor VIII, plt GP, & collagen.
- Main functions: 1. Factor 8 carrier molecule (protecting it from proteolysis & prolongs its plama life); 2. Mediates plt adhesion to subendothelial collagen whenever a break in endohelial cells occurs.

Front 13

Congenital vWD type I.

Back 13

- Quantitative vWF deficiency; account for 70% of vWD.
- Caused by one of several autosomal dominant mutations.
- Mild- moderate bleeding following hemostatic challenge (surgery, dental extractions, menorrhagia).

Front 14

Congenital vWD type 2.

Back 14

- Qualitative vWF defects
- Divided into four subtypes- 2A, 2B, 2M, 2N.
- vWF levels may be normal or mildly increased, but abnormal function.

Front 15

Cngenital vWD type 3.

Back 15

- Autosomal recessive mutation.
- Most severe form of vWD: vWF is nearly or entirely absent--> severe mucocutaneous & anatomic hemorrhage.
- Factor 8 is proportionally decreased or absent, resulting in impairmenet of both primary & secondary hemostasis.

Front 16

Acquired vWD

Back 16

- Pathogenesis varies & can include decreased production, autoantibodies, or adsorption of vWF to abnormal cell surfaces.
- Shuld be suspected in any pt. w/ recent onset of bleeding w/ no past hx.
- Can occur in association w/ hypothyroidism, autoimmune d/o, lymphoproliferative or MPD, HUS, Wilms tumor, congenital heart dz.

Front 17

vWD clinical features.

Back 17

- ABO blood group (Grp. O lowest vWF levels, while Grp. AB the highest).
- Pregnancy, age, exercise, stress
- vWF is an acute phase reactant (APR).

Front 18

vWD diagnosis.

Back 18

- Family hx.
- CBC to r/o thrombocytopenia.
- PT (normal) & PTT (abnormal because factor 8 is an intrinsic cofactor) to assess coagulation.
- Immunoassay to quantitate vWF.
- Ristocetin cofactor activity assay: to determine ability of vWF to bind to plts.
- Factor VIII activity level assay (abnormal)

Front 19

vWD treatment.

Back 19

- Depends on type/subtype.
- Mild bleeding: local measures, i.e. limb elevation, pressure, ice packs, etc.
- Moderate bleeding: tx w/ estrogen & desmopressin acetate (DDAVP)--> trigger release of vWF from storage organelles.
- Type 3 requires administration of supplemental vWF & factor VIII.
-

Front 20

Hemophilia A.

Back 20

- Classic Hemophilia (factor VIII deficiency)
- Affecting 1/5000 male births in the US.
- X- linked recessive d/o (from mother to male babies).
- Factor VIII deficiency w/ normal vWF.

Front 21

Factor VIII

Back 21

- Found on the X chromosome.
- Aka anti-hemophilic factor
- Found in plasma; cofactor in intrinsic tenase complex.
- Acted upon by thrombin during coagulation.
- Normal activity: 50-150%
- Labile & has a half-life of 8-12hrs.

Front 22

General clinical findings.

Back 22

- Anatomic bleeding; deep muscle & joint hemorrhage.
* Acute: painful & cause immobility
* Chronic: inflammation & eventually cause permanent loss of mobility.
- Hematomas
- Wound oozing after trauma/surgery.
- Bleeding into the CNS.
- Common bleeds: bruises, joints, nose, mouth, & deep muscle.
Life threatening: bleeding in head, eye, neck/throat, abdomen, stomach, kidney, bladder.

Front 23

Diagnosis of Hemophilia A.

Back 23

- Infants are tested after birth if an abnormal bleed occurs or if family hx suggest inheritance.
- PT= normal
- PTT= prolonged (normal PTT is 25-35 sconds)
- Normal thrombin time
- Normal plt count & plt function tests.

Front 24

Levels of Hemophilia.

Back 24

- Severity of sx is inversely proportional to Factor VIII activity.
- Mild: 5-20% activity; bleeding secondary to serious injury/surgery; not discovered usually until first episode.
- Moderate: 1-5% activity; bleeding after injuries & sometimes w/o obvious cause.
- <1%: 60% of the hemophilia population; bleeding following injury; frequent spontaneous bleeding episodes; bleeding into the joints & muscles.

Front 25

Treatment for Hemophilia A

Back 25

- Replacement therapy:
* Infusion of factor 8 concentrate to replace missing factor 8.
* Injected or infused directly into the vein.
* Recombinant factor (artificial).
* DDAVP used to tx small bleeds.

Front 26

Hemophilia A: complications

Back 26

- Chronic joint deformities
- Recurrent transfusions (HIV, hepatitis)
- Intracerebral hemorrhage
- Inhibitors

Front 27

Factor VIII inhibitors

Back 27

- IgG alloantibodies (30% w/ severe hemophilia & 3% w/ moderate)
- Presence of alloantibodies persist bleeding or plasma factor 8 fails to increase to target levels despite tx.
- Detected by Factor 8 assay (<30%); mixing studies; & Bethesda assay (quantitates).

Front 28

Hemophilia B

Back 28

- Fatcor IX deficiency
- 14% of US hemophilia
- X-linked
- Inhibitors develop in 3% of pts.; detected by Bethesda assay.

Front 29

Diagnosis of Hemophilia B

Back 29

- PTT= prolonged (Factor 9 unique to intrinsic pathway)
- PT= normal
- Factor 9 assay for definitive dx.
- Rx: plasma derived Factor IX concentrate or recombinant factor IX.

Front 30

Hemophilia C

Back 30

- Factor XI deficiency
- Autosomal dominant
- >50% of cases: Ashkenazi Jews
- Frequency/severity of bleeding do not correlate w/ factor XI levels.

Front 31

Fibrinogen (Factor I) Deficiency

Back 31

- Afibrinogenemia: inherited; homozygous form in w/c no detectable fibrinogen is found.
-Hypofibrinogenemia: inherited; heterozygous form in w/c fibrinogen is <100 mg/dL.
- Ref. range: 200-400 mg/dL
- Dysfibrinogenemia: structural alteration on the molecule.
- >50% no bleeding sx; 25% usually do (mild bleeding that occurs only after trauma).

Front 32

Afibrinogenemia

Back 32

- More severe dz.
- Abnormal prolonged PT, aPTT, & thrombin time.
- D- dimers= decreased

Front 33

Prothrombin (Factor II) Deficiency

Back 33

- Extremely rare
- A variety of mutations in prothrombin gene: decreased production or productionof dysfunctional molecule.
- Prolonged PT & aPTT due to Factor II in common pathway

Front 34

Factor V Deficiency

Back 34

- Intrinsic cofactor req'd to convert prothrombin to thrombin, along w/ Factor Xa, PL, & Ca+
- Prolonged PT & aPTT
- Factor V assay for definitive dx (<30%)
- Rx: FFP to increase to 75%

Front 35

Factor VII Deficiency

Back 35

- Rare: 1 in 500,000
- PT= prolonged (extrinsic)
- aPTT= normal
- Definitive dx: Factor VII (<30%)
Rx: FFP, activated Factor VII concentrate

Front 36

Factor X Deficiency

Back 36

- PT & aPTT= prolonged (common pathway)
- Russell's viper venom (RVV)= prolonged
- RVV contains an enzyme that directly activates factor X
- Definitive dx: Factor X assay (<30%)

Front 37

Factor XIII Deficiency

Back 37

- Very rare
- PT & aPTT= normal
- Nothing wrong in intrinsic, extrinsic, & common pathway
- Screening test: based on dissolution of the clot in 5M urea (Occurs in extremely low factor XIII, otherwise clot remains insoluble)