Module 6 Path

Front 1

The most common inherited coag disorders are...?

Back 1

Classic hemophilia
-- factor VIII deficiency

Christmas disease
-- factor IX

BOTH are inherited as sex-linked disorders

Front 2

All other coagulation factors are...?

Back 2

autosomal recessive, and therefore, very rare

Front 3

The most frequently acquired bleeding disorders due to abnormalities in plasma coagulation are...?

Back 3

liver disease

DIC

Front 4

Iatrogenic bleeding may be caused by...?

Back 4

treatment w/ anticoagulants

antiplatelet medication

Front 5

Vitamin K is a key molecule in the synth of...?

Back 5

Factors II, VII, IX, X

Protein C and S

Front 6

Deficiency of VitK leads to...

Back 6

dysfxnal forms of II, VII, IV, X, C & S and a bleeding diathesis

Front 7

Evaluation of thrombocytopenia requires...?

Back 7

determining rate of platelet production

in almost all cases requires BM aspirate to access megakaryocytes

Front 8

reactive vs. primary thrombosis?

Back 8

Reactive is rarely a clinical problem

Primary (myeloproliferative) may be assoc w/ thrombosis OR hemorrhage

Front 9

The most common inherited platelet disorder?

Back 9

vonWillebrand's disease
-- not a platelet disorder
-- decrease or abnormality of a plasma protein (vWF) required for normal platelet adhesion

Front 10

Retained organic acids from uremia can result in...?

Back 10

significant bleeding diasthesis w/ abnormalities in all platelet fxns

Front 11

What are the clinical manifestations of hemophilia?

Back 11

1. severity proportional to coag factor activity

2. normal skin bleeding times, but delayed bleeding from small skin wounds

3. soft tissue, joint hemorrhage is most common

4. progressive crippling
-- b/c of joint destruction and muscle atrophy

5. social disability and cost
-- loss of time at school/work
-- decreased employability
-- emotional difficulties

Front 12

Genetics of hemophilia?

Back 12

Sex-linked:
-- Factor VIII (hemophilia A)
-- Factor IX (hemophilia B)

Autosomal:
-- all others

Front 13

What causes Hemophilia A?

Back 13

PROPERTIES
-- coagulant activity (FVIIIc)
-- circulates bound to and is stabilized by vWF

DEFECT
--defective or absent coagulant protein

Front 14

What causes Hemophilia B?

Back 14

-- production of abnormal protein factor IX

OR

-- reduced amount of normal IX

Front 15

How do you determine how much factor replacement is needed in hemophilia?

Back 15

1. Estimate plasma volume:
5% of body weight (kg) = plasma volume (L)

2. multiply by unit level desired
1 unit = activity in 1mL of pooled normal plasma

Front 16

What is the half-life of replacement VIII and IV?

Back 16

FVIII is approx 8-12h

FIX is approx 20-26h

Front 17

Therapeutic materials in the treatment of hemophilia?

Back 17

1. AVOID aspirin and other meds that inhibit platelet fxn

2. FFP
-- factors other than II, VII, IX, X, VIII, vWF
-- approx 300u/bag
-- dose = 15mL/kg

3. cryoprecipitate
-- factor VIII, NOT IX

4. Lyophilized materials for factors II, VII, IX, X, VIII, vWF
-- high potency
-- reliability
-- low volumes
-- relative safety

5. For vWB disease and factor VIII deficiency (A) in mild forms:
-- desmopressin (DDAVP)

Front 18

Comprehensive vs home care for hemophiliacs?

Back 18

COMPREHENSIVE
1. hemophilia centers
2. multi-disciplne approach
3. health maintenance

HOME CARE
1. less total cost
2. less social, physical morbidity
3. indications

Front 19

Complications of therapy?

Back 19

1. hepatitis -- all blood products carry risk to patient and his family
-- risk now reduced w/ heat-treated concentrates

2. acquired immune deficiency
-- reduced/absent w/ new, heat treated concentrates

3. thrombosis
-- factor IX preps

4. inhibitor
-- incidence 5-20% in A (same rate for severe B)
THERAPY:
-- none
-- excess FVIII concentrates
-- immunosuppression
-- frequent low dose VIII infusion
-- "activated" II, VII, IX, X
-- exchange transfusion
-- animal prep --> porcine
-- affinity column apheresis or plasmapheresis
-- factor VIIa concentrates

Front 20

How are deficiency states involving other coag factors treated?

Back 20

FFP

Cryoprecipitate if hypofibrinogenemia

Front 21

How do we treat a deficiency of Protein C, S and antithrombin?

Back 21

treat w/ anticoagulation b/c leads to thrombosis

In homozygous deficiency of C or S, can treat w/ factor IX concentrates

Front 22

Acquired coagulation disorders?

Back 22

1. liver disease

2. vitamin K deficiency

3. bleeding secondary to anticoag meds

Front 23

How does the liver play a role in coagulation?

Back 23

The liver is responsible for:
1. synth of all hemostatic proteins
2. clearance of activated proteins
3. clearance of FDP
4. production of bile (necessary for VitK absorp)

Front 24

Hemostatic effects of liver disease?

Back 24

1. decreased bile w/ decreased VitK absorption

2. decreased clearance of FDP

3. decreased synth plasminogen

4. decreased synth alpha2antiplasmin

5. decreased synth coag factors

6. decreased clearance activated coag factors

7. decreased synth coag inhibitors
-- AT
-- protein C, S
-- alpha2macroglobulin

Front 25

Vitamin K's role in hemostasis?

Back 25

It is a fat soluble quinone derived from plants (K1) or microorganisms (K2) in which there is no substantial storage in the body

Takes part in redox cycle that brings about gamma carboxylation of glutamic acid residues in precursors of factors II, VII, IX, X, Protein C & S.
-- confers ability of factors to bind Ca
-- essential for S and C

Front 26

What can cause a vitamin K deficiency?

Back 26

1. hemorrhagic disease of the newborn

2. Malabsorption syndromes
-- biliary obstruction
-- other causes fat malabsorption

3. intestinal sterilization
-- loss of K2 from enteric bacteria

Front 27

What anticoagulant meds can cause bleeding?

Back 27

1. warfarin
-- narrow therapeutic interval w/ INR 2-3
-- signif complications of increased or decreased drug -- assay of therapeutic effect is not ideal

2. Heparin
-- narrow therapeutic window w/ aPTT approx 70-100s
-- signif complications of increased or decreased drug -- assay of therapeutic effect is not ideal

Front 28

What are the quantitative platelet disorders?

Back 28

1. thrombocytopenia

2. thrombocytosis

Front 29

Common sites of bleeding due to thrombocytopenia?

Back 29

skin: petechiae, ecchymosis
GI mucous mbrns
kidney
brain

Front 30

What are causes of thrombocytopenia?

Back 30

1. decreased BM production

2. ineffective thrombopoiesis

3. increased platelet destruction

4. abnormal sequestration of platelets

5. excessive loss of platelets

Front 31

Causes of decreased platelet production by bone marrow?

Back 31

1. aplastic anemia
-- idiopathic
-- secondary to exposure to radiation or cytotoxic drugs

2. myelophthisic disease
-- carcinoma
-- leukemia, etc

3. drugs
-- EtOH
-- estrogens
-- thiazides

4. cyclic thrombocytopenia

5. paroxysmal nocturnal hemoglobinuria

6. congenital thrombocytopenia w/ skeletal malformations

7. congenital rubella infection

Front 32

Causes of ineffective thrombopoiesis?

Back 32

Megakaryocytes present; may appear abnormal

1. megaloblastic anemia (B12/folate deficiency)

2. erythroleukemia

3. some familial thrombocytopenias

4. alcoholism

5. myelodysplasia

6. myeloprolif syndromes

Front 33

Increased platelet destruction can be due to _____ or _____ causes.

Back 33

immune

non-immune

Front 34

Non-immune causes of increased platelet destruction?

Back 34

1. DIC

2. Hemolytic uremic syndrome

3. TTP

Front 35

Immune causes of increased platelet destruction?

Back 35

AUTOIMMUNE
1. chronic idiopathic thrombocytopenia purpura (ITP)
2. lupus
3. lymphoproliferative disorders

IMMUNE COMPLEX MEDIATED:
1. drug purpura (quinine, digoxin, others)
2. acute (post-infectious) ITP
3. post-transfusion purpura

ALLOANTIBODY MEDIATED
1. neonatal alloimmune thrombocytopenia (NAIT)

Front 36

Causes of hypersequestration of platelets?

Back 36

hypersplenic thrombocytopenia

Front 37

Causes of excessive platelet loss?

Back 37

massive bleeding and replacement w/ stored blood

Front 38

How do we treat thrombocytopenia?

Back 38

1. treat underlying disorder

2. for autoimmune:
-- immunosuppression
-- IV Ig
-- anti-Rho(D) Ig for Rho(D)+ patients
-- splenectomy

3. platelet transfusions
-- most effective if decreased production
-- refractory state will occur after multiple transfusions due to alloimmunization

4. splenectomy

Front 39

Clinical manifestations of thrombocytosis?

Back 39

platelet count > 1 million

Thrombosis OR
Bleeding

Front 40

Causes of thrombocytosis?

Back 40

1. myeloproliferative disorders

2. inflammatory disorder

3. "stimulated" bone marrow

4. others

Front 41

Which myeloproliferative disorders can cause thrombocytosis?

Back 41

1. essential thrombocythemia
-- can be increased or abnormal

2. polycythemia vera

3. chronic granulocytic leukemia

4. myelofibrosis w/ myeloid metaplasia

Front 42

Which inflamm disorders can cause thrombocytosis?

Back 42

1. infection

2. RA

3. ulcerative colitis

Front 43

What can "stimulate" the BM to cayse thrombocytosis?

Back 43

1. acute blood loss

2. hemolytic anemia

3. treated pernicious anemia

Front 44

"Other" causes of thrombocytosis?

Back 44

1. iron deficiency

2. Hodgkin's disease

3. post-splenectomy (reactive change)

4. post-operative

5. CML

Front 45

Inherited qualitative platelet disorders?

Back 45

1. vonWillebrand's disease

2. Bernard-Soulier syndrome

3. Thrombasthenia

4. "Storage Pool" disorders

Front 46

Clinical manifestations of vWB disease?

Back 46

1. bleeding in skin, mucous mbrns, GI and urinary tract

2. variable severity

3. autosomal (both sexes involved)

4. epistaxis, easy bruising, gingival bleeding, post-dental bleeding, post-trauma bleeding

Front 47

How do we diagnose vWB disease?

Back 47

1. prolonged bleeding time

2. low FVIIIc

3. low vWF

4. low vWag

Front 48

How is vWB disease classified?

Back 48

Type 1:
-- heterozygous disease
-- mild bleeding disorder
-- >70%

Type 2:
-- dysfxnal vWF molecule
-- subtype a: reduced large multimers (10-15%)
-- subtype b: reduced large multimers, sensitivity to Ristocetin (<5%)
-- subtype m: abnormal platelet fxn w/ normal multimers (rare)
-- subtype n: abnormal FVIII binding

Type 3:
-- homozygous or double heterozygous disorder
-- severe bleeding
-- <0.1%

Front 49

Pathogenesis of vWB disease?

Back 49

1. quantitative or qualitative defect in vWF subunit structure

2. defective platelet-vWF interaction

Front 50

vWB disease therapy?

Back 50

1. avoid ASA

2. vWF replacement
-- FFP, cryoprecipitate
-- lyophilized conc of FVIII is NOT effective

3. Desmopressin (DDVP) in mild to moderate forms

4. monitor bleeding time if prolonged prior to therapy

Front 51

What is Bernard-Soulier Syndrome?

Back 51

Platelet mbrn defect
-- GPIb-IX complex absent
-- platelet cannot bind to vWF b/c it lacks receptor

Decreased aggregation in response to vWF (+ristocetin)

Normal aggregation to collagen, ADP, thombin, epi

Front 52

What is thrombasthenia?

Back 52

Platelet mbrn defect:
-- GPOObIIIa is absent

Decreased aggregation in response to collagen, ADP, thrombin, epi

Normal aggregation to human vWF (+ristocetin) and to bovine vWF

Front 53

What are the "storage pool" disorders?

Back 53

1. defective serotonin uptake into platelet granules (and granule ADP)

2. defective ADP/serotonin release from platelet granules

3. decreased aggregation

Front 54

Causes of acquired qualitative platelet disorders?

Back 54

1. uremia

2. myeloproliferative d/o's

3. paraproteinemias

4. liver disease

5. drug-induced defects

Front 55

Result of uremia?

Back 55

Uremia is retained organic acids

1. clinical bleeding
-- prolonged bleeding time test
-- BUN > 50mg/dL

2. Poor platelet fxn
-- inhibited by retained grandinosuccinic acid, phenolic acids, and others

Front 56

Which drugs can cause platelet disorders?

Back 56

ASA, NSAIDS, EtOH, antihistamines, antibiotics, some sedatives, many others
-- inhibitory effect on release of platelet ADP

Plasma expanders such as dextran and hydroxyethyl starch have been assoc w/ prolonged bleeding time