252. Coagulation and Inherited Bleeding Flashcards
Physiologic Antithrombotic Mechanisms
- 2 substances generated by endothelium to inhibit coag
- 5 mechanisms of antithrombosis
- Prostacyclin and NO inhibit platelet activation
1. Antithrombin III
2. Protein C and S
3. Tissue Factor Pathway Inhibitor
4. Thrombomodulin
5. Fibrinolytic System
What is the difference between primary and secondary hemostasis?
What are the differences in coag tests?
What positive feedback does thrombin have?
Natural inhibitors for thrombin, 5, 8, 10, 7
Primary: VC, aggregated platelets temporarily plug vessel
Secondary: fibrin formation to achieve more permanent clot
PT: tests extrinsic and common pathway (F VII; 1 2 5 10)
aPTT: tests intrinsic and common pathway (12, 11, 9, 8; 1 2 5 10)
TT: tests conversion time of fibrinogen to fibrin
Thrombin: stim thrombin, 5, 8, 11 to further increase thrombin
thrombin inhibitor: ATIII
5/8-i: Protein C (cofactor Protein S)
10/7-i: TFPI (tissue factor pathway inhibitor)
What factor activates plasminogen? What 3 factors inhibit plasminogen activation?
tPA activates
inhibitors: PAI-1/2 (plasminogen activator inhibitor), APC inhibitor, TAFI (thrombin activatable fibrinolysis inhibitor)
What are the causes of elevated PT, PTT, and both PT/PTT?
What other test can help narrow the ddx?
When does a factor deficiency become abnormal?
only elevated PT:
- Factor 7 deficiency
- early vit K deficiency/early warfarin tx
- Liver disease
only elevated PTT:
- Factor 8, 9, 11, 12 deficiency
- decreased HMWK (kininogen)
- inhibitor present (Lupus anticoaguluant, F 8 inhibitor)
- heparin use
both elevated
- factor II, V, X deficiency (common path)
- hypofibrinogenemia or dysfibrinogenemia
- late vit K deficiency (low 2, 7, 9, 10)
- liver disease
- late warfarin therapy
PT or PTT Mixing Study
- mix blood with normal plasma 1:1
- if PT/PTT normalizes = factor deficiency
- if no normalizing = inhibitor present
Factor deficiency must be below 30-40% to have abnormal PT/PTT!!
What do the following PE clues indicate:
- petechiae
- ecchymoses
- soft tissue hemorrhage
- telangiectasias (skin, nasal, oral, nails)
Petechiae: thrombocytopenia
Echhymoses: non-specific - clotting factor disorder, von Willebrand’s disease, C.T. disorders, meds, platelet disorders
Soft Tissue Hemorrhage: coag factor deficiency
Telangiectasias: Hereditary Hemorrhagic Telangiectasia
What is an example of vascular purpura?
- describe CP
- inheritance
- tx
- dx
Hereditary Hemorrhagic Telangiectasia
- abnormality in vascular wall
- CP: mucocutaneous telangiectasias (dermis, lips, tongue, fingernail beds, nose), AVMs (GI tract, pulmonary, liver, brain)
- AD disorder mutation in 5 genes (endoglin or ALK1) causing dysregulated TGF-beta
- more problems with age (recurrent epistaxis, iron deficient anemia)
- no tx
- dx: clinical (epistasis, multiple mc telangiectasia, visceral involvement, FamHx)
Hemophilia A
- genetics (most common mutation, inheritance)
- deficiency
- CP: mild/moderate vs. severe
- carrier state
- tx, complications
Factor VIII Deficiency
- XLR (1/3 cases spontaneous)
- most common mutation: inversion of intron 22 in F8
- Severe: spontaneous joint hemorrhages (Hemophilic arthropathy - loss of joint space over time), intramuscular hemorrhage, intracranial hemorrhage, serious bleeding with trauma or injury
- Mod/Mild: bleeding with surgery/dental procedures, bleeding with trauma/injury
- carriers: women, can have low factor levels and bleeding complications (need testing before surgery/pregnancy if pos FAMHX)
- tx: severe: prevent/tx bleed, early tx of joint bleeds and prophylactic tx to prevent joint bleed
mild: prevent bleeding with surgery or trauma, DESMOPRESSIN (raise F8 in mild deficiency only) - Factor Concentrates for F8
- Cryoprecipitate for F8 (emergency)
- complication: antibodies develop against concentrate 25% time = tx resistance!
Hemophilia B
- genetics
- deficiency
- CP
- tx, complications
Factor IX Deficiency
- XLR, 1/3 spontaneous
- Same CP as Hemophilia A
- tx: same as HA but:
- Factor concentrates for F9
- FFP for F9 (emergency)
- tx resistance due to ab development only occurs <5% time
von Willebrand Disease
- epi
- roles of vWF
- tests
- type 1 vs 2 vs 3
- tx
MOST COMMON INHERITED BLEEDING DISORDER
role of vWF: 1. binds platelet to epithelium, 2. binds protein F8 to increase F8 half life
- synthesized by endothelial cells and megakaryocytes = stored in Weibel-Palade bodies (EC) or alpha-granules (platelets)
tests: PTT (low if reduced F8), vWF Antigen/Activity (specific - Ristocetin factor activity/induced platelet aggregation), vWF multimer analysis, F8 test
T1: partial quantitative vWF deficiency
- MOST COMMON
- mildly low vWF, low VWF activity, low F8
- mild sx (epistaxis, bleeding with dental procedures)
- Type O blood = lower vWF levels
T2: functional/qualitative vWF defect
2A: abnormal platelet adhesion
2B: increased binding and clearance of vWF to platelets
2N: abnormal binding of F8 to VWF (F8 deficiency)
T3: severe quantitative vWF deficiency
- SEVERE low vWF, low F8
- severe bleeding similar to Hemophilia A (low F8)
Tx: Desmopressin (stim vWF release - makes T2B WORSE = increase dysfx platelet binding)
- vWF concentrate for T1 or T3
Hemophilia C
- what is it
- inheritance
- epidemiology
- PPhys
Factor XI Deficiency
- epi: RARE (higher prev in Ashkenazi Jews)
- XIa: role in feedback to enhance thrombin
- deficiency in XI = less thrombin generation and less TAFI (increased fibronolysis) = less strong clots that are more prone to breakdown
- variable bleeding
- tx: FFP (may develop inhibitor), Antifibrinolytics (aminocaproic acid, tranexamic acid) - help clots form and stay formed
Factor XIII Deficiency
- what is F13 role?
- what are unique about labs
- sx
- tx
Role: cross link fibrin! Deficiency = weak clots that dissolve more easily
Labs: NOT reflected in PT or PTT (normal findings!)
CP: heterozygotes asx
Homozygotes: severe deficiency, bleeding from birth, intracranial hemorrhage, easy bruising
Tx: FFP, Cryoprecipitate, Plasma-Derived FXII Concentrate
Fibrinogen Disorders
- tx
Cyroprecipitate or Plasma-derived Fibrinogen Concentrate
