Robbins 14: Bleeding and Clotting Flashcards
Disorders due to ABNL platelets vs coagulation facts cause WHAT findings
- 1. ABNL platelets = Mucosal/skin bleeding => peteechiae
- 2. ABNL coagulation factors = JOINT bleeding, deep tissue bleeding
High platelet counts may indicate _____________
Myeloproliferative disease (essential thrombocythemia)
What are causes of thrombocytopenia?
- Decreased production
- Decreased platelet survival
- Sequestration in the red pulp of enlarged spleens
- Dilution due to massive transfusions
What are causes of decreased platelet production ==> thrombocytopenia?
- Aplastic anemia
- Leukemia
- HIV (one of the MC hematologic manifestations of HIV)
- Myelodysplastic syndromes
What are causes of decreased platelet survival?
- ↑ consumption (seen in DIC, TTP, HUS)
-
Immune-mediated platelet destruction (seen in antiplatelet Ab or immune complex deposition on platelets)
- Seen in AI thrombocytopenia: allo-antibodies against platelets are produced when platlets are transfused or cross placenta from fetus => mom.
How may alloantibodies against platelets be generated?
When platelets are transfused or IgG cross placenta from fetus —> mother
What are the 2 most important non-immunologic causes of decreased platelet survival leading to thrombocytopenia?
- DIC
- Thrombotic microangiopathies (TTP and HUS)
Primary AI causes of destruction of platelets => ↓ platelet survival
- Crhronic Immune Thrombocytopenia Purpura (ITP)
- Acute immune Thrombocytopenia Purpura (ITP)
Chronic immune thrombocytopenic purpura (ITP) is most commonly seen in whom?
Young women < 40YO
Chronic immune thrombocytopenic purpura (ITP)
- Definition
- Pathogenesis
- IgG autoantibody destruction of platlets that can be primary or secondary (due to SLE, HIV and B-cell neoplasms/CLL).
-
Pathogensis:
- IgG antiplatelet Ab are directed against membrane glycoproteins
- IIb/IIIa – Glanzmann Thrombocytopenia
- Ib/IX – Bernard-Soulier Syndrome
- Anti-platelet Abs are recognized by IgG Fc receptors on phagocytes
- ↑ platelet destruction by the spleen, however NO splenomegaly occurs.
- IgG antiplatelet Ab are directed against membrane glycoproteins
In Chronic Immune Thrombocytopenic Purpura (ITP), IgG anti-platlet AB are directed against what?
- IIb/IIIa
- Ib/IX
What is seen in the bone marrow and peripheral blood with chronic immune thrombocytopenic purpura (ITP)?
- Marrow: moderately ↑ number of megakaryocytes
- Peripheral blood: abnormally large platelets (megathrombocytes)
What are the clinical signs/sx’s of chronic immune thrombocytopenic purpura (ITP); often there is a history of what?
- Insidious onset characterized by bleeding into the skin and mucosal surfaces
- Initially, as pinpoint hemorrhages (petechiae) => ecchymoses
- Often there is hx of epistaxis, easy bruising, gum bleding and hemorrhages into soft tissues w/ minor trauma
_________ moderately improves thrombocytopenia seen in chronic immune thrombocytopenic purpura (ITP).
Splenectomy
Labs in Chronic Immune Thrombocytopenic Purpura (ITP)
- Low platlet count (those seen on peripheral blood smear are large)
- NL PT and PTT
- NL or ↑ megakaryocytes
How is the diagnosis of chronic immune thrombocytopenic purpura (ITP) made?
Diagnosis of exclusion after all other causes of thrombocytopenia ruled out
Chronic ITP may sometimes first manifest with what signs/sx’s?
- Melana
- Hematuria
- Excessive menstrual flow
How does acute ITP differ from chronic ITP in terms of population affected and pathogenesis?
- Children (M=F)
- Sx’s appear abruptly, 1-2 weeks after self-limited viral infection
- Self-limited (spontaneously resolves within 6 months)
What are 2 serious and sometimes fatal complications of chronic ITP?
- Subarachnoid hemorrhage
- Intracerebral hemorrhage
Which 3 drugs are most commonly indicated in causing drug-induced thrombocytopenia?
- Quinine
- Quinidine (Malaria drugs)
- Vancomycin
MOA of
Drug-Induced Thrombocytopenia
- Drugs act as haptens to glycoproteins on platets => creating AB that can bind to it or form immune complexes that deposit on platelet surfaces
What are the complications which may arise with heparin-induced thrombocytopenia, type II?
Life threatening venous and arterial thrombosis.
*This is thrombosis occurring in the setting of thrombocytopenia, which is paradoxical to what should be happening.
- Clots within large arteries may lead to vascular insufficiency and limb loss
- Emboli from DVT’s can cause fatal PE
HIV-Associated Thrombocytopenia: Explain how HIV can cause both ↓ production and survival of platelets?
- HIV binds CD4 and CXCR4 on megakarytocytes; causing these cells to become prone to apoptosis and ↓ platelet production
- HIV causes B-cell hyperplasia => form autoantibodies, which may opsonize platelets => destroy
2 Thrombotic Microangiopathies (cause ↓ platelet survival)
- TTP (thrombotic thrombocytopenic purpura)
- HUS (hemolytic uremic syndrome)
What are thrombotic microangiopathies?
Disorder that causes thrombosis formation in small vessels, which consumes platelets and leads to thrombocytopenia
- Disorders charactersitzed by:
- Thrombocytopenia
- Microangiopathic hemolytic anemia
- Fever
- Transient neurological deficits (in TTP) or renal failure (in HUS)
What important process in DIC is NOT a feature of TTP and HUS?
-
Activation of the coagulation cascade is NOT of a primary feature; so the PT and PTT = NL in TTP and HUS
- DIC: PT/PTT is ABNL
What is TTP?
Disorder that causes thrombosis formation in small vessels, which consumes platelets and leads to thrombocytopenia due to ↓ ADAMTS13 (aka “vWF metalloprotease”/ eznyme that cleaves vWF) bc thery develop an aquired autoAB to it (either acquired or inherited)
- Normally, ADAMTS13 breaks down vWF multimers
- With disease = large vWF multimers => abnormal platelet adhesion and microthrombi
- Worse with endothelial injury
- Thrombotic thrombocytopenic purpura (TTP) is due to a deficiency in what?
- Pentad of symptoms?
- ADAMTS13 (aka “vWF metalloprotease) because of autoAB to it
- Fever
- Thrombocytopenia
- Microangiopathic hemolytic anemia (MAHA)
- Transient neuro deficits
- Renal failure
3. Pur
How is Hemolytic Uremic Syndrome (HUS) different from TTP?
- Occurs in children
- No neuro symptoms
- Acute renal failure
- Due to GI infection form E.coli O157:H7, which produces Shiga-like toxin => microthrombi.
How do typical vs. atypical HUS differ from eachother?
- Typical = commonly caused by shiga-like toxin from E. coli O157:H7 infection, most commonly affecting children/older adults
- Atypical= commonly caused by complement gene mutation (factor H, membrane cofactor protein (CD46) or factor I) or AI response—> which normally prevent activation of alternative complement pathway
TTP typically occurs in _____
HUS typically occurs in _____.
- TTP = Females
- HUS = children
3 categories of inherited defective Platelet Dysfunction
- Defects of adhesion
- Defects of aggregation
- Disorders of platelet secretion (release reaction)
What is a cause of defective platelet adhesion?
Bernard-Soulier Syndrome
What is
Bernard-Soulier Syndrome?
-AR deficiency in GPIb/IX platelet receptor, which allows them to bind to vWF so that platlet can adhere to damaged endothelium
What findings do we see in Bernard-Soulier Syndrome?
- Prolonged bleeding time
- Large platelets****
- Will aggregate to ADP, collagen, EPI, or thrombin
- DO NOT aggregate to ristocetin
What is Glanzmann Thrombasthenia?
AR deficiency in GPIIB/IIIA, which is the platelet receptor that allows platelets to aggregate and form platelet plug.
What findings do we see with Glanzemann Thrombasthenia?
- NL platelets
- Isolated platelets on blood smear (because no clumping)
- WILL NOT aggregate to ADP, collagen, EPI, or thrombin
- WILL aggregate to ristocetin;
What are the 2 most clinically significant acquired defects of platelet function?
- Aspirin/ other NSAIDs; potent irreversible inhibitor of COX-I, which is needed to make thromboxane A2 and prostaglandins
- Uremia which involves defects in platelet adhesion, granule secretion, and aggregation
How does bleeding due to clotting factor abnormalities differ from those seen with platelet deficiencies?
- Spontaneous petechiae/purpura = uncommon
- Bleeding manifests as large excxymoses or hematomas after injury or prolonged bleeding after laceration/surgery.
- Often occurs into the GI/GU tracts and into weight-bearing joints (hemarthrosis)
hemarthrosis after minor stress on a knee joint is suggestive of what?
hemophilia (A or B), not vWF
