Module 5. Cardiovascular System and Blood

Secondary TTP • Drug-induced – Acute immune mediated: Ticlopidine & plavix. – Dose-related: mitomycin, tacrolimus, pencillin, cyclosporine, cisplatin, bleomycin, OCP – Quinine: HUS like illness. • Pregnancy and post-partum. • Allogenic bone marrow transplant. • Autoimmune disorders (SLE,scleroderma) • HIV infection. George, Blood Aug 2000

TTP - etiology • May be associated with an antibody against or a deficiency of the protease which cleaves the ultra-high molecular weight multimers of von Willebrand’s factor. These very high molecular weight vWF multimers cause abnormal platelet activation. • Can be induced by drugs, including ticlopidine, quinine, cyclosporine, tacrolimus, mitomycin C. • Increased incidence with pregnancy or HIV

Renal Arteriole Occluded by Thrombus in TTP • Platelet microthrombi cause vascular occlusion and tissue hypoxia, particularly in the brain, kidneys, heart, lungs and spleen • Red cells are mechanically destroyed • Thrombi are rich in vWF and platelets, but not fibrinogen or fibrin



vWF Multimers • vWF monomers (280KD) polymerize to form enormous (20MD+) multimers • The larger the multimer, the more adhesive for platelets • Proteolysis degrades multimers as they leave EC (Weibel Palade Bodies) or platelets (alpha granules)

Platelets • Normal platelet lifespan is 10d. • Every day, 1/10 of platelet pool is replenished. • Normal platelet count is between 150,000 and 450,000/mm3 • 150,000 - 50,000: no symptoms • No treatment generally required. • 50,000 - 20,000: first symptoms • Generally need to begin therapy • 20,000-10,000: life-threatening • Generally requires hospitalization • <10,000: risk for spontaneous intracranial haemorrhage

Von Willebrand Factor http://www.en.wikipedia.org 207 Neyrinck & Vrielink - Febr 2015 207 http://stroke.ahajournals.org/content/43/2/599/F1.expansion.html

Platelet adhesion (adhesion to vascular endothelial cells) platelet von Willebrand factor Neyrinck & Vrielink - Febr 2015 Endothelial cells 208 208

Platelet aggregation platelet platelet platelet platelet von Willebrand factor fibrinogen Neyrinck & Vrielink - Febr 2015 Endothelial cells 209 209

ADAMTS13 (Adisintegrin and Metalloproteinase with a Thrombospondintype I motif member 13) • Congenital or autoimmune dysfunction of ADAMTS13 prevents the normal proteolysis of large VWF multimers as they are secreted from injured endothelial cells • Circulating UL VWF multimers are capable of supporting platelet aggregation more efficiently than normal multimers (especially at high shear)





ULVWF Model

How von Willebrand Factor and ADAMTS13 Regulate Clotting



Relationship between vWF &ADAMTS13

Avoid Platelet Transfusions! UCSF Series (n=55) of TTP patients, mortality was 7 times greater in patients receiving platelet transfusion • (Gordon et al , 1987; Harkness et al 1981) – Unless life-threatening bleeding is present. – Provide additional substrate for thrombus formation. – MI and strokes have reportedly occurred after transfusion

Treatment • Plasma exchange: – Untreated TTP has 80-90% mortality. – Removes autoantibody – FFP as the replacement fluid is most widely used and cost effective.

Response To Treatment • Thrombocytopenia require several days. • Parameters of haemolysis improve promptly, yet anemia may continue to worsen. • Recovery from renal failure is unpredictable and often slow. • Prolonged courses of PE, with frequent exacerbations is characteristic of idiopathic TTP

Treatment of TTP • Infusion of FFP 30 cc/kg/day until ready for plasma exchange • Daily plasma exchange with either FFP or cryopoor FFP (45 to 55 cc/kg/day) • Steroids (Prednisone 1 mg/kg/day) • Red Blood Cells if needed • Platelets only if absolutely necessary

Adjuvant Therapy • Antiplatelet agents: – Aspirin (325mg), dipyrimadole ( 400mg) – Ticlopidine maintenance for 1 year. • Corticosteroids – Presence of auto antibodies to ADAMTS13 supports the autoimmune disease. – Reserved for patients refractory to PE. British J of Hemat 2000

Treatment • Splenectomy (Crowther et al, 1996) • Chemotherapy: Cytoxan, Vincristine, Rituxan, CHOP. • High- dose IV IgG • Protein A immunoadsorption columns. British J of Hematology 200

Splenectomy is a reasonable treatment option for TTP patients refractory to standard plasma exchange therapy or who have experienced multiple and/or complicated relapses. We believe this is the first series that demonstrates efficacy of splenectomy in plasma exchange-refractory TTP.



Systemic lupus erythematosus (SLE) • A minority of patients with SLE (an inflammatory connective tissue disease which is caused by antibodies directed toward one's own tissues) may also develop TTP. • Usually the episode of TTP follows the diagnosis of SLE by some years but it can sometimes precede it. Screening tests for SLE may therefore be performed.

HUS - Hemolytic Uremic Syndrome • Usually classified along with TTP as “TTP/HUS” • Has fewer neurologic sequelae, more renal manifestations. • Usually precipitated by diarrheal illness, especially E. coli O157:H7 or Shigella • Seen more in pediatric patients, usually has better prognosis. May respond less well to plasma exchange.

TTP vs. HUS TTP HUS thrombocytopenia thrombocytopenia Microangiopathic haemolytic Microangiopathic haemolytic anaemia anaemia fever fever neurological deficits (transient) mostly no neurol. sympt. renal failure acute renal failure DOMINANT! adult women children; E. coli O157:H7, verotoxin

TTP in Pregnancy • Pregnancy may trigger TTP • Differential Diagnosis: – HELLP (hemolysis, elevated liver enzyme levels and low platelet count) syndrome – DIC – ITP – Pre-ecclampsia

TTP vs. DIC



DIC • secondary complication of some serious condition • consumption coagulopathy • Thrombo haemorrhagic diathesis • acute, sub acute, chronic

DIC • obstetrics – 50%; abruptio placentae, retained dead fetus, septic abortion, amniotic fluid embolism, toxemia • 2. neoplasms – 30%; adenocarcinomas, AML • 3. infections – gram-negative sepsis • 4. trauma, burns, extensive surgery • 5. Other – snakebite, heat stroke, giant hemangioma, aortic aneurysm etc.

ITP - Immune/Idiopathic Thrombocytopenic Purpura • Definition: isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia. • Etiology: autoantibodies directed against platelets coat platelet surface. IgG-coated platelets are taken up by RE system. • Incidence: approximately 100 per million; half of these are children. In adults, two peaks: – one are young (<40) with female predominance, – one are older (>60), no gender predominance.



HYPERVISCOSITY IN MONOCLONAL GAMMOPATHIES (I)

Hyperviscosity in monoclonal gammopathies (I) • Waldenstrom’s macroglobulinemia: IgM • Multiple myeloma: IgA, IgG • Large amounts of paraprotein increase blood viscosity by causing sludging of RBCs and results in occlusion of microvasculature

Waldenstrom’s macroglobulinemia: IgM • A type of non-Hodgkin lymphoma. • Cancer cells make large amounts of abnormal protein - Macroglobulin

Waldenstrom’s Macroglobulinemia: IgM Complications • Hyperviscosity syndrome • Visual disturbances secondary to hyperviscosity syndrome • Diarrhoea and malabsorption secondary to gastrointestinal (GI) involvement • Renal disease (less common) • Amyloidosis of the heart, kidney, liver, lungs, and joints • Bleeding manifestations secondary to platelet dysfunction and coagulation factor and fibrinogen abnormalities due to interaction with plasma IgM • Raynaud phenomenon secondary to cryoglobulinemia • Increased predisposition to infection due to B-cell dysfunction (disease related) or T-cell dysfunction (therapy related, particularly after nucleoside analogues) • Cardiac failure • Increased incidence of lymphomas, myelodysplasia, and leukemias

RED CELL ALLOIMMUNIZATION IN PREGNANCY (III)

• Anti-D, anti-K, anti-C, anti-e, anti-PP1Pk

ABO INCOMPATIBLE HEMATOPOIETIC PROGENITOR CELL TRANSPLANTATION (II)

Thank you for your attention

References • INF-DSC-083, REV 0 (30/08/13) • WHO. The Clinical use of Blood • Technical Training Manual INF-TTR-001. REV 0 (05/04/13) • Tortora and Grabrowski • Schwartz et al., 2016. Guidelines on the use of therapeutic apheresis in clinical practice--evidence- based approach from the Apheresis Applications Committee of the American Society for Apheresis. Wiley Online Library (wileyonlinelibrary.com). • Images on types of Oedema - CHAPTER 12: The Peripheral Vascular System. https://healtheappointments.com/chapter-12-the-peripheral-vascular-system-essays/ accessed 08/06/17 @ 14h15. • https://www.cardiosmart.org/~/media/Documents/Fact%20Sheets/en/zp3950.ashx. Accessed 23/06/14@15h10 • Perseghin P, Capra M, Baldini V, Sciorelli G. Bradykinin production during donor plasmapheresis procedures. Vox Sang. 2001 Jul;81(1):24-8. PubMed PMID: 11520412.