To Clot Or not Jason Corbeill PA-C

Thrombus—pathologic blood coagulation –Thrombi “embolize” and travel to new places Clot—the normal coagulation of blood in the healthy body

How to make a clot Start the clot –Contact factors (intrinsic) –Tissue factors (extrinsic)

Grow the clot in a specific location FAST!!!!!

Stop the clot –There needs to be a means for modulating clot production

Destroy the clot –In an orderly fashion so as not to cause emboli.

Normally all of these steps are happening simultaneously throughout the body However, there can be a problem with any one of these steps resulting in either excess clot formation (hypercoagulable state) or not enough clot formation (bleeding tendency)

The players Starter Growers –Clotting factors –Thrombin –Platelets –VWF –Homocysteine –Lupus anticoagulant Anticardiolipin Ab Antiphospholipid Ab –Vit K –Factor V Leiden Stopper Destroyers –Protein C –Protein S –Antithrombin III –Plasmin –Medications such as Heparin Warfarin Aspirin/plavix

Sources of Bleeding Platelet dysfunction: –Petechiae –bruises Clotting factor dysfunction: –Hemorrhage joints muscles

Sources of Clot Reason for the clot 1. Too many clotting proteins. 2. Abnormal clotting proteins. 3. Too little thrombolysis. 4. Endothelial damage Location of the clot Arterial = platelet activation or endothelial damage Venous = stasis and factor activation, APS Both = abnormal clotting proteins or homocysteine

Screening tests for hemostasis –CBC/PLT –PT –aPTT –TT

Tests for prolonged PT or PTT –Mixing studies –Individual factor assays –D-dimer, FDP, fibrinogen-tests for DIC –Lupus anticoagulant –Clot stability assay (F XIII)

Tests for thrombosis –Protein C&S –Antithrombin III –Factor V Leiden –Homocysteine –Lupus anticoagulant

CASES

Case 1-Mr. D 55 y/o male presents with complaint of easy bruising Hx? PE?

Case 1-Mr. D Labs –Cbc normal –PT 20 (12) –PTT 48 (32) –What factor abnormality could cause a prolonged PT and PTT?

Case 1-Mr D Vit K dependent factors: –II, VII, IX, X and protein C and S

Case 1-Mr. D Diagnosis: hepatic insufficiency –Lack of production of Vit K –Leads to deficiency of Vit K dependent factors and protein C and S. Treat with Vit K (oral, IV, subq)

Case 2-Mr. H 35 y/o male presents with chest pain. He runs marathons Hx? PE? Cbc normal PT normal PTT normal

Case 2-Mr. H

What conditions would cause a young, healthy male to be in a hypercoagulable state? –Protein C deficiency –Protein S deficiency –Antithrombin III deficiency –Hyperhomocysteinemia

Case 2-Mr. H

Diagnosis—Hyperhomocysteinemia Treatement—vit B6/folate

Case 3-Isabel 4 y/o female presenting with rash post URI Recent URI lasting 4 days Now feels normal Little sister is ok Hx? PE?

Case 3-Isabel Labs –WBC 7 ( ) –Hgb 13 ( ) –PLT 9 ( ) –PT 11 (12) –PTT 28 (32)

Case 3-Isabel ITP-idiopathic thrombocytopenic purpura –Antibodies directed against platelets causing destruction of platelets in spleen Treatment: platelet transfusion if bleeding or less than 10k. Steroids/IVIG, splenectomy ? What would you have to include in your differential diagnosis if she was older, had confusion or AMS and creatinine (CR) was 2.5 (elevated)?

Case 4-Mrs. D 30 y/o female with metastatic breast cancer Admitted for left leg pain, found acetabular bony mets and fractures. This am on rounds, noticed left lower extremity edema 2-3+, dusky. Labs: CBC, PT, PTT normal

Case 4-Mrs. D DVT –Virchow’s triad-hypercoagulable state, venous stasis, intimal trauma –More Labs: D dimer positive but not very specific. –Treatment: anticoagulation (put the brakes on the cascade), elevate, compression stockings, hydration, IVC filter

Case 4-Mrs. D Try to avoid this…

Case 5-Howie 5 y/o with scalp wound that isn’t healing well-just keeps oozing. Has had delayed wound healing all of his life, bled more than expected with circumcision. Little brother seems to have similar problem

Case 5-Howie Family History: mother’s father died of bleeding ulcer age 49 PE: Labs: –PT 11 (12) –PTT 54 (32) –Cbc normal –More labs?

Case 5-Howie

Tests for prolonged PT or PTT –Mixing studies –Individual factor assays –D-dimer, FDP, fibrinogen-tests for DIC –Lupus anticoagulant –Clot stability assay (F XIII)

Case 5-Howie Mixing studies: Barium sulfate absorbed plasma: lacks II, VII, IX and X, but contains I, V, VIII and XIII. Serum: lacks I, V, VIII, and XIII, but contains II, VII, IX and X. Modification PTT Ref Pt + barium sulfate abs plasma 53 (22-34) Pt + serum 24 (22-34)

Case 5-Howie Factor IX deficiency (Hemophilia B) –Factors II and X are in common pathway and their deficiency would cause both PT and PTT elevation. –Factor VII is in the extrinsic pathway and it’s deficiency would cause elevated PT as well. –So it must be factor IX deficiency

Case 5-Howie Hemophilia A (factor VIII) deficiency Hemophilia B (factor IX) deficiency –X linked recessive –Severity depends on how much factor Treatment: Factor IX concentrates after wounds and prior to surgery

Case 5-Howie

Case 6-Mrs. R 35 y/o female presenting with joint stiffness, right leg pain and edema Hx fetal loss x 2 Maternal grandmother died of “blood clot in the lung” at age 40

Case 6-Mrs. R –PT 11 (12) –PTT 48 (32) –WBC 12.4 ( ) –Hgb 13.3 ( ) –PLT 118 ( ) –RF 126 (0-40) –ANA 1:80 (neg)

Case 6-Mrs. R Antiphospholipid Antibody Syndrome? –PTT prolonged in vitro only, patient is actually hypercoagulable –PTT will not correct with mixing study –Lupus anticoagulant –Check Anticardiolipin Ab –Anti beta 2 glycoprotein-I –ANA positive –Anti ss DNA –Antiphospholipid antibodies

Case 6-Mrs. R Treatment: –Heparin to coumadin. –Goal INR over 3. –What about the thrombocytopenia? Due to APL Ab binding to phospholipid on platelet cell surfaces.

Case 7-Mrs. KL 28 y/o female presents with easy bruising Bleeds excessively with dental procedures History of menorrhagia Pregnant with her first child FH significant for bleeding problems –Male and female –Scared because her aunt supposedly died in childbirth due to hemorrhage

Case 7-Mrs. KL Labs: –PT 11.2 (12) –PTT 42 (32) –WBC 11.2 ( ) –Hgb 11.2 ( ) –PLT 160( )

Case 7-Mrs. KL ? Von Willebrands Disease? Autosomal dominant –VWF is produced in the endothelial cells and platelets –Promotes platelet adhesion to endothelial cells and each other –Labs include VWF antigen (decreased) –Level of VWF Ristocetin cofactor activity (down) –Measurement of the activity of VWF

Case 7-Mrs. KL Why is PTT prolonged? –VWF also binds to FVIII to create a complex which ultimately promotes the conversion of X to Xa. –Decreased function of F VIII (as in hemophilia A)

Case 7-Mrs. KL Treatment: –Factor VIII concentrates –DDAVP (desamino-D-arginine vasopressin) Promotes the production of VWF

Case 8-Mr. P 22 y/o male hotel clerk presents with chest pain, sob, hemoptysis. VS: BP 138/88 R 36 P 96 Exam: CTA ABG –PO2 83 (80-100) –PCO2 26 (35-45) –pH 7.28 ( )

Case 8-Mr. P So, Mr. P has a pulmonary embolism. CT shows it but you susupected it sooner and have already given him heparin/LMWH. Why does he have a PE?

Case 8-Mr. P Reason for the clot 1. Too many clotting proteins. 2. Abnormal clotting proteins. 3. Too little thrombolysis. 4. Endothelial damage Location of the clot Arterial = platelet activation or endothelial damage Venous = stasis and factor activation, APS Both = abnormal clotting proteins or homocysteine

Case 8-Mr. P PT 11 (12) PTT 29 (24-34) CBC normal

Tests for thrombosis –Protein C&S –Antithrombin III –Factor V Leiden –Homocysteine –Lupus anticoagulant

Case 8-Mr. P Factor V Leiden –Leiden is an abnormal Factor V protein It is unable to be inhibited. 5% of the caucasian population has Factor V Leiden (1:20) Heterozygotes 7x increased risk clot Homozygotes 80x increased risk of clot

statistic 60% of inherited hypercoagulable states are due to: Factor V Leiden Prothrombin polymorphism Mutations of Protein C, S and antithrombin III

Case 8-Mr. P Lifelong coumadin