Hemostatic Disorders Flashcards
Heparin/heparin-like molecules
- Enhance anti-thrombin III
* Neutralize coagulation factors 7, 9-12, thrombin
PGI2
- Synthesized from PGH2 in epithelial cells
* Vasodilator, inhibits platelet aggregation
Protein C
- Vit K dependent
* Inactivates factors 5 and 8
Thromboxane A2
- Synthesized from PGH2 by platelets
* Vasoconstrictor, enhances fibrinogen binding to GpIIb-IIIa receptors
What does aspirin do?
Irreversible COX inhibitor, inhibits TXA2 formation
vWF
- Synthesized by endothelial cells and megakaryocytes
- Aids platelet adhesion to exposed collagen by binding to Gp1b receptor
- Prevents degradation of factor 8c
What does tissue thromboplastin (factor 3) do?
Activates factor 7
What is the platelet receptor for fibrinogen and which drugs interfere with it?
- Gp2b-3a
* Ticlopidine, clopidigrel, abciximab
What is Glanzmann disease?
Deficiency in Gp2b-3a
What is in platelet dense bodies?
- ADP, aggregating agent
* Calcium, binding agent for vit K-dependent factors
What is in platelet α-granules?
vWF, fibrinogen, PDGF, platelet factor 4 (neutralizes heparin)
What do platelets do?
- Stabilize intercellular adherens jxns, esp. in postcapillary venules
- Form fibrin thrombus in small vessel injury
- PDGF stimulates smooth muscle hyperplasia (see: pathogenesis of atherosclerosis)
Why do petechiae appear?
Thrombocytopenia causes disassembly of intercellular jxns and RBCs leak out
How is the extrinsic coagulation system activated?
Damaged tissue activates factor 7, which activates factors 9 and 10
What does factor 12 do?
- Initiates intrinsic coagulation system when exposed to subendothelial collagen
- Activates factor 11, plasminogen (—> plasmin) and kiminogen (—> kallikrein, bradykinin)
What factors are involved in the intrinsic coagulation system?
Factors 8, 9, 11, 12
What factors are involved in the final common coagulation pathway?
Factors 1, 2, 5, 10
How is thrombin formed?
Prothrombin is cleaved by prothrombin complex (product of final common coagulation pathway) into thrombin
What are 4 functions of thrombin?
- Converts fibrinogen —> fibrin
- Activates factor 13, which enhances fibrin cross-linking
- Activates factor 8
- Activates protein C, which inactivates factors 5 and 8
Where is vitamin K activated and what does it do?
- Activated in liver by epoxide reductase
* Along with calcium, activates factors 2, 7, 9, 10 and protein C
Which factors are consumed in clot formation?
1 (fibrinogen), 2, (prothrombin), 5, 8
Name 5 activators of the fibrinolytic system.
tPA, factor 12, streptokinase (from streptococci), urokinase, anistreplase
What does aminocaproic acid do?
Blocks plasminogen activation
What does plasmin do?
Breaks up cross-linked fibrin into fragments called D-dimers
What happens in the vascular phase?
- Transient local vasoconstriction
- Activation of factor 7 by TTP
- Activation of factor 12 by exposed collagen
What happens in the adhesion step of the platelet phase?
Platelet GpIb receptors adhere to vWF in damaged endothelial cells
What is Bernard-Soulier disease?
Absence of GpIb receptors
What happens in the release reaction step of the platelet phase?
Platelet dense bodies release ADP, which primes GpIIb-IIIa receptors to bind fibrinogen
What is the temporary platelet thrombus?
Held together with fibrinogen, marks end of bleeding time
What happens in the coagulation phase?
Thrombin converts fibrinogen —> fibrin to form STABLE platelet thrombus
What happens in the fibrinolytic phase?
Plasmin cleaves fibrin, breaking clot
What does the PT (prothrombin time) test, and what are 3 of its uses?
- Tests extrinsic coagulation system
- Warfarin monitoring
- Liver synthetic function
- Detects factor 7 deficiency if PTT is normal
What does the PTT (partial thromboplastin time) test, and what are 2 of its uses?
- Tests intrinsic coagulation system
- Heparin monitoring
- Factor deficiencies in intrinsic coagulation system
What does FDPs stand for and what does it test?
- Fibrin(ogen) degradation products
* Tests plasma degradation of fibrin(ogen)
What does a D-dimer test? What conditions is it used for? What are the major pro and con?
- Specific for lysis of FIBRIN thrombi
- Monitors fibrinolytic therapy OR tests for clot-related conditions (DVT, PE, DIC, etc.)
- High sensitivity—can use to r/o diseases
- Low specificity—frequent false positives with inflammation, liver disease, trauma, etc.
Acute idiopathic thrombocytopenic purpura
- Children 2-6 yrs
- 1-3 weeks after viral infection
- Epistaxis, easy bruising, petechiae
- IgG vs. GpIIb-IIIa receptors (type II hypersensitivity)
- Steroids or IV IG
Chronic idiopathic thrombocytopenic purpura
- Adults, esp. women 20-40 yrs
- Gradual onset, may be caused by SLE, HIV, etc.
- Epistaxis, easy bruising, petechiae
- IgG vs. GpIIb-IIIa receptors (type II hypersensitivity)
- Splenectomy; acute bleeding may be stopped w/ IV gamma-globulin
Neonatal alloimune thrombocytopenia
- Feto-maternal mismatch in platelet-specific PlA1 antigen
- Maternal IgG crosses placenta and attacks PlA1
- Neonate: few days of petechiae; in severe cases, CNS hemorrhage
Post-transfusion purpura
- Mothers who have developed anti-PlA1 IgG and receive PlA1-positive transfusion
- Severe thrombocytopenia 7-10 days after transfusion
Type I heparin-induced thrombocytopenia
Early in heparin course, self-limiting
Type II heparin-induced thrombocytopenia
- 5-14 days after heparin therapy
- Activation of coagulation system + vessel thrombosis
- Treat with thrombin antagonists
Thrombotic thrombocytopenic purpura
- Women 10-50 yrs old
- Increased vWF multimers promoting platelet activation
- Endothelial damage with drugs, infection, HTN, autoimmune disease, malignancy, radiation
- Platelets are consumed
- Clinical pentad: fever, thrombocytopenia, renal failure, schistocytes, CNS deficits
- Plasma exchange therapy, steroids; in severe cases splenectomy
- Mortality rate 10-20%
How can portal HTN lead to thrombocytopenia?
Platelets become sequestered in spleen (hypersplenism)
Name 3 common causes of thrombocytosis.
Chronic iron deficiency, malignancy, splenectomy
What are 3 common signs of platelet dysfuncion?
Epistaxis, bleeding from superficial scratches, easy bruising (all may also occur with coagulation deficiency)
What is senile purpura?
Purpura in elderly associated with trauma; normal result of aging
What are 2 common signs of coagulation deficiency?
Late rebleeding after surgery, hemarthroses (severe deficiency)
Hemophilia A
- XLR
- Factor 8 deficiency (intrinsic coagulation system)
- Increased PTT
- Treat mild cases with desmopressin acetate
- Treat severe cases with factor 8 infusion
Hemophilia B (Christmas disease)
Factor 9 deficiency; clinically indistinguishable from hemophilia A
Classic von Willebrand disease
- Autosomal dominant
- May be produced by angiodysplasia or severe aortic valve stenosis (repaired with AV replacement)
- Increased PTT in 50% or fewer of cases; gene analysis to confirm diagnosis
- Treat with desmopressin acetate or OCPs (increases vWF release, stabilizes factor 8)
- In severe cases, infuse cryoprecipitate
Antibodies against coagulation factor(s)
- Most common vs. factor 8, can occur postpartum or in hemophiliacs receiving factor 8 transfusion
- Increased PT and/or PTT; mix with normal plasma to differentiate immune destruction (no correction of PT/PTT) from decreased factor quantity (correction of PT/PTT)
Cirrhosis-caused hemostasis disorders
- Decreased synthesis of coagulation factors, anticoagulants, fibrinolytic agents
- Decreased clearance of fibrin(ogen) degradation products, D-dimers, tPA
- Increased PT/PTT, FDPs, D-dimer
DIC (disseminated intravascular congestion)
- Fibrin thrombi throughout microcirculation —> ischemia (mostly composed of RBCs with trapped leukocytes and platelets)
- Bleeding from nose, GI tract, puncture sites —> anemia w/ schistocytes
- May be caused by damaged tissue (massive trauma, shock, malignancies, obstetrical problems, ARDS, acute pancreatitis, rattlesnake bite)
- May be caused by endothelial cell injury (Gram-negative septicemia [MCC], deposition of immune complexes [ex. SLE], severe temp. alterations)
- Bleeding from consumption and trapping of platelets, activation of fibrinolytic system
- Increased PT/PTT thrombocytopenia, positive FDPs/D-dimer
- TREAT UNDERLYING CAUSE!
- Infuse frozen plasma, packed RBCs, cryoprecipitate for fibrinogen deficiency
Primary fibrinolysis
- Causes: open heart surgery, radial prostatectomy, cirrhosis
- Increased PT/PTT, FDPs; NEGATIVE D-dimer, normal platelets
- Treat w/ aminocaproic acid to block plasminogen
Secondary fibrinolysis
- Compensatory reaction in DIC
* Increased FDPs, D-dimer; thrombocytopenia
Antiphospholipid syndrome
- Commonly associated w/ SLE, other autoimmune disorders
- Venous and arterial thrombi
- May cause false positive syphilis serology test with anticardiolipin Ab (ACA)
- Sx include DVT, stroke
- Best test is ACA
- Treat w/ warfarin therapy
Name 5 acquired causes of thrombosis syndromes.
Stasis of blood flow, malignancy, folic acid/B12 deficiency, OCPs, hyperviscosity
Factor 5 Leiden disorder
- Autosomal dominant; clots at early age
* Factor 5 cannot be degraded
Antithrombin 3 deficiency
- Autosomal dominant; clots at early age
- ATIII normally neutralizes several factors (serine proteases)
- Normal PTT after heparin
Proteins C and S deficiency
- Autosomal dominant; clots at early age
- Activated factors 5 and 8 cannot be inhibited
- Warfarin therapy, but at low dose to avoid cutaneous vessel thrombosis and skin necrosis
