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56 Cards in this Set

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The most common inherited coag disorders are...?
Classic hemophilia
-- factor VIII deficiency

Christmas disease
-- factor IX

BOTH are inherited as sex-linked disorders
All other coagulation factors are...?
autosomal recessive, and therefore, very rare
The most frequently acquired bleeding disorders due to abnormalities in plasma coagulation are...?
liver disease

DIC
Iatrogenic bleeding may be caused by...?
treatment w/ anticoagulants

antiplatelet medication
Vitamin K is a key molecule in the synth of...?
Factors II, VII, IX, X

Protein C and S
Deficiency of VitK leads to...
dysfxnal forms of II, VII, IV, X, C & S and a bleeding diathesis
Evaluation of thrombocytopenia requires...?
determining rate of platelet production

in almost all cases requires BM aspirate to access megakaryocytes
reactive vs. primary thrombosis?
Reactive is rarely a clinical problem

Primary (myeloproliferative) may be assoc w/ thrombosis OR hemorrhage
The most common inherited platelet disorder?
vonWillebrand's disease
-- not a platelet disorder
-- decrease or abnormality of a plasma protein (vWF) required for normal platelet adhesion
Retained organic acids from uremia can result in...?
significant bleeding diasthesis w/ abnormalities in all platelet fxns
What are the clinical manifestations of hemophilia?
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
Genetics of hemophilia?
Sex-linked:
-- Factor VIII (hemophilia A)
-- Factor IX (hemophilia B)

Autosomal:
-- all others
What causes Hemophilia A?
PROPERTIES
-- coagulant activity (FVIIIc)
-- circulates bound to and is stabilized by vWF

DEFECT
--defective or absent coagulant protein
What causes Hemophilia B?
-- production of abnormal protein factor IX

OR

-- reduced amount of normal IX
How do you determine how much factor replacement is needed in hemophilia?
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
What is the half-life of replacement VIII and IV?
FVIII is approx 8-12h

FIX is approx 20-26h
Therapeutic materials in the treatment of hemophilia?
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)
Comprehensive vs home care for hemophiliacs?
COMPREHENSIVE
1. hemophilia centers
2. multi-disciplne approach
3. health maintenance

HOME CARE
1. less total cost
2. less social, physical morbidity
3. indications
Complications of therapy?
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
How are deficiency states involving other coag factors treated?
FFP

Cryoprecipitate if hypofibrinogenemia
How do we treat a deficiency of Protein C, S and antithrombin?
treat w/ anticoagulation b/c leads to thrombosis

In homozygous deficiency of C or S, can treat w/ factor IX concentrates
Acquired coagulation disorders?
1. liver disease

2. vitamin K deficiency

3. bleeding secondary to anticoag meds
How does the liver play a role in coagulation?
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)
Hemostatic effects of liver disease?
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
Vitamin K's role in hemostasis?
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
What can cause a vitamin K deficiency?
1. hemorrhagic disease of the newborn

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

3. intestinal sterilization
-- loss of K2 from enteric bacteria
What anticoagulant meds can cause bleeding?
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
What are the quantitative platelet disorders?
1. thrombocytopenia

2. thrombocytosis
Common sites of bleeding due to thrombocytopenia?
skin: petechiae, ecchymosis
GI mucous mbrns
kidney
brain
What are causes of thrombocytopenia?
1. decreased BM production

2. ineffective thrombopoiesis

3. increased platelet destruction

4. abnormal sequestration of platelets

5. excessive loss of platelets
Causes of decreased platelet production by bone marrow?
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
Causes of ineffective thrombopoiesis?
Megakaryocytes present; may appear abnormal

1. megaloblastic anemia (B12/folate deficiency)

2. erythroleukemia

3. some familial thrombocytopenias

4. alcoholism

5. myelodysplasia

6. myeloprolif syndromes
Increased platelet destruction can be due to _____ or _____ causes.
immune

non-immune
Non-immune causes of increased platelet destruction?
1. DIC

2. Hemolytic uremic syndrome

3. TTP
Immune causes of increased platelet destruction?
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)
Causes of hypersequestration of platelets?
hypersplenic thrombocytopenia
Causes of excessive platelet loss?
massive bleeding and replacement w/ stored blood
How do we treat thrombocytopenia?
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
Clinical manifestations of thrombocytosis?
platelet count > 1 million

Thrombosis OR
Bleeding
Causes of thrombocytosis?
1. myeloproliferative disorders

2. inflammatory disorder

3. "stimulated" bone marrow

4. others
Which myeloproliferative disorders can cause thrombocytosis?
1. essential thrombocythemia
-- can be increased or abnormal

2. polycythemia vera

3. chronic granulocytic leukemia

4. myelofibrosis w/ myeloid metaplasia
Which inflamm disorders can cause thrombocytosis?
1. infection

2. RA

3. ulcerative colitis
What can "stimulate" the BM to cayse thrombocytosis?
1. acute blood loss

2. hemolytic anemia

3. treated pernicious anemia
"Other" causes of thrombocytosis?
1. iron deficiency

2. Hodgkin's disease

3. post-splenectomy (reactive change)

4. post-operative

5. CML
Inherited qualitative platelet disorders?
1. vonWillebrand's disease

2. Bernard-Soulier syndrome

3. Thrombasthenia

4. "Storage Pool" disorders
Clinical manifestations of vWB disease?
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
How do we diagnose vWB disease?
1. prolonged bleeding time

2. low FVIIIc

3. low vWF

4. low vWag
How is vWB disease classified?
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%
Pathogenesis of vWB disease?
1. quantitative or qualitative defect in vWF subunit structure

2. defective platelet-vWF interaction
vWB disease therapy?
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
What is Bernard-Soulier Syndrome?
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
What is thrombasthenia?
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
What are the "storage pool" disorders?
1. defective serotonin uptake into platelet granules (and granule ADP)

2. defective ADP/serotonin release from platelet granules

3. decreased aggregation
Causes of acquired qualitative platelet disorders?
1. uremia

2. myeloproliferative d/o's

3. paraproteinemias

4. liver disease

5. drug-induced defects
Result of uremia?
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
Which drugs can cause platelet disorders?
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