Other Disorders of Hemostasis: Heparin-Induced, DIC, Fibrinolysis Disorders

Severe Intravascular Hemolysis (breakdown RBC in vessel) is a common etiology of DIC. What are 2 examples associated with Severe Intravascular Hemolysis a common etiology of DIC?

1. Acute Hemolytic Transfusion... 2. Severe Malaria

Malignancy a common etiology of DIC. Why is Malignancy a common etiology of DIC?

1. Adenocarcinoma produces cancer procoagulant (like other mucinous tumors) that activate Factor X... 2. Acute promyelocytic leukemia releases primary granules activating coagulation

What are 5 specific manifestations of Acute DIC?

1. Bleeding... 2. Acute renal failure secondary to microthrombi and/or hypotension... 3. Hepatic dysfunction... 4. Pulmonary disease...pulmonary hemorrhage... 5. Neurologic disease (i.e. delirium, focal neurologic findings resulting from microthrombi)

What are the 4 steps in the pathogenesis of Disseminated Intravascular Coagulation?

1. Exposure of excess tissue factor... 2. Coagulation (primary hemostasis; secondary hemostasis)... 3. Thrombosis and Fibrinolysis...creating fibrin degradation products (FDPs)... 4. Hemorrhage...consumption of clotting factors and fibrinolysis

What are other disorders of hemostasis?

1. Heparin-Induced Thrombocytopenia 2. Disseminated Intravascular Coagulation 3. Disorders of Fibrinolysis

Classically, the differential will present the patient with DIC or Fibrinolysis Disorder... What are 2 ways to determine the cause of concern is Fibrinolysis Disorder and NOT DIC?

1. Increased Bleeding time with NORMAL platelet count 2. Increased Fibrin Degrade Products (FDP) but with NO D-dimer

DIC is always secondary to another disease process (something ongoing causes DIC). STOP Making New Thrombi is a mnemonic to remember the common causes of DIC. What are the most common etiologies of DIC?

1. Sepsis S... 2. Trauma T... 3. Obstetric complications O... 4. Pancreatitis P... 5. Malignancy M... 6. Nephrotic Syndrome N... 7. Transfusion reaction

[rx] What is Disseminated Intravascular Coagulation? What are 2 principle mechanisms leading to widespread activation of clotting?

1. Widespread activation of clotting --> deficiency of clotting factors --> bleeding state... 2. Mechanisms a. release of tissue factor [trhomboplastin or factor III] in general circulation; widespread fibrin deposition within microcirculation... b. widespread injury to endothelial cells; attracts platelets to stie of injury; activates coagulation pathway [consuming platelets and coagulation factors].

What are 3 examples of non-heparin anticoagulant?

1. argatroban... 2. bivalirudin... 3. fondaparinux

Sepsis a common etiology of DIC. Why is sepsis a common etiology of DIC?

1. bacterial LPS (endotoxin)... 2. Cytokines Il-1 and TNF... induce endothelial cells to secrete Tissue Factor...activating coagulation cascade

What are 3 roles Plasmin has in promoting fibrinolysis while inhibiting clotting?

1. cleaves fibrin and fibrinogen... 2. destroys coagulation factors... 3. blocks platelet aggregation

[rx] What are lab findings of DIC?

1. decreased PC; increased BT PT PTT 2. shistocytes 3. increased fibrin degradation [elevated D-dimers] 4. decreased fibrinogen 5. decreased factors V VIII

What treatments are indicated for Heparin-Induced Thrombocytopenia?

1. discontinuation of heparin... 2. administration of non-heparin anticoagulant... 3. Protamine Sulfate

What are 2 supportive measures that can be indicated for pateints wtih DIC?

1. for patients with platelets < 50 K/uL and serious bleeding plateets should be transfused... 2. for pts. with active bleeding, marked INR elevation, and/or decrease in fibrinogen, Fresh Frozen Plasma (FFP) or cryoprecipitate should be administered... FFP and cryoprecipitate have coagulation factors

What are the laboratory findings of fibrinolysis disorders?

1. increased PT/PTT time (plasmin destroys coagulation factors)... 2. Increased bleeding time (plasmin blocks platelet aggregation)... 3. Increased fibrin split products with D-dimers (no thrombus was formed because fibrin was already cleaved)

Activation of plasminogen to plasmin causes hemorrhagic diathesis in DIC... 1. what is hemorrhagic diathesis?... 2. What 2 mechanisms does plasmin use to cause hemorrhagic diathesis

1. increased unusual susceptibility to bleeding due to hypocoaguability [defection in coagulation cascade]... 2. Cleavage of fibrin; Degradation of clotting factors V and VIII

What are some mucosal surfaces patients with DIC bleed from? What are IV sites that patients with DIC bleed from?

1. mucosal surfaces (orifices of body)...mouth, lung (hemoptysis), hematuria ... 2. see picture...cephalic vein

What are 2 consequences of widespread fibrin deposition within microcirculation?

1. organ ischemia... 2. microangiopathic hemolytic anemia leading to shistocytes

Obstetrical complications refer to disruptions of pregnany, labor, delivery, and early neonatal period... What are 3 examples of obstetrical complications leading to DIC?

1. preeclampsia ( pregnancy disorder...high BP and often significant proteinuria)... 2. retained dead fetus... 3. fatty liver during pregnancy

What are 2 examples of etiolgies of fibrinolysis disorders?

1. radical prostatectomy...release of urokinase activates plasmin... 2. Cirrhosis of liver...reduced productionof alpha 2 antiplasmin (inhibitor of plasmin) leads to overactivity of plasmin...

Thrombosis results, paradoxically, from Heparin-Induced Thrombocytopenia...typically venous thrombosis as opposed to arterial. What are the 4 common sequalae of thrombosis in patients with HIT?

1. skin necrosis at site of heparin injections... 2. Limb gangrene... 3. Organ ischemia or infarction (if arterial thrombosis is present)... 4. thrombocytopenia

What is the role of tissue plasminogen activator tPA?... What is the role of Plasmin?... Describe the interplay between tPA and Plasmin in degrading fibrin during fibrinolysis?

1. tPA binds fibrin and converts plasminogen to plasmin... 2. Plasmin cleaves fibrin into Fibrin Degradation products (FDPs)...FDPs inhibit thrombin (factor II)...

What 4 patient populations are highest at risk for Heparin-Induced

1. unfractioned vs low-molecular weight heparin... 2. higher doses of heparin... 3. female gender... 4. recent surgery

What are the 5 lab findings indicative of Acute DIC?

Increased thrombin production: 1. decreased platelet count... 2. Increased PT and PTT... 3. Decreased fibrinogen Increased fibrinolysis (last step in coagulation cascade) evidenced by... 4. elevated fibrin degradation products (FDP) and D-dimer... 5. Microangiopathic Hemolytic Anemia leading to shistocytes on Peripheral Blood Smear

What is purpura fulminans associated with? How is it, in turn, treated?

Inherited Protein C deficiency... Intravenous Protein C administration

What are fibrinolysis disorders?

Pathologic activation of plasmin leads to inappropriate cleavage/blockage of... 1. fibrin and fibrinogen... 2. coagulation cascade... 3. platelet aggregation

What are the differences between laboratory diagnostics for Acute vs Chronic DIC?

Patients with Chronic DIC presents with elevated FDPs and D-dimer and shistocytes on Peripheral Blood Smears (as do pts. with Acute DIC, but pts. with Chronic DIC present with... 1. No thrombocyotpenia... 2. Normal PT and PTT... 3. Normal fibrinogen levels

What type of hemorrhage or bleeding is observed in patients with Acute DIC?

Petechiae... Ecchymoses... classically blood oozes from any IV or catheter sites

What is a rare, potentially fatal complication of DIC? How does this complication present?

Purpura fulminans... Extensive tissue thrombosis and skin necrosis

Diagnostically, acute and chronic DIC presentation differs. First, what must be excluded from the differential in diagnosing DIC?

Thrombotic Thrombocytopenic Purpura (TTP) & Hemolytic Uremic Syndrome

Heparin administration is stopped immediately in Heparin-Induced Thrombocytopenia and replaced with other anticoagulants or blood thinners except for 1. What other anticoagulant is not indicated in patients with Heparin-Induced Thrombocytopenia?

Warfarin (Coumadin)... increased risk of Warfarin/Coumadin skin necrosis in patients with Heparin-Induced Thrombocytopenia.

What is the treatment or management of DIC?

address the underlying condition... blood product transfusion... cryoprecipitate (contains coagulation factors)...

What inhibits or blocks plasmin?

alpha 2 antiplasmin inactivates plasmin

What is Chronic (Compensated) DIC?

bloodstream continuously exposed to small amount of tissue factor... patients asymptomatic or predilection for thrombosis

What is Acute (Decompensated) DIC?

bloodstream is flooded with large amount of tissue factor in brief period of time...resulting in... consumptive coagulopathy... severe bleeding diathesis (unusual susceptibility to hemorrhage due to hypocoaguability caused by coagulopathy)

What is fibrinolysis? What are the 2 fibrinolytic agents?

breaking down blood clots by targeting fibrin... 1. tissue Plasminogen activator tPA... 2. Plasmin

What are 2 major complications of heparin-induced thrombocytopenia?

deep venous thrombosis... pulmonary embolism

Paradoxically, Heparin-Induced Thrombocytopenia leads to thrombosis formation at first. Why and when does thrombocytopenia occur?

destruction and consumption of platelets... 5-10 days following exposure to heparin products

A transfusion reaction is a common etiology of DIC. What is a transfusion reaction?

destruction of donor RBC by host immune system in blood transfusion

What is Heparin-Induced Thrombocytopenia HIT?

immune-mediated reaction occurs following exposure to any heparin products, resulting in paradoxically pro-thrombotic state and then thrombocytopenia

Refresher... What is fibrinolysis? What are the mediators of fibrinolysis?

last step of coagulation which helps remove the "band-aid" or thrombus... tissue plasminogen activator tPA cleaves plasminogen to plasmin... plasmin... 1. degrades fibrin (Fibrin degraded products) and fibrinogen... 2. destroys coagulation cascade... 3. blocks platelet aggregation

What is Disseminated Intravascular Coagulation DIC?... What 2 consequences result from Disseminated Intravascular Coagulation...DIC?

pathologic activation of coagulation cascade (secondary hemostasis)... systemic process of both thrombosis and hemorrhage resulting from underlying disease... 1. Microthrombi: microthrombi formation in microvasculature results in ischemia...infarction 2. Hemorrhage: formation of microthrombi, over time, leads to consumption of platelets and thus, excessive hemorrhage and bleeding from mucosal surfaces and IV sites

Tissue Plasminogen Activator (tPA) is indicated in what group of patients?

patients who... 1. experienced ischemic strokes presenting from 3-4.5 hrs. of onset...and... 2. are not at risk for hemorrhage...

What antidote is used for heparin toxicity? [Protamine Sulfate]

rapid reversal of heparin... antidote to heparin positively charged and binds negatively charged heparin... low-molecular weight heparin not easily reversible

Nephrotic syndrome is a common etiology of DIC. What is nephrotic syndrome?

renal disorder causing body to excrete too much protein in urine.

Rattle Snake Bites are common etiology of DIC. Why is Rattle Snake Bites are a common etiology of DIC?

venom induces coagulation cascade

What is the pathogenesis of Heparin-Induced Thrombocytopenia HIT?

Heparin binds to PF4 on platelets... autoantibodies IgG binds to Heparin-PF4 complex leading to splenic clearance... Fragmentation of these complexes can lead to platelet fragments released from spleen... Platelet fragments will induce platelet-thrombosis...(thrombus in blood vessel)... consumption and destruction of thrombocytes leads to thrombocytopenia 5-10 days later

Why is the platelet count normal Fibrinolysis Disorder but low in DIC?

In fibrinolysis, no thrombi are formed because fibrin cleaved by plasmin prior to thrombi formation... In DIC, thrombi are formed, thus, lower serum concentration of platelet

Why are D-dimers NOT present in Fibrinolysis Disorders but are present in DIC?

In fibrinolysis, no thrombi are formed because fibrin cleaved by plasmin prior to thrombi formation...no D-dimers In DIC, thrombi are formed, thus, D-dimer exist upon fibrinogen to fibrin cleavage (via thrombin) and fibrin stabilization between platelets

What are 2 types of DIC?

Acute... Chronic

What treatment is indicated in patients with Fibrinolysis Disorders?

Aminocaproic acid... Aminocaproic acid blocks activation of plasminogen

Obstetrical complications are common etiology of DIC. Why is Obstetrical complications are a common etiology of DIC?

Amniotic fluid contains tissue thromboplastin (tissue factor); burst of amniotic fluid leads to release of tissue thromboplastin...activation coagulation cascade...

Trauma a common etiology of DIC. Why is Trauma a common etiology of DIC?

CNS trauma, especially, activates coagulation cascade...

What test is helpful in DIC?

D-dimer test... fibrin degradation product FDP is elevated in DIC

What 2 bacteria, especially, cause sepsis, which can then lead to DIC?

E. coli... N. meningitidis