488	N. Amin and V. Patil

Step 8: Use less allergenic blood products

•In patients with multiple blood transfusion and transfusion-related complications, alternatively processed blood products should be considered (Table 61.1).

Step 9: Consider threshold for blood transfusion

•If the bleeding has stopped and serum lactate is normal, do not transfuse any more blood or blood products.

•In the absence of active bleeding, keep a transfusion threshold of less than 7.0 g% and keep 7–9 g/dL Hb in critically ill patients who are hemodynamically stable.

•RBC transfusion may be beneficial in anemic patients with acute coronary syndrome (keep Hb >10 g/dL).

Step 10: Use blood products judiciously

•In the absence of bleeding, do not correct high INR with FFP.

•Patients having inadequate intake or on anticoagulants and broad-spectrum antibiotics are likely to have vitamin K deficiency, which can cause deranged INR.

•They will benefit from intravenous vitamin K supplementation.

Suggested Reading

1.Napolitano LM, Kurek S, American College of Critical Care Medicine of the Society of Critical Care Medicine, Eastern Association for the Surgery of Trauma Practice Management Workgroup. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37:3124–57.

These are evidence-based guidelines on the use of RBC transfusions in adult trauma and critical care endorsed by SCCM.

2.Klein HG, Spahn DR. Series on transfusion medicine. Lancet. 2007;370:415–48.

An excellent review on red cell transfusion, platelet transfusion, and coagulation factor concentrates.

3.BCSH. Guidelines for management of massive blood loss. Br J Haematol. 2006;135:634–41.

It is an evidence-based guideline on management of massive blood loss.

Websites

1.www.transfusionguidelines.org.uk

2.www.asahq.org/publicationsAndServices/transfusion.pdf

3.www.bcshguidelines.com

Disseminated Intravascular Coagulation	62
and Thrombocytopenia

Vijaya Patil, Nayana Amin, Reshma Ambulkar,

and Atul Kulkarni

A 40-year-old male patient was admitted with acute pancreatitis. He developed fever, tachycardia, hypotension, and respiratory distress on the third day of admission. His abdomen was severely tender and distended. Next morning the nurse noticed excessive oozing from arterial and central line insertion site, and his abdomen was further distended.

Bleeding manifestation due to disseminated intravascular coagulation (DIC) occurs in 1% of hospital admission. Assessing and managing these patients require a systematic approach as DIC is a reflection of underlying systemic disease affecting the coagulation system, resulting in procoagulant activation, fibrinolytic activation, consumption coagulopathy, and end organ damage, which needs to be recognized and treated.

Step 1: Initial resuscitation

•Special emphasis should be placed on stabilizing hemodynamics, and if needed, blood and blood product transfusion should be started.

•Care should be taken in establishing venous access in actively bleeding patients who may be coagulopathic.

•Peripheral access is preferable to central.

•Use ultrasound-guided venous cannulation if possible and preferably choose compressible sites like internal jugular or femoral vein.

•Avoid arterial punctures.

V. Patil, M.D. (*) • N. Amin, M.D. • R. Ambulkar, M.D., F.R.C.A. • A. Kulkarni, M.D. Department of Anaesthesia, Critical Care & Pain, Tata Memorial Hospital,

Mumbai, India

e-mail: [e-mail]

R. Chawla and S. Todi (eds.), ICU Protocols: A stepwise approach,	489
DOI 10.1007/978-81-322-0535-7_62, © Springer India 2012

490	V. Patil et al.
Table 62.1 Conditions associated with DIC
Infections	Bacterial—Gram-negative and Gram-positive sepsis
	Viral—cytomegalovirus, HIV, hepatitis, dengue
	Fungal
	Parasitic—malaria, leptospirosis
Malignancy	Solid tumors
	Hematological—acute promyelocytic leukemia is
	commonly associated with DIC
Obstetric	Amniotic fluid embolism
	Placenta abruption
	Preeclampsia
	Intrauterine fetal death/retained products of conception
Toxic and immunological insults	Viper snake bites
	Massive transfusion
	ABO transfusion incompatibility
	Transplant rejection
Massive inflammation	Severe trauma
	Crush injuries
	Massive burns
	Fulminant liver failure
	Severe hypo-/hyperthermia
	Severe pancreatitis
Vascular disorders	Aortic aneurysms
	Giant hemangiomas

Step 2: Take relevant history and perform focused physical examination

•Take history of known systemic conditions associated with DIC and coagulation disorders (Table 62.1).

•Review the drug history, particularly the use of heparin and warfarin, and consumption of antiplatelet agents including nonsteroidal anti-inflammatory drugs.

•Look for bleeding manifestation, superficial like skin and mucosal (petechiae, purpura) or visceral and deep seated (gastrointestinal bleeding).

•Look for thrombotic manifestations like deep vein thrombosis (DVT) of lower limbs or venous or arterial thrombosis at any other site (e.g., cerebral).

Step 3: Investigate to ascertain the type and cause of bleeding (Table 62.2)

•Complete blood count, including platelet count and peripheral smear, for the presence of fragmented RBCs.

•Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT).

•Fibrinogen level, fibrin degradation product (FDP), D-dimer.

•Renal and liver function tests.

•The commonest laboratory abnormality is thrombocytopenia followed by elevated FDPs, prolonged PT, prolonged APTT, and a low fibrinogen.

Table 62.2 Coagulation profile
Test	What does it monitor	Normal value	Inference
Prothrombin time	Factors that are in the extrinsic	11–13 s	Prolongation of the PT is most often a result of deficiencies in factor
	pathway and common pathway:		VII but can also be caused by any of the extrinsic and common
	factors VII, X, V, and II		pathway factors. Decreased fibrinogen, levels less than 100 mg/dL,
			will also prolong the PT
			Cholestatic jaundice
			Acute or chronic liver failure
			DIC
			Malabsorption
			Vitamin K deficiency
			Coumadin (warfarin) therapy
			Factors I, II,V, VII, X deficiency
Activated partial	Factors that are designated in the	28–34 s	Heparin therapy
thromboplastin time	intrinsic pathway: factors XII, XI,		Factor deficiency
	IX, VIII, X, V, II, and fibrinogen		Presence of an inhibitor like lupus anticoagulants
Platelet count	Quantifies platelet number	130–400 × 109/L	Decreased production (bone marrow disorder), increased destruction,
			idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocy-
			topenic purpura, sequestration (hypersplenism)
Thrombin time	Evaluates the last step of	13–15 s	Heparin therapy
	coagulation (conversion of		DIC
	fibrinogen to fibrin)		Qualitative fibrinogen abnormalities or hypofibrinogenemia
			Elevated FDPs (fibrin degradation products)
Fibrinogen level		200–500 mg/dL	Congenital and acquired hypofibrinogenemia
			DIC
D-dimer	Cross-linked D fragments of the	500 ng/mL	Deep venous thrombosis, DIC, pulmonary embolism, thrombolytic
	protein fibrinogen		treatment, postoperative

Thrombocytopenia and Coagulation Intravascular Disseminated 62

491

492	V. Patil et al.
Table 62.3 ISTH diagnostic
	Platelet count
scoring system for DIC	>100 × 109/L	0
	<100 × 109/L	1
	<50 × 109/L	2
	Fibrin marker (e.g., D-dimer, FDP)
	No increase	0
	Moderate increase	2
	Strong increase	3
	Prolonged PT
	<3 s	0
	>3 but <6 s	1
	>6 s	2
	Fibrinogen level
	>1 g/dL	0
	<1 g/dL	1

•D-dimer, FDP, and antithrombin levels can be used for rapid and specific diagnosis of DIC, with antithrombin providing an indicator for severity and prognosis.

•Diagnosis of DIC is essentially confirmed by demonstrating increased thrombin generation (decreased fibrinogen) and increased fibrinolysis (elevated D-dimer or FDP).

Step 4: Ascertain severity and prognosticate outcome

•Calculate the DIC score (Table 62.3) with the ISTH (International Society of Thrombosis and Haemostasis) scoring system which provides objective measurement of DIC and correlates with outcome.

Step 5: Continue resuscitation

•Continue resuscitation and maintain hemodynamic stability using crystalloids and/or colloids.

•In colloids, preferably use gelatins as they do not interfere with clotting.

•If you are using starches, use tetrastarch preferably, as they have less effect on the coagulation profile, but do not exceed maximum dose (50 mL/kg/day).

Step 6: Correct coagulopathy (see Table 61.2 in Chap. 61)

•Repeat the coagulation profile and complete blood count frequently and replace blood and blood products.

•In the presence of ongoing blood loss, try to normalize prothrombin time and APTT and aim to maintain platelet count of more than 50,000.

•Do not use antifibrinolytic agents as they may aggravate thrombosis.

•Patients who have DIC with a primary hyperfibrinolytic state and who have severe bleeding can be treated with lysine analogues, such as tranexamic acid (e.g., 1 g every 8 h).

•There is no role of heparin in actively bleeding patients.

62 Disseminated Intravascular Coagulation and Thrombocytopenia	493

•It should be considered only where thrombosis predominates such as arterial or venous thromboembolism or severe purpura fulminans associated with vascular skin infarction.

Step 7: Treat the underlying disorder

•Repeat the tests to monitor the dynamically changing scenario and continue treatment based on clinical observation and laboratory results.

•Once patient stops bleeding, do not try to correct laboratory abnormalities as transfusion of blood and blood products should be based on clinical condition and bleeding rather than laboratory values only.

Calculate score

•More than 5 overt DIC: repeat score daily.

•Less than 5 suggestive for nonovert DIC: repeat for the next 1–2 days.

Thrombocytopenia

A 50-year-old male patient was admitted with acute pancreatitis. His blood investigations showed Hb 10.7 g%, WBC 12,000/mm3, and platelets 110,000/ mm3. On the third day, he worsened clinically. His WBC count was 20,000/mm3 and platelets were 70,000/mm3. However, the next day, he further deteriorated requiring inotropes and ventilatory support. His Hb dropped to 6.4 g%, WBC count rose to 28,000 mm3, and platelets further dropped to 40,000/mm3.

Step 1: Resuscitate

•Resuscitate, monitor, and stabilize in the ICU (refer to Chap. 78). In patients with low platelets and coagulopathy, ultrasound-guided jugular venous catheter insertion for fluid resuscitation should be performed.

•Send blood for peripheral blood smear, grouping, cross-matching, coagulation profile, and biochemistry.

Step 2: Assess severity of thrombocytopenia

•	Thrombocytopenia is defined as a platelet count less than 150 × 109/L.
•	In critically ill patients, a threshold of less than100 × 109/L may be taken.

•The ability to form a hemostatic plug is retained until the platelet count drops to less than 100 × 109/L

Step 3: Assess cause of thrombocytopenia (Table 62.4)

•Careful history, physical examination, previous medical records, and current chart review usually reveal the cause of low platelet count.

•Ask about bleeding from other sites in past, for example, frequent nosebleeds, gum bleeds, melena, hemoptysis, and blood in stool or urine.

494	V. Patil et al.
Table 62.4 Causes of thrombocytopenia
Pseudothrombocytopenia seen in	EDTA causes in vitro clumping of platelets. Presence of
asymptomatic patients	platelet clumps in the peripheral smear and a normal repeat
	platelet count in citrated blood confirm pseudothrombocy-
	topenia. In some patients, automated blood reports show
	thrombocytopenia due to presence of giant platelets that are
	counted as RBCs in automated machines; however, manual
	platelet count is normal
Dilutional thrombocytopenia	Massive blood transfusion
Ambulatory patients	ITP
	Drug-induced—chemotherapy, miscellaneous drugs
	Infections—Epstein–Barr virus (EBV), HIV, others
	Connective tissue disorders—rheumatoid arthritis, systemic
	lupus erythematosus (SLE), antiphospholipid antibody
	syndrome
	Hypersplenism
	Primary marrow disorder
Acutely ill patients	Infection/sepsis
	DIC
	TTP-HUS
	Posttransfusion purpura
Pregnant patient	Gestational (platelet count >70 resolves after pregnancy)
	ITP
	HELLP—hemolysis, elevated liver enzymes, low platelets
Cardiac patients	HIT
	Cardiac bypass
	Dilutional
	Gp IIb/IIIa inhibitor-related
	TTP related to clopidogrel or ticlopidine
Patient with thrombosis	HIT
	Antiphospholipid antibody syndrome
	Paroxysmal nocturnal hemoglobinuria

•History of previous platelet counts.

•History of previous blood or platelet transfusion.

•Medication history and review medication chart—particularly, use of heparin, warfarin, and antiplatelet agents including nonsteroidal anti-inflammatory drugs (Table 62.5).

•Heparin-induced thrombocytopenia (HIT) should be considered if the platelet count decreases by 50% and/or thrombosis occurs 5–14 days after starting heparin.

•History of known systemic conditions associated with defects in platelets like alcoholism, cirrhosis, HIV infection, systemic lupus erythematosus (SLE), and uremia.

•Family history of excessive bleeding.

62 Disseminated Intravascular Coagulation and Thrombocytopenia					495
Table 62.5 Drugs associated with thrombocytopenia
Mechanism		Drugs
Drug-specific antibody		H2 receptor blockers		Ranitidine, cimetidine
		Gp IIb/IIIa inhibitors		Abciximab
Drug-dependent antibody		Antibiotics		Vancomycin, rifampicin,
				chloroquine, amphotericin B,
				sulfonamides
		Salicylates/NSAIDs		Aspirin, diclofenac, ibuprofen
		Antiepileptics		Valproate, carbamazepine,
				phenytoin
		Antiarrhythmics		Amiodarone
		Miscellaneous		Quinine, furosemide, thiazide,
				morphine
Hapten-dependent antibody		Antibiotic		Penicillin, some cephalosporins
Induction of autoantibodies		Antiarrhythmics		Procainamide
		Miscellaneous		Gold salts
Myelosuppression		Antibiotics		Linezolid
		Chemotherapeutic agents
Unknown		Antibiotics		Fluconazole, daptomycin,
				ganciclovir, nitrofurantoin,
				piperacillin
		Miscellaneous		Digoxin, haloperidol
		Gp IIb/IIIa inhibitors		Eptifibatide
Immune complex with PF4		Heparins		Unfractionated and low-molecular-
				weight heparin
Interference with folate		Antibiotic		Meropenem
metabolism
Thrombotic microangiopathy				Clopidogrel, ticlopidine
Preexisting antibodies				Abciximab
Table 62.6 Factors associated with platelet refractoriness
Nonimmune factors	Clinical factors		Splenomegaly, fever, infection, bleeding, dissemi-
			nated intravascular coagulation
	Drugs		Amphotericin B, vancomycin, ciprofloxacin, heparin
	Patient factors		previous pregnancies, previous transfusions
Immune factors	Antibodies		HLA, platelet specific, erythrocyte
	Others		Length of time the platelets are stored

•Perform physical examination to look for:

–Evidence of bleeding in skin, mucous membrane, joints, soft tissue

–Lymphadenopathy

–Splenomegaly

Step 4: Transfuse platelets (Table 62.6)

•Three types of platelet products are commonly used in clinical practice:

– Random-donor platelets (RDP)

Table 62.7 Approach for management of thrombocytopenia
Etiology	Mechanism	Presentation	Treatment
ITP, after viral illness, may be	IgG antibodies against platelet antigens, platelet	All ages, common in young adult females	Steroids, prednisolone 1 mg/kg/day
associated with antiphospho	clearance by spleen, inadequate platelet		for 1–2 weeks, taper
lipid antibody syndrome, may	production response	Severe thrombocytopenia with normal	IVIG infusion 1g/kg/day for 2 days
be initial presentation of		RBC and WBC morphology and number
connective tissue disease,		Diagnosis by exclusion	Anti RhD antibodies 50–75 m/kg IV
lymphoploriferative malignancy
			(Rh + Ve patients with intact spleen)
TTP-HUS	-Inherited or acquired deficiency of von	Microangiopathic hemolytic anemia,	FFP transfusions until the patient is
	Willebrand factor cleaving protease	thrombocytopenia, renal insufficiency,	ready for plasma exchanges
	(ADAMTS13)	fever, and mental status changes
	Idiopathic or secondary to Escherichia coli	Schistiocytes in peripheral smear, raised	Plasma exchanges
	diarrhea, HIV infection, certain drugs	LDH, normal coagulation profile	Platelet transfusions only in
	(ticlopidine, clopidogrel, quinine, cyclosporine		life-threatening bleeding
	A, mitomycin A, cisplatin, etc.), pregnancy, bone
	marrow transplant, and metastatic carcinomas
Drug-induced thrombocytopenia	Antiplatelet agents’ and other drugs’ immune	History—no other blood or coagulation	Stop the offending drug
	mechanism	abnormalities	Supportive care
	Chemotherapy and alcohol—directly inhibit	Most chemotherapeutic drugs—nadir of	Supportive care
	megakaryocytes	blood counts in 7–10 days, recovers over
		2–3 weeks Nitrosureas and mitomycin
		cause prolonged myelosuppression
	Heparin—antibodies against heparin–platelet	Type I—modest transient thrombocytopenia	Spontaneous recovery
	factor 4 complex	in 2–3 days after heparin therapy
		Type II—less common, occurs 4–14 days	Stop heparin
		after heparin therapy
		ELISA assay for anti-PF 4 antibody,	Doppler to rule out thrombosis
		serotonin release assay, platelet aggregation	Use direct thrombin inhibitors
		studies	(argatroban, lepirudin) Fondaparinux
			should be used with caution
			LMWH and UFH should not be used