SM_259b: Acquired Coagulation Disorders Flashcards
____, ____, ____, and ____ interplay to achieve normal hemostasis
Vascular integrity, platelet function, clotting proteins / coagulation, and fibrinolysis interplay to achieve normal hemostasis
Describe conditionns resulting from issues with vascular integrity
Vascular integrity issues
- Telangiectasias
- Allergic purpura: Henoch-Schonlein purpura
- Atherosclerotic disease
- Rheumatologic disease: vasculitis
- Weak connective tissue: steroids, senile purpura
- Vascular infiltration: AML
- Mechanical issues
Describe quantitative defects in platelets
Quantitative defects in platelets
- Autoimmune, medications, sequestration, consumption
- > 50k: minimal risk of bleeding
- 20-50k: minimal risk of spontaneous bleeding, high risk of surgical bleeding
- <20k: variable risk spontaneous bleeding, consider comorbidities
Describe qualitative defects in platelets
Qualitative defects in platelets
- Immune mediated
- Toxins: uremia
- Medications: aspirin, clopidogrel, ticlopidine, eptifibatide, high dose beta-lactams
- Other acquired defects: myelodysplastic syndrome, acquired von Willebrand’s disease
Third phase of hemostasis is ___
Third phase of hemostasis is coagulation
Describe causes of acquired coagulopathy
Causes of acquired coagulopathy
- Associated with bleeding: Vitamin K deficiency, liver disease, disseminated intravascular coagulation, drug-induced, inhibitors of coagulation factors (acquired hemophilia), abnormal fibrinolysis, essential thrombocytosis
- Associated with clotting: antiphospholipid syndrome, liver disease, disseminated intravascular coagulation, drug-induced, polycythemia, nephrotic syndrome, and essential thrombocytosis
___ and ___ are causes of acquired coagulopathy associated with both bleeding and clotting
Liver disease and disseminated intravascular coagulation are causes of acquired coagulopathy associated with both bleeding and clotting
Vitamin K is a ___
Vitamin K is a co-factor in enzymatic post-translational modifications of specific factors
- Changes N-terminal glutamic acid residues into gamma-carboxyglutamic acids (G1a): Ca2+ chelation, allows binding to phospholipids
- Procoagulants: factors II, VII, IX, X
- Anticoagulants: Protein C and S
- Factor synthesis mainly hepatic
Vitamin K sources are ___ and ___
Vitamin K sources are diet (leafy green vegetables) and intestinal flora
- Severe malnutrition can lead to Vitamin K deficiency
- Antibiotics and malnutrition can lead to Vitamin K deficiency
Vitamin K is ____ and absorbed in the ____
Vitamin K is fat soluble (bile acids) and absorbed in the termianl ileum
- Malabsorption syndromes can lead to Vitamin K deficiency
Vitamin K deficiency occurs in ____ and bleeding occurs because of non-administration of Vitamin K deficiency at birth or parental refusal
Vitamin K deficiency occurs in newborns and bleeding occurs because of non-administration of Vitamin K deficiency at birth or parental refusal
- Presentation
- Early: maternal use of drugs, with ICH
- Classic: as GI bleeding or bleeding from venipuncture in 1st week of life
- Late: between 3 weeks and 8 months of life, can progress to ICH
Describe treatment of acquired Vitamin K deficiency
Acquired Vitamin K deficiency treatment
- No overt bleeding: oral Vitamin K
- Overt bleeding: Vitamin K, plasma products such as FFP or PCC
Low levels of ____, ____, ____, and ____ are present in Vitamin K deficiency
Low levels of Factrs II, VII, IX, and Protein C are present in Vitamin K deficiency
Describe normal functions of liver
Normal hepatic function
- Synthesis of all coagulation factors
- Synthesis of inhibitors of coagulation
- Thrombopoietin synthesis
- Clearance of activated hemostatic proteins and inhibitor complexes from circulation
Describe platelet effects in liver disease
Platelet effects in liver disease
- Quantitative: decreased levels
- Qualitative: decreased aggregation
____ including ____, ____, and ____ lead to bleeding in coagulopathy of liver disease
Clotting factor abnormalities including decreased synthesis, decreased Vitamin K absorption, and decreased fibrogen synthesis / dysfibrinogenemia lead to bleeding in coagulopathy of liver disease
___ including ___ and ___ leads to clotting in coagulopathy of liver disease
Decreased production of anticoagulants such as antithrombin III and protein C and S leads to clotting in coagulopathy of liver disease
- Decreased production and increased consumption of antithrombin III
Fibrinolysis is ____ in liver disease
Fibrinolysis is increased in liver disease
- Decreased clearance of tPA -> increased levels
- Decreased levels of plasminogen, a2-plasmin inhibitor, Factor XIII, thrombin activatable fibrinolytic inhibitor
aPTT is ____, PT is ____, platelets are ____, and fibrinogen is ____ in liver disease
aPTT is prolonged, PT is prolonged, platelets are low, and fibrinogen is low in liver disease
- However, bleeding and thrombosis occur at the same time
Liver disease coagulopathy treatment involves ____
Liver disease coagulopathy treatment involves focus on active bleeding or clotting as they occur
- Do not treat the lab values
- Blood products: > 50k platelets, FFP, cryoprecipitate, Vitamin K
2-year old boy admitted to PICU with transaminitis and direct hyperbilirubinemia. Platelet count is 90,000/mm3.
____ will be elevated in coagulopathy of liver failure
2-year old boy admitted to PICU with transaminitis and direct hyperbilirubinemia. Platelet count is 90,000/mm3.
PT will be elevated in coagulopathy of liver failure
Describe disseminated intravascular coagulation
Disseminated intravascular coagulation
- Systemic process involving both thrombosis and hemorrhage
- Exposure of blood to procoagulants
- Circulating fibrin
- Concurrent fibrinolysis
- Depletion of clotting factors and platelets
- End organ damage
Describe coagulation in DIC
Coagulation in DIC
Describe bleeding in DIC
Bleeding in DIC
Describe acute DIC
Acute DIC
- Decompensated intravascular coagulation
- Depletion of platelets, fibrinogen, prothrombin, clotting factors
- FDP generation: hemostasis interference
- Clinically: bleeding diathesis
- Can also see microangiopathic hemolytic anemia
Describe chronic DIC
Chronic DIC
- Liver compensates for clotting factor consumption
- Bone marrow compensates for platelet loss
- Clinically see more thrombotic manifestations
- Malignancies (except APML)
Describe causes of DIC
DIC causes
- Infection / sepsis: bacterial and nonbacterial
- Tissue damage: surgery or trauma
- Cancer
- Obstetrical complications
Describe how infection / sepsis causes DIC
Infection / sepsis causes DIC
- Both bacterial and nonbacterial
- Shock -> decreased blood flow and tissue damage -> thrombin generation
- Impaired hepatic perfusion -> decreased removal of activated procoagulants
Describe how tissue damage causes DIC
Tissue damage causes DIC
- Surgery or trauma (particularly head trauma)
- Release of tissue enzymes and phospholipids from damaged tissue
Describe how cancer causes DIC
Cancer causes DIC
- TF expression by circulating tumor cells
- Cancer procoagulant
Describe how obstetrical complications cause DIC
Obstetrical complications cause DIC
- > 50% of cases due to amniotic fluid embolus or abruptio placenta (release of thromboplastin-like material)
Describe clinical presentation of acute DIC
Clinical presentation of acute DIC
- Usually profound bleeding w/ ischemic tissue injury
- Petechiae / ecchymosis, oozing from lines / mucosal surfaces
- Microangiopathic hemolytic anemia
- Shock
- Hyperbilirubinemia: hemolytic anemia, liver dysfunction / shock liver
- Thromboembolic phenomena
- AKI: microthrombi in afferent arterioles w/ cortical ischemia, hypotension -> ATN
- Pulmonary hemorrhage / ARDS
- CNS hemorrhag
Describe clinical presentation of chronic DIC
Clinical presentation of chronic DIC
- Tend to be thrombotic complications
- Can be both arterial and venous
- Malignancy is most common cause
DIC is diagnosed ___
DIC is diagnosed clinically with aid of some labs
- Lab values depend on rapidity of evolution and ability of normal systems to compensate
- Moderate-severe thrombocytopenia (< 100)
- Fibrinolysis: FDP and D-dimer elevations
- Prolonged PT and PTT
- Fibrinogen usually low
Describe treatment of DIC
DIC treatment
- Treat underlying cause
- Blood product used only if bleeding
Compare and contrast Vitamin K deficiency, liver disease, and DIC
Vitamin K deficiency, liver disease, and DIC
You are consulting on an elderly woman in the hospital who is admitted with a severe pneumonia and bacteremia. She is on broad spectrum antibiotics but is oozing from venipuncture sites and has widespread ecchymosis. She has elevated PT, PTT, and low platelets. You suspect she has DIC.
Need ___ for diagnosis of DIC
You are consulting on an elderly woman in the hospital who is admitted with a severe pneumonia and bacteremia. She is on broad spectrum antibiotics but is oozing from venipuncture sites and has widespread ecchymosis. She has elevated PT, PTT, and low platelets. You suspect she has DIC.
Need increased D-dimers for diagnosis of DIC
Describe pathologic inhibitors of coagulation
Pathologic inhibitors of coagulation
- Circulating antibodies directly inhibit clotting proteins
- Associated with clinical bleeding syndrome
- Acquired FVIII inhibitors occur in a few situations: all antibody in congenital hemophilia A, autoantibodies
Describe acquired FVIII inhibitor
Acquired FVIII inhibitor (autoantibodies)
- IgG specific to FVIII: most epitopes specific for A2 and C2, no interference w/ vWF
- Symptoms: easy bruising / bleeding, large muscle hematomas, GI / GU bleeding
Describe normal hemostasis
Normal hemostasis
Describe labs for acquired FVIII inhibitor
Labs for acquired FVIII inhibitor
- Low factor VIII activity: undetectable
- Prolonged PTT: normal PT
- No correction on 1:1 mixing study
Describe the mixing test
Mixing test
Describe labs for acquired FVIII inhibitor
Labs for acquired FVIII inhibitor
- Quantify titer of Ab with Bethesda assay (BU): low titer inhibitors ≤ 5 BU
Describe treatment of acquired Factor VIII inhibitors
Acquired Factor VIII inhibitors treatment
- Bleeding if low titer: desmopressin trial, FVIII concentrates
- Bleeding if low titer: prothrombin complex concentrates, recombinant FVIIa
- Eradication of antibody: immunosuppressives (steroids, cytoxan), rituximab
May spontaneously resolve but relapse is common
Describe differences in congenital and acquired hemophilia
Congenital and acquired hemophilia
He has ____
He has low Factor VIII activity level
Describe where phospholipids are involved in the coagulation cascade
Phospholipids are involved in the coagulation cascade
Describe antiphospholipid antibodies
Antiphospholipid antibodies
- Autoantibodies directed against anionic phospholipids and plasma proteins: B2 glycoprotein I and prothrombin are antigen targets, antibodies are lupus anticoagulant / anticardiolipin antibody, and B2 glycoprotein antibody
Antiphospholipid antibodies can interfere with ___
Antiphospholipid antibodies can interfere with normal clotting times
- Lupus anticoagulant is a common cause of elevated PTT
- Does not confer a bleeding risk but associated with thrombosis
Describe pathophysiology of antiphospholipid syndrome
Antiphospholipid syndrome pathophysiology
- Complex interplay of endothelial cells, monocytes, platelets, and complement
- Increase tissue factor, thromboxane, complement activation -> procoagulant state
- Second hit may lead to clinical thrombosis: often other cardiovascular risk factors
Describe cells involved in antiphospholipid syndrome
Antiphospholipid syndrome
- Endothelial cells: antiphospholipid antibodies recognize B2 glycoprotein I bound to endothelium -> binding -> endothelial activation -> expression of adhesion molecules and upregulation of tissue factor
- Monocyte activation: upregulation of tissue factor, cytokine production
- Platelet activation: increase glycoprotein 2b-3a production and thromboxane A2 production
Describe clinical manifestations of antiphospholipid syndrome
Clinical manifestations of antiphospholipid syndrome
- Venous thrombosis (most common)
- Arterial thrombosis
- Adverse pregnancy outcomes: recurrent miscarriage, preterm birth, preeclampsia and placental insufficiency, intrauterine growth restriction
- Other: thrombocytopenia, hemolytic anemia, livedo reticularis, cognitive deficits, cardiac valvular disease
Antiphospholipid antibodies can ___, ___, and ___
Antiphospholipid antibodies can interfere with normal clotting times, be transiently detected, and found in association with autoimmune conditions
Describe differences in antiphospholipid antibody and acquired hemophilia
Antiphospholipid antibody and acquired hemophilia
Antiphospholipid syndrome diagnosis involves ___ and ___
Antiphospholipid syndrome diagnosis involves at least 1 clinical and 1 lab criteria
Catastrophic antiphospholipid antibody syndrome is ___
Catastrophic antiphospholipid antibody syndrome is life-threatening with ≥ 3 organs involved
- Plasma exchange to decrease antiody load may be helpful
Most appropriate lab test is ___
Most appropriate lab test is aPTT mixing study
