Pathoma Ch 4: Hemostasis and Related Disorders
Terms in this set (37)
Life span 120 days
Can only use glucose for fuel
Membrane contains Cl/HCO₃⁻ antiporter
*Erythrocytosis* - polycythemia, ↑ hematocrit
Life span 8-10 days; 1/3 stored in spleen
Derived from megakaryocytes
Dense granules - ADP, calcium
Alpha granules - vWF, fibrinogen
Normal Platelet Count
150k to 300k
Low platelet count:
Always rule out artifactual due to platelet clumping
Look for evidence of peripheral consumption
High platelet count:
Evaluate for myeloproliferative disorder
Possible Causes of Acquired Platelet Disorders
Cirrhosis (AST:ALT greater than 1.2)
Blood bank platelets
Medications Associated with Clinically Significant Bleeding
Aspirin: Irreversible Cox-1/TXA2 inhibitor
Non-Aspirin NSAIDS: Reversible Cox-1 inhibitors
Cox-2 Inhibitors: No direct platelet receptor, but decreases PGI2, which normally vasodilates and inhibits platelet aggregation, so decreasing PGI2 is pro-thrombotic
Clopidogrel (Plavix): Irreversibly binds ADP receptor P2Y12, which inhibits platelet aggregation by both exogenous ADP and ADP released from dense core granules.
GP IIb/IIIa Inhibitors: Abciximab (ReoPro ), Tirofiban (Aggrastat ), and Eptifibatide (Integrilin)
B-Lactam Antibiotics: Penicillins > Cephalosporins; especially in hypoalbuminemia and with coexisting homeostatic defects like uremia, thrombocytopenia, and *vitamin K deficiency* (PT and PTT increased)
Causes of Thrombocytosis
Reactive thrombocytosis (most common; driven by cytokines IL1, 4, 6 and CRP)
Familial thrombocytosis (autosomal dominant)
Secondary non-clonal processes
Myeloproliferative Disease (MPD)
*Essential thrombocytopenia (ET)*: TPO is elevated in Essential Thrombocytosis and usually normal in Reactive Thrombocytosis
Chronic myeloproliferative diseases
*Secondary feature in other types of MPD*
PV, CML, CMML, MMM, MF
Platelet count less than 100k
Spontaneous bleeding ~ 20k; Mucosal membranes; Intracranial bleeding
Periprocedural and post-traumatic bleeding ~ 20k-50k
PT and PTT may be normal
*Four major categories of thrombocytopenia*
Decreased production in bone marrow
Decreased survival in peripheral circulation
Sequestration in spleen (hypersplenism, splenomegaly)
Dilution due to massive transfusions
The HIV receptors (CD4 and CXCR4) are on megakaryocytes, which allows for their infection;
Megakaryocytes undergo apoptosis
Nonspecific autoantibodies opsoninize platelets
Specific anti-gpIIb-IIIa antibodies are directed at platelets.
Immune Thrombocytopenic Purpura (ITP)
Typically *IgG directed against gpIIb-IIIa or gpIb-IX* are found in plasma, opsonize platelets, and are cleared from circulation primarily by a normal-sized spleen.
- MCC of thrombocytopenia
Caused by platelet autoantibodies, *usually children, post-viral*
Usually self limited (~6 months); 20% become chronic ITP
Also caused by platelet autoantibodies, usually adults
Can be primary or secondary (e.g. SLE) phenomenon.
May cause short-lived thrombocytopenia in newborns as IgG can cross placenta.
Deep soft tissue bleeding after minor trauma
PT and PTT are *normal*
*Increased bleeding time*
↑ megakaryocytes in bone marrow
Thrombotic Thrombocytopenic Purpura (TTP)
Platelets are consumed in the formation of *microthrombi*.
RBC's are sheared resulting in hemolytic anemia and *schistocytes*.
Ultra-large vWF multimers are usually clipped down in size by a metalloproteinase called *ADAMTS13*, which is decreased usually due to an *acquired autoantibody*.
Presents with *fever*, thrombocytopenia, *microangiopathic hemolytic anemia*, renal impairment, and *neurologic symptoms*. *Normal PTT/PT*; *increased bleeding time*. ↑ megakaryocytes in bone marrow.
*Treatment:* plasmapheresis and corticosteroids
Hemolytic Uremic Syndrome, HUS
Due to endothelial damage by drugs or infection. Classically seen in children with *E. coli O157:H7 dysentery* (undercooked beef).
Presents with *fever*, thrombocytopenia, *microangiopathic hemolytic anemia*, *renal impairment*, and neurologic symptoms. *Normal PTT/PT*. ↑ megakaryocytes in bone marrow.
AR Disorder: Deficiency/dysfunction of *glycoprotein IIb-IIIa*
*Increased Bleeding Time* due to defective *platelet aggregation*
- No agonist will cause platelets to aggregate;
- No response from ADP, collagen, or epinephrine
- Has a partial aggregation response to ristocetin
AR Disorder: Deficiency of *GPIb* complex on platelet membrane surface
- *Increased Bleeding Time* due to *defective platelet adhesion* to subendothelial matrix
- Blood smear shows mild thrombocytopenia with *enlarged platelets*
- Platelet aggregation test negative for ristocetin
AR Disorder: Inherited *defect in phagolysosome function*;
defective fusion of phagosomes and lysosomes in phagocytes.
Genetic mutation that codes for large protein *LYST*
LYST is believed to regulate lysosomal trafficking
Oculo-cutaneous albinism due to melanocyte defects
Increased susceptibility to infection
Nervous system defects causing weakness, clumsiness, difficulty with walking, and seizures
- Bleeding diathesis
- Both humoral and cellular immunodeficiency
- Recurrent bacterial infections of the sinuses and lungs.
- *Decreased/absent WAS protein (WASp)*; intracellular protein that regulates actin polymerization cellular signaling
Gray Platelet Syndrome
Both autosomal dominant and recessive forms
*Alpha-granules virtually empty on electron microscopy*
Alpha granule contents released in marrow
Causes *bone marrow fibrosis* (myelofibrosis)
Mild to moderate bleeding diathesis
The gene mutation on chromosome 3p; Mutation called NBEAL2
Encodes a protein used in cytoplasmic vesicle trafficking
Features of Secondary Hemostasis Disorders
Deep tissue bleeding into muscles and joints and rebleeding after surgery (e.g. wisdom teeth extraction).
X-linked deficiency in Factor VIII.
↑ PTT; normal PT
Normal platelet count and bleeding time.
X-linked deficiency in Factor IX.
↑ PTT; normal PT
Normal platelet count and bleeding time.
Coagulation Factor Inhibitor
Antibody against Factor VIII most common. Resembles Hemophilia A.
Differential: PTT does NOT correct following mixing of normal plasma with patient's plasma; does correct with hemophilia A.
Von Willebrand Disease
MC type is AD with decreased levels of vWF.
Mild mucosal and skin bleeding due to impaired platelet adhesion.
*↑ bleeding time*
*↑ PTT, normal PT* due to decreased factor VIII half life (normally stabilized by vWF)
*Abnormal ristocetin test* (no agglutination)
*Treatement:* desmopressin causes ↑ vWF release from Weibel-Palade bodies of endothelial cells
Heparin Induced Thrombocytopenia
Platelet destruction secondary to heparin therapy.
Fragments may activate remaining platelets leading to thrombosis.
Don't give warfarin to these patients.
Disseminated Intravascular Coagulation, DIC
Widespread microthrombi; consumption of platelets and factors results in bleeding especially from IV sites and mucosal surfaces.
1. Obstetric Complications: *tissue thromboplastin* in amniotic fluid activates extrinsic pathway.
2. Sepsis (E. coli or N. Meningitidis): endotoxins and cytokines stimulate endothelial cells to make tissue factor (intrinsic pathway).
3. Adenocarcinoma: mucin activates coagulation
4. Acute Promyelocytic Leukemia
5. Rattle snake bite
↓ platelet count
*↑ bleeding time, PT and PTT*
microangiopathic hemolytic anemia
*↑ D-dimer* best screening tool; derived from splitting of cross-linked fibrin
*Treatment:* treat underlying cause and transfusion of blood products and cryoprecipitate (contains clotting factors)
Disorders of Fibrinolysis
Due to plasmin overactivity. Presents with increased bleeding resembling DIC.
1. radical prostatectomy - release of urokinase activates plasmin
2. liver cirrhosis - reduced α₂-antiplasmin
↑ PT and PTT
↑ bleeding with normal platelet count
Treatment: aminocaproic acid (blocks activation of plasminogen)
Secreted by endothelial cells; redirects thrombin to activate protein C, which inactivates factors V and VIII.
High Homocysetine Levels
Promotes endothelial cell damage, increasing risk of thrombosis. Caused by *low B12 and folate* or *cystathionine beta synthase deficiency*.
cystathionine beta synthase deficiency
CBS converts homocysteine to cystathionine.
Deficiency leads to vessel thrombosis, mental retardation, lens discoloration and long slender fingers.
Protein C or S Deficiency
Leads to increased coagulability; increased risk for warfarin skin necrosis.
Factor V Leiden
Mutated form of factor V that lacks the cleavage site for deactivation by protein C and S. R506Q mutation.
Prothrombin 20210A Mutation
Inherited point mutation that results in increased gene expression → increased thrombin → thrombosis.
Decreased protective effect of heparin-like molecules secreted from endothelial cells that normally activate ATIII, which inactivates thrombin and clotting factors.
PTT does not rise with standard heparin dosing.
High dose heparin will work and warfarin can be given to maintain anti-coagulant state.
Amniotic Fluid Embolus
Amniotic fluid can enter maternal circulation during labor or delivery. Tissue thromboplastin can cause DIC.
Presents with SOB, neurologic symptoms and DIC.
Characterized by squamous cells and keratin debris in embolus.
MC source is DVT. Most likely clinically silent; only 10 % of PE's cause infarction.
SOB, hemoptysis, pleuritic chest pain and pleural effusion
Spiral CT shows vascular filling defect in lung
D-dimer is elevated
infections, autoimmune diseases, pregnancy
polycythemia, sickle cell anemia, CHF, microcytosis, hypofibrinogenemia
Acute Intermittent Porphyria
Rare AD metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme *porphobilinogen deaminase*.
*Labs:* accumulation of porphobilinogen, δ-ALA, coporphobilinogen (urine)
*Symptoms:* painful abdomen, *pink urine*, polyneuropathy, psychological disorders
*Tx:* glucose and heme (inhibits ALA synthase)
Porphyria cutanea tarda
MC subtype of porphyria.The disease is named because it is a porphyria that often presents with skin manifestations later in life. Deficient in *uroporphyrinogen decarboxylase*. Associated with * Hypertrichosis and HepC*.
Presents with *tea colored urine* due to uroporphyrin, *blistering cutaneous photosensitivity*.