Hemostasis and Related Disorders (Pathoma) Flashcards
Primary Hemostasis
Disruption of vessel wall.
- Blood vessel constricts - mediated by neural reflex and *endothelium (substance released from endothelial cell.
- Adhesion - vWf (from platelet itself and *endothelial cells –> Weibel-Palade body contain alpha granules made up of vWf and p-selectin) binds to exposed collagen. Platelets bind vWF using Gp1b.
- Aggregation - Platelet adhesion causes degranulation and the release ADP (dense granules) and TXA2. ADP induces platelets to express GP2b3a which facilitates aggregation. TXA2 allows for futher aggregation via linker molecule fibrinogen.
Results in formation of platelet plug.
Clinical features of primary hemostasis pathology
Mucosal and Skin bleeding
Mucosal - Epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia
Intracranial bleeding occurs w/ severe thrombocytopenia.
Skin bleeding - petechiae, purpura, ecchymoses, brusing.
Petichiae are a sign of thrombocytopenia and are not usually seen in qualitative disorders.
Useful laboratory studies
Platelet count
Bleeding time
Blood smear
Bone marrow biopsy
ITP (Idiopathic Thrombocytopenic Purpura)
AI production of IgG vs. platelet antigens (i.e. GPIIb/IIIa
**MCC of thrombocytopenia in children and adults
Autoantibodies are producd by plasma cells in spleen. Antibody bound platelets are consumed by splenic macrophages –> thrombocytopenia.
Acute form arises in children –> weeks after viral infection or immunization. Self limited w/ in weeks of presentation
Chronic form arises in adults –> usually middle aged women. May be primary or secondary to SLE*. May cause short-lived thrombocytopenia in offspring; anti-platelet IgG can cross the placenta.
Lab findings:
low platelets; normal PT/PTT; Increase megakaryoctyes on bone marrow biopsy
Rx: Corticosteroids. (children respond well; adults relapse). IVIG in symptomatic bleeding (spleen eats IVIG instead of platelets –> effect is short lived.)
Splenectomy eliminates primary source of antibody and site of destruction. Only in refractory cases.
Microangiopathic hemolytic anemia
Pathologic formation of platelet microthrombi in small vessels. As RBC crosses microthrombi –> lyses RBC –> schistocyte and hemolytic anemia.
Platelets are consumed in formation of microthrombi.
Classically seen in TTP and HUS
Thrombotic Thrombocytopenic Purpura (TTP)
Microthrombi due to decreased ADAMSTS13 which is needed to degrade vWf –> large multimers of vWf –> abnormal platelet adhesion.
Due to genetic defect or autoantibodi destruction (MC).
MC seen in adult female.
Clinical findings:
- Skin and mucosal bleedings
- Microangiopathic hemolytic anemia
- Fever
- Renal insufficiency
- CNS abnormalities (predominant in TTP)
Lab findings:
- Thrombocytopenia and increased bleeding time
- Normal PT/PTT
- Anemia w/ schistocytes
- Increased megakaryocytes in bone marrow
Rx: Plasmapheresis and corticosteroids (esp. in TTP).
Hemolytic Uremic Syndrome
Due to endothelial damage by drugs or infection.
Ecoli O157:H7 infection releases verotoxin (Shiga-like toxin) –> damages endothelial cells (esp. in kidney and brain) –> microthrombi –> microangiopathic hemolytic anemia.
Classically seen in children w/ dysentery from undercooked beef.
Clinical findings:
- Skin and mucosal bleedings
- Microangiopathic hemolytic anemia
- Fever
- Renal insufficiency (predominant in HUS)
- CNS abnormalities
Lab findings:
- Thrombocytopenia and increased bleeding time
- Normal PT/PTT
- Anemia w/ schistocytes
- Increased megakaryocytes in bone marrow
Rx: Plasmapheresis and corticosteroids (esp. in TTP).
Bernard-Soulier Syndrome
Genetic GP1b deficiency; platelet adhesion is impaired
Blood smear shows mild thrombocytopenia (increased destruction due to mutated receptor) w/ enlarged platelets (young platelets).
Glanzmann thombasthenia
Genetic GIIb/IIIa deficiency; platelet aggregation is impaired.
Aspirin Use
ASA irreversibly inactivates cyclooxygenase –> lack of TXA2 –> impaired aggregation
Uremia
Uremia disrupts platelt function by creating both adhesion and aggregation problems.
Secondary Hemostasis
Goal is to stabilized primary platelet plug by making thombin to convert fibrinogen to fibrin.
Factors produced in liver in inactive state.
Activation requires:
- Exposure to an activating surface
- Phospholipid
- Ca++ (from dense granules)
Disorders are due to factor abnomalities
Clinical features of disorders of secondary hemostasis
Deep tissue bleeding into muscles and joints (hemarthrosis)
Rebleeding after surgical procedures
PT
Measures extrinsic and common pathway
Measures Coumadin better
PTT
Measures intrinsic and common pathways.
Measures Heparin better
Hemophilia A (8)
Genetic Factor VIII deficiency
X-linked recessive (predominately affects males)
Can arise from a new mutation w/o family hx
Presents w/ deep tissue, joint, and postsurgical bleeding. Severity depends on degree of deficiency.
Lab findings:
- increased PTT and normal PT
- decreased factor VIII
- Normal platelet and bleeding time
Rx: Factor VIII
Hemophilia B
Genetic Factor IX deficiency
Resembles hemophilia A, except F IX levels decreased instead of F VIII.
Coagulation factor inhibitor
Acquired antibody against coagulation factor resulting in impaired factor funciton.
MC vs. VIII
Clinical and lab findings are similar to hemophilia A.
***Key is PTT doesn’t correct w/ mixing normal plasma w/ patient’s plasma (mixing study) due to inhibitor. PTT does correct in hemophilia A.
Von Willebrand Disease
*MC inherited coagulation disorder.
Genetic vWF deficiency
Cause quantitative or qualitative deficiency
MC type is auto dominant w/ decreased vWF levels.
Presents w/ mild mucosal and skin bleeding (due to decreased platelet adhesion)
Labs:
- Increased bleeding time
- Increased PTT(need vWF to stabilize factor VIII*) normal PT
- *Abnormal ristocetin test (ristocetin doesn’t cause platelet aggregatoion)
Rx: *Desmopressin –> increases vWF release from Weibel-Palade bodies
Vitamin K defiency
Disrupts function of gamma-carboxylation of factors (2,7,9,10 C and S).
Deficiency occurs in:
- Newborns (lack of gut flora)
- Long-term abx therapy (kill gut flora)
- Malabsorbtion (fat soluble)
Liver failure
Decreased production of coag factors
Decreased activation of vitamin K by epoxide reductase
Effect of liver failure on coagulation is followed using PT
Large-volume transfusion
Dilutes coagulation factors
Results in relative deficiency.
Heparin-Induced-Thrombocytopenia (HIT)
Platelet destruction that arises secondary to heparin therapy. Heparin binds to Platelet Factor 4 –> autoantibodies.
Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis.
Don’t give these patients Warfarin when taking of Heparin –> increased risk for skin necrosis
Disseminated Intravascular Coagulation
Pathologic activation of coagulation cascade
Widespread microthrombi result in ischemia and infarction
Consumption of platelets and factors results in bleeding, especially IV sites and mucosal surface.
Almost always secondary to another disease process:
- Obstetric complication (placenta includes thromboplastin –> DIC)
- Sepsis (endotoxin and macrophage cytokines activate cascade)
- Adenocarcinoma (mucin activates cascade)
- Acute Promyelocytic Leukemia
- Rattlesnake bite (venom)
Lab findings:
- decreased platelet count
- PT/PTT increased
- Decreased fibrinogen
- Microangiopathic hemolytic anemia
- Elevated fibrin split products (D-dimer) –> best screening test
Rx: Address underlying cause. Transfuse blood products and cryoprecipitate as needed.
Plasmin actions
Activated by tPa
Shut off by alpha-2 anti-plasmin
3 jobs:
- Cleaves fibrin and fibrinogen
- Destroys coag factors
- Blocks platelet aggregation.
Disorders result from plasmin overactivity.
Radical prostatectomy fibrinolysis
Release of urokinase –> activates plasmin
*Presentation resembles DIC
Labs:
- Increased PT/PTT
- Increased bleeding time w/ *normal platelet count
- Increased fibrinogen split products, but No d-dimers w/
Rx; Aminocaproic acid: blocks activation of plasminogen
Cirrhosis related fibrinolysis
Reduced production of alpha-2-antiplasmin
*Presentation resembles DIC
Labs:
- Increased PT/PTT
- Increased bleeding time w/ *normal platelet count
- Increased fibrinogen split products, but No d-dimers w/
Rx; Aminocaproic acid: blocks activation of plasminogen
Characterstics of thrombus
- Lines of Zahn (layers of RBCs and platelet fibrin)
- Attachment to vessel wall
Both features distinguish thrombus from postmortem clot.
Risk factors for thrombosis
Virchow’s Triad:
- Stasis or turbulent flow (i.e. immobilization, cardiac wall dysfunction, aneurysm)
- Endothelial damage (exposed collagen, no PGI2 or NO produced, no heparin like molecules secreted, no tPA production, and no thrombomodulin.) Caused by atherosclerosis, vasculitis, and high levels of homocysteine (secondary to B12 or folate deficiency or cystathionine beta synthase)
- Hypercoaguable state (classically present w/ recurrent DVTs or DVTs at a young age)
Homocystinuria
Deficiency in cystathionine beta synthase
Results in high homocysteine levels w/ homocystinuria.
Characterized by vessel thrombosis, mental retardation, lens dislocation, and long slender fingers.
Protein C and S defiency
Decreases negative feedback on coagulation cascade
Protein C and S normally inactivate factors V and VIII
Increased risk for Warfarin skin necrosis
Warfarin skin necrosis
Warfarin blocks gamma carboxylation of factors 2,7,9,10,C, and S.
First factors gone are C and S.
Increased risk for thrombus early –> heparin bridge.
If deficient in C and S –> very increased risk for hypercoaguable state and skin thrombi –> warfarin skin necrosis.
Factor V Leiden
Mutated form of factor V that lacks cleavage site for deactivation by proteins C and S.
MC inherited cause of hypercoaguable state.
Prothrombin 20210A
Inhertited point mutation in prothrombin
Results in increased gene epression.
Promotes thrombus formation
ATIII deficiency
Decreases protective effects of heparin-like-molecules produced by endothelium. Increasing the risk for thrombus.
PTT does not rise w/ standard heparin dosing.
High doses of heparin activate limited ATIII; Warfarin is then given to maintain anticoagulated state.
OCP
Associated w/ hypercoaguable state due to estrogen increasing production of coag factors.
Increases the risk for thrombosis.
Thromboembolus
MCC of embolus (95%)
Atherosclerotic embolus
Due to plaque that dislodges.
Characterized by the presence of cholesterol clefts in the embolus.
Fat embolus
Associated w/ bone fractures, particularly long bones and soft tissue trauma
Develops while fracture is still present or shortly after repair
Dyspnea and peteciae on the skin overlying chest.
Gas embolus
Seen in decompression sickness
Presents w/ joint and muscle (bends) pain and respiratory sx (chokes)
Chronic form (Caisson disease) characterized by multifocal ischemic necrosis of bone.
May also occur during laparoscopic surgery –> air pumped into the abdomen enters blood stream.
Amniotic fluid embolus
Amniotic fluid enters circulation during labor or delivery.
Presents w/ shortness of breath, neurologic sx, and DIC (from tissue thromboplastin in embryonic fluid)
Characterized by squamous cells and keratin debris from fetal skin in embolus
PE
Usually due to thromboembolus from femoral, ileach, or popliteal veins.
Most ofen is clinically silent.
Lung tissue has dual blood supply and emboli are usually small.
Pulmonary infarction possible if large or medium sized artery w/ pre-existing cardiopulmonary compromise.
Only 10% of PEs present w/ pulmonary infarction.
Clinical featurs:
- SOB, hemoptysis, pleuritic chest pain, and pleural effusion.
- V/Q scan shows mismatch
- Spiral CT shows a vascular filling defect
- Lower extremity doppler US detects DVT
- D-dimer is elevated
Gross exam reveals hemorrhagic (second blood supply and loose tissue) wedge-shaped infarct
Sudden death if large saddle embolus due to electromechanical dissociation of heart.
Pulmonary HTN in pts w/ chronic emboli that are reorganized
Systemic embolism
Usually due to thromboembolus.
MC arise in left heart.
Travel down systemic circulation to occlude flow to organs; MC the lower extremities.
