Hemostasis and Related DIsorders Flashcards

Question

Name the Qualitative platelet disorders

Answer 1

* **B**ernard-Soulier syndrome * **G**lanzmann thrombasthenia * **A**spirin * **U**remia Remember, you don't see petechiae in qualitative disorders (do you ever see petechiae if you take too much aspirin? I didn't think so)

Answer 2

Qualitative platelet disorder due to a **genetic _GPIb deficiency_** --\> ** platelet adhesion is impaired**. Blood smear shows **_mild thrombocytopenia_ (platelets don't live as long so they get destroyed) with $_enlarged platelets (more immature)._**

Answer 3

**A qualitative platelet disorder in which there is a** **_genetic GPIIb/IIIa deficiency_** --\> **_platelet aggregation_** is impaired. *Remember: ADP causes the GpIIb/IIIa receptor to flip out and allow platelets to aggregate with fibrinogen linker molecules.*

Answer 4

Aspirin **irreversibly inactivates cyclooxygenase**; lack of **TXA₂** impairs **_aggregation_** *Remember: it is thromboxane A₂ from COX that calls in platelets and says "lets aggregate!"*

Answer 5

* Stabilizes the weak platelet plug via the coagulation cascade * Coagulation cascade generates **thrombin**, which converts fibrinogen in the platelet plug to **fibrin**. * Fibrin is then cross-linked, yielding a **_stable platelet-fibrin thrombus_**

Answer 6

Factors of the coagulation cascade are produced by the **liver in an inactive state**. Circulate in blood in the **inactive form**. **Activation requires:** 1. Exposure to an **activating substance** * **Tissue thromboplastin** activates **factor VII (extrinsic pathway)**. * **Subendothelial collagen** activates factor **XII (intrinsic pathway)**. 2. **Phospholipid surface** of platelets 3. **Calcium** (derived from platelet dense granules)

Answer 7

* Usually due to factor abnormalities * Clinical features include **deep tissue bleeding** into muscles and joints (**hemarthrosis**) and **rebleeding after surgical procedures** (e.g., circumcision and wisdom tooth extraction)

Answer 8

**Factor VII** Activated by **tissue thromboplastin**

Answer 9

**factors 12, 11, 9, 8** **subendothelial collagen** activates 12

Answer 10

**10, 5, 2, fibrinogen**

Answer 11

**Prothrombin time (PT)**-measures extrinsic (factor VI I) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade **Partial thromboplastin time (PTT)** - measures intrinsic (factors XII, Xl, IX, VIII) and common (factors Il, V, X, and fibrinogen) pathways of the coagulation cascade

Answer 12

**Genetic factor VIII (FV Ill) deficiency** * **X-linked recessive** (predominantly affects males) * Can arise from a **new mutation (de novo) without any family history**

Answer 13

**Presents with deep tissue, joint, and postsurgical bleeding - **Clinical severity depends on the degree of deficiency. Laboratory findings include * *1. ↑ PTT; normal PT (PT may be elevated according to Goljian) 2. ↓ FVIII 3. Normal platelet count and bleeding time** Treatment involves **recombinant FVIII**

Answer 14

**Genetic factor IX deficiency - **Resembles hemophilia A, except FIX levels are decreased instead ofFVIII

Answer 15

**Acquired antibody against a coagulation factor resulting in impaired factor function; anti-FVIII is most common.** 1. Clinical and lab findings are similar to hemophilia A. $ 2. **MIXING STUDY! **PTT does not correct upon mixing normal plasma with patient's plasma (mixing study) due to inhibitor; PTT does correct in hemophilia A because you are replacing factor with the addition of normal plasma that contains factor 8. *Factor 8 is KILLED immediately by the antibody to factor 8 (the INHIBITOR) and you still have a prolonged PTT even after adding normal plasma to the patients blood!!!!*

Answer 16

**VON WILLEBRAND DISEASE** * **Genetic vWF deficiency** - Multiple subtypes exist, causing quantitative and qualitative defects * the most common type is **autosomal dominant** with **decreased vWF levels**.

Answer 17

**Clinical features** * Presents with **mild mucosal and skin bleeding** * low vWr impairs **platelet adhesion** **Labs** * **↑ bleeding time** * **$ ↑ PTT** * **$ normal PT** - Decreased FVIll half-life (vWF normally stabilizes FVIII); however, deep tissue, joint, and postsurgical bleeding are usually not seen. * **$ Abnormal ristocetin test **- Ristocetin induces platelet aggregation by causing vWF to bind platelet GPIb; lack of vWF -\> impaired aggregation -\> abnormal test.

Answer 18

Treatment is **_desmopressin_ (ADH analog)**, which **increases vWF release from Weibei-Palade bodies** of **endothelial cells.**

Answer 19

Disrupts function of multiple coagulation factors * Vitamin K is activated by **epoxide reductase** in the liver. * $ Activated vitamin K **gamma carboxylates factors II, VII, IX, X, and proteins C and S** -\> gamma carboxylation is necessary for factor function.

Answer 20

* **Newborns**- due to lack of GI coloni:tation by bacteria that normally synthesize vitamin K; vitamin K injection is given prophylactically to all newborns at birth to prevent hemorrhagic disease of the newborn. * **Long-term antibiotic therapy**- disrupts vitamin K-producing bacteria in the GI tract * **Malabsorption** - leads to deficiency of fat-soluble vitamins, including vitamin K - leads to deficiency of fat-soluble vitamins, including vitamin K

Answer 21

**Liver failure** - decreased production of coagulation factors and decreased activation of vitamin K by **epoxide reductase** **Large-volume transfusion** - dilutes coagulation factors, resulting in a relative deficiency

Answer 22

* effect of liver failure on coagulation is followed using **PT *(Liver synthesis of factor 7 good indicator)*** * **Liver failure** - decreased production of coagulation factors and decreased activation of vitamin K by **epoxide reductase**

Answer 23

* Platelet destruction that arises secondary to heparin therapy * ***$ _Platelet factor 4_ combines with heparin to make HEP-PF4 complex -\> IgG antibodies are developed to this complex*** * Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis.

Answer 24

**Pathologic activation of the coagulation cascade** * **Widespread microthrombi** result in **ischemia and infarction**. * **Consumption of platelets** and **factors results in bleeding**, especially from **IV sites **and **mucosal surfaces** (bleeding from body orifices).

Answer 25

1. **Obstetric complications **- **_Tissue thromboplastin_** in the amniotic fluid activates coagulation. 2. **Sepsis** (especially with *E Coli* or *N meningitidis*)- **_Endotoxins_** from the **_bacterial wall_** and **_cytokines from macrophages_** (e.g., TNF and IL-1) induce endothelial cells to make tissue factor. 3. **Adenocarcinoma** - **Mucin** activates coagulation. 4. **Acute promyelocytic leukemia** - Primary granules activate coagulation. 5. **Rattlesnake bite** - Venom activates coagulation.

Answer 26

* **↓ platelet count** (activating all platelets) * **↑ PT/PTT** (consume coagulation factos) * **↓ fibrinogen** * **Microangiopathic hemolytic anemia** * **_$ ↑ fibrin split products, particularly ↑ D-dimer_** * **_↑ D-dimer is the best screening test for DIC_** * Derived from **splitting of cross-linked fibrin**; _D-dimer is not produced from splitting of fibrinogen._

Answer 27

* Treatment involves addressing the **underlying cause** and **transfusing blood products** * **cryoprecipitate** (contains coagulation factors), as necessary.

Answer 28

Normal fibrinolysis removes thrombus after damaged vessel heals. 1. **_Tissue plasminogen activator (tPA_**_)_ converts **plasminogen** to **plasmin**. 2. **_Plasmin_** cleaves **fibrin** and **serum fibrinogen**, **destroys coagulation factors**, and **blocks platelet aggregation**. $ 3. **_alpha₂-antiplasmin_** inactivates **plasmin**.

Answer 29

Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage of serum fibrinogen. * **Radical prostatectomy** - Release of urokinase activates plasmin * **Cirrhosis of liver** - reduced production of **_alpha₂-antiplasmin_**

Answer 30

Primary differential dx is DIC, **disorder of fibrinolysis (presents like DIC!)**, or finbinolytic drug OD.

Answer 31

1. **↑ PT/PTT**- Plasmin destroys coagulation factors. 2. **↑ bleeding time ** 3. **_$ normal platelet count _**- _**Plasmin blocks platelet aggregation. *(platelet count reduced in DIC b/c platelets are activated)***_ 4. **↑ fibrinogen split products $ _without D-dimers_** - Serum fibrinogen is Lysed (↑ fibrinogen split products); however, **_D-dimers are not formed because fibrin thrombi are absent_**, never had any thrombi formed, no fibrin to cleave!.

Answer 32

Treatment is _aminocaproic acid_, which _blocks activation of plasminogen_. *Plasmin can't be formed without plasminogen, (and plasmin is the culprit that (1) fucks up fibrin and serum fibrinogen, (2) knocks the shit out of coagulation factors, and (3) blocks platelet aggregation)*

Answer 33

1. *Cleaves* **fibrin** and **serum fibrinogen** 2. *Destroys* **coagulation factors** 3. _*$ Blocks* **platelet aggregation**_ Inactivated by **alpha₂-antiplasmin** (produced by the liver)

Answer 34

**Pathologic formation of an intravascular blood clot (thrombus)** 1. Can occur in an artery or vein 2. Most common location is the deep veins (DVT) of the leg below the knee. Characterized by (I) **lines of Zahn** (alternating layers of platelets/fibrin and RBCs, Fig. 4.3) and (2) **attachment to vessel wall** 1. Both features distinguish thrombus from postmortem clot.

Answer 35

* **disruption in blood flow** * **endothelial cell damage** * **hypercoagulable state** (Virchow triad).

Answer 36

A. **Stasis and turbulence of blood flow increases risk for thrombosis.** 1. Blood flow is normally continuous and laminar; keeps platelets and factors dispersed and inactivated B. Examples include 1. **Immobilization**- increased risk for deep venous thrombosis 2. **Cardiac wall dysfunction** (e.g., arrhythmia or myocardial infarct ion) 3. **Aneurysm**

Answer 37

Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis. 1. **Block exposure to subendothelial collagen** and underlying **tissue factor** 2. **Produce prostacyclin (PGI2)** and **NO-vasodilation** and inhibition of platelet aggregation 3. Secrete **heparin-like molecules-augment antithrombin III (ATIII)**, which inactivates thrombin and coagulation factors 4. **Secrete tissue plasminogen activator (tPA)**- converts plasminogen to plasmin, which (l) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors, and (3) blocks platelet aggregation 5. **Secrete thrombomodulin**- redirects thrombin to activate protein C, which inactivates factors V and VIII

Answer 38

Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of homocysteine.

Answer 39

$ 1. **_Vitamin B12 and folate deficiency_** result in mildly elevated homocysteine levels, increasing the risk for thrombosis. * i. Folic acid (tetrahydrofolate, THF) circulates as methyl-THF in the serum. * ii. Methyl is transferred to cobalamin (vitamin Bl2), allowing THF to participate in the synthesis of DNA precursors. * iii. Cobalamin transfers methyl to homocysteine resulting in methionine. * iv. Lack of vitamin Bl2 or folate leads to decreased conversion of homocysteine to methionine resulting in buildup of homocysteine. 2.$ **_Cystathionine beta synthase (CBS) deficiency results_** in high homocysteine levels with homocystinuria. * i. CBS converts homocysteine to cystathionine; enzyme deficiency leads to * homocysteine buildup. * ii. Characterized by vessel thrombosis, mental retardation, lens dislocation, and * long slender fingers.

Answer 40

Due to excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired

Answer 41

Classic presentation is **recurrent DVTs or DVT at a young age. **Usually occurs in the deep veins of the leg; other sites include hepatic and cerebral veins.

Answer 42

* *Protein C or S deficiency (autosomal dominant) decreases negative feedback on the coagulation cascade.** 1. Proteins C and S normally **inactivate factors V and VIII**. * *_$ 2. Increased risk for warfarin skin necrosis_** * i. Initial stage of warfarin therapy results in a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VIT, TX, and X * ii. In preexisting C or S deficiency, a severe deficiency is seen at the onset of warfarin therapy increasing risk for thrombosis, especially in the skin.

Answer 43

**factor V Leiden** is a mutated form of factor V that **lacks the cleavage site for deactivation by proteins C and S. C+S shut it down by cleaving it.**

Answer 44

Prothrombin 202lOA is an inherited **point mutation** in prothrombin that results in increased gene expression. 1. Increased prothrombin results in **increased thrombin**, promoting thrombus formation.

Answer 45

A TIll deficiency decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus. 1. Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors. 2. In ATIll deficiency, PTT does not rise with standard heparin dosing. * i. Pharmacologic heparin works by binding and activating ATlll. * ii. High doses of heparin activate limited ATIII; coumadin is then given to maintain an anticoagulated state.

Answer 46

Estrogen induces increased production of coagulation factors, thereby increasing the risk for thrombosis.

Answer 47

Amniotic fluid embolus enters maternal circulation during labor or delivery $ 1. Presents with **shortness of breath, neurologic symptoms**, and **_DIC (due to the thrombogenic nature of amniotic fluid - loaded with tissue thromboplastin)_** 2. Characterized by **squamous cells and keratin debris, from fetal skin, in embolus**

Hemostasis and Related DIsorders Flashcards

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