10b- Intro to Hemostasis- Bleeding Disorders Flashcards
What are 5 defects in primary hemostasis?
- skin and mucosal membrane hemorrhages are common (eg petechiae, epistaxis, menorrhagia)
- Vascular abnormalities (eg Ehlers-Danlos)
- Platelet function disorders
- von Willebrand disease
What are 3 defects in secondary hemostasis?
- bleeds into soft tissues or joint
- clotting factor deficiencies
- hemophilia
- liver disease
- exogenous
- anticoagulants
What is thrombocytopenia? What 4 things are also on the differential diagnosis?
- usually defined as <100,000/uL
- Differential
- decreased bone marrow: aplastic anemia
- increased destruction (immune mediated, non-immune mediated)
- dilutional: decreased platelets bc increased fluid
- sequestration: big spleen harbors platelets
Thrombocytopenia is decreased platelets due to decreased _______
What 7 things cause thrombocytopenia?
Thrombocytopenia is decreased platelet production due to decreased megakaryocytes
- aplastic anemia
- vitamin B12/folate deficiency
- leukemia, lymphoma, MDS
- metastatic carcinoma
- alcohol, toxins
- drugs
- infections
Thrombocytopenia caused by increased destruction can be immune mediated or non-immune mediated? What are 4 examples of immune mediated thrombocytopenia?
immune thrombocytopenia purpura (ITP)
Heparin-induced thrombocytopenia (HIT)
Transfusion/preganncy-associated allo-immune thrombocytopenia
drug (quinine, vancomycin)
What are 4 non-immune mediated causes of thrombocytopenia?
Disseminated intravascular coagulation (DIC)
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Drug
WHat is Immunt Thrombocytopenia Purpura (ITP)
Caused by autoantibodies made against PLT antigens (GpIIb/IIIa, GpIb)
destruction of PLTs occurs by phagocytosis, Fc receptor mediated, loction is the spleen
What are the 2 categories of immune thrombocytopenia purpura (ITP)
- Primary: unknown etiologies
- Secondary: diseases we can identify
- lupus
- leukemia/lymphoma (eg CLL/SLL)
- Drugs
- Viruses (eg HIV, Hepatitis)
What are the clinical features of Immune Thrombocytopenia Purpura (ITP)? WHat are the 2 variant/the difference between them?
- skin, mucosal bleeds
- normal size spleen
- variants:
- Acute: self limited (< 6 months, post-viral, children)
- Chronic: adults (females), persistent>6 months
What are the pathologic findings of ITP?
Thrombocytopenia (often quite low), large platelets (circled)
normal to increased megakaryocytes in marrow
white pulp expansion
How do we diagnose ITP?
presumptive
iagnosis of exclusion
no diagnostic test
normal clotting tests
bone marrow not required
How do we treat ITP?
- May not be needed in children with self-limited disease
- immunosuppresant therapy
- steroids, intravenous immunoglobin (IVIG)
- Anti-CD20 antibody
- Thrombopoietin agonist
- Splenectomy
What happens in drug-induced thrombocytopenia?
drug binds to IIa/IIIb to elicit antibody reaction.Phagocytic cells then localize to the antibody and destroy the platelet
What is dilutional thrombocytopenia? Sequestration thrombocytopenia?
Dilution: Massive transfusion of trauma patients
Sequestration: Seen with hypersplenism, increased storage fo Platelelets
What are platelet function disorders? List 5
heterogenous group of inherites and acquired, qulitative disorders with variable clinical presentation
Bernard Soullier
Glanzmann’s thrombasthenia
Storage pool disease
Aspirin
Uremia
What is the pathophysiology of Bernard Soullier?
Inherited vs acquired
Clinically severe or variable?
Gp1b deficiency on platelet memebrane
inherited
severe
What s the pathophysiology of Glanzmann’s thrombasthenia?
Inherited or acquired
severe or variable
GpIIb/IIIa deficiency on platelet memebrane
inherited
severe
What is the pathophysiology of storage pool disease?
inherited or acquired
clinically severe or variably
granule, transit defect
inherited
variable
What is the pahtology of aspirin platelet dysfunction? inherited or acquired? clinically sever or variable?
Cox inhibition
acquired
variable
What is the most common inherited bleeding disorder? How is it inherited and how does that relate to severity of disease?
vonWillebrand disease
- usually autosomal dominant, incidence may be underestimated given mild presentation. rarely acquired
- clinically heterozygous
- mild, revealed with surgery, dental procedure, trauma
- moderate to severe, menorrhagia, spontaneous bleeding
- dependent on clinical type
Where is vW factor produced? What is the function? What is the structure of vWF
- produced by endothelial cells, megakaryocytes/PLTs
- Function:
- When circulating: stabilize F8 (T1/2=2.4 hrs free to 12 hours bound)
- Fixed: adhere to collagen and platelets through Gp1b
- Structure: multimers-metalloproteases cleave freshly cut vWF into multimers. there should be equal amount of all of the multimers
What are the 3 types of vWD? What are the characteristics of each of them?
- Type 1: Quantitative: most common A/D
- clinically heterogenous usually mild (how much factor they have determines how severe the disease is)
- Type 2: Qualitative
- 2A, 2B, 2M, 2N is A/R; others are usually A/D
- moderate to severe bleeding (They make vWF but it is dysfunctional)
- Complete absence (Quantitative)
- Rare, A/R
- severe bleeding disorder, mimichking heterophilia
How do we treat vWD?
desmopressin stimulates vWF release
factor concentrates
anti-fibrinolytics
oral concentration (to stop menorrhagia)
What are the laboratory tests used to screen for vWD and what would we expect the results to be? What are the confirmatory studies? (sorry this is a long card)
- Screen
- CBC (normal PLT count)
- PT (normal), aPTT (normal or prolonged)
- vWF antigen levels
- vWF activity (ristocetin)
- Factor 8 activity
- Confirmatory studies
- multimer electrophoresis
- specific biinding assays
- platetlet aggregation
In type 1, type 2 and type 3 vWD what would we expect for the vW antigen, vW activity, F8 activity?
Type 1: vW antigen decreased, vW activity normal or decreased, F8 activity Normal
Type 2: vW antigen normal, vW activity decreased, F8 activity normal or decreased
Type 3: vW antigen none, vW activity none, F8 activity very decreased
What are 2 types of defects in secondary hemostasis?
Single clotting factors: hemophilia
Multiple clotting factors: liver disease, Vitamin K deficiency, exogenous: anticoagulants
**these are what Goljian calls late bleeding disorders**
How is Hemophilia inherited?
- X-linked recessive for hemophilia A, B
- mostly males, females are carriers
- 30% are sporadic new mutations
What are the different types of hemophilia?
- Hemophilia A- F8 deficiency, most common inherited disease associated with life threatening bleeds
- Hemophilia B- F9 deficiency
- Hemophilia C- F11 deficiency
- A/R inheritance
- not predicatable bleeding
What is the clinical presentation of Hemophilia A,B
- Spontaneous bleeds
- hemarthrosis ledingin to progressive deformity
- deep muscle bleeds
- Easy bruising with trauma
- Bleeding tracks with factor levels
What are the results of the lab tests that are done for evaluation of Hemophilia?
- aPTT prolonged, PT normal
- aPTT mixing study shows correction
- factor levels/activities relate to severity
- severe= <1% F8 or F9
- moderate= 1-5% F8 or F9
- Mild= 6-50% F8 or F9
A deficiency in what factor is asymptomatic? What are the clinical manifestations and associated conditions of deficiencies in factor 1 (fibrinogen), 2, 5, 7, 10, 12, 13?
Factor 12 is asymptomatic and all the rest are associated with bleeding.
5=exposure to topical bovine thrombin
10= Amyloid
13= Poor wound healing infertility in men
inhibitors (autoantibodies) against any clotting factor can develop and cause a deficiency in the setting of _______, ______ and ________
Inhibitors (auto-antibodies) against any clotting factor can develop and cause a deficieicny in the setting of autoimmune disorders, medications, and malignancies
How can liver disease cause coagulopathy?
-
Deficiency of mulitple coagulation factors:
- procoagulants: factors 2, 5, 7, 9, 10
- anticoagulants: antithrombin III, Protein C, Protein S
- Thrombocytopenia: hypersplenism (in pts w cirrhosis-associated splenomegaly), decreased thombopoietin production
- Vitamin K deficiency
- Fibrinogen abnormalities (low fibrinogen, dysfibrinogenemia-dysfunctional protein)
- Therapy of coagulation disorder
What is the therapy for coagulation disroders from liver failure?
- Treatment is not required if patient is not bleeing
- If bleeding
- Vtamin K replacement (rarely corrects PT)
- Replacement: plasmsa, cryoprecipitate, platelets
- Therapy specific for bleed site (ex: banding varicies)
When do we see coagulopathy of liver disease?
- Acute liver injury: Hepatitis, toxin (acetominophen, alcohol)
- Chronic liver disease: Cirrhosis
What do the labs show during evaluation of coagulopathy due to liver disease?
Prolonged (PT, PTT, TT)
Low fibrinogen activity
N/ decreased platelets
low factor activities except F8, vWF
How is vitamin K related to coagulation? What things cause VItamin K deficiency?
- Dependent factors: F2, F7, F9, F10, Protein C and S
- Cofactor for gamma carboxylation
- provided by diet and bacterial flora
What causes Vitamin K deficiency and what is the treatment?
- Deficiency caused by:
- Drugs (warfarin, antibiotics bc they decrease bowel flora)
- malabsorption or dietray deficiency
- liver disease
- new borns
- Treatment:
- Vitamin K replacement
- Fresh frozen plasma for emergencies
- Newborns receive injection at birth
What are the lab results of vitamin k deficiency?
prolonged PT, aPTT, decreased protein C, S
What clotting factors does Warfarin inhibit? How about Heparin? What are 2 direct thrombin inhibitors? Factor X inhibitors?
Warfarin: F2, f7, F9, F10, protein C and S
Heparin: F2, F9, F10, accelerates AT3 activity
Direct thrombin inhibitors: F2
Factor X inhibitors: F10
How do we measure anticoagulation activity?
Warfarin: INR
Heparin: PTT/anti- Xa assay
Some DTIs: PTT
What is the bleeding mechanism of platelet granule deficiency?
Hemophilia A
Hemophilia B
Hemophilia C
Liver disease
Vitamin K deficiency/warfarin
platelet granule deficiency: platelet dysfunction
Hemophilia A: Factor 8 deficiency
Hemophilia B: Factor 9 deficiency
Hemophilia C: Factor 11 deficiency
Liver disease: Factor deficiencies or dysfunction
Vitamin K deficiency/warfarin: Deficiency factors 2, 7, 9, 10
