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63 Cards in this Set

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What factors are deficient in vit K deficiency?
II, VII, IX, X, protein C, protein S
What does antithrombin do and what activates it?
Inhibits thrombin and factors VIIa, IXa, Xa, XIa, and XIIa. Activated by heparin
What are some natural inhibitors of coagulation released by surrounding endothelium? Natural promoter of aggregation?
Nitric Oxide (NO) from ECs and plts inhibits platelet aggregation and promotes vasodilation.

Prostacyclin synthesized by ECs and inhibits platelet aggregation and promotes vasodilation.

Pro-aggregator = thromboxane A2
Whats clopidogrel?
Plavix. Blocks ADP binding to platelet P2Y1,12 and prevents aggregation. Anticoagulant.
How does aspirin work?
irreversibly inhibits or decreases cyclooxegenase (COX) activity, decreasing thromboxane A2 synthesis. Anticoagulant. Ibuprofen does the same thing but mechanism is reversible.
Name the major classes of PLATELET inhibitors.
Anti-ADP, block ADP platelet receptors (clopidogrel).
COX inhibitors
IIb/IIIa inhibitors
Increasing plt cAMP (dipyrimadole)
Name categories of platelet pathology
Low platelets (mucosal bleeding). Abnormal platelets. Too many platelets (thrombosis
Differentiate clinical findings of factor and platelet deficiencies.
Platelet deficiency: petechiae, superficial ecchymosis, persistent oozing, equal M/F, rarely a family history of bleeding.

Factor deficiency: No petechiae, large and deep ecchymoses, delayed bleeds common, superficial bleeds uncommon, 90% males (hemophilia), FH component common
What does the bleeding time test tell you?
Is prolonged if platelets are decreased or qualitatively abnormal. Not extremely accurate but if abnormal think PLATELET problem, not factors.
Whats a platelet aggregation test?
Test ability of platelets to aggregate with various agonists applied.
What is ristocetin? how is it used clinically?
First used as an AB, no longer since caused platelet aggregation. Platelet binding directly related to amount of vWF bound to platelet. If ristocetin aggregation test is abnormal (ie plts don't aggregate in its presence) you have either a deficiency of vWF (vWF disease), or inability of plts to bind vWF (Bernard Soulier Syndrome, no GpIb)
What is hereditary hemmorhagic telangiectasia?
Dilated microvasculature lesions of mucosal surfaces in CNS, lungs. caused by genetic defect of endoglin, part of the endothelium. AD inheritance.

common sx = epistaxis, GI bleeds. iron deficiency possible.
tx = estrogen, laser, embolization
Ehlers-Danlos syndrome?
CT disorder present with increased bruising/purpora from abnormal platelet/CT interaction. May heal poorly and have hyperextensibility.
What are causes of ACQUIRED vascular defects?
Senile purpora - atrophy of collagen
Scurvy - vit C deficiency causing collagen defects (see bleeding around hair follicles)
Steroids - weakening of supportive CT
What are qualitative platelet defects and what causes them?
Disorders of platelet function. Abnormal bleeding and aggregation tests in presence of normal plt count. Mucosal bleeding is highly suspicious of this. Hereditary causes rare, more common secondary to certain drugs.

Can affect adhesion (GPIb, a probs), aggregation (GPIIa/IIB probs), or activation (ADP binding, thromboxane, thrombin, deficient granules, list goes on)
details of bernard-soulier syndrome
AR inheritance.
Defect in GpIb which binds vWF. Will not aggregate with ristocetin but will with all others. Presents in childhood with nosebleeds, mucosal bleeding. BT prolonged, vWF level is normal.

Tx = plt transfusion
details of Glanzmann's Thromasthenia
Rare, AR inheritance.
GpIIa/GpIIIb mutation, interferes with aggregation and fibrinogen binding. Platelets aggregate only with ristocetin, none of the others. BT prolonged. Presents in childhood with mucocutaneous bleeding.

Tx = plt transfusion
What are storage pool disorders?
Platelet condition where granules are low or nonexistent. On BT don't get secondary peak that indicates further aggregation resulting from granule release.
What causes most qualitative bleeding disorders?
anticoagulant drugs like clopidogrel and aspirin as well as medical diseases like renal failure. Tx by withholding drug, treating illness, or giving plts if nec.
What are some inherited and acquired causes of thrombocytopenia?
Inherited is rare: thrombopoietin mutation, may heggelin anomaly (giant plts, usually asymptomatic), wiskott-aldrich syndrome

Acquired: infiltrative BM disease ie cancer, viral infection (HIV, hepatitis), drugs (chemo, etoh), nutritional deficiency
What is ITP?
Idiopathic (autoimmune) thrombocytopenic purpura. Circulating IgG against GPIIa/IIIb usually. Very low plt count. increased megakaryocytes in BM. other blood normal. may be caused by infection, IBD, collagen vascular disease, lymphoma.

tx: steroids help 80%, gammaglobin infusions compete with spleen macrophages, splenectomy. Rituximab is new drug, anti-b cell.

New evidence shows megakaryocytes may be targeted by ABs as well.
Drug induced Thrombocytopenia
quinine-quinidine, heparin. induce antibodies. withdraw drug. with heparin give alternative anticoag.
Thrombotic Thrombocytopenic Purpura (TTP)
Caused by deficiency of (or inhibition via drugs/autoantibody) ADAMTS14 a Mettaloprotease that cleaves vWF multimers. Causes platelet adherence and plt thrombi.

Sx: fever, thrombocytopenia, small vessel occlusion of kidney and cns, microangiopathic hemolytic anemia.

SCHISTOCYTES. lab values consistent with hemolytic anemia (high LDH, retic count, tbili, decrease haptolobin). coag tests normal.

Tx: replace enzyme (via FFP) or decrease antibody (plasmapheresis)
Hemolytic Uremic Syndrome (HUS)
Symptoms of hemolytic anemia, renal failure. Schistocytes present, ADAMST normal. Can be associated with e.coli or shigella infection. may require temporary dialysis
Differences of PT and aPTT?
Prothrombin time (PT) is a measure of extrinsic and common pathways. It is sensitive to VII, V, X, prothrombin, thrombin, fibrinogen.

activated Partial Thromboplastin Time (aPTT) measures intrinsic and common pathways.
What do mixing studies tell you?
If mix patient's plasma and normal plasma and still prolonged, an inhibitor of a factor is present. If normalizes, then a factor is deficient.
Hemophilia A and B?
A = factor VIII deficiency (1/10,000 males), B = factor IX deficiency at birth (1/20,000 males). X-linked. spontaneous mutation in hem A possible, happens 20% time.

In hemophilia A first intron disease discovered (intron 22 defect, inversion causes 56% cases). Missense mutation in most mild cases.

clinical manifestations = hemarthrosis, hematomas, intracranial bleeds, other bleeding at mouth, gi tract, kidney
Coag factor deficiency classification scheme?
severe: factor >1% of normal, sustain spontaneous hemmorhage.
moderate: factor of 1-5% normal.
Mild: Factor >5% normal, bleed only with surgery or trauma
hemophilia treatment?
Factor replacement therapy in severe cases. Side effects of allergy and antibody development.

For mild cases consider factor VIII, not IX. Desmopressin.

fibrinolysis inhibitors - AMICAR

nowadays prophylactic factor replacement.

model for gene therapy.
What is special about factor XII deficiency?
Patients don't bleed. PTT prolonged and may have thrombolysis.
What's in cryoprecipitate?
cold insoluble plasma proteins. vWF, factors VIII, XIII, fibrinogen, fibronectin.
Where is vWF made?
endothelial cells and megakaryocytes.carries factor VIII.
What are different types of vWF disease?
Quantitative: Type 1 (mild-moderate, most common), type 3 (severe)

Qualitative: loss of function, gain of function, mutation in FVIII binding (all different type 2s)

Remember in vWD you have reduced aPTT due to decreased FVIII that vWF carries.
what is most common bleeding disorder?
vWD type 1. Autosomal dominant.
What does liver damage cause in terms of coagulation/
Decreased clotting factors, low plts, causing oozing and bleeding. vit K dependent factor particulary affected, especially VII. decreased fibrinogen, incr factor consumption, fibrinolysis activation.

prolonged PTT and PT. enlarged spleen low platelets.

tx: FFP, platelets, cryoprecipitate?
Pathophys of DIC
pathologic activation of coagulation by an underlying disease process leading to fibrin clot formation and secondary fibrinolysis which consumes factors, platelets, red cells. May manifest as thrombosis, bleeding, or both. The fulminant syndrome is life threatening.Thrombosis of small and medium size vessels leads to organ failure.

Key mediator is tissue factor from damaged endothelium or due to pro-inflammatory cytokines TNF, IL1, endotoxin. Massive thrombin activation. Fibrinolysis also activated, leading to fibrin degradation products.

oozing and bleeding.

Tx: TREAT UNDERLYING DISORDER. Replace factors AND platelets.
What are the acquired coagulation disorders?
Liver disease, vit K deficiency, DIC, acquired inhibitor antibodies to FVIII.
What is Virchow's Triad (risk factors for arterial and venous thrombosis)?
Endothelial injury, abnormal blood flow, hypercoagulability. In arterial, vascular injury important. In venous, hypercoag and stasis important.
Characteristics of arterial clot
damaged endothelium usually ie artherosclerotic plaque. "White thrombus". PDGF stimulates migration and proliferation of smooth muscle cells and fibroblasts in the intima of artery. Vessel wall thickens. Emboli of platelets/fibrin can lead to TIA or limb gangrene.
Risk factors for arterial thrombosis
FH, hyperlipids, male gender, diabetes, tobacco, elevated factors, HTN, age

occur mostly in elderly. usually vascular not hematological.

tx with antiplatelets, anticoags, tx of medical conditions
Characteristics of venous clot
Stasis and hypercoagulability important. "Red thrombus" due to stasis, platelet incorporate RBCs. Can propogate, resolve, embolize, recanalize.
Whats a DVT foo?
Deep vein thrombosis. mostly in legs, can occur in arms and lungs. Can also be superficial, deep more dangerous (greater risk of pulmonary embolism).

swelling, redness, pain. Doppler for dx.

RFs = immobilization, obesity, cancer, surgery

plasma d-dimer is breakdown product of crosslinked fibrin, negative predictive value (if negative, pt prob doesn't have DVT).
RFs for PE
prolonged bed rest, surgery especially orthopedic, BCP, cancer, pregnancy, crushing trauma, airplanes
What are natural inhibitors of coagulation?
Antithrombin inhibits serine proteases including thrombin.
protein C and S . inhibit factors VIIIa and Va.
Tissue Factor Pathway Inhibitor (TFPI) binds Xa and VIIa-TF complex
What is fibrinolysis?
Degradation of fibrin clots by PLASMIN. tissue plasminogen activator (tPA) converts plasminogen to plasmin forming D-dimer (DVT !) and FDPs.
What is factor V leiden mutation?
Factor V can't be inactivated, leads to hypercoagulable state. found more in caucasians. can't be inactivated by prot C. single pt mutation. COMMON. Homozygotes at much higher VTE risk. Does not increase risk of arterial thrombosis.
describe familial thrombophilia
hereditary condition of too much coagulation (thrombophilia). Causes venous thrombo embolism.
Examples of inherited deficiencies of coagulation inhibitors?
Protein C, S, antithrombin. AD transmission. Higher risk of VTE than favtor V mutation .
What are the main acquired thrombophilic disorders?
Antiphospholipid antibodies, malignancy, myeloproliferative disorders, nephrotic syndrome, PNH, drugs, BCPs
Whats APS?
Antiphospholipid syndrome. IgG to plasma protein antigens, causing venous and arterial thrombosis. recurrent fetal loss due to microthrombi. Can be associated with lupus. Prolonged PT or PTT but has thrombosis not bleeding!
What does heparin do?
Potentiates antithrombin effects by helping it bind and inactivate thrombin, IXa, XIa, Xa. Infused not good oral bioavailability. binds many plasma proteins, dose carefully.

long chain heparin necessary to inhibit thrombin, not necessary to inhibit Xa. Unfractioned heparin not often given for treatment, usually as prophylaxis.

side effect is bleeding. can give protamine to reverse effects.>2months increases osteoporosis risk.

heparin induced thrombocytopenia in 5% cases. thrombosis due to autoimmune response.
What is LMWH?
low molecule weight heparin. given subQ not IV. Xa > AT. less platelet interaction than heparin. doesnt bind plasma proteins. LONGER half life. HIT much lower. no antidote, protamine doesnt really work
Factor Xa inhibitors?
Xa activates thrombin from prothrombin, II to IIa. Drug called Fondaparinux. AT cofactor inactivates Xa. Prophylactic and tx of DVT. no antidote.
If pt has HIT what can you give?
Direct thrombin/Xa inhibitors like argatroban, lepirudin, bivalrudin. not used frequently. Could also use indirect Xa inhibitors
Most common oral anticoagulant?
Warfarin (Coumadin). long half life of 36-48hrs. inhibits vit k dependent factors. takes 3-5 days to take effect. narrow therapeutic window. Affects VII most, so monitor with PT not PTT like heparin. Keep INR between 2-3.

side effects of bleeding, skin necrosis. vit k antidote.
how calculate INR?
patient PT over control PT raised to ISI
basics of treating venous clot?
LMWH or UFH for 5 days with warfarin. hep continued until INR >2. Antiplatelets NOT useful
basics of treating arterial clot?
heparin, ASA, and or coumadin. tPA used acutely as in heart attack. Clopidogrel used with stents.
how do you calclulate the corrected count increment?
This is used post platelet transfusion to see if recipient body is accepting platelets. Equation is CCI = ((Post Tx Plt - Pre Tx Plt)/# plts transfused) * BSA. Expect >7500 within an hr and >5000 in 24hrs.
What are some reasons/risk factors for failed plt transfusion?
Pt factors: multiple transfusion, male, multiparity, alloimmunization.

clinical factors: fever, sepsis, splenomegaly, clinical bleeding, rbc transfusion, DIC, TTP, neutropenia

blood bank factors: ABO match, storage time, HLA match
how do you reduce risk of alloimmunization?
Decrease leukocytes in transfusion product, these typically contain the antigens that donor APCs will present to recipient Tcells. (TRAP study showed that reducing leukocytes in product does reduce incidence of alloimmunization).
What is platelet cross matching?
assay to determine if donor platelets and patient plasma interact via antibodies to avoid this occuring in the pt.
Concerning side effect of platelet transfusion?
Transfusion related acute lung injure (TRALI), much higher incidence post-platelet transfusion than RBC transfusion. Some studies suggest no improved outcome due to platelet transfusion in terms of bleeding but increased TRALI incidence.