MHD exam 4- Hemostasis

Activation of coagulation cascade requires

1. exposure to activating substance- extrinsic and intrinsic activators 2. phospholipid surface of platelets- have coagulation proteins 3. Calcium - released from dense granules

Hemophilia A

Classical genetic factor 8 deficiency - X linked recessive- males- or can arise from a new mutation without a family history - deep tissue, joint, postsurgical bleeding -sex linked recessive increased PTT normal PT decreased F8 - normal platelet count and bleeding time

Subendothelial Disorders

Congenital 1. Ehler Danos syndrome- autosomal dominant - hypermobile joints, hyperflexible skin, osteogenesis imperfecta, tendency to bleed 2. White pregnant- drugs, infections, amyloidosis Acquired- Purpura simplex, amyloids, drugs, Cushing's syndrome, etc

Endothelial Disorders

Congenital - most common- 1. hereditary hemorrhagic telangiectasia HHT- Autosomal dominant disorder resulting in thin-walled blood vessels, especially in the mouth and GI tract 2. arteriovenous malformation 3. giant hemangioma Acquired- inflammation, vasculitis- from drugs, viruses, Rickettsia

fibrinolytic system

network of enzymes that dissolve the clot plasmin- and fibronolysin- breaks fown both fibrin and fibrinogen

Fibrinolysis

normal fibrinolysis removes thrombus after damaged vessel heals- plasmin activated by tPA and cleaves fibrin and fibrinogen/ destroys coagulation factors and blocks platelet aggregation alpha-2-antiplasmin inactivates plasmin

A2 antiplasmin deficiency

not common deficiency of plasmin inhibitor so plasmin can increase and digest fibrinogen or fibrin---> increased bleeding cant inactivate plasmin- increased fibrinolysis

Microangiopathic hemolytic anemia

pathologic formation of platelet microthrombi in small vessels -platelets are consumed in formation of microthrombi--> thrombocytopenia RBCs are sheared as they cross microthrombi-->hemolytic anemia with schistocytes seen in TTP and HUS

thrombosis

pathologic transition of state of blood from fluidity to non fluidity thrombus can evantually become an embolius thrombogenic mechanism differ in arterial and venous system because of lood flow, endothelial cell composition, blood vessel size, and degree of oxygenation

Inhibitors of coagulation system

plasma proteins that can inhibit serine protease enzymes that regulation clotting process Antithrombin 3 (AT3)- plasma inhibitor that mediates anticoag actions of heparin heparin cofactor 2- week inhibitor of thrombin Tissue factor pathway inhibitor TFPI- potent inhibitor of TF

inhibitors of fibrinolytic system

plasminogen activator inhibitor- PAI- high levels in cancer, hypertension, diabetes a2 antiplasmin- inhibi plasmin a2 macroglobulin thrombin activatable fibrinolytic inhibtor (TAFI)

qualitative disorders

platelet numbers are usually normal, however platelet function is impaired

Primary Hemostasis

platelets adhere to cell surface, become activated, form layer, recruit other platelets, no fibrin involved

Adhesion platelets

platelets attach to subendothelial collagen through molecular bridge platelets plasma membrane, GP1b attaches to the vWF which attaches to collagen

Tissue factor

procoagulant released from various cells- promotes coagulation

tissue plasminogen activator

released by endothelium-- lyses clot/dissolves fibrin

thrombomodulin

released from blood and blocks the coagulation cascade- do inhibit clot

hemolytic uremic syndrome

skin and mucosal bleeding, fever, renal insufficiency, microangiopathic hemolytic anemia - due to endothelial damage by drugs or infection- classically seen in children with E.coli 0157 dysentery Lab findings: thrombocytopenia with increased bleeding time, normal PT/PTT , anemia with schistocytes, increased megakaryocytes in bone marrow Rx. corticosteroids and plasmaphoresis

thrombus

stationary clot -that forms in a vein consolidated platelet-fibrin clot forms a permanent plug that seals the hoel in the vessel wall erythrocytes and leukocytes become part of the thrombus formation of thrombus leads to thrombocytosis (increased platelets)

Thrombin

stimulates recruitment and activation of additional platelet and converts fibrinogen to fibrin thorombin has a R on platelets and can cause constriction and send feedback to coagulation factor formation of thrombin and coagulation cascade ultimately leads to reduction of blood loss

Disorders of Secondary Hemostasis

usually due to factor abnormalities- clinical features: deep tissue bleeding of muscles and joints, hemarthrosis and rebleeding after surgery Lab results: PT measures extrinsic factor 7 and common factor 2, 5, 10, and fibrinogen PTT measures intrinsic- 12,11,9,8, and common path 2,5,10, and fibrinogen

non-thrombocytopenic purpuras

vascular disorders- can be subendothelial and endothelial capilaries weaken- cap defects - common but dont result in severe bleeding diathesis Dx. easy bruising, bleeding from mucosa, purpura, vasculitis- inflam of blood vessels BUT platelet function and coagulation are normal

DIC presentation

widespread microvascular thrombosis/ contusion

Gray platelet syndrome

-Inherited disorder of platelets -congenital disorders resulting in bleeding diathesis -purpura of unknown origin- from cap leakage -platelets look gray instead of white -lack alpha granules -not common

uremia

-acquired disorders of platelets- metabolic disorders - bleeding

glanzmann's thrombasthenia

-congenital disorders resulting in bleeding diathesis -seen in pediatric patients -Inherited qualitative disorder of platelets autosomal -recessive- GP2b/3a defect- aggregation defect so bleeding time increases

myeloproliferative disorders

-polycythemia vera- cancer of RBC-- hematocrit increases -granulocytic leukemia-- WBC increases -myelofibrosis- fibrosis of bone marrow neoplastic proliferation of MATURE myelocytes Neoplastic proliferation of mature myeloid cells→ ↑↑ WBC (↑ in *all* myeloid lineages), hypercellular bone marrow, classified based on dominant myeloid cell type

causes of thrombogenesis

1. endothelial damage 2. activation of platelets 3. release of tissue factor from cells

Drug induced bleeding disorders

- aspirin- dont have antagonist to control this like with heparin - bleeding with thrombolytic drugs- anticoagulation becasue of release of fibrinogen degredation products bleeding with anticoagulants- heparin- can be controlled with proteamine sulfate antibplatelet and thrombolytic drugs most common drug induced/ heparin induced thrombocytopenia

Type 2 vWF disease

- qualitative defect in the protein - structural defect

bernard Soulier disease

-Inherited disorder of platelets -autosomal recessive- GP1b defect- so adhesion defect and bleeding time increases - bloodsmear shows mild thrombocytopenia with enlarged platelets- -qualitative and quantitative issue -congenital disorders resulting in bleeding diathesis -seen in pediatric patients

Storage Pool disease

-Inherited disorder of platelets -congenital disorders resulting in bleeding diathesis -decrease dense granule content- no aggregation- - platelets are not active/ not released ADP, 5HT, His, Ca, PF4 so they all decrease can cause bleeding

Fibrinogen group of Coagulation factors

1, 5, 8, 13

Steps of Secondary Hemostasis

1. Tissue factor released from endothelial cells 2. Phospholipid complex expression- surface phospholipids are expressed to provide matrix that clot can enter and stabilize - coagulation proteins form complexes on platelet surface using phospholipids of platelet membrane 3. thrombin activation by coagulation cascade 4. Thrombin converts fibrinogen to fibrin 5. Fibrin polymerization- fibrin is polymerized and becomes solid by factor 8a and stabilizes the clot

Anti-thrombotic Effect of Endothelium

1. antiplatelet effect- 2. anticoagulant effect- 3. fibrinolytic effect normal endothelial cells inhibit platelet adherence and prevent blood clotting

regulation of hemostasis

1. blood vessel wall- endothelium and sub-endothelium 2. platelets 3. coagulation and fibrinolytic systems any disruption can result in bleeding or thrombotic complications -only in pathologic conditions - the state of these components are altered

Acquired causes of qualitative platelet disorders

1. disease induced platelet defects 2. liver disorders- decrease production of certain coagulation factors 3. paraproteinemia- myeloma proteins are paraproteins 4. drug induced platelet defects- aspirin irreversibly inactivates COX-- lack of TXA2 impairs platelet aggregation NSAIDS- nonsteroidal antiinflammatory drugs decrease platelet function so they dont aggregate upon activation 5. diet induced platelet defects- people who eat a lot of fish or take fish oil- blocks thromboxane 6. taking omega 3 fatty acids/ ocean fish- decrease function of platelts

Common Pathway

10, 5, 2, 13 fibrin (1) Ca is very important hear- a chelating agent would preent thrombosis initiation of extrinsic or intrinsic pathway leads to this pathway and results in formation of thrombin which transforms fibrinogen to fibrin factor X plays a central role in generation of thrombin by intrinsic and extrinsic path- lead to common path

contact group

11, 12, Fletcher factor - prekallikrein, Fitzgerald factor, HMW Kininogen

Prothrombin group

2, 7, 9, 10 -syntehsized in liver and all bind Ca all contain gamma-carboxy glutamic acid - to bind Ca warfarin inhibits carboxylation process of these factors liver failure---> bleeding because of these factors being deficient

Virchow's Triad- Pathogenesis of Thrombosis

3 Factors 1. injury to endothelium--> release of TF 2. Alterations in blood composition 3. Stasis

Aggregation

5HT and thromboxane A2 --> vasoconstriction- reducing blood flow and the likelihood that the plug can detatch thrombin formed by intrinsic pathway thrombin, ADP, and thromboxane A2--> accelerate platelet aggregation thrombin- converts fibrinogen to fibrin which holds platelets in a secondary irreversible hemostatic plug

Extrinsic Pathway

7 activated by TF activated by external trauma that causes blood to escape teh vacular system PT/INR

Activated protein C deficiency- APC deficient

APC digests factor 5 and 8 ---> molecular defect- coag factor has a mutation and is not digestible

Which of the blood clotting test is commonly used for diagnosis of hemophilias

APTT- activated partial thromboplastin time can also monitor heparin

anticoagulant effect-

Anti-thrombotic Effect of Endothelium endothelial cell membrane has R that have an indirect role in anticoagulation. heparin-like molecules combine with antithrombin-->anticoag effect thrombomodulin- combines with thrombin as soon as it is formed--> inactivates thrombin and activates protein C endothelium secretes protein S - cofactor for protein C activation

fibrinolytic effect

Anti-thrombotic Effect of Endothelium endothelial cells secrete tPA - promote fibrinolysis plasminogen is converted to plasmin by tPA and dissolves the clot

antiplatelet effect

Anti-thrombotic Effect of Endothelium intact endothelium prevents platelet and coagulation proteins from coming into contact with subendothelial collagen- -endothelial cells secrete prostocylcin (antiplatelet substance) and NO (potent vasodilator and antiplatelet) to prevent platelet aggregation

Christmas Disease

Hemophilia B

Heparin induced thrombocytopenia

Heparin causes a decrease in platelet count because of the formation of a complex with platelet factor 4, IgG antibodies against platelet-heparin complex that the spleen proceeds to destroy - heparin mobilizes PF4 from light granules of platelets - and Heparin and PF4 complex together- can form AB to the complexed structure-- HeparinPF4 antibodies--> this activates platelets and endothelial cells -can get gangrene

Intrinsic Pathway

Intrinsic pathway - 12 (activated by HMWcollagen, 11 (activated by thrombin 2a), 9 (activated by 11a), 8 (actiated by thrombin) endogenous cause - caused by trauma inside teh vascular system- activated by platelets, exposed endothelium, PTT, Heparin, Hemophilias

Coagulation Cascade

Intrinsic pathway - 12 (activated by HMWcollagen, 11 (activated by thrombin 2a), 9 (activated by 11a), 8 (actiated by thrombin) endogenous cause - caused by trauma inside teh vascular system- activated by platelets, exposed endothelium, chemicals, or collagen, slower extrinsic pathway- 7 activated by TF common pathway 10, 5, 2, 13 fibrin (1)

Primary Fibrinolysis

Lab: increased PT and PTT -( plasmin destroys coagulation factors), increased bleeding time with normal platelet count- cant aggregate causes: 1.condition seen in dead fetus syndrome- Abruptio placenta 2. snake bite 3.can happen in pregnancy or cancer 4. OD in thrombolytic agents can also cause this pathogenesis: direct conversion of plasminogen to plasmin which converts fibrinogen--> degradation products -only fibrinogen is converted into fibrinogen degradation products-activation of fibrinolysis without any formation of clot---> digestion of fibrinogen before fibrin can even form -bleeding from decreased fibrinogen levels and increased fibrinogen degradation products which also have anticoagulant effects

Factor V Leiden

Molecular Dx of thrombophilias- PCR method that can tell you if they have this in 30% of idiopathic thrombosis in patients who develop DVT -Factor V is resistant to degradation by Protein C/S. Most common inherited hypercoagulable state * Symptoms: *Hypercoagulability leading to DVTs and pulmonary embolism. * Lab Values: *Low PTT that is not corrected with addition of Protein C * Pathophysiology: *Mutated factor V is resistant to degradation by protein C.* Treatment: * Clinical Tests: APC resistance assay, sensitivity and specificity for factor V Leiden approaches 100

Fate of the thrombus

Once clot is formed... it is subject to endogenous lysis by fibrinolytic enzymes- Tissue plasminogen activator TpA lyses clot/ dissolves fibrin thrombomodulin released into the blood can block the coagulation cascade and inhibit clot formation clot size can be increased by cellular recruitment composition of the clot depends on vascular sites and patients' pathophysiologic state thrombus can break apart and travel to another location in the vasculature- embolus

Mechanical disorders

Orthostatic pupura- from sitting a long time Mechanical purpura- centrifuge too fast -- so mechanical pressure causes this in lab increased transluminal pressure

Secondary Fibrinolysis

Pathogenesis: -Disseminated intravascular coagulation- have formation of fibrin and then digestion of fibrin - both fibrin and fibrinogen are digested by plasmin, digestion of clotting factors, and consumption of platelets -uncontrolled fibrolysis and coagulation/ uncontrolled release of plasmin S/S: consumption of platelets and factors results in bleeding especially from IV sites and mucosal surfaces, widespread microthrombi--> ischemia and infarction, leakage of cap- esp in renal a, petichiae, cap leakage, contusion- blood in interstium coag and fibrinolytic process activated, endothelium damaged, and results in widespread microvascular thrombosis Lab: have both fibrinogen and fibrin degredation products, decreased platelet count, increased PT and increased PTT, decreased fibrinogen, microangiopathic hemolytic anemia, increased fibrin split products especially INCREASED D-DIMER from fibrin breakdown Lab: D-dimer positive, fever, abnormal platelet count, prev E.coli Causes:, -commonly seen if simultaneous activation of coagulation and fibrinolysis, almost always secondary to another disease process..... 1. OB complications- tissue thromboplastin in amniotic fluid activates coagulation 2. sepsis - esp E.coli and n. meningitis- exotoxins from bacterial wall induce endothelial wall to make TF 3. Adenocarcinoma- mucin activates coag 4. acute protelytic leukemia- primary granules activate coagulation 5. rattlesnake venum bite

Primary Hemostasis step 4

Platelet aggregation- at the site of injury via GP2b/3a using fibrinogen from plasma as a linking molecule--> platelet plug formed that is weak--> coagulation cascade (secondary hemostasis stabilizes it

Nutritional disorders

Scurvy- vit C deficiency

Sepsis associated Disseminated Intravascular coagulation- DIC - pathogenesis

Secondary FIbrinolysis

Primary Hemostasis step 1

Step 1: Vasoconstriction-immediately and briefly with reflex neurogenic mechanisms and endothelin released from endothelium--> reduces blood loss - vessel narrowed so blood can't escape as easily

Primary Hemostasis step 2

Step 2- platelet adherence/ adhesion of the surface of disrupted vessel 1.-injury damages endothelial cells and exposes subendothelial collagen which attracts platelets-- 2. platelets adhere to collagen surface and become activated- vWF binds exposed endothelin collagen using GP1b R

Primary Hemostasis step 3

Step 3- platelet activation adhesion induces platelet shape change (anchor into blood vessel) and release chemicals like Adenosine diphosphate, thromboxane A2, and serotonin that recruit more platelets to the site of injury and promote aggregation--> hemostatic plug ADP released from dense granules and promote exposure to Gp2b and 3a R on platelets TXA2 syntheized and released promotes platelet aggregation

D-dimer

The laboratory test of choice for assisting in diagnosing disseminated intravascular coagulation (DIC) is....

hyperhomocysteinemia

abnormally high level of homocysteine in the blood, > 15 µmol/L deficiencies of vitamin B6, folic acid, and vitamin B12 can lead to high homocysteine levels. MTHFR defect leads to this and related to thrombosis -methotrexate- anticancer drug inhibits MTHFR- used for leukemia but patients can develop this thrombosis because of its inhibition

Secondary hemostasis

after primary hemostasis- platelets aggregate at the site of injury via GP2b/3a using fibrinogen - Secondary hemostasis converts fibrinogen to fibrin process in which TF is released from injured site and triggers coagulation cascade that forms clotting matrix proteins that stabilize clot stabilizes platelet plug and is mediated by the coagulation cascade which converts fibrinogen ---> fibrin platelet fibrin crosslink in the plug tissue factor- released at site of injury from endothelial cells which combine with platelet factors to initiate plasma coagulation cascade forming thrombin coagulation proteins form complexes on platelet surface using phospholipids of platelet membrane

abnormal hemostasis

blood forms clot in intact blood vessel- vessels which have not ruptured, pathologic process that represents activation of clotting system when there are no ruptured vessels/ no trigger/ can result in the loss of blood into the surrounding soft tissues , body cavity, or from body

normal hemostasis

blood in the vascular system remains liquid and free from clots, and permits the rapid formation of solid clots to plug defects (holes) in ruptured or injured blood vessels - regulation that keeps blood in state of fluidity

Dark granules

contain ADP, ATP, Ca2+, His, 5HT, Epi cause vasoconstriction of vessels and recruit more platelets

Type 1 and 3 vWF disease

decrease in circulating level of vWF

thrombocytopenia

decreased platelet count-->bleeding Causes: 1. alterations in bone marrow (chemo or cancer or congenital) 2. hereditary thrombocytopenia (less common) 3. Abnormal hematopoiesis- acquired- from a B12/ folate deficiency or from preleukemia 4. Drug induced thrombocytopenia- from Heparin, gold, GP2b/3a inhibitors, etc. 5. Dilutional- becuase blood is too dilated- hemodialysis or heart lung machine

hyperhomocystanemia

defect in MHF reductase

Platelets

discoid, anuclear cells has many glycoprotein R that allow attachment of platelets to subendothelial proteins (via vWF) and allow interadherance between platelets (via fibrinogen) and secretion of substances from intra-cytoplasmic platelet granules - cytoplasm have alpha and beta granules undergo adhesion, activation, and aggregation

Fibrinolysis abnormalities

due to plasmin overactivity---excessive cleavage of serum fibrinogen- excessive activation of system bleeding decrease in fibrinogen concentration and increase in degredation product formation (on its own also has an anticoagulation effect)--> contribute to bleeding resembles DIC- increased bleeding

example of regulation of hemostasis

endothelial damage (ex. in angioplasty) activation of platelets and release of tissue factor from cells--> thrombogenesis thrombus can obstruct blood flow and produce inflammatory response - endothelial damage, cellular activation, plasma protein compositional changes--> pathologic transition

PT Lab

extrinsic measurement- prothrombin time measures function of factors 2, 5, 7, 10, and fibrinogen- activating plasma and measuring clotting time

Extrinsic pathway deficiencies

factor 7 deficiency- uncommon Warfarin can prolong PT

Prothrombin 20210

gene defect- overproduction of prothrombin 2nd most common inherited clotting disorder Inherited pt mutation in prothrombin that results in increased expression -gene defect- overproduction of thrombin

Hemophilia B

genetic factor 9 deficiency - deep tissue, joint, postsurgical bleeding - Sex linked recessive increased PTT normal PT decreased F8 - normal platelet count and bleeding time

von Willebrand's Disease

genetic vWF deficiency- most common inherited coagulation disorder -hemostatic defect due to vWF defect -can cause qualitative and quantitative defects depending on subtypes normally- vWF binds to platelet R- Gly1b,2b-3a and to collagen and subendothelium Clinical features: mild mucosal/skin bleeding because low vWF impairs platelet adhesion Lab: increased bleeding time (because vWF cant initiate adhesion), normal PT, abnormal ristocetin test (impaired agglutination), APTT slightly elevated (mild reduction in factor 8c), hemostatic function impaired due to impaired adhesion of platelets to collagen Rx. desmopressin- ADH analog-- increase vWF from endothelial cells Type 1 and 3 vWF disease- decrease in circulating level of vWF Type 2 vWF disease- qualitative defect in the protein - structural defect

Light granules

have fibrinogen, coag factors, platelet factor 4 (neutralizes heparin and heparin like anticoag in blood, growth factors, PDGF, TGFBeta PF4 complexes with heparin and causes formation of antibody that causes heparin induced thrombocytopenia

hypercoagulable state

imbalance of blood coagulation mechanisms leading to thrombotic transitions- can be caused by age, smoking, oral contraception and diet can lead to thrombotic stroke, MI, and peripheral arterial thrombosis Primary- genetic mainly- molecular thrombophilias (defects of coag factors), or inhibitor deficiency of coag factors Secondary problem- High risk if sepsis, cancer, or trauma, and low risk from pregnancy, hyperlipidemia, and drugs

thrombocythemia

increased platelet count when it is clonal proliferation- neoplastic- both bleeding and thrombosis can occur autonomous thrombocytosis- thrombocythemia- clinal disorder platelets increase >1,000,000/uL-- clusters of platelets in circulation-bleeding may occur overproduction of platelets, leading to thrombosis or bleeding disorders due to platelet malformations often cluster

thrombocytosis

increased platelet count- benign Causes: 1. splenectomy- platelet function is normal- spleen is pooling site/ regulatory site for platelets 2. reactive thrombocytosis- due to cancer, infection, drugs 3. autonomous thrombocytosis- thrombocythemia- dif mechanism of action- chromosomal issue 4. iron deficiency can cause thrombocytosis

Activation

initiated by molecules binding to platelet membrane GP2b/3a R--> platelets release granular content like coag factors, ADP, Ca and thromboxade phospholipid complex is activated by negativeley charged phospholipids on plasma surface phospholipid complex is the site where coagulation factors combine with ionized calcium to activate intrinsic pathway

Prothrombotic effect

injury causes a loss of the anticoagulant mechanisms 1. endothelial cells secrete vWF- forms a bridge between platelets and subendothelial collagen--> platelet adhesion to endothelail cells 2. endothlial cells synthesize and secrete TF-- activates extrinsic coag cascade and cytokines released by injured endothelial cells can stimulate cells to syntehsize more TF 3. TF promotes generation of thrombin and formation of clot 4. clot is formed and traps other cells like erythrocytes and leukocytes

APTT Lab

intrinsic measurement- measures function of factors 8, 9, 11, and 12- actually measures all factors but 7, 13, protein C and S

Immune Thrombocytopenic purpura ITP

most common bleeding disorder/ cause of thrombocytopenia in children and adults is this autoimmune production of IgG against platelet Ag GP2b/3a--> get-excessive destruction of platelets in toddlers/preschoolers *Ab's vs. Gp IIb/IIIa* on platelets; an acquired autoimmune condition where autoAB are directed against platelet surface proteins leading to platelet destrictureion IgG mediated- spleen produces IgG autoAB against platelet Ag most common GP2b/3a on membrane AB bound platelets are consumed by splenic macs---> thrombocytopenia can be induced by viruses, autoimmune disease Clinical manifestations: petechia, purpura, easy bruising, epistaxis, gingival bleeding, menorrhagia, GI bleeding and intracranial hemorrhage (rare) - acute formation- weeks after viral infection in children- self limited - chronic formation- in women of childbearing age usually- IgG an cross to baby too but short lived in baby Dx. rule out all other causes, may see larget platelets on peripheral smear, normal PT/PTT - because coagulation factors not effected, increased megkaryotes thrombocytopenia, purpura (purpleish bruising), normal bone marrow, increased megakaryocytes in smear, petichiae, ecchymosis, mucouctaneous bleeding, could have antecedent viral or autoimmune infection Tx. corticosteroids, IVIG, (short term) splenectomy- if refractory- long term treatment

HIV induced bleeding disorders

mostly from thrombocytopenia

thrombic thrombocytopenic purpura TTP

○ Diag = thrombocytopenia, hemolytic anemia, renal failure, fever, microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic disturbance - can get arterial thrombi body activates platelets and these platelets aggregate endogenously without any trigger and block microvascular system--> microangiopathic syndrome due to an acquired autoAB to ADAMSTS13--> have a deficiency of ADAMSTS13 which codes for teh enzyme that digests vWF multimers---> aggregates can form and lead to formation of endogenous platelet aggregation/ get abnormal vWF multimers- where platelet aggregates and forms big complexes that arent binding to the cell wall get arterial thrombi- platelet rich skin and mucosal bleeding, fever, CNS abnormalities- confusion, hematoma, microangiopathic hemolytic anemia common in adult females Lab findings: thrombocytopenia with increased bleeding time, normal PT/PTT , anemia with schistocytes, increased megakaryocytes in bone marrow Rx. corticosteroids and plasmaphoresis