Pathology of Hemostasis Disorders Flashcards
thrombocytopenia - defined
*defined by platelets < 150,000
*spontaneous bleeding occurs at platelets < 20,000
-usually involves small vessels of skin, mucous membranes, GI/GU tracts
-intracranial bleeding can be serious!
causes of thrombocytopenia
- decreased platelet production = bone marrow problems (aplastic anemia, MDS, vitamin deficiency, tumors)
- decreased platelet survival
a. immunologic (circulating anti-platelet antibodies to GpIIb/IIIa or GpIB) - ex. ITP, HIV, drugs
b. mechanical destruction/consumption - ex. MAHA, prosthetic heart valves - sequestration
- dilutional
thrombocytosis - defined
*defined by platelets > 350K
*complications:
-thrombotic episodes, due to increased number of active platelets
-bleeding episodes, as platelet function may also be defective
causes of thrombocytosis
- primary causes: myeloproliferative neoplasms (essential thrombocytosis, CML, PV, PMF)
- secondary/reactive causes: infections, iron deficiency, inflammatory disorders, etc
immune thrombocytopenic purpura (ITP) - pathogenesis
*antiplatelet antibodies to GpIIb/IIIa or GpI/IX:
-coat platelets, which are selectively removed from circulation by the spleen
immune thrombocytopenic purpura (ITP) - causes
*may be secondary or primary (idiopathic)
1. acute:
-children
-self-limiting
-post acute viral infection
- chronic:
-adults
-autoimmune syndromes, infections, drugs, HIV
immune thrombocytopenic purpura (ITP) - diagnosis
*isolated thrombocytopenia in otherwise healthy pt (no other cell counts low)
*NORMAL PT, aPTT
*normal/increased numbers of megakaryocytes in bone marrow
*RULE OUT: no known exposure to thrombocytopenic agents
ddx for: increased PT, normal aPTT, normal platelets
*VII, X, V deficiencies
*Vitamin K deficiency
ddx for: normal PT, elevated aPTT, normal platelets
*VIII, IX, XI deficiencies
*VWD
*heparin
ddx for: elevated PT, elevated aPTT, normal platelets
liver disease
ddx for: elevated PT, elevated aPTT, decreased platelets
DIC
ddx for: normal PT, normal aPTT, decreased platelets
*hypersplenism
*platelet destruction/production (ITP, TTP, HUS)
ddx for: normal PT, normal aPTT, increased platelets
reactive vs. myeloproliferative disorder
D-dimer lab test
*specific plasmin-mediated breakdown product of cross-linked fibrin
*normal < 200 ng/mL
*useful for:
-DIC (level usually very elevated)
-DVT, post-op, acutely ill level elevated, not as high as seen in DIC
RBC fragmentation syndromes
- mechanical/vascular hemolysis: direct mechanical trauma from hemodynamic defect or extreme turbulence
-prosthetic heart valves, vascular malformations, malignant hypertension, severe burns, “March hemoglobinuria” - microangiopathic hemolytic anemias (MAHA): endothelial damage in microvasculature
-DIC, TTP, HUS
microangiopathic hemolytic anemias (MAHA)
*RBCs are damaged when passing through obstructed or narrowed vessels
*causes intravascular hemolysis
*examples:
1. disseminated intravascular coagulation (DIC)
2. thrombotic thrombocytopenic purpura (TTP)
3. hemolytic uremic syndrome (HUS)
disseminated intravascular coagulation (DIC) - overview
*a secondary condition in which microthrombi develop throughout the bloodstream, blocking small blood vessels and depleting platelets and clotting factors needed to control bleeding
disseminated intravascular coagulation (DIC) - pathogenesis
*simultaneous systemic activation of:
- coagulation system:
-widespread expression of tissue factor (TF)
~intravascular thrombus formation (compromising blood supply to various organs)
~exhaustion of platelets and coagulation factors, resulting in hemorrhage - fibrinolytic system:
-plasmin degrades fibrinogen and fibrin, producing fibrin degradation products, exacerbating bleeding
disorders associated with disseminated intravascular coagulation (DIC)
*malignancies (solid tumor, hematologic)
*obstetric emergencies (amniotic fluid embolism, abruptio placentae)
*organ destruction (severe pancreatitis, severe hepatic failure)
*sepsis/severe infection
*severe toxic or immunologic reactions
*trauma
*vascular abnormalities
disseminated intravascular coagulation (DIC) - common triggers
- massive tissue destruction
- sepsis
- endothelial cell injury
note - all three of these cause mass release of tissue factor
disseminated intravascular coagulation (DIC) - clinical features
*usually severe bleeding:
-petechiae/ecchymoses of skin/mucous membranes
-shock
*signs of the underlying disease are usually present
*organ(s) involved with accompanying clinical signs must also be taken into consideration
disseminated intravascular coagulation (DIC) - LABS
*increased PT
*increased aPTT
*decreased platelets (thrombocytopenia)
*increased D-dimers
*microangiopathic hemolytic anemia with SCHISTOCYTES on peripheral smear
thrombotic thrombocytopenic purpura (TTP) - clinical pentad
*microangiopathic hemolytic anemia (decreased Hb, schistocytes, and increased LDH)
neurologic abnormalities**
**renal insufficiency (decreased creatinine)
*fever
*thrombocytopenia
thrombotic thrombocytopenic purpura (TTP) - pathophysiology
inhibition or deficiency of ADAMTS13 (a vWF metalloprotease) -> decreased degradation of vWF multimers -> increased large vWF multimers -> increased platelet adhesion and aggregation (microthrombi formation)
thrombotic thrombocytopenic purpura (TTP) - lab diagnosis
*deficiency of vWF metalloprotease ADAMTS13 (results in accumulation of very-high-molecular-weight multimers of vWF, promoting platelet aggregation)
*consumptive thrombocytopenia (LOW PLATELETS)
*NORMAL PT and PTT
*MAHA with schistocytes in blood smears (low Hb, high LDH)
hemolytic uremic syndrome (HUS) - clinical features
*microangiopathic hemolytic anemia (decreased Hb, schistocytes, increased LDH)
*thrombocytopenia
*renal insufficiency
*bloody diarrhea
hemolytic uremic syndrome (HUS) - pathogenesis
*predominantly caused by Shiga toxin-producing E. coli (STEC) infection (serotype 0157:H7), which causes profound endothelial dysfunction
hemolytic uremic syndrome (HUS) - lab diagnosis
*E. coli 0157:H7 infectious gastroenteritis:
-elaborates shiga-like toxin absorbed by GI tract and binds to endothelial cells, initiating platelet activation
*consumptive thrombocytopenia
*NORMAL PT and PTT
*MAHA with schistocytes in blood smears (low Hb, high LDH)
what can help you distinguish TTP from HUS?
- HUS = bloody diarrhea; TTP = neuro symptoms
- HUS = E. coli 0157:H7; TTP = ADAMTS13 deficiency
von Willebrand Factor (vWF) - functions
- binds to GpIb receptor on platelets adhesion to damaged epithelium
- carrier protein for VIII (stabilized VIII, increasing serum half life)
von Willebrand Disease (VWD) - epidemiology
*most common bleeding disorder
*affects 1% of general population
*autosomal dominant OR recessive:
-multiple genetic mutations
-results in either a QUANTITATIVE or QUALITATIVE deficiency of vWF
von Willebrand Disease (VWD) - diagnostic approach
*hematologic evaluation of peripheral blood
*screening for hemostasis (platelet count, PT, aPTT, etc)
*VWD panel (esoteric testing):
-decreased factor VIII activity
-decreased vWF antigen
-decreased ristocetin cofactor activity
Factor VIII deficiency (Hemophilia A) - labs
*prolonged PTT, normal PT
*factor VIII-specific assays are required
acquired coagulopathies
- liver disease:
-liver is the major site of clotting factor synthesis
-hepatitis/cirrhosis
-results in bleeding diathesis - Vitamin K deficiency
-biliary obstruction, malabsorption syndromes, nutritional deficiencies
-drugs affecting gut flora
-results in bleeding diathesis - DIC
-tissue factor express
-results in purpuric manifestations
Factor V Leiden - epidemiology
*most common inherited thrombotic disorder
*accounts for 20-50% of thrombotic disorders
*autosomal dominant:
-point substitution resulting in Arg506 -> Gln
-mutation in Factor V renders it resistant to proteolysis by activated Protein C
Factor V Leiden - clinical features
*recurrent venous thromboembolism, may be asymptomatic
Factor V Leiden - diagnosis
DNA mutational analysis
Factor V Leiden - treatment
*prophylactic anticoagulation (warfarin)
